Mucopolysaccharidosis Type VII (Sly Syndrome) and Overview of the Mucopolysaccharidoses

An autosomal recessive lysosomal disease caused by deficiency of β-glucuronidase, encoded by GUSB, with accumulation of dermatan sulphate, heparan sulphate and chondroitin sulphate, whose presentation ranges from lethal non-immune hydrops fetalis to attenuated adult forms; the article includes an overview of the class of mucopolysaccharidoses (types I to X, MPS-plus syndrome and related entities) and mucopolysaccharidosis type IX due to hyaluronidase deficiency.

Literature and regulatory information updated: 27 October 2026.

0. Initial Reference Table

Table 0.2. The class of mucopolysaccharidoses and related entities.

Sources for Table 0.2: [4, 8, 9, 26–45]. The phenotype MIM numbers, cytobands and modes of inheritance match the OMIM entries consulted on 28 October 2026; numbers preceded by an asterisk are those of the gene entries. The abbreviations DS, HS, KS, C4S and C6S denote dermatan sulphate, heparan sulphate, keratan sulphate and chondroitin-4- and -6-sulphate. The gene table of the 2025 French PNDS uses outdated cytobands for several genes (GUSB at 7q21.11, ARSB at 5q11-q13, HYAL1 at 3p21.3-p21.2, GLB1 at 3p21.33) and names the MPS VI enzyme as arylsulfatase A, whereas the deficient enzyme is arylsulfatase B; Table 0.2 follows OMIM [18].

1. Introduction

1.1. From clinical descriptions to corrective factors

The mucopolysaccharidoses (MPS) were first recognised as clinical syndromes and only later as biochemical diseases. Hunter described in 1917 two brothers with the disease now designated MPS II, Hurler published in 1919 the severe form of MPS I, Morquio described in 1929 the dysplasia that bears his name, Scheie and colleagues characterised in 1962 the mild form of MPS I and Sanfilippo and colleagues defined in 1963 the predominantly neurological disease with isolated excretion of heparan sulphate; Stevenson and colleagues delineated in 1976 the intermediate Hurler–Scheie form [46]. McKusick brought these entities together in 1972, in “Heritable Disorders of Connective Tissue”, in a numbered classification that assigned type I to Hurler disease and which, after the demonstration that Scheie disease shared the same α-L-iduronidase deficiency, gave rise to the subdivisions IH and IS [27].

The transition from clinical description to mechanism came from studies in cultured fibroblasts. Fratantoni, Hall and Neufeld showed in 1968, using sulphate labelled with sulphur-35, that patients’ cells incorporated sulphate into mucopolysaccharides but did not turn it over. In subsequent experiments, mixing normal fibroblasts with cells from Hurler or Hunter patients normalised the degradation kinetics, Hurler and Hunter cells corrected each other, and culture medium from normal or Hunter cells corrected Hurler cells. From this arose the concept of “corrective factors” secreted by cells and taken up by other cells; the existence of two distinct factors separated Sanfilippo forms A and B, and the failure of the factor from Hurler cells to correct Scheie cells demonstrated the allelism of the two diseases. This work led to the identification of the enzyme defects in the early 1970s and laid the biological foundations of ERT [27]. Prenatal diagnosis of the MPS also began with these methods, through the incorporation of labelled sulphate into cultured amniocytes [27].

1.2. The description of Sly syndrome and the role of β-glucuronidase in lysosomal biology

In 1973, Sly, Quinton, McAlister and Rimoin published in the Journal of Pediatrics the report of a patient with a previously unknown MPS, with deficiency of lysosomal β-glucuronidase, describing the clinical, radiological and biochemical features of the new entity [47]. Complementation studies in fibroblasts presented by Quinton and colleagues in 1971 had already shown that this patient’s cells behaved differently from the known MPS, and Glaser and Sly described in 1973 the methods for enzymatic diagnosis of the deficiency [48, 49]. The original patient was seen at 7 weeks of age for metatarsus adductus and unusual facies, had hepatosplenomegaly, hernias and a thoracolumbar gibbus, and eventually died suddenly [48]. In the original description he also had sternal protrusion, vertebral deformities, granulocyte inclusions and intellectual disability, and β-glucuronidase activity in fibroblasts was below 2% of control, with intermediate values in the parents and in several of the mother’s siblings [9]. The follow-up published by Shipley and colleagues in 1993 added cardiac valvular anomalies and progressive deformities of the chest, spine, hips and knees and places the sudden death at 19 years, possibly due to dysrhythmia, whereas Nyhan’s atlas gives 20 years; the same work identified in the patient compound heterozygosity for W627C and R356X in historical nomenclature (= NM_000181.4:c.1881G>T p.(Trp627Cys) and c.1069C>T p.(Arg357Ter); section 2.5) [6, 9, 48].

β-glucuronidase holds a special place in the history of cell biology. Studies with this enzyme by Kaplan, Achord and Sly in 1977 identified for the first time mannose-6-phosphate as the recognition signal that directs lysosomal hydrolases to the lysosome and allows their uptake from the extracellular medium, which explains the nature of the “corrective factors” and underlies the cellular uptake of all recombinant enzymes used in ERT [27, 48]. Oshima and colleagues cloned and sequenced in 1987 the cDNA of human placental β-glucuronidase and showed that the mature enzyme begins at amino acid 23, after cleavage of a 22-amino-acid signal peptide [50].

Therapeutic development followed the animal models. A first patient with advanced disease received experimental recombinant human β-glucuronidase on a compassionate-use basis [51], and the clinical programme of vestronidase alfa, with the phase 3 trial of “blind start” design, led to approval by the United States Food and Drug Administration (FDA) on 15 November 2017, the first specific therapy for MPS VII, and to marketing authorisation in the European Union on 23 August 2018 [24, 52, 53].

1.3. The types added to the class: MPS IX, MPS X and MPS-plus syndrome

Natowicz and colleagues described in 1996, in the New England Journal of Medicine, hyaluronidase deficiency in a girl with periarticular masses and elevated serum hyaluronan, the first human disease due to a defect in hyaluronan degradation [12, 54]. Triggs-Raine and colleagues identified in 1999 the responsible HYAL1 variants and designated the entity MPS IX [55], and Imundo and colleagues described in 2011 a second family, with three siblings investigated for familial juvenile idiopathic arthritis [20].

In 2017, Kondo and colleagues described in children of the Yakut population (Republic of Sakha, Russia) a disease with an MPS phenotype, increased urinary GAGs and normal lysosomal enzymes, caused by a homozygous VPS33A variant, which was included in OMIM that year as MPS-plus syndrome [4, 56]. Verheyen and colleagues published in 2022 arylsulfatase K deficiency in four patients from two consanguineous families and proposed the designation MPS X [57]; the same enzyme had been studied in deficient mice, for which the authors had proposed the name “MPS IIB”, which was not adopted [58].

1.4. Nomenclature and current classifications

The numbering of the MPS is not continuous. The designations MPS V and MPS VIII are no longer used and are considered obsolete [27]. The reasons differ. MPS V was the number assigned in 1965 to Scheie syndrome, then regarded as a separate entity; when it was shown to share the α-L-iduronidase deficiency of Hurler disease, it became MPS IS and the number was left vacant [34]. MPS VIII (DiFerrante syndrome) designated a patient described in 1977–1978 with features of Morquio and Sanfilippo and excretion of keratan and heparan sulphate, attributed to N-acetylglucosamine-6-sulfatase deficiency; the enzyme later proved normal, the data from the originating laboratory were called into question on suspicion of fraud and the designation was withdrawn, which is why the next entity received the number IX [8]. The current literature recognises eleven classical enzyme deficiencies (MPS I, II, IIIA–D, IVA–B, VI, VII and IX), to which are added MPS X due to ARSK deficiency and the putative “MPS IIIE” due to arylsulfatase G (ARSG) deficiency, described only in animal models; in humans, biallelic ARSG variants cause Usher syndrome type IV and not an MPS [4]. MPS-plus syndrome is not an enzyme deficiency but a defect of endosomal trafficking, and its inclusion in the class is debated in the literature [4, 59].

Three axes of classification coexist. The first is biochemical and genetic, by enzyme and gene. The second is clinical and by severity: MPS I is divided into Hurler (IH), Hurler–Scheie (IH-S) and Scheie (IS), with a proposal to replace these with neuronopathic and non-neuronopathic forms; MPS II is divided into neuronopathic and attenuated; MPS III, IV and VI have severe and attenuated forms, and in MPS III rapidly and slowly progressing forms are distinguished [26]. The third is that of Orphanet, which groups the MPS in category ORPHA:79213 and, higher up, among the lysosomal diseases with skeletal involvement (ORPHA:93448), and which organises subtypes as clinical (for example, rapidly and slowly progressive MPS VI) or aetiological (Sanfilippo A to D) [29, 60]. MPS VII has no formalised subtypes in Orphanet or OMIM; the literature describes a continuum with three presentation forms, which are presented in section 3 [1, 19]. The first grouping was proposed by Sewell and colleagues in 1982, from a review of the cases then published: an early, severe and lethal form; an intermediate form, with mild organomegaly and moderate skeletal anomalies; and a very mild form, with late presentation and longer survival [9].

1.5. Common syndromic description

The MPS are lysosomal storage diseases caused by deficiency of one of the hydrolases that sequentially degrade GAGs (or of several, in multiple sulfatase deficiency), with progressive accumulation of these polysaccharides in the lysosomes of many tissues and increased urinary excretion [26, 27]. They are chronic, progressive and multisystem diseases; patients usually appear normal at birth, although accumulation begins before birth and may cause hydrops fetalis and intrauterine death, as in MPS VII, or skeletal deformities already present at birth, such as the thoracolumbar kyphosis of MPS IH [26]. The 2025 French national protocol counts eleven enzyme deficiencies distributed across seven types (I, II, III, IV, VI, VII and IX), describes in all of them a continuum between severe and moderate forms and notes that the most severe forms may begin before birth, in particular with hydramnios [18].

Three presentation patterns are recognised. In the first, facial dysmorphism, growth deficiency, umbilical and inguinal hernias, a prominent abdomen and musculoskeletal disease appear early, as in MPS IH, IH-S, II, VI and VII. In the second, skeletal dysplasia predominates with mild dysmorphism, as in MPS IV. In the third, typical of MPS III, there is cognitive slowing, especially of language, and behavioural disturbance, followed by cognitive decline with only mildly coarse facies [26]. Central nervous system (CNS) disease with progressive cognitive impairment is characteristic of the MPS that accumulate heparan sulphate: severe forms of MPS I and II, MPS VII and all classical forms of MPS III [26, 61]. Valvular disease is more frequent in the MPS that accumulate dermatan sulphate (I, II, VI and VII), the most abundant GAG in the cardiac valves [26]. Dysostosis multiplex, the set of radiographic changes of endochondral and membranous growth, is present in all MPS and is most pronounced in MPS I, II, IVA, VI and VII [26]. Table 1.1 summarises the features that distinguish each type.

Table 1.1. Distinguishing features of the MPS types and discriminating test.

1.6. Scope and definition of the entities in this article

MPS VII is defined by absent or markedly reduced β-glucuronidase activity with accumulation of dermatan, heparan and chondroitin sulphate, shown by elevated urinary GAGs and confirmed by biallelic pathogenic GUSB variants, with exclusion of pseudodeficiency being mandatory [1, 21]. MPS IX is defined by hyaluronidase 1 deficiency with elevated serum hyaluronan and biallelic HYAL1 variants [12]. MPS X is defined by biallelic ARSK variants in a compatible skeletal picture, because no validated clinical enzyme assay exists [65, 68]. MPS-plus syndrome is defined by biallelic VPS33A variants with an MPS phenotype, normal lysosomal enzymes and renal, haematopoietic and cardiac involvement [56]. Multiple sulfatase deficiency, due to SUMF1 variants, and VPS16-related MPS-like disease are treated as differential diagnoses [26, 69]. MPS I, II, III, IV and VI (Hurler and Hunter, Sanfilippo, Morquio A and B, Maroteaux–Lamy) are presented here from the comparative perspective of the class. Non-immune hydrops fetalis of lysosomal cause is dealt with across sections, because MPS VII is the lysosomal disease most frequently identified in this setting [70, 71].

2. Molecular Genetics and Pathophysiology

2.1. GAGs and sequential degradation

GAGs are linear, ubiquitous polysaccharides of the extracellular matrix and cell surfaces, classified by their repeating disaccharide units and heterogeneous in molecular mass, composition and degree of sulphation. Dermatan, heparan, chondroitin and keratan sulphate bind covalently to core proteins to form proteoglycans; hyaluronan is neither sulphated nor protein-bound [26]. Lysosomal degradation is sequential, from the non-reducing end, and each enzyme removes a specific residue or sulphate group; the lack of one of them interrupts the pathway and partially degraded fragments accumulate in the lysosomes [26, 27]. The relative abundance of each GAG in different tissues explains part of the phenotype of each type: dermatan sulphate in the valves, skin and ligaments, heparan sulphate in the CNS and keratan sulphate in cartilage and the cornea [26]. Accumulation of GAGs and their fragments alters intercellular signalling and the biomechanical properties of tissues and activates inflammatory pathways, which affects the growth plate, osteoclasts and osteoblasts and underlies dysostosis multiplex [26].

2.2. The GUSB gene and β-glucuronidase

The GUSB gene is located at 7q11.21 (gene MIM 611499); mapping by fluorescence in situ hybridisation placed the gene at 7q11.21-q11.22 and identified two pseudogenes at 5p13 and 5q13, and the cytoband 7q21–q22 that still appears in reference texts and in the Brazilian protocol is outdated [4, 5, 48]. That older location resulted from exclusion studies with interstitial 7q deletions, published between 1986 and 1991, which placed the locus at 7q21.11; in situ hybridisation by Speleman and colleagues, in 1996, placed it proximal to the elastin gene (7q11.23), and OMIM records 7q11.21, with GRCh38 coordinates 7:65,960,684–65,982,213 [6]. The 2020 HAS opinion still reproduces the location 7q21–q22 [72]. In addition to the signals at 5p13 and 5q13, amplification of exons 2–4, 3, 6–7 and 11 revealed GUSB pseudogenes on chromosomes 5, 6, 7, 20, 22 and Y, which made molecular analysis particularly difficult before modern sequencing and led Speleman and colleagues to consider in situ hybridisation the most reliable method for locating the locus [6]. The gene spans about 21 kb and 12 exons and encodes a polypeptide of 651 amino acids, with a 22-amino-acid signal peptide [4, 48, 50]. There is an alternative transcript with a 153 bp deletion in the coding region (corresponding to much of exon 6), which does not give rise to active enzyme [48, 50].

β-glucuronidase (EC 3.2.1.31) is a homotetrameric lysosomal hydrolase, with subunits of about 75 kDa, synthesised as a precursor with carboxy-terminal processing [13, 48]. After cleavage of the signal peptide, the mature 629-amino-acid protein has four potential N-glycosylation sites; the 78 kDa glycosylated monomer is transported to the lysosome and there cleaved into the 60 kDa and 18 kDa subunits of the active enzyme [6]. It removes terminal glucuronic acid residues from dermatan sulphate and heparan sulphate and also acts on chondroitin-4- and -6-sulphate [48, 73]. According to Nyhan’s atlas, chondroitin sulphates do not accumulate or appear in urine because they are also degraded by the hyaluronidase pathway [48]; GeneReviews and the monitoring programme, by contrast, describe elevated urinary chondroitin sulphate and use it as a marker of response to ERT, alongside dermatan sulphate [1, 74]. Patients generally have cross-reacting immunoreactive material, demonstrated by immunoassay by Bell and colleagues in 1977 in fibroblasts from four unrelated patients, with titration patterns suggestive of allelic heterogeneity [9], and residual activity measured with synthetic substrates correlates poorly with clinical severity [21, 48].

2.3. Tissue and physiological mechanism

Loss of β-glucuronidase function causes accumulation of partially degraded GAGs in the lysosomes of many tissues, with cellular and organ dysfunction [1]. In the MPS VII mouse, accumulation of chondroitin-4-sulphate in the growth plates reduces expression of leukaemia inhibitory factor (LIF) and tyrosine phosphorylation of a transcription factor, a proposed mechanism for bone shortening [48]. Deposition of dermatan and chondroitin sulphate in the valve leaflets causes progressive thickening, and the subendocardial fibrosis, macrophage infiltration and arterial luminal stenosis described at autopsy of an 11-year-old child explain the dysrhythmias and vascular disease [1, 75]. Deposition in the dura mater and ligaments of the craniocervical junction narrows the spinal canal [1].

Hydrops fetalis is more frequent in MPS VII than in any other MPS. The proposed mechanisms are hepatic sinusoidal infiltration with obstruction, visceromegaly with impaired venous return, reduced erythropoiesis and hypoproteinaemia; neonatal cholestatic jaundice, which is not characteristic of the other MPS, has been attributed to fetal hepatic sinusoidal congestion [1, 19, 22]. The blood–brain barrier prevents effective amounts of intravenous enzyme from reaching the CNS, so the cognitive impairment associated with heparan sulphate is not corrected by ERT [1, 26].

2.4. Inheritance

MPS VII is autosomal recessive [1]. The parents of an affected individual are, as a rule, asymptomatic heterozygotes. When only one parent is a carrier, with confirmed parentage, a de novo variant in the proband or post-zygotic mosaicism in a parent should be considered; apparent homozygosity may correspond to a deletion of one or more exons not detected by sequencing (false homozygosity) or to uniparental isodisomy [1]. All MPS are autosomal recessive, with the exception of MPS II, which is X-linked [26]. Heterozygosity for a GUSB variant does not cause disease, although a deletion allele (1801ΔT in historical nomenclature) has been associated with very low serum activity in a carrier, with a dominant-negative effect suggested by the authors [76].

2.5. Spectrum of GUSB variants

By 2009, 49 unique pathogenic variants had been described, in addition to a pseudodeficiency allele, an amino-acid-changing polymorphism and a silent variant [73]. Of 103 alleles analysed, 78.6% were missense, 12.6% nonsense, 5.8% deletions and 2.9% splice-site; 40.8% were transitions at CpG dinucleotides; five variants (p.Leu176Phe, p.Arg357Ter, p.Pro408Ser, p.Pro415Leu and p.Ala619Val) accounted for 44 of the 103 alleles [73]. Variants are distributed throughout the gene, without hotspot regions [4]. In 17 patients with NIHF or severe early disease, Vervoort and colleagues found marked allelic heterogeneity, with 14 novel variants scattered across the gene; three of four variants with a premature termination codon altered mRNA abundance or structure [77]. The 2021 Brazilian protocol cites 63 described variants [21]. Targeted dosage analysis identified a single deletion, homozygous for exon 9, in a fetus with NIHF [1, 78].

Table 2.1 brings together the variants of clinical or population relevance, with nomenclature normalised in VariantValidator and classification in ClinVar. The historical GUSB protein numbering used in the classic articles (Tomatsu, Vervoort) includes the signal peptide and matches that of NP_000172.2; the historical cDNA numbering of Vervoort 1995 (“480G→A”) differs from the current one by 26 nucleotides, and the conversion to c.454G>A was confirmed in VariantValidator. The 38 bp deletion at positions 1642–1679 of exon 10 describes the effect on the mRNA and not a genomic deletion: it results from a C>T transition which, together with the preceding guanine, creates a premature splice donor site, and ClinVar records this variant, with the same dbSNP identifier (rs377519272), as NM_000181.4:c.1617C>T p.(Ser539=), without amino acid change and pathogenic through its effect on splicing [6, 79]. The designation “1900ΔGA” is retained as historical nomenclature, because it has not been converted in a validation tool [48, 77, 80].

Table 2.1. Normalised GUSB, HYAL1, VPS33A and ARSK variants (GRCh38; VariantValidator and ClinVar consulted on 27 October 2026).

ClinVar classifies p.Pro408Ser and p.Pro415Leu alone as variants of uncertain significance (VUS), although the complex allele in cis is a founder in Mexico, and classifies as VUS the HYAL1 variant p.Glu268Lys of the MPS IX index patient; these classifications reflect the paucity of submissions and do not contradict their historical association with the disease [4, 79]. The Brazilian protocol also presents p.Asp362Asn as associated with a severe phenotype and p.Leu176Phe, p.Arg382Cys, p.Pro408Ser and p.Pro415Leu as associated with an attenuated phenotype [19, 21]. Other historical variants described in index patients and hydropic fetuses include W627C and R356X (Sly’s original patient; = NM_000181.4:c.1881G>T p.(Trp627Cys) and c.1069C>T p.(Arg357Ter)), R382C, P148S and W507X, all in historical protein nomenclature. Nyhan’s atlas spells “R256X” (published designation, with no correspondence in the gene; it corresponds to R356X) and associates R382C with a hydropic fetus, whereas OMIM records R356X in the original patient and R382C in homozygosity in a 7-year-old girl with severe bone deformities and normal intelligence (Table 2.2) [6, 48].

Table 2.2 brings together the 16 allelic variants selected by OMIM, with the correspondence to current nomenclature obtained in ClinVar from the dbSNP identifier of each entry. OMIM protein numbering matches that of NP_000172.2, with one exception: R356X corresponds in ClinVar to c.1069C>T p.(Arg357Ter), the R357X of the Tomatsu series. The cDNA numbering of the original articles is not uniform: in some entries it differs from the current one by 26 nucleotides (“672C→T” for R216W, “552C→T” for L176F), in others it already matches it (c.1061C>T for A354V, c.442C>T for P148S), and W446X, described as “1363G→A”, corresponds to c.1338G>A; conversions should therefore not be done by hand [6, 79].

Table 2.2. GUSB allelic variants selected by OMIM (entry *611499), with NM_000181.4 nomenclature and ClinVar classification (consulted on 28 October 2026).

Sources: [6, 79]. The label “no criteria” corresponds to the ClinVar review status “no assertion criteria provided”.

2.6. Founder variants and populations

The distribution of variants follows a population pattern. In Brazil, 12 of the 13 patients alive in 2020 were homozygous for c.526C>T p.(Leu176Phe), most from the Northeast [81]; analysis of genomic ancestry in five Brazilian patients showed a predominant European contribution, significantly greater than the African one (p = 0.0031), which led the authors to propose a European origin for this variant [85]. In Mexico, the variant c.1244C>T p.(Pro415Leu) and the complex allele c.[1222C>T;1244C>T] are founders; in Japan, c.1856C>T p.(Ala619Val) [4, 73]. Carrier frequency in these populations has not been established [1]. In the international disease monitoring programme, 20% of the 35 patients were homozygous for p.Leu176Phe and 9% had the Mexican allele, and 14% had no variant recorded [74]. The p.Leu176Phe variant was first identified in two siblings from a Mennonite family (Wu and colleagues, 1994) and later found in other populations, and accounted for about 20% of mutant GUSB alleles in a 2002 estimate; patients’ cells have less than 1% activity, although expression of the cDNA in COS cells produces almost as much activity as the normal allele, and most homozygotes described up to then had a mild phenotype [6]. In Brazil, Schwartz and colleagues described in 2003 three homozygous siblings with peripheral oedema at birth and prolonged neonatal jaundice, one of whom was alive at 18 years and attending special education, in a course compatible with the intermediate form [6].

2.7. Genotype–phenotype correlations

Correlations have been proposed from small samples. Nonsense variants and deletions are associated with severe phenotypes [1, 4]. In the review by Tomatsu and colleagues, the most severe phenotypes were associated with truncating variants, such as W507X, and with those affecting the hydrophobic core or packing of the protein, such as R216W, P148S and Y495C, and the mild form of the patient followed until 37 years was attributed to residual catalytic activity of the K350N allele [6]. In an analysis of 53 published patients, residual β-glucuronidase activity in fibroblasts above 1.4% of normal and urinary GAG excretion below 602% of normal were associated with later onset and longer survival [94]. The p.Ala619Val variant is associated with an attenuated phenotype, as in the Japanese patient followed for 22 years after HSCT [82], and the mouse model of the p.Leu176Phe variant has low activity and a milder phenotype, although in Brazil this variant, almost always homozygous, is accompanied by cognitive impairment in all patients [48, 81]. Affected siblings appear to have a similar course, based on few families [1, 95]. In the class of MPS in general, the genotype–phenotype correlation is weak, with the exception of some IDUA variants that predict the Hurler form [26].

2.8. Pseudodeficiency

The c.454G>A p.(Asp152Asn) allele, known as D152N, markedly reduces β-glucuronidase activity measured in vitro without causing disease. It was identified in the mother of a patient with MPS VII, who had markedly reduced activity and no clinical manifestations; it is present in about 1 in 100 normal individuals; the mechanism is accelerated intracellular turnover and reduced secretion of the enzyme, with a new glycosylation site used in about half of the molecules [83]. A healthy mother of a patient, with systemic activity of 6–10% of controls, normal sulphate incorporation and normal urinary GAGs, illustrates apparent compound heterozygosity between a pathogenic allele and a pseudodeficiency allele [96]. In patients with very mild symptoms and low activity, a D152N homozygote was pseudodeficient, whereas two siblings with other variants probably had very mild MPS VII; the distinction required a combination of investigations [76]. In 2026, an asymptomatic 31-year-old woman was described, identified through a haematology analyser flag and an Alder–Reilly anomaly on the blood film, with elevated urinary dermatan and heparan sulphate, activity of about 2–3% of normal, a likely pathogenic frameshift variant and the c.454G>A allele, without organ involvement on detailed phenotyping [84]. The Brazilian protocol designates this allele “p.D512N”, a typographical error: the correct designation is p.(Asp152Asn) [21, 83]. Pseudodeficiency complicates carrier detection and prenatal diagnosis by enzyme assay, and the existence of pseudogenes is a technical risk in molecular analysis [1, 13, 48].

2.9. Allelic disorders and modifiers

No other phenotypes associated with germline GUSB variants are known [1]. Phenotypic modifiers have not been identified; a history of NIHF was associated, in males, with greater decline in height and weight [97]. There are seven murine, one feline and one canine model of the disease, the canine model being closest to the human disease [48, 73]. In the spontaneous mutant mouse (gus mps/mps), the disease is due to a 1 bp deletion in exon 10 of Gusb; the canine model results from homozygous p.(Arg166His), with 2–5% activity in the retinal pigment epithelium of affected animals and 40–60% in carriers, and the feline model from p.(Glu351Lys) [6]. In the murine models, ERT started at birth reduced neuronal storage and skeletal dysplasia more than ERT started at 6 weeks; ERT followed by bone marrow transplantation reduced lysosomal distension in the meninges, cornea and bone; ERT from birth improved spatial learning and hearing; a single neonatal intravenous injection of AAV carrying the human cDNA reduced or prevented storage in the CNS; and an enzyme fused to an IGF-II fragment, taken up independently of mannose-6-phosphate, reduced deposition in podocytes and osteoblasts [6]. These are preclinical data.

2.10. HYAL1 and MPS IX

HYAL1 is located at 3p21.31, in tandem with HYAL2 and HYAL3, and encodes hyaluronidase 1, a 435-amino-acid protein (57 kDa in serum and 45 kDa in urine) active at acidic pH, the main hyaluronidase of human plasma [7, 12, 55]. Degradation of extracellular hyaluronan begins at the cell surface through HYAL2, which generates fragments that are endocytosed and degraded in the lysosome by HYAL1 [7]. HYAL1 reaches the lysosome via a secreted precursor and the mannose receptor, independently of mannose-6-phosphate [12]. The absence of visceral accumulation, despite hepatic, splenic and renal expression of the gene, is explained by compensation by other enzymes, such as HYAL3 and the exoglycosidases β-hexosaminidase and β-glucuronidase [12]. The gene has 3 exons over about 3.5 kb; the 2.6 kb transcript is most abundant in the liver, kidney and heart, and PCR screening of cDNA libraries did not detect it in the brain, which is consistent with the absence of neurological involvement [10]. The index patient was compound heterozygous for p.(Glu268Lys) and an allele with a premature termination codon [55]. In current nomenclature (NM_033159.4, by dbSNP–ClinVar correspondence), the first is c.802G>A p.(Glu268Lys), originally described as 1412G→A at a residue thought to belong to the active site and classified in ClinVar as a VUS, and the second is the historical complex rearrangement “1361del37ins14”, now c.751_787delinsTTCCGTGTGGCCCG p.(Val251fs), classified as pathogenic [10, 79]; the crystal structure showed that Glu268 is distant from the active site, and loss of bonds with Asn229 and Arg271 is expected to destabilise the protein [12]. The three siblings of the second family were homozygous for c.104del [20], identified by homozygosity mapping (shared region of about 40.5 Mb at 3p22.3-p13) followed by sequencing of the three hyaluronidase genes in the region; the parents and two unaffected siblings were carriers, and the variant was absent from population databases and from 100 controls of the same origin [10]. The OMIM phenotype entry attributes this variant to the HYAL3 gene in the molecular genetics text, but refers to allelic variant .0003 of HYAL1, which describes it as c.104delT p.(Val35AlafsTer25) in HYAL1; the article follows the gene entry and the original article [8, 10, 20]. The Hyal1−/− mouse is viable and fertile, but loses articular proteoglycans from 3 months and develops osteoarthritis, with hyaluronan accumulation in chondrocytes and without increased serum hyaluronan, which reinforces the articular character of the disease [98]. These mice had no macroscopic changes at 20 months and showed increased Hyal3 expression in the liver and in the testis of males, interpreted as compensation in non-skeletal tissues [10]. A 2025 review cites 40 pathogenic or likely pathogenic HYAL1 variants in databases, a number that does not correspond to described patients [4]. Other genes of hyaluronan degradation cause distinct diseases: HYAL2 is associated with syndromic cleft lip and palate, HYAL3 with oligospermia and CEMIP with deafness [12].

2.11. ARSK and MPS X

Arylsulfatase K removes the 2-O-sulphate group from 2-sulfoglucuronate at the non-reducing ends of heparan, chondroitin and dermatan sulphate [26, 58]. In the original description, the p.(Leu187Ter) variant produced no protein and p.(Arg84Cys) had markedly reduced activity; two patients had slightly elevated urinary dermatan sulphate by liquid chromatography–tandem mass spectrometry (LC-MS/MS) [57]. The Arsk−/− mouse accumulates moderate amounts of heparan and chondroitin sulphate with 2-O-sulphated glucuronate and has a mild phenotype, with behavioural changes and no bone pathology [58]. A homozygous p.Tyr417Ter variant was also described in two siblings, in the penultimate exon, with predicted nonsense-mediated mRNA decay [4]; OMIM attributes this family to Rustad and colleagues (2022) [43]. The two Verheyen families were consanguineous, one Turkish and one Indian, and the variants were identified by exome sequencing, confirmed by Sanger sequencing and co-segregated with the disease; the functional study was carried out in HT1080 cells [43]. The ARSK gene (gene MIM 610011) is located at 5q15 [43].

2.12. VPS33A, VPS16 and defects of endosomal trafficking

VPS33A encodes a protein of the Sec1/Munc18 family, a core subunit of the HOPS and CORVET tethering complexes, which, with Rab GTPases and SNARE proteins, drive fusion of the early with the late endosome and delivery of endosomes and autophagosomes to the lysosome [99]. In MPS-plus syndrome there is no deficiency of a GAG-degrading enzyme: the defect in delivery to the lysosome retains GAGs in endosomes, the lysosomes are not enlarged, there is lysosomal hyperacidification and plasma heparan sulphate reaches about 60 times normal and 6 times the level of the classical MPS [4, 56]. The p.(Arg498Trp) variant destabilises VPS33A and reduces the other components of the complexes; fibroblasts show vacuolation, endolysosomal disorganisation and abnormal lactosylceramide trafficking, with elevated galactosylsphingosine (psychosine) and, in the urine of three Yakut patients, increased sialylated conjugates alongside dermatan and heparan sulphate, suggesting a combined defect of sphingolipids and GAGs [44, 100]. Kondo’s initial description had, by contrast, found normal intracellular trafficking, endocytosis and autophagy in patients’ fibroblasts, alongside heparan sulphate accumulation and lysosomal hyperacidification; OMIM records both interpretations, and the later study by Pavlova, with reduction of VPS18 and VPS41 and increased vacuoles, prevails in the current interpretation [44, 56, 100]. Deficiency of VPS16, another subunit of the same complexes, due to a homozygous intronic splice variant that reduces the protein by about 85% (and also VPS33A), caused an MPS-like picture in two patients in one study [69]. The Saudubray textbook classifies MPS-plus syndrome among the defects of vesicular trafficking and autophagy [101].

2.13. Comparative genetics of the class

All MPS genes have been identified and genetic testing is available for all of them, for confirmation and carrier detection [26]. In MPS II, in addition to intragenic variants (82%), there are exonic or whole-gene deletions (9%) and rearrangements with the IDS2 pseudogene (9%), which requires sequencing and dosage analysis [62]. In MPS I, up to 70% of variants are recurrent and useful in predicting the phenotype, and homozygosity in a patient justifies studying the parents, because cases of uniparental disomy have been described [46]. Female heterozygotes for MPS II may have mild to moderate symptoms when X inactivation is skewed [102]. β-galactosidase deficiency due to GLB1 variants causes MPS IVB and GM1 gangliosidosis [26, 64].

3. Clinical Spectrum and Manifestations by System

3.1. The three presentation forms of MPS VII

MPS VII has a broader phenotypic spectrum than any other MPS, from fetal death due to hydrops to oligosymptomatic adult forms [19, 48]. In the international physician survey by Montaño and colleagues, published in 2016, with 56 patients from 11 countries, three groups were distinguished: NIHF with neonatal disease (n = 10); infantile or adolescent form with a history of NIHF (n = 13); and infantile or adolescent form without known NIHF (n = 33). Overall, 41% had a history of NIHF, a proportion the authors considered unexpectedly high and which distinguishes MPS VII from MPS I and II [19]. The 13 survivors with a history of NIHF had mild to severe manifestations, and NIHF alone does not predict severity when the patient survives infancy [19, 103]. Nyhan’s atlas considers the classic presentation, a moderately severe Hurler-type MPS with modest cognitive impairment, to be a relatively uncommon intermediate form, the severe prenatal and neonatal forms probably being the most frequent, although many are never diagnosed [26, 48]. The INFARMED assessment report describes the same spectrum: antenatal death from hydrops, possibly the most frequent presentation; infantile or adolescent forms, with or without neonatal hydrops, sometimes with survival into adulthood; and forme fruste limited to mild kyphosis and scoliosis [104].

Table 3.1. MPS VII cohorts and series with natural history data.

3.2. Frequency of manifestations

Table 3.2 combines the frequencies compiled by GeneReviews from four series with those of the Montaño survey, restricted to the 46 patients with the infantile or adolescent form. The two sources measure different populations, and the percentages are not additive.

Table 3.2. Frequency of the manifestations of MPS VII.

Sources: [1, 19]. ENT denotes ear, nose and throat (otorhinolaryngology).

3.3. Fetal and neonatal period

The perinatal presentation includes fetal or neonatal death, NIHF, cholestatic jaundice and hepatosplenomegaly [1]. In the fetal and neonatal form, dysostosis multiplex is present at birth, with coarse facies, pitting oedema, ascites, hepatosplenomegaly, talipes equinovarus and congenital hip dislocation; cardiomyopathy may be progressive, and death may occur in the first 6 months [48]. Recurrent hydrops in the same family, a family with three hydropic siblings, three reports of fetal death and families with an excess of miscarriages have been described [48, 95]. Stangenberg and colleagues described hydrops at 18 weeks in a first-cousin couple with two previous similar fetal deaths, and Walter-Nicolet and colleagues an Algerian infant girl, born to consanguineous parents, with NIHF detected at 20 weeks (ascites, bilateral pleural effusions, hydramnios), moderate hydrocephalus, facial dysmorphism, pterygium colli, hepatosplenomegaly, axial hypotonia with peripheral hypertonia and moderate hypertrophic cardiomyopathy, with a normal skeletal radiograph; the mother had had two unexplained miscarriages [9]. In a Japanese newborn described in 2026, fetal ascites appeared at 17 weeks and progressed to hydrops; caesarean delivery at 31 weeks, for a non-reassuring fetal status, was followed by death on day 1 from respiratory failure with pulmonary hypoplasia, without recognisable hepatosplenomegaly or skeletal dysplasia under the generalised oedema, and the couple’s previous pregnancy had been terminated at 21 weeks for hydrops [107]. In the literature reviewed by Montaño, 35 of 90 patients (38.8%) had a history of NIHF, and there were cases of isolated neonatal ascites and four patients with neonatal cholestasis [19]. In the neonatal group of the survey, those who survived gestation mostly died in early childhood, from cardiac, renal or respiratory failure [19]. Hydrothorax associated with MPS VII presents early (before 26 weeks), is bilateral, is accompanied by oedema and ascites and has poor survival, as in two fetuses treated with thoracoamniotic shunting, of which one died in utero at 35 weeks and the other survived after delivery at 30 weeks [108]. At birth, lymphoedema, camptodactyly with absent distal phalangeal creases, thrombocytopenia and lymphocytes with Alder-type inclusions on the blood film may be observed [48, 86]. The INFARMED report estimates that about half of MPS VII mortality is fetal or infantile and that about 25% of deaths occur between 1 and 15 years [104].

3.4. Growth

Disproportionate short-trunk short stature, due to vertebral dysplasia and spinal curvatures, often appears before 2 years; even with normal initial stature, growth velocity slows early and adult height is very likely to be below −2 standard deviations (SD) [1]. In 20 patients from three trials assessed before ERT, the height Z-score was close to normal until the 1st year and then declined, especially in males; body mass index (BMI) was above normal in males and slightly below in females, and boys with a history of NIHF had a greater decline in height and weight [97]. In the Montaño survey, growth was normal until 18–24 months and mean height at 18 years was 151.8 ± 7.9 cm in boys (n = 7; Z −3.3) and 114.3 ± 25.4 cm in girls (n = 5; Z −7.8) [19]. The weight of adolescents tends to be above the 50th centile, with more overweight in those who do not walk independently [1].

3.5. Musculoskeletal system

Dysostosis multiplex may be one of the first manifestations [1]. Progressive scoliosis, kyphosis, thoracolumbar gibbus, canal stenosis, mainly cervical, and atlantoaxial instability due to odontoid hypoplasia follow [1]. GAG deposition in capsules and ligaments restricts mobility and causes contractures, especially at the hip, where shallow acetabula cause pain, walking difficulty and osteoarthritis in late childhood or adolescence; genu valgum, talipes equinovarus and carpal tunnel syndrome are added [1]. In the Montaño survey, 63% reported hip or back pain, 57% walked unaided, 21% used a wheelchair, 11% a walker or crutches and 11% had no mobility [19]. INFARMED notes that more than 40% of patients eventually lose independent walking and that some with hip dysplasia depend on a wheelchair while still in the first decade [104].

3.6. Nervous system and development

Canal stenosis results from GAG deposition in the dura mater and instability of the craniocervical junction; spinal cord compression may arise between 1–2 years and adolescence, and young children or those with cognitive impairment may not report symptoms, so hyperreflexia and ankle clonus on examination are the signs to look for [1]. Hydrocephalus is rare and of unknown prevalence [1]. Conductive or mixed hearing loss contributes to language delay, usually recognised only after 18–24 months, and gross and fine motor delay may be evident in the 1st year [1]. Most patients have moderate to severe intellectual disability, and behavioural problems (impulsivity, hyperactivity, insomnia, physical aggression) are among the most difficult aspects for caregivers [1, 19]. In the monitoring programme, 24 of 35 patients had intellectual disability: profound in 5, severe in 6, moderate in 3, mild in 6 and unspecified in 4 [74]. According to the INFARMED report, the impairment is in most cases moderate and non-progressive, mainly affects language, and some patients have normal intellectual development [104]. Limited vocabulary was reported in 94% of the patients in the survey [19].

3.7. Face, eye, ear and oral cavity

Macrocephaly, coarse hair and gingival hypertrophy may be present in the neonatal period; the facies becomes coarser with age, with macroglossia, thick eyebrows and lips, widely spaced teeth and poor enamel [1]. Corneal clouding appeared at 8 years in the original patient and earlier in others, and is demonstrable on slit-lamp examination [48]; optic nerve oedema, glaucoma and visual impairment have been described in 37% of the patients in the survey, with photosensitivity in 30% [19, 103, 109]. Deposition in the upper airway and Eustachian tubes causes recurrent acute otitis media, chronic otitis and conductive hearing loss; many children develop sensorineural deafness [1, 104].

3.8. Respiratory system

Macroglossia and adenotonsillar hypertrophy obstruct the upper airway and make it a difficult airway; OSAS, lower respiratory tract infections and restrictive lung disease are added, and with age respiratory complications become among the main causes of morbidity and mortality; some patients require tracheostomy [1, 19]. In the monitoring programme, 13 of 32 patients were unable to follow instructions for spirometry and one was ventilator-dependent [74]. In the European caregiver survey, 30% had been hospitalised for respiratory problems [106].

3.9. Cardiovascular system

Accumulation of dermatan and chondroitin sulphate in the valves causes progressive leaflet thickening, usually visible on echocardiography before 5 years, first without dysfunction and later with regurgitation or stenosis; it affects all four valves, with the mitral and aortic valves most relevant, and valve replacement is rare [1, 110]. LVH and cardiomyopathy are common, and potentially fatal dysrhythmias, probably due to subendocardial fibrosis, are a recurrent cause of death [1, 75]. In the class of MPS, conduction disturbances may progress to high-grade atrioventricular block, and very premature coronary disease, due to diffuse intimal proliferation, may be silent [102]. In a 14-year-old boy with a mild form, the main manifestation was hypertension with fibromuscular dysplasia and narrowing of the aorta and femoral arteries [48]. In the monitoring programme, echocardiography of treated patients showed aortic regurgitation in 25.0%, mitral in 14.3% and tricuspid in 7.1% [74]. In Brazil, cardiomyopathy was less frequent than in other MPS [81].

3.10. Abdomen and other organs

Hepatosplenomegaly is common, and umbilical, inguinal and hiatus hernias are frequent; unlike the other MPS, cholestatic jaundice is a recognised, although infrequent, manifestation of MPS VII [1]. In a severe case with death at 2.5 years there was jaundice, recurrent diarrhoea and hypoalbuminaemia, attributed to giant cell hepatitis and carbohydrate intolerance [48]. Feeding difficulties may require thickeners or gastrostomy [1]. Renal failure was the cause of death in childhood in some cases [19, 104]. Hypertrichosis and thick skin complete the picture [103].

3.11. Attenuated forms and diagnosis in adults

Mild forms may begin after 4 years or much later, with skeletal predominance [48]. A girl described by Pfeiffer and colleagues in 1977, diagnosed at 7 years because of short stature, mild craniofacial dysmorphism, corneal clouding, broad-based gait and mild intellectual disability, was followed until 37 years: she attended special education and worked as a telephone operator in her parents’ company; at 34 years she had increasing spasticity of the upper limbs, with odontoid dysplasia, pseudarthrosis, a hypoplastic atlas arch and C1–C3 ligamentous thickening with spinal cord compression, treated surgically; at 37 years she measured 146 cm and had macrocephaly, macroglossia, prognathism, corneal clouding stable since 5 years, normal hearing, thoracolumbar scoliosis, contractures of the large joints and spastic tetraplegia, and she died unexpectedly that year, presumably from cardiac arrest; she was compound heterozygous for K350N and R577L [6, 9]. Nyhan’s atlas describes this patient as having normal height and moderate cognitive impairment, whereas OMIM, based on the follow-up by Storch and colleagues (2003), records 146 cm at 37 years and mild intellectual disability [9, 48]. A 20-year-old man, described by de Kremer and colleagues in 1992, was oligosymptomatic despite severe spondyloepiphyseal dysplasia, with flattening and collapse of the T7, T8 and T10 vertebral bodies and irregularity and fragmentation of the proximal femoral epiphyses, without hepatosplenomegaly, hernias, corneal clouding or neurological changes, with Alder-type granules in polymorphonuclear cells and without significant excess of urinary GAGs [9, 48]. Gitzelmann and colleagues described in 1978 two siblings whose main manifestation was asymptomatic thoracic kyphosis with mild scoliosis, without hernias, hepatosplenomegaly, corneal clouding or short stature, with radiological changes limited to the spine, increased urinary GAGs, granules in polymorphonuclear cells and about 10% activity in fibroblasts; the elder, aged 19 years, was then the oldest known patient [9]. In the intermediate form, a Turkish girl described by Sewell and colleagues presented in the 1st year with facial asymmetry, deformed feet and motor delay and, at 5 years, disproportionate dwarfism, sternal protrusion, kyphosis, scoliosis, hypertrichosis, a small umbilical hernia and mild hepatomegaly, with normal motor function and language delay; serum activity was practically nil and fibroblast activity was 5.6% of control [9]. In France, an untreated patient with two missense variants had bilateral inguinal hernia repaired at 1 year, bilateral femoral osteotomy at 7.5 years, learning difficulties and visual and hearing impairment, worked full time, received a hip prosthesis, was diagnosed with glaucoma at 33 years and died at 52 years [109]. In the United Kingdom, a man diagnosed at 28 years following suspicion raised by the spinal surgeon had developmental delay, scoliosis, kyphosis, corneal clouding, hearing loss and mildly coarse facies, with only slightly elevated urinary GAGs, and remained stable with symptomatic treatment alone [89]. The number of diagnoses in adults with MPS is increasing, and the attenuated phenotypes of MPS VII may resemble those of MPS I, II and VI [26, 106].

3.12. Natural history and treated disease

The data in sections 3.1 to 3.11 describe mainly untreated patients, because vestronidase alfa only became available in 2017 and the Montaño (2016) and Zielonka (2017) series predate or are nearly contemporary with approval [19, 53, 94]. In treated patients, ERT reduces urinary GAGs and enlarged liver and spleen volume and may improve walking endurance and growth when started before 5 years, but it does not alter cognitive impairment and does not reverse established skeletal deformities; these data are presented in section 7 [24, 111]. In the monitoring programme, the mean age at start of vestronidase was 8.1 years and mean height at enrolment was at Z −2.40 in patients treated before enrolment [74].

3.13. MPS IX

Natowicz’s index patient, at 14 years, had presented at 7 years with a soft-tissue mass at the left ankle; she had multiple periarticular masses, sometimes painful and swollen, joint effusions, acetabular erosion, short stature (below the 5th centile), a flat nasal bridge, bifid uvula and submucous cleft palate, without neurological or visceral involvement; biopsies showed vacuolated histiocytes with material removable by hyaluronidase, plasma hyaluronidase activity was nil (about 50% in the parents) and plasma hyaluronan was 30 to 90 times above normal [12, 54]. The OMIM synopsis adds details of the course. Before the ankle mass, removed at 7.5 years, the patient had had recurrent otitis media and a wrist “ganglion” excised at 6 months; in the following year masses appeared near a finger, the knee and both malleoli. From 9.5 years she had self-limiting episodes of painful swelling of the masses and generalised cutaneous oedema, triggered by exertion or fever and resolving within 72 hours. Between 8.5 and 14 years, growth fell from the 15th centile to below the 5th centile (145.5 cm at 14 years). Joint mobility was full, without scoliosis or organomegaly. MRI of the knee at 10 years showed nodular synovium, a popliteal cyst and a large effusion, and computed tomography and MRI of the hips at 12 years showed bilateral masses, erosions and effusions. A mixing experiment excluded an enzyme inhibitor. Plasma activity in the parents was 30% and 53% of normal, with low or intermediate values in two grandparents, and the parents’ hyaluronan was normal. The specificity of the finding was assessed in 56 patients with 25 other lysosomal storage diseases, all with normal plasma hyaluronidase; in 16 of them hyaluronan was not markedly increased [8]. The authors attributed the masses to aggregates of histiocytes that take up hyaluronan via receptors without being able to degrade it and explained the erosions, limited to the acetabula, by local osteoclast activation mediated by macrophage cytokines [8]. In the second family, consanguineous and from the Middle East, three siblings (aged 11, 13 and 22 years at publication) had pain and swelling of the knees and hips, diffuse proliferative synovitis on magnetic resonance imaging (MRI) and macrophages with vacuolated cytoplasm on synovial biopsy, with a phenotype confined to the joints [20]. The 13-year-old presented with knee pain, swelling and a Baker’s cyst, and ultrasound showed generalised synovitis, including in the small joints of the hands; the eldest began at 16 years with hip pain and limping, had scoliosis at 18 years and persistent knee pain from the same age; the youngest sister had knee pain and limping since 4 years and hyperextensible thumbs. Synovial biopsy in all three showed papillary hypertrophy with an infiltrate of vacuolated histiocytes, without bone erosions on MRI of the 13-year-old [8]. The review by Fink and Triggs-Raine considers MPS IX the rarest and mildest of the MPS [12]. Table 75.1 of Nyhan’s atlas indicates intellectual disability in MPS IX, which does not correspond to any of the four patients described; the article follows the primary descriptions [12, 20, 27]. The natural history in adulthood is unknown [7].

3.14. MPS X

In 10 patients from 6 families, the median age at presentation was 9.5 years, with hip or knee pain, waddling gait and progressive hip changes, variable coarse facies, genu valgum and joint restriction, and none had hepatosplenomegaly, neurological or cognitive impairment [65]. In the original description, two of four patients had cardiac and ophthalmological changes identified by targeted phenotyping [57]. These were the Turkish siblings, a 16-year-old girl and a 14-year-old boy, with normal length at birth, macrocephaly, coarse facies, short-trunk short stature, mild scoliosis and genu valgum. Echocardiography showed mild aortic stenosis and regurgitation with cusp thickening in both, and mild left ventricular hypertrophy in the sister. Both had mild lens and vitreous opacities and retinal pigmentation, and the sister had myopia. The Indian siblings, aged 17 and 18 years, had short-trunk short stature, macrocephaly, coarse facies and genu valgum, one of them with mild scoliosis. In both families hearing and cognition were normal [43]. Rustad’s two siblings show the mild end of the spectrum. The boy had had a waddling gait since early childhood and pain and stiffness of the lower limbs, hands and back at 7 years; radiographs suggested epiphyseal dysplasia, and at 8 years showed unossified carpal bones and osteonecrosis of the femoral heads. The sister had pain in the knees, thighs and hips from 9 years, with anterior vertebral wedging and delayed carpal ossification. Both had mildly hypomineralised dental enamel, vertical metaphyseal striations and hypermobility of the interphalangeal joints, without short stature or coarse facies; urinary dermatan sulphate was increased in both and heparan sulphate slightly increased in the sister [43]. In a series of three patients, intelligence, hearing and eyes were normal, without organomegaly or typical dysostosis multiplex; vertebral involvement regressed during follow-up and hip dysplasia progressed [66]. In 2026, a 12-year-old girl with developmental delay and progressive skeletal dysplasia since 2–3 years and an ARSK variant among children with bilateral femoral head dysplasia resembling Legg–Calvé–Perthes disease were described [93, 112].

3.15. MPS-plus syndrome and VPS16-related disease

MPS-plus syndrome combines an MPS-type core (coarse facies, dysostosis multiplex, hepatosplenomegaly, respiratory distress, developmental delay, pyramidal signs) with renal, haematopoietic and cardiac involvement: progressive anaemia and thrombocytopenia with hypoplastic marrow; massive proteinuria with hypoalbuminaemia and rising creatinine, cholesterol and uric acid, with glomerular destruction by foamy podocytes; and congenital heart defects [56, 99, 113]. Height and weight are initially normal and decline from 6–12 months in some patients [113]. The two initial series define the picture. In Kondo’s Yakut series, 13 children presented in the first year with obstructive lung disease and frequent respiratory infections and with congenital heart defects (patent ductus arteriosus, atrial septal defect, hypertrophic cardiomyopathy). They had macroglossia, thick skin, barrel chest, contractures and progressive skeletal dysplasia, and some had optic atrophy and leucopenia; three had changes on brain imaging (delayed myelination, atrophy and calcifications). Eleven died of cardiorespiratory failure between 1 and 2 years [44]. Dursun’s two Turkish sisters died at 6 years and at 10 months. Respiratory symptoms began at 3.8 years and at 5 months, with imaging and histology of acute respiratory distress syndrome. The elder had coarse facies, synophrys, hirsutism and macroglossia and developed pyramidal signs with spasticity at around 5 years. Both had dark blue granules in lymphocytes, hepatosplenomegaly with macrovesicular steatosis and proteinuria, and renal biopsy showed focal glomerulosclerosis with enlarged podocytes with foamy cytoplasm. The elder’s bone marrow aspirate had no storage cells, and electron microscopy of the conjunctiva showed endosomes, multivesicular bodies and large vacuoles. Urinary GAGs were negative on the first analysis and only later showed small amounts of dermatan and heparan sulphate [44]. By 2020, 19 patients had been described (17 Yakut and 2 Turkish), with death usually at 10–20 months [67, 90]; by 2024 the total was 41 patients, and usual survival does not exceed the 2nd year [59]. An Italian child with symptoms from 4 months and secondary haemophagocytic lymphohistiocytosis at 2 years was alive at 6 years on prolonged corticosteroid therapy [114]. The attenuated juvenile form due to homozygous p.(Arg200Pro) has been described in two patients [91, 92]. The two patients with VPS16 deficiency had psychomotor regression, delayed myelination, cerebral atrophy, neutropenia, skeletal anomalies and MPS-type dysmorphism [69].

3.16. Manifestations by system in the class of MPS

Table 3.3 summarises the manifestations common to the class; the particular features of each type appear in Table 1.1.

Table 3.3. Manifestations of the class of MPS by system.

Sources: [26, 102, 115].

The 2025 French PNDS adds age data by type. In MPS IH, children have few symptoms at birth and the diagnosis is made between 4 and 18 months; in MPS IS, signs appear after 5 years and diagnosis occurs in the 2nd or 3rd decade, with disabling polyarticular stiffness, carpal tunnel, corneal clouding, deafness and sometimes valvular disease and spinal cord compression. In neuronopathic MPS II, diagnosis occurs between 18 months and 4 years and neurological deterioration between 6 and 10 years, sometimes with epilepsy, and ivory-coloured nodular lesions may be present over the sacral region, buttocks and upper limbs; in the attenuated form there is no corneal clouding. In MPS III, episodes of unexplained crying may appear from the 1st month, and the course leads to loss of autonomy and dementia in the 2nd decade, with more attenuated forms in types C and D. In MPS IVA there are severe forms with signs before 1 year, sometimes with hydrops fetalis, intermediate forms (1–5 years) and slow forms with onset after 20 years, and the mean age at diagnosis is 5 years; in MPS IVB, symptoms begin between 1 and 3 years, without neurodegeneration or corneal clouding. In severe MPS VI, diagnosis is usually made before 2 years, with complex craniosynostosis and exorbitism. In MPS VII, the disease is mainly revealed prenatally, by hydrops, with a guarded prognosis, and the picture approaches that of MPS I, severe or attenuated, when the disease begins in childhood. In MPS IX, the picture is limited to multiple periarticular soft-tissue masses and synovial cysts [18]. Table 3.4 reproduces the frequency grading that the same protocol assigns to the main manifestations.

Table 3.4. Frequency of the main manifestations by MPS type according to the 2025 French PNDS.

Key: +++ major feature; ++ frequent; + sometimes present; (+) rare; 0 absent. Source: [18].

The grading of MPS VII in the PNDS falls below the frequencies of the published series: cardiac involvement appears as “sometimes present”, whereas valvular disease has been described in 30–50% of patients in the GeneReviews compilation and in 50% in the Montaño survey, and neurodegeneration as occasional, whereas intellectual disability affects 85–86% of patients in the same sources (Table 3.2) [1, 18, 19]. In MPS IX, the only graded manifestation is coarse facies, whereas the primary description mentions only a flat nasal bridge, bifid uvula and submucous cleft palate, without visceromegaly (section 3.13) [12, 18].

4. Clinical Recognition and Warning Signs

4.1. In the prenatal period

MPS VII should be considered in any NIHF without a cause after initial evaluation, and all the more so if there is hepatomegaly, splenomegaly, isolated ascites, bone anomalies, fetal growth restriction, consanguinity or recurrence in a previous pregnancy [22, 70, 116]. In a US centre, hepatomegaly was present in 76.2% of NIHF with lysosomal disease and in 33.8% of controls with NIHF of other cause, splenomegaly in 60.0% and 24.1%, and hepatosplenomegaly in 50.0% and 22.4% (all differences with p <0.05) [116]. In the prenatal exome meta-analysis by Makhamreh and colleagues, 68% of NIHF with lysosomal disease were isolated, consanguinity was present in 57% and hydrops recurred in 75% of families with information [70]. A single effusion (ascites, pleural or pericardial effusion) belongs to the “NIHF spectrum” and merits the same investigation [22]. In MPS-plus syndrome, increased prenasal thickness in the 2nd trimester was the finding that led to prenatal diagnosis in two pregnancies [117].

4.2. In the newborn and infant

In the newborn, the combination of oedema or ascites, hepatosplenomegaly, cholestatic jaundice, coarse facies, talipes equinovarus, hip dislocation and hernias should prompt urinary GAGs and enzyme studies [1, 48]. Hepatosplenomegaly with signs of storage in the neonatal period has its own differential (section 6), and the presence of vacuolated lymphocytes or Alder-type inclusions on the blood film is a useful clue, as in Dubot’s patient, identified at 10 days [86, 118]. In the classic form, the original patient was seen at 7 weeks for metatarsus adductus and unusual facies, with hepatosplenomegaly, diastasis recti, umbilical hernia, oedema of the dorsum of the hands and feet and a thoracolumbar gibbus [48].

4.3. In childhood

In childhood, suspicion arises from the combination of a short neck, short-trunk short stature, chest deformity, gibbus, scoliosis, contractures and joint stiffness, genu valgum, macrocephaly, coarse facies, corneal clouding, macroglossia and gingival hypertrophy, with recurrent otitis and respiratory infections, snoring, hepatosplenomegaly, hernias and developmental delay, the latter typically evident at 2 years [1]. In Brazil, coarse facies was the sign that most often raised suspicion [81]. The Brazilian protocol recommends suspicion in the presence of at least one, and especially two or more, of the following: storage facies, early and recurrent upper respiratory infections, hearing loss, reduced growth velocity, hepatosplenomegaly, hernias, a history of hydrops fetalis, dysostosis multiplex, gibbus or joint limitation, claw hands, valvular disease or cardiomyopathy, bilateral corneal clouding or a sibling with MPS VII [21]. The diagnostic delay is long: in the European caregiver survey, suggestive symptoms, excluding hydrops, were recognised only from a median of 3 years, and diagnosis occurred at a mean of 1.9 years in patients with NIHF and 6.1 years in the others [106].

4.4. In adolescence and adulthood

Attenuated forms present with hip dysplasia, coxa valga with subluxation, scoliosis, kyphosis, mild short stature, corneal clouding or hearing loss, sometimes with only slightly elevated or normal urinary GAGs [21, 89, 109]. In the class of MPS, mild cases are often discovered in adolescence or adulthood because of skeletal anomalies or valvular disease [102]. A haematology analyser flag with an Alder–Reilly anomaly on the blood film led to biochemical diagnosis in an adult woman without organ disease, who had a pseudodeficiency allele [84].

4.5. MPS IX, MPS X and MPS-plus syndrome

MPS IX should be considered in a child with arthritis of the knees and hips resembling juvenile idiopathic arthritis, with periarticular masses, proliferative synovitis on MRI, several affected relatives or resistance to corticosteroids [12, 20]. Systematic testing for hyaluronidase deficiency in 108 Turkish children with juvenile idiopathic arthritis was negative in all, so the authors do not recommend systematic screening [17]. MPS X enters the diagnosis of hip pain in the school-age child with femoral head dysplasia, mild platyspondyly and metaphyseal striation of the long bones, including the differential of bilateral Legg–Calvé–Perthes disease and of spondyloepiphyseal and multiple epiphyseal dysplasias [66, 112]. MPS-plus syndrome should be considered in an infant with an MPS phenotype, proteinuria, anaemia and thrombocytopenia, especially of Yakut or Turkish ancestry [56, 67].

4.6. Warning and emergency signs

The emergency signs are spinal cord compression (weakness, hyperreflexia, clonus, incontinence, cervical or lumbar pain), upper airway obstruction and apnoea, dysrhythmias and heart failure and, in the newborn, refractory ascites and respiratory distress [1, 24, 119]. Atlantoaxial instability makes intubation and accidental cervical hyperextension dangerous, and a 12-year-old child died during dental anaesthesia [19, 104]. The sudden death of the original patient, at 19 or 20 years depending on the source, was associated with odontoid hypoplasia and extensive cardiovascular lesions, with dysrhythmia as the probable cause [9, 19, 48]. Anaphylaxis during vestronidase alfa infusion is an emergency that may arise as early as the first dose [23].

In France, the reference or competence centre may give the patient a personal emergency card, in credit-card format and sometimes bilingual, with the diagnosis, contacts and recommended actions and those to avoid, and the G2M filière publishes an emergency certificate common to the MPS (October 2023 version), summarised in Table 4.1 [18]. The certificate stresses that no specific MPS examination or treatment is urgent, that ERT is a chronic treatment, never urgent, which may be cancelled or postponed when the situation prevents its administration, and that management is symptomatic, taking into account the airway, the cervical spine and current treatments [18].

Table 4.1. Emergency situations according to the G2M filière emergency certificate for the MPS.

4.7. Dysostosis multiplex: the guiding imaging

Skeletal radiography is an effective way of screening for the MPS and is reliable in all of them except MPS III [27]. The major signs of dysostosis multiplex are grouped into seven regions: skull (macrocephaly, J-shaped sella turcica, thick calvarium); chest (broad, oar-shaped ribs, broad clavicles, bulky scapulae); spine (oval and hook-shaped vertebral bodies on the lateral view); pelvis (excessive constriction of the iliac bodies, flared wings, dysplasia of the proximal femoral epiphyses, coxa valga); long bones (irregular diaphyseal modelling, submetaphyseal constriction, shortening); short bones (shortening, metaphyseal widening, proximal pointing of the 2nd to 5th metacarpals, bullet-shaped phalanges); and bone structure (osteoporosis with coarse trabeculation) [120]. Periosteal cloaking in the infant is not characteristic of the MPS and points rather to GM1 gangliosidosis type I or mucolipidosis II [120]. In MPS VII, the findings described include a J-shaped sella turcica, spatulate ribs, short vertebrae with anterior beaking, possible odontoid hypoplasia, hypoplastic ilia with narrow sciatic notches, hip dysplasia and proximally pointed metacarpals [48, 103]. Spranger’s atlas classifies the severity of dysostosis in MPS VII as moderate, with a broad phenotypic spectrum [120].

4.8. Newborn screening

Some programmes in the USA, Taiwan and northern Italy screen for some MPS, mainly MPS I, and high-throughput enzyme assays by tandem mass spectrometry (MS/MS) or fluorimetry allow multiplexed screening for MPS I, II and VI [26]. MPS VII is not included in the newborn screening programmes described in the sources consulted; methods for quantifying GAG disaccharides and enzymes in dried blood spots by HPLC-MS/MS are applicable to all MPS, but their population use for MPS VII has not been described [4, 26].

4.9. Warning signs common to the class in the French protocol

The 2025 French PNDS lists signs that, alone or in combination, should lead to consideration of an MPS [18]. In growth, an advance in height and weight in the first 2 to 3 years is usual, followed by a break in the height curve, whereas in MPS IVA and VI the deceleration is early; head circumference often shows progressive macrocephaly or, when there is craniosynostosis, stagnation. Craniosynostosis is possible in MPS I, II and VII and is complex in the early forms of MPS VI. In the skeleton, thoracolumbar kyphosis is highly suggestive, the sternum may be keeled (MPS IV) or excavated (MPS I), and progressive joint stiffness with camptodactyly (“claw hand”) in MPS I, II and VI contrasts with the distal hyperlaxity of MPS IV. Carpal tunnel syndrome, and more rarely cubital tunnel syndrome, is highly suggestive when it appears in a child. In the skin, extensive Mongolian spots are classic in MPS I, II and VI, and MPS II may give a pebbled, orange-peel appearance over the scapulae or thighs. An inguinal hernia in an infant not born preterm should prompt a search for other signs of MPS, and recurrence of hernias after surgical repair is characteristic. Chronic rhinopharyngeal congestion and recurrent ENT and bronchial infections may be the first signs; delayed tooth eruption, enamel anomalies, limited mouth opening, gingival hypertrophy and dental cysts or abscesses are suggestive, although not exclusive. The absence of facial dysmorphism does not exclude the diagnosis, especially in moderate forms, and spinal cord compression may be the presenting feature, particularly in adults [18].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no formal international diagnostic criteria for MPS VII [1]. According to GeneReviews, the diagnosis is established in a proband with suggestive findings and increased urinary GAGs when there is absent or reduced β-glucuronidase activity in leucocytes, fibroblasts or dried blood spots on filter paper, and/or biallelic pathogenic or likely pathogenic GUSB variants; two VUS, or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis [1]. The 2021 Brazilian protocol defines the criterion for diagnosis and for starting ERT in the Unified Health System (SUS) as increased total urinary GAGs, or increased heparan and dermatan sulphate, with β-glucuronidase activity below 10% of the lower reference limit (fibroblasts, leucocytes or filter paper), together with normal α-L-iduronidase and iduronate-2-sulfatase activity in the same sample or biallelic pathogenic GUSB variants [21]. The requirement for a second normal enzyme or molecular confirmation is intended to exclude pseudodeficiency and non-specific sample degradation [13, 21].

5.2. Urinary GAGs: usefulness and limitations

The laboratory workflow for the MPS begins with quantification of urinary GAGs and their separation. Spot tests (Berry spot test with toluidine blue) are only qualitative and unreliable, with false positives and negatives; quantification with dimethylmethylene blue (DMB) or cetylpyridinium chloride and fractionation by electrophoresis, thin-layer chromatography or HPLC are the next steps, and MS/MS methods, with greater sensitivity, are now the standard for urinary screening [4, 26, 27]. In MPS VII, the expected profile is elevated dermatan and chondroitin sulphate, with increased total GAGs [1]. MPS VII is, however, difficult to identify on qualitative tests, because the excretion pattern is variable and sometimes similar to that of controls; in moderate forms, especially in adults, GAGs may be normal or only slightly increased [4, 21, 48]. In the oligosymptomatic 20-year-old man described by de Kremer and colleagues, the urine contained no significant excess of GAGs despite β-glucuronidase deficiency [9]. False negatives are also possible in MPS III and IV; false positives occur with connective tissue destruction, rickets, malabsorption with osteomalacia, neoplasms and leukaemias, systemic lupus erythematosus, rheumatoid arthritis, Marfan syndrome and in the newborn, and heparin and some nappy chemicals interfere [4, 115]. In multiple sulfatase deficiency, GAGs may be normal [26]. A negative result does not exclude MPS [102]. Urinary GAGs do not identify the enzyme defect, but they are the pharmacodynamic marker of ERT [13].

5.3. Enzyme assay and pseudodeficiency

β-glucuronidase activity is measured in leucocytes (traditional specimen), cultured fibroblasts, plasma or serum, dried blood spots, amniocytes or chorionic villi, with artificial fluorogenic (4-methylumbelliferyl) or chromogenic (p-nitrophenol) substrates [4, 13, 48]. Nil or very low activity is diagnostic in a compatible setting, and higher residual activity requires molecular confirmation and demonstration of substrate accumulation [4]. Carriers have low-normal or slightly deficient activity, so carrier status can only be defined by molecular testing [1]. An isolated low activity does not establish MPS VII, because the pseudodeficiency allele c.454G>A p.(Asp152Asn) reduces activity in vitro without disease; confirmation requires elevated urinary GAGs, a compatible phenotype and genotype [13, 21, 83]. When a sulfatase is deficient, at least one other sulfatase should be measured to exclude multiple sulfatase deficiency, a rule that applies to the differential diagnosis of MPS VII [18, 26]. The 2025 French PNDS reserves these analyses for reference medical biology laboratories and confirms the diagnosis by the enzyme deficiency in leucocytes, from dried blood spots on filter paper or a leucocyte pellet, accepting serum or plasma in MPS I, II, IIIB and VII, as well as fibroblasts, cultured amniocytes and chorionic villi [18]. The same protocol stresses that activity measured with synthetic substrates does not distinguish severe from attenuated forms [18].

5.4. Blood film, histology and imaging

Alder–Reilly inclusions, coarse lamellar granules in granulocytes of peripheral blood and bone marrow, and lymphocytes with Alder-type cytoplasmic inclusions are low-cost findings that guide the diagnosis, even at birth [48, 84, 86]. Vacuolated hepatocytes, membrane-bound cytoplasmic vesicles on electron microscopy and material staining with Alcian blue, also in cultured fibroblasts, complete the morphological study [48]. After fetal death or termination, histology of the placenta, liver, spleen, heart and bone marrow, with diffuse microvacuolated histiocytes, provides clues, as in the 22-week fetus in whom histology supported MPS VII in the presence of two GUSB VUS [22, 121]. In the Van Dorpe family, with three affected fetuses, the highly vacuolated Hofbauer cells of the placenta and the foamy macrophages in the liver, spleen and marrow were the guiding findings, and the authors stressed the value of morphological examination of the fetus and placenta [9]. Histochemical stains may be negative: in the 2026 Japanese newborn, autopsy showed foamy histiocytes in the liver and spleen, but toluidine blue staining for acid mucopolysaccharides and CD68 immunohistochemistry were negative, and it was the foamy histiocytes that prompted genetic testing [107]. Skeletal radiography and spinal MRI are part of the initial assessment (section 4.7 and Table 11.1).

5.5. Genetic testing

GeneReviews proposes two options [1]. In the first, when the phenotype and biochemistry point to MPS VII, GUSB is sequenced and, if the second variant is not found, gene-targeted deletion/duplication analysis is performed; in patients of Mexican, Brazilian or Japanese ancestry, testing may begin with the founder variants. Alternatively, a multigene MPS panel is used, which includes GUSB and the genes of the differential, with the coverage and VUS caveats specific to each panel. In the second option, more often used when the phenotype is atypical or in the fetal setting, exome or genome sequencing is used. In France, the 2025 PNDS systematically proposes study of the gene of the deficient enzyme, which in some cases helps predict severity, and considers study of the parents essential to confirm segregation of the alleles and prepare for prenatal diagnosis [18]. Three French reference laboratories (Lyon, Paris-Necker and Rouen) sequence a panel that includes GUSB, SUMF1, HYAL1, ARSK, ARSG, VPS33A and VPS16, a fourth (Toulouse) the ten genes of the classical MPS, and five measure β-glucuronidase activity [18].

Table 5.1. GUSB molecular tests and their limitations.

Sources: [1, 6, 13, 78].

A negative molecular test does not exclude the disease when the biochemistry is unequivocal, because undescribed or undetectable variants may exist [115]. The report should state the gene, the transcript with version (NM_000181.4), the HGVS c. and p. nomenclature, the zygosity, the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and, for c.454G>A, its nature as a pseudodeficiency allele; the phase of variants (cis or trans) should be confirmed by parental testing, especially when there are two variants on the same allele, as in the Mexican allele or the Dubot case [1, 79, 86]. Amniotic fluid biochemistry (GAGs in the supernatant and enzyme activity in amniocytes) allowed two GUSB variants, one of them a VUS, to be reclassified in a fetus with NIHF at 20 weeks [122]; in prenatal exome series, the four NIHF cases with VUS in lysosomal genes all had GUSB VUS, and the authors advocate pairing the exome with enzyme studies [70].

5.6. Practical algorithm

Table 5.2. Diagnostic algorithm for MPS VII by setting.

Sources: [1, 21, 22, 118, 123].

5.7. Investigation of non-immune hydrops fetalis

Hydrops is defined by two or more abnormal fluid collections (ascites, pleural effusion, pericardial effusion >2–3 mm, skin oedema >5 mm), with or without placentomegaly (≥4 cm in the 2nd trimester, ≥6 cm in the 3rd) and polyhydramnios [22]. NIHF accounts for about 90% of hydrops and occurs in 1/1700–3000 pregnancies [22, 123]. The initial evaluation includes a three-generation pedigree (fetal losses, anaemia, consanguinity), ethnic origin, detailed anomaly ultrasound, fetal echocardiography, exclusion of alloimmunisation, infection (parvovirus B19) and fetal anaemia, and examination of the parents for signs of Noonan syndrome [123]. The 2026 Society for Maternal-Fetal Medicine (SMFM) Consult No. 75, which replaces the 2015 guideline No. 7, makes seven recommendations, all GRADE 1C, summarised in Table 5.3 [22, 124].

Table 5.3. SMFM recommendations (Consult Series No. 75, 2026) for NIHF.

Source: [22].

Inborn errors of metabolism cause about 1–5% of NIHF, and MPS VII is, together with infantile free sialic acid storage disease and galactosialidosis, one of the most common examples [22]. The exome identifies a monogenic disease in at least one third of unexplained NIHF, and the RASopathies are the most frequent monogenic cause; in a study of 127 pregnancies with NIHF, the exome found pathogenic or likely pathogenic variants in 29%, a metabolic panel would have covered only 11% of the genes and variants identified and an extended hydrops panel would have yielded 18% [22, 125]. Panels miss 38–89% of the diagnoses detectable by exome, and the exome is more cost-effective at all gestational ages [22]. The Canadian guideline of the Society of Obstetricians and Gynaecologists of Canada (SOGC) No. 363, from 2018, emphasises causes treatable prenatally and recurrent genetic aetiologies [126]. A rapid amniotic fluid protocol, with GAGs in the supernatant and four enzyme activities in cultured amniocytes, covers the seven lysosomal diseases most frequent in NIHF with five determinations; in 30 NIHF it identified two lysosomal diseases (6.6%), one of which was MPS VII [127]. When the fetus dies, clinical photography, skeletal radiography, autopsy with placenta and storage of tissue (fibroblast line) and DNA allow diagnosis and counselling in future pregnancies [118, 123]. Genomic autopsy, which combines conventional autopsy with sequencing, has been applied to neonatal-onset MPS VII: in a Japanese newborn who died on day 1 of life, trio exome sequencing, performed with stored DNA from the patient and blood from the parents, identified NM_000181.4:c.1838_1839del p.(Arg613ThrfsTer19), novel, of maternal origin and located in a region predicted to escape nonsense-mediated mRNA decay, and c.1618G>A p.(Glu540Lys), previously described and with a slight reduction in activity, of paternal origin; the nomenclature was confirmed in VariantValidator [80, 107]. The authors state that genomic autopsy provides a definitive diagnosis or information useful for counselling in about half of the pregnancy losses and perinatal deaths studied, and that autopsy rates in neonatal intensive care can be as low as 20% [107].

5.8. Diagnosis of MPS IX, MPS X and MPS-plus syndrome

In MPS IX, the diagnosis is based on deficient plasma hyaluronidase activity, elevated serum hyaluronan and biallelic HYAL1 variants; complete deficiency was confirmed enzymatically in the three siblings of the Imundo family, and urinary GAGs are not the relevant test [7, 20]. Joint MRI, synovial biopsy and radiography (periarticular masses, acetabular erosions) support the diagnosis [7]. In MPS X, urinary dermatan sulphate is variable and a normal GAG profile does not exclude the disease; there is no validated clinical enzyme assay, and the diagnosis rests on biallelic ARSK variants in a compatible radiological picture, in which metaphyseal striation of the long bones was found in all patients of one series [65, 66, 68]. In MPS-plus syndrome, urinary GAGs are increased, plasma heparan sulphate is markedly elevated and the lysosomal enzyme panel is normal, which separates it from the classical MPS; full blood count, bone marrow aspirate (hypoplasia), proteinuria and renal function, skeletal radiography and echocardiography complete the assessment, and the diagnosis is confirmed by VPS33A sequencing [56, 99]. A first normal urinary GAG measurement does not exclude the syndrome, as happened in the elder sister of the Turkish family, and dark blue granules in lymphocytes on the blood film may be the first clue [44].

5.9. Prenatal and preimplantation diagnosis

Once both familial variants have been identified, prenatal diagnosis on chorionic villi or amniocytes and preimplantation genetic testing (PGT) are possible [1, 128]. Biochemical prenatal diagnosis measures β-glucuronidase in villi or cultured amniocytes and GAGs in amniotic fluid, but pseudodeficiency may mimic an affected or heterozygous fetus; in one family, a fetus was considered heterozygous in an enzyme study complicated by maternal pseudodeficiency, which led the authors to recommend complete enzyme studies of obligate carriers before prenatal diagnosis [83, 96]. In families with known variants, molecular analysis is the method of choice [48]. Enzyme assay in cord blood in the last trimester is mentioned as an alternative [115]. Biochemistry was the historical method: Lissens and colleagues diagnosed in 1991 an NIHF at 26 weeks by the deficiency in cultured amniocytes and fetal plasma, and in the next pregnancy chorionic villi at 10 weeks had normal activity; Kagie and colleagues demonstrated the deficiency in amniotic fluid at 25 weeks; and Van Eyndhoven and colleagues made in 1998 the first early diagnosis on chorionic villi, at 11 weeks, in a family with two previous hydropic pregnancies, with early signs of hydrops in the fetus after termination at 12 weeks [9].

6. Differential Diagnosis

6.1. Comparative table

Table 6.1. Differential diagnosis of MPS VII and related entities.

AD denotes autosomal dominant inheritance; XL, X-linked.

6.2. Differential of MPS VII among the MPS and the oligosaccharidoses

MPS I, II and VI share with MPS VII the Hurler-type somatic phenotype, and the distinction is biochemical [1, 115]. Three features favour MPS VII: NIHF, also described in MPS I and IVA but more frequent in VII; neonatal cholestatic jaundice; and a urinary profile with dermatan and chondroitin sulphate, sometimes only slightly abnormal [1, 4]. The oligosaccharidoses and glycoproteinoses (mucolipidoses, mannosidosis, sialidosis, galactosialidosis, fucosidosis, aspartylglucosaminuria) and sialic acid storage disease produce the same dysostosis multiplex; the radiological changes are specific in that they indicate a defect in the degradation of complex carbohydrates and non-specific in that they occur in many different diseases, and periosteal cloaking points to mucolipidosis II and GM1 gangliosidosis [120]. Multiple sulfatase deficiency must be excluded whenever a sulfatase is low [26]. In this disease, failure of the post-translational conversion of a conserved cysteine residue into formylglycine, catalysed by the enzyme encoded by SUMF1, leaves all sulfatases, lysosomal and microsomal, inactive. The phenotype combines that of at least six isolated deficiencies: metachromatic leukodystrophy, MPS II, IIIA, IVA and VI and X-linked ichthyosis [45]. A neonatal form, the most severe, with an MPS picture and death in the first year; a late-infantile form (0–2 years), the most frequent, resembling late-infantile metachromatic leukodystrophy with skeletal changes, which has an attenuated variant with onset after 2 years; and rare juvenile forms, slowly progressive, are distinguished [45]. Some patients are initially diagnosed as MPS II when iduronate sulfatase deficiency predominates; in one report, the urinary profile (heparan sulphate 39%, dermatan sulphate 21%, chondroitin sulphate C 40%) differed from that of the MPS. Early-onset ichthyosis, broad halluces, neurological regression and leukodystrophy point to multiple sulfatase deficiency [45]. Persistently low maternal urinary oestriol during pregnancy, due to lack of fetal steroid sulfatase, was the first sign in one case, and secondary haemophagocytic lymphohistiocytosis has been described. Severity correlates with the stability and residual activity of the mutant protein [45]. The multisystem recommendations of Ahrens-Nicklas and colleagues (2018), with surveillance of cervical instability, hips, scoliosis, airway, eyes, hearing, nutrition, gallbladder, heart and seizures, overlap with those for the MPS [45].

6.3. Non-immune hydrops fetalis of lysosomal cause

The causes of hydrops are highly diverse. In the systematic review by Bellini and colleagues (n = 5437), syndromic causes, which include inborn errors of metabolism, accounted for 5.5% of cases (Table 6.2) [123, 129]. The mechanisms invoked are fetal hypomobility, congestive heart failure and obstruction of lymphatic flow [123, 130].

Table 6.2. Causes of hydrops fetalis in the Bellini 2009 systematic review (n = 5437).

Sources: [123, 129].

Table 6.3. Frequency of lysosomal storage diseases (LSDs) and MPS VII in NIHF series.

The lists of metabolic diseases presenting with hydrops include, in addition to MPS VII, MPS I and IVA, mucolipidosis II, galactosialidosis, sialidosis, GM1 gangliosidosis, Gaucher disease, Niemann–Pick diseases A and C, Wolman disease (with adrenal calcifications), Farber disease, ISSD and Salla disease, multiple sulfatase deficiency, glycogen storage disease IV (with akinesia and arthrogryposis), carnitine transporter deficiency, the congenital disorders of glycosylation (PMM2, ALG1, ALG8, ALG12), neonatal haemochromatosis, Pearson syndrome, Barth syndrome and defects of cholesterol synthesis [118, 123, 134]. More than 40% of the LSDs most common in NIHF have possible postnatal treatment [71]. A systems-based approach guides the investigation: hepatomegaly suggests LSD, hyperechogenic kidneys suggest congenital nephrosis and pulmonary stenosis suggests a RASopathy [135]. In Brazil, LSDs were found even without consanguinity or family history, so these antecedents should not determine whether investigation is undertaken [133].

6.4. Neonatal hepatosplenomegaly with signs of storage

The differential of neonatal hepatosplenomegaly with signs of storage includes GM1 gangliosidosis, sialidosis type II, mucolipidosis II, Niemann–Pick disease A, MPS VII, galactosialidosis, prosaposin deficiency, Wolman disease, ALG1-CDG and congenital erythropoietic porphyria; a cherry-red spot and vacuolated lymphocytes are suggestive of storage disease, and Pearson syndrome and several congenital disorders of glycosylation may present with hydrops and mimic a storage disease [118].

6.5. Differential of MPS IX, MPS X and MPS-plus syndrome

MPS IX may be confused with juvenile idiopathic arthritis and pigmented villonodular synovitis; the clues are the periarticular masses, familial occurrence and resistance to corticosteroids [12]. MPS X is confused with spondyloepiphyseal and multiple epiphyseal dysplasias and with bilateral Perthes disease; in a series of 40 children from 36 families with bilateral femoral head dysplasia, the exome gave a diagnosis in 12 (33.3%), mainly in COL2A1 (6) and COL9A1 (2), with one ARSK case and candidate VUS, including in ARSK, in another 5 families [112]. MPS-plus syndrome is distinguished from the MPS by the normal enzymes and the renal and haematopoietic involvement, and from VPS16-related disease by genetics [56, 69].

7. Treatments and Risk Management Strategies

7.1. Guidelines and general principles

There is no international guideline or MetabERN consensus specific to MPS VII; the 2024 GeneReviews states that no clinical practice guidelines have been published, and the 2024 review by Grant and colleagues calls for their development [1, 14]. The only specific clinical document found is the Clinical Protocol and Therapeutic Guidelines (PCDT) for MPS VII of the Brazilian Ministry of Health, approved by Joint Ordinance SAES/SCTIE No. 8 of 21 May 2021, which defines criteria for diagnosis, inclusion, exclusion, treatment and discontinuation of ERT [21]. The health technology assessments of INFARMED (2022), the French Haute Autorité de Santé (HAS) (2020) and the National Commission for the Incorporation of Technologies in the SUS (CONITEC, 2020) reached different conclusions on the value of vestronidase alfa, as detailed in section 7.7 [72, 104, 136]. For the class of MPS there are expert guidelines for MPS I, II, IVA and VI and topic-specific recommendations on spinal cord compression, orthopaedics, thoracolumbar kyphosis, hip dysplasia, anaesthesia and airway, sleep apnoea, heart disease and the eye, which apply by analogy to MPS VII [26].

Treatment rests on three pillars: multidisciplinary supportive care, coordinated by a lead physician, ideally in a centre with experience in lysosomal diseases; disease-modifying therapy with ERT; and HSCT in selected cases, with limited experience [1, 21, 26]. Supportive care is, according to the Saudubray textbook, the most important aspect of treatment of the MPS, and pain, very common, should be addressed directly [26]. The PCDT recommends that the patient and family receive a written report describing the disease and its risks, to present in emergency situations [21].

For the class, the HAS published on 21 January 2025 the PNDS for the MPS, prepared by the CRML and the Committee for the Evaluation of Treatment of Mucopolysaccharidoses and Glycoproteinoses (CETMPS-GP), with the G2M filière, according to the 2012 HAS method; it covers MPS I, II, III, IVA and IVB, VI, VII and IX, within the framework of long-term condition No. 17 (hereditary metabolic diseases requiring prolonged specialised treatment) [18]. It is not a document specific to MPS VII and does not state the dose of vestronidase alfa, but its recommendations on organisation, HSCT, anaesthesia, surveillance, transition and pregnancy cover MPS VII [18]. The PNDS sets as objectives improving or slowing the multisystem course, improving quality of life and social, educational or occupational integration, and informing and supporting the patient and family. Assessment and follow-up are coordinated by a hospital physician in a reference or competence centre for hereditary metabolic diseases, lysosomal diseases or constitutional bone diseases, with a paediatrician, paediatric neurologist or rehabilitation physician in children and an internist, rheumatologist, neurologist or rehabilitation physician in adults, and with organ specialists, rehabilitation, psychology, the genetic counsellor and social services as required; hospital-at-home is useful for infusions and for symptom control in the place of residence. ERT should be started in a reference or competence centre, and each initial prescription is validated case by case by a multidisciplinary expert decision [18].

7.2. Vestronidase alfa: mechanism and presentation

Vestronidase alfa (Mepsevii®; in the USA, vestronidase alfa-vjbk) is a recombinant human lysosomal β-glucuronidase produced in Chinese hamster ovary (CHO) cells, a homotetramer of 629-amino-acid monomers with a sequence identical to that of the human enzyme, taken up by cells through mannose-6-phosphate residues and surface receptors and targeted to the lysosome [23]. It is a highly sialylated enzyme, with 10 times more sialic acid per mole of monomer than the earlier experimental version; half-maximal uptake in MPS VII fibroblasts occurs at about 1 nM, and the intracellular half-life after uptake is about 40 days, compared with 3–4 days for other enzymes used in the MPS [137]. In MPS VII mice, weekly injections of 0.1–20 mg/kg distributed the enzyme to all tissues, including bone and brain, with dose-dependent reduction of GAG storage and longer survival; these are preclinical data [137]. In patients, the enzyme is not expected to cross the blood–brain barrier, and ERT does not treat CNS disease [1, 24].

The presentation is a concentrate for solution for infusion of 2 mg/ml, in a 5 ml single-dose vial (10 mg), with histidine and polysorbate 20 among the excipients and 17.8 mg of sodium per vial (35.5 mg per vial with the diluent, 1.8% of the maximum daily intake recommended by the World Health Organization) [23, 24]. In Portugal, the medicinal product is authorised and marketed under registration No. 5758263, as a restricted-prescription medicine for exclusive hospital use [104, 138]. In Brazil, the approved package leaflet (alfavestronidase, 10 mg/5 ml, adult and paediatric use; “restricted to hospitals” in the 2021 text, “restricted to healthcare establishments” in the version approved on 2 December 2025) lists as excipients sodium chloride, sodium phosphate monobasic dihydrate, histidine and polysorbate 80, whereas the European SmPC states polysorbate 20 [24, 139].

7.3. Dose and administration

The dose recommended by the Brazilian PCDT, the only specific clinical guideline, is the same as in the labels: 4 mg/kg by intravenous infusion every 2 weeks [21, 23, 24]. GeneReviews states 4 mg/kg rounded up to the next whole vial [1]. The difference between sources lies in the maximum infusion time: the PCDT allows it to be extended up to 20 hours if infusion reactions occur, whereas the labels state about 4 hours and do not set this maximum [21, 23]. Pharmacokinetic and pharmacodynamic modelling showed that 4 or 8 mg/kg every 4 weeks would give less time above the uptake concentration than 4 mg/kg every 2 weeks, and that the effect on urinary GAGs is close to maximal with the latter regimen [140]. The 2025 French PNDS does not state a dose of vestronidase alfa: it records the European marketing authorisation and the lack of reimbursement in France, owing to insufficiently documented short- and medium-term benefit, with reassessment planned when longer-term efficacy data become available [18]. The reference dose remains that of the PCDT, which coincides with the labels. The PNDS’s generic statement that ERT is given as weekly infusions applies to the enzymes for the other MPS and not to vestronidase alfa, which is given fortnightly [18, 23].

Table 7.1. Posology and administration of vestronidase alfa.

Sources: [18, 21, 23, 24, 72, 139].

Table 7.2. Examples of the FDA label infusion rate schedule (4 mg/kg; total volume = drug + diluent, over 4 h).

Source: [23].

Pharmacokinetics, assessed in 23 patients, showed a maximum concentration of 17.3 ± 9.6 µg/ml, area under the curve of 50.9 ± 32.2 µg·h/ml, steady-state volume of distribution of 251 ± 140 ml/kg, clearance of 83.6 ± 43.2 ml/h/kg and plasma half-life of 2.33 ± 0.75 h (2.6 ± 0.6 h in the European SmPC), with 52% variability in clearance, similar concentrations below 5 years and dose proportionality between 1 and 4 mg/kg [23, 24]. The short plasma half-life contrasts with the long intracellular half-life, which underpins the 2-week interval [137, 140].

7.4. Safety and management of adverse effects

The FDA label carries a boxed warning for anaphylaxis, which has occurred as early as the first dose; the infusion should take place with medical support available, with observation during and for at least 60 minutes afterwards, and be stopped immediately in the event of anaphylaxis [23]. Anaphylaxis occurred in 2 of 20 patients in the clinical programme (respiratory distress, cyanosis, desaturation, hypotension), one of them at the first dose, and both tolerated subsequent infusions [23]. In the pooled 23 patients from four trials, aged 5 months to 25 years and with exposure up to 187 weeks, the most frequent reactions were rash (17.4%), urticaria (17.4%), infusion-site extravasation (17.4%), anaphylactoid reaction (13%), infusion-site swelling (8.7%), pruritus (8.7%) and diarrhoea (8.7%), mostly mild to moderate; one patient had a febrile seizure at week 66, within 3 days of diphtheria, tetanus and pertussis vaccination, without recurrence on rechallenge [24]. In the phase 3 trial, rates per patient-year were 0.5 for extravasation (0.4 with placebo), 0.4 for diarrhoea (0 with placebo), 0.4 for rash (0.7 with placebo) and 0.2 for anaphylaxis (0 with placebo), with 8.3 patient-years of active exposure and 2.7 of placebo [23]. GeneReviews reports 2 infusion-associated hypersensitivity reactions in 215 infusions (0.9%) [1]. The version of the SmPC cited by the HAS in 2020, with maximum exposure of 136 weeks in the same 23 patients, gave lower frequencies for some reactions (urticaria 13%, infusion-site swelling 13%, extravasation 8.7%, rash 8.7%), reflecting the updating of frequencies with longer follow-up [24, 72].

Anti-drug antibodies developed in 18 of 23 patients (78%), 10 with neutralising antibodies at least once, not persistent, with decreasing titres on chronic exposure and with no effect on the reduction in urinary GAGs or on reactions [24]. In the monitoring programme, 4 patients positive at baseline became negative, 7 became positive and 2 with neutralising antibodies did not lose efficacy; there were no serious hypersensitivity reactions or discontinuations in 52.0 patient-years [74].

The 2025 French PNDS gives rules common to the ERTs for the MPS. The infusion is given in a setting with resuscitation equipment, because of the risk of infusion-associated reaction, sometimes severe, up to anaphylactic shock; manifestations include headache, fever, erythema, flushing, urticaria, pruritus, oedema, vomiting, abdominal pain, diarrhoea, malaise, hypotension or hypertension, tachycardia, dyspnoea, bronchospasm and angioedema [18]. The risk increases with an intercurrent infection, especially respiratory, or with a history of allergy, which require clinical assessment before the infusion, and is greatest between the 6th and 15th infusion, although it may arise after months or years of treatment [18]. Antibodies against the enzyme are frequent, and their titre does not correlate with the walk test or GAG excretion; neutralising antibodies may reduce the benefit, and their measurement, requested through the manufacturer’s laboratory, is reserved for repeated reactions or unexpected loss of efficacy [18]. Annex 6 of the PNDS grades the management of a reaction (Table 7.4) and escalates premedication (Table 7.5); it is a protocol common to the ERTs for the MPS, and its application to vestronidase alfa is a class extrapolation [18].

Table 7.3. Management of adverse effects and precautions with vestronidase alfa.

Table 7.4. Management of ERT infusion-associated reactions according to annex 6 of the French PNDS for the MPS (class protocol).

Source: [18], which reproduces in the anaphylaxis tables the 2016 French emergency medicine recommendations.

Table 7.5. ERT premedication levels according to annex 6 of the French PNDS for the MPS.

Source: [18].

The PNDS premedication differs from that of the vestronidase alfa labels: the PNDS uses a sedating antihistamine (hydroxyzine) 1 hour before, combined with paracetamol or ibuprofen, and adds corticosteroids at two time points after severe or recurrent moderate reactions, whereas the FDA and EMA labels recommend a non-sedating antihistamine, with or without an antipyretic, 30 to 60 minutes before, and the PCDT an antipyretic or an antihistamine [18, 21, 23, 24]. For vestronidase alfa, the reference is the premedication of the PCDT and the labels; the PNDS escalation with corticosteroids is a class option for patients with recurrent reactions.

7.5. Comparative regulatory status

Table 7.6. Regulatory and access status of vestronidase alfa.

Sources: [18, 23, 24, 53, 72, 104, 136, 138, 139, 141].

The difference in indication between the USA and the EU has a practical consequence: the European label limits the indication to non-neurological manifestations and thereby makes explicit that ERT is not intended for cognitive impairment, whereas the American label treats the same issue as a limitation of use [23, 24]. The European authorisation under exceptional circumstances requires annual provision of data from the disease monitoring programme on efficacy, safety and natural history [24]. The FDA post-marketing requirements include the prospective study UX003-CL401 of immunogenicity and hypersensitivity, with at least 12 new patients, of whom at least 6 are under 1 year of age, with a final report expected in May 2026, and the registry of genotype, baseline enzyme activity and outcomes up to 2032–2033 [53]. The Brazilian package leaflet follows the American model: indication for all ages with the CNS caveat, no contraindications and a highlighted warning for anaphylaxis, and in the pregnancy section it reproduces the organogenesis studies in female rats and rabbits without the pre- and postnatal study added to the FDA label in 2019; the version of 2 December 2025 moved pregnancy, lactation and geriatric use to the warnings and precautions section and classified the product in pregnancy risk category B, still stating that no pre- and postnatal development studies have been performed, without changing indication, dose or contraindications [23, 139]. The nature of the changes to the FDA label of November 2025 and of the European procedure of July 2026 is not described in the sources consulted.

7.6. Clinical trials of vestronidase alfa

Table 7.7. Trials and studies of vestronidase alfa.

The minimal important differences defined for the MDRI were: 6MWT ≥23 m and ≥10%; FVC with an absolute change of 5% or relative change of 10% of predicted FVC; shoulder flexion of 20°; visual acuity of 3 lines; and specific thresholds for the fine and gross motor domains of the Bruininks–Oseretsky Test of Motor Proficiency (BOT-2) [24, 104]. In the phase 3 trial, 10 of 12 patients improved in at least one MDRI domain, 3 of 6 evaluable patients reached the minimal difference in the 6MWT at 24 weeks (+65, +80 and +83 m) and about 32% of assessments (23 of 72) were not feasible at baseline, owing to disease severity [1, 24, 52]. Liver volume, measured by imaging in 7 patients, went from 1591 ml (742–2207) to 1459 ml (876–1851), and spleen volume from 325 ml to 360 ml, without mean change, because baseline volumes were normal or below normal; in expanded access, a child on continuous ventilation came to tolerate 9 hours a day off the ventilator after 164 weeks [23]. The first patient treated on a compassionate-use basis, a boy with advanced disease, received 2 mg/kg every 2 weeks and, after 24 weeks, had a reduction of about 60% in urinary GAGs, reduction of the liver and spleen, greater tolerance of periods off the ventilator, return to school and partial oral feeding [19, 51]. In a patient from Taiwan with a history of NIHF, diagnosed at 4 years and treated from 6, three years of ERT eliminated oxygen dependence (with non-invasive ventilation only during sleep) and height went from 110 to 118 cm, but the 6MWT fell from 130 to 70 m and recovered to 95 m after several orthopaedic operations, and splenomegaly persisted [88].

The limitations of this evidence are structural. The pivotal trial had 12 patients, a biochemical primary endpoint and a composite clinical endpoint that did not reach statistical significance in the group, and the analysis including fatigue was post hoc [24, 52]. The “blind start” design compares each patient with themselves at different time points and does not provide, for most clinical endpoints, a comparison with placebo [104]. The INFARMED assessment rated the certainty of evidence as very low for all outcomes, owing to incomplete data, absence of parallel arms and imprecision from the sample size [104]. The correlation between the reduction in urinary GAGs and clinical benefit has not been established, one of the arguments of the HAS [72]. The data from the studies should not be compared indirectly with those of other ERTs. No published negative trials were identified; the only registered study withdrawn was BioSly, without enrolment [144].

7.7. Health technology assessment and access

The three public assessments consulted diverge. In Portugal, the INFARMED Health Technology Assessment Committee compared vestronidase alfa with best supportive care in children and adults with non-neurological manifestations and concluded, from CL301, CL202 and CL203, that there is an indication of non-quantifiable added therapeutic value: the overall results of CL301 were considered insufficient for a decision, and the individual data suggest improvement in walking in some patients, with no way of identifying those who benefit; the committee recommended reassessing the benefit within 2 years, and the cost-effectiveness and budget impact results were considered acceptable after negotiation, with funding granted on 16 June 2022 and use in hospital [104]. The report estimates that, in the absence of Portuguese epidemiological data and given the birth rate, no more than 3–4 patients will have been born in Portugal in the last decade [104].

In France, the HAS Commission de la Transparence, on reassessment on 24 June 2020, considered the SMR insufficient and concluded that vestronidase alfa has no place in the therapeutic strategy, citing efficacy demonstrated only on a biological criterion, the lack of an established correlation between the reduction in urinary GAGs and clinical benefit, the lack of effect on neurological symptoms, the tolerability profile (infusion and hypersensitivity reactions, diarrhoea, ataxia, confusion, abdominal pain, vomiting, febrile seizure), the burden of fortnightly infusion and the lack of demonstrated benefit on quality of life [72]. The first opinion, of 27 February 2019, had already considered the SMR insufficient and asked for development to continue in patients at an early stage, accepting that results from the monitoring programme might justify reassessment [72]. The committee estimated the target population in France at about twenty patients and noted that, at the time, vestronidase alfa was reimbursed in Germany but not in Belgium, Italy or the United Kingdom, with assessment under way in Spain, the Netherlands and Portugal [72]. In the extension data analysed by the HAS (CL202, 144 weeks), the urinary GAG factor relative to the upper limit of normal went from 27.5 before treatment to 12.7 at week 48 and 2.6 at 144 weeks (n = 3); 5 of 10 evaluable patients reached the minimal important difference at week 48 (3 on the 6MWT and 2 on fatigue); in 580 infusions there were 78 infusion reactions (3.4 per patient-year), grade 1–2, without anaphylactoid reactions in the extension [72]. The quality-of-life and function questionnaires (MPS HAQ, PROMIS and CHAQ, in 5 to 11 patients) showed small changes in an open-label phase, without formal conclusion [72]. In France, five named-patient ATUs were granted, of which two never started treatment, because of the patient’s death or parental reluctance, and three patients were treated (a 25-year-old woman, a 4-month-old infant and a 1-year-old child); the two children received ERT for about 1 year before HSCT and 6 months to 1 year afterwards, and treatment was stopped, in one case at the parents’ request and in the other after normalisation of GAGs [72]. The HAS concluded that the reduction in GAGs did not correlate with clinical improvement, that it was difficult to distinguish the natural history from the treatment effect and that no impact on morbidity and mortality or quality of life was expected [72]. In the CL202 extension, two patients who had delayed entry, having felt clinical improvement and less fatigue at the end of CL301, returned to treatment after 61 weeks without ERT because of clinical deterioration, without returning to baseline values; at 48 weeks of the extension, echocardiography showed a slight mean increase in left ventricular mass (7.2 ± 8.9 g) and left ventricular diastolic volume (20.5 ± 13.2 ml), with stable ejection fraction, the number of steps in the 3-minute stair climb test went from 100.2 to 108.0 (n = 9) and only 2 patients completed pulmonary function tests [72]. One patient had anti-vestronidase antibody titres above 1:5000 and 7 had in vitro neutralising activity, without apparent effect on GAG reduction; in the paediatric study CL203 there were 31 infusion reactions in 380 infusions (2.1 per patient-year, in 4 of 8 patients, all grade 1–2), including a grade 1 anaphylactoid reaction (agitation, nausea, vomiting, arterial hypertension) resolved with diphenhydramine, and a possibly related grade 3 febrile seizure, without recurrence after reintroduction [72]. The risk management plan considered by the committee identified as important risks infusion reactions, including hypersensitivity, and compression of cervical roots or the spinal cord, as potential risks immunogenicity and hepatic or renal impairment, and as missing information pregnancy, breastfeeding and long-term use [72]. The committee also considered that the product was not likely to have an additional public health impact and, as a consequence of the insufficient SMR, declared the target population “not applicable”, although it had estimated about 20 French patients; it maintained the request for data in patients at an early stage and from the monitoring programme, which it identifies by the code UX003-CL401 (the same as the post-marketing study required by the FDA) and which was then planned in 15 centres in the USA, France, Portugal, Germany, the Netherlands, Spain, Turkey and Brazil, for about 35 patients treated or not, without supply of the product [53, 72]. The prescribing conditions in France were those of the marketing authorisation: use restricted to hospitals, supervision by a professional specialised in MPS VII or other hereditary metabolic diseases and administration by a professional trained in emergency measures; the named-patient ATU ended on 5 November 2018, and the ATC code is A16AB18 [72].

In Brazil, CONITEC recommended in 2020 incorporation into the SUS, conditional on outcome monitoring, reassessment after 3 years and preparation of the PCDT; the estimated budget impact was 467 million reais over 5 years, for 28 to 31 eligible patients, and the report states that vestronidase alfa had not been assessed by the main international assessment agencies [21, 136].

7.8. Brazilian PCDT criteria for starting, excluding and stopping ERT

The PCDT includes patients who meet the biochemical and genetic criteria of section 5.1 [21]. It excludes patients with an irreversible condition and probable survival of less than 6 months, by agreement of more than one specialist, including the severe neonatal form with multisystem manifestations and hydrops fetalis, and those over 18 years who refuse treatment after being informed [21]. The discontinuation criteria are: a reduction in urinary GAGs of less than 50% at 3 months of treatment; absence, at 6 months, of improvement in at least one of four domains of the modified multi-domain index (6MWT, FVC, shoulder flexion, visual acuity), of reduction in hepatosplenomegaly or of improvement on the PedsQL fatigue scale; and adherence below 50% of infusions after an educational programme [21]. The European SmPC recommends periodic assessment of benefit and consideration of discontinuation if there is no clear benefit, including stabilisation, and warns that discontinuation may worsen the clinical condition and that ERT does not reverse irreversible complications such as skeletal deformities [24].

The 2025 French PNDS sets out qualitative criteria for stopping ERT, common to the MPS: severity of lesions or progression of neurological involvement, loss of the expected benefits and excessive risk of the infusion, for example reactions poorly controlled by antihistamines and corticosteroids; the decision is taken collegially at a multidisciplinary team meeting of the CETMPS-GP, with the collaboration of the palliative care team, weighing benefit, risk and burden [18]. The PCDT criteria are quantitative and with fixed deadlines (GAGs at 3 months, functional domains at 6 months, adherence), whereas those of the PNDS depend on clinical assessment and collegial decision [18, 21].

The exclusion of the severe neonatal form diverges from other sources: the PEARL trial admits fetuses with hydrops “because ERT has the potential for significant benefit”, and newborns with a history of NIHF treated with vestronidase alfa have been published, such as those described in section 7.12 [119, 122, 144]. The exclusion is an access rule within the SUS and not a demonstration of absence of benefit.

7.9. Haematopoietic stem cell transplantation

Experience with HSCT in MPS VII is limited to case reports. Table 41.3 of the Saudubray textbook lists a single patient transplanted on an experimental indication, and the review by Dubot and colleagues brought together, up to 2019, the published patients with bone marrow transplantation or HSCT: a Japanese girl transplanted at 12 years (stabilisation, end of infections and motor improvement over 14.5 years of follow-up); five patients from the Montaño survey, transplanted between 2 and 7 years, of whom three survived and two died of complications of the procedure; a child transplanted at 6 months; two children transplanted at 2 and 3.5 years, one with an intelligence quotient of 100 at 9 years; and the Dubot case, at 13 months [26, 86]. The authors concluded that HSCT has preventive value, that in symptomatic patients it does not reverse but appears to slow the disease, that very severely affected patients before transplantation died and that results are limited in the valves, cornea and bone [86]. In the initial description of this patient, homozygous for p.Ala619Val, Yamada and colleagues recorded in 1998 improvement in motor function and activities of daily living and fewer respiratory and ear infections, without cognitive improvement [9]. The same patient had, 22 years after transplantation, normal leucocyte enzyme activity and urinary GAGs and, at 34 years, maintained simple conversation, an intellectual level of about 6 years and independent walking, with occipitocervical fusion [82]. In a Brazilian patient, bone marrow transplantation caused fatal complications [48].

The sources diverge on the indication. The Brazilian PCDT states that HSCT is not indicated, owing to the heterogeneity and limitations of the studies [21]. The HAS noted in 2020 that the French national protocol then in force (2016 MPS PNDS) did not mention it and that, according to experts, it was sometimes performed in the absence of an alternative and with a matched donor [72]. The 2025 PNDS, based on the 2022 recommendations of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), recommends HSCT in MPS IH as early as possible, before 24–30 months and before any cognitive regression, does not recommend it in MPS III and allows it to be discussed case by case in MPS IH-S, II, IV, VI and VII when the diagnosis is early, at a multidisciplinary team meeting with transplant physicians, paediatric neurologists and metabolic disease specialists [18]. INFARMED describes benefits in patients with prolonged follow-up (delayed neurological progression, improved motor function and walking, fewer respiratory infections and less snoring), without improvement in or prevention of bone progression in those transplanted after 3 years, with high morbidity and mortality, and does not consider it standard treatment [104]. GeneReviews allows it to be considered if performed before irreversible damage, especially neurological and skeletal [1, 145]. Trials of HSCT in metabolic diseases that include Sly syndrome are registered, such as NCT02171104 of the University of Minnesota, phase 2, active and not recruiting [144]. HSCT has a defined role in MPS IH, in which it is the preferred treatment before about 2.5 years, and is largely ineffective in MPS III [26].

The modalities described in the PNDS for the MPS are as follows: myeloablative conditioning with busulfan and fludarabine; preferred donor an HLA-identical sibling who is not heterozygous; second line, an 8/8 or 7/8 cord blood unit, preferred for its rapid availability, better chimerism and higher enzyme activity after transplantation, at the cost of a greater risk of rejection and autoimmune cytopenia; third line, a 10/10 unrelated donor; and, in all cases, a cell-rich graft, because the risk of rejection or graft failure is greater in these non-malignant diseases [18]. In MPS IH, peritransplant ERT from diagnosis is recommended, as it reduces morbidity and mortality and ENT obstruction, is continued until there is full donor chimerism, normal or subnormal enzyme activity and normal urinary GAGs (on average 3 to 6 months after transplantation), and anti-enzyme antibodies are not related to engraftment [18]. Follow-up is shared between the transplant team and the reference team, with enzyme assay and chimerism frequently and then annually; HSCT reduces tissue burden and GAG excretion and may stabilise neurological involvement, although cognitive difficulties persist, but it has non-negligible morbidity and mortality and does not prevent skeletal, ocular, cardiac and, sometimes, ENT and neurological progression [18]. As busulfan impairs fertility, the PNDS recommends offering fertility preservation before transplantation (cryopreservation of ovarian or testicular tissue) [18]. The application of these modalities to MPS VII is an extrapolation from experience in MPS IH; the two French children treated with ERT before and after HSCT under an ATU followed a regimen close to the peritransplant one (section 7.7) [72].

7.10. Supportive treatment by system

Table 7.8. Treatment of the manifestations of MPS VII.

Physiotherapy, with or without analgesia, should focus on the prevention or stabilisation of osteoarticular deformities and the maintenance of range of motion [21]. Mobility support was not available to half of the families in the European survey, more than 80% of patients had undergone surgery and caregivers reduced their working hours in 46.2% of cases and stopped working in 30.8% [106]. The PNDS adjusts doses of symptomatic treatments to body size in low-weight adults and to ideal body weight in obese patients, and each medicinal product is used within the terms of its marketing authorisation [18].

7.11. Anaesthesia and the perioperative period

Anaesthesia is high-risk in the MPS, because of upper airway obstruction (dysostosis and soft-tissue deposition), restrictive lung disease, cardiovascular disease and instability of the craniocervical junction, and should be undertaken by an experienced team after full clinical information [26]. The PCDT recommends preoperative assessment, an anaesthetist experienced in difficult airways, intubation frequently with fibreoptic bronchoscopy, laryngeal mask, tubes of smaller diameter than predicted, monitoring for postoperative obstruction, preparation for tracheostomy and avoidance of cervical hyperextension, which may cause acute spinal cord compression; general anaesthesia should be avoided when possible [21]. During anaesthesia, cardiac rhythm should be monitored by MPS experts, because of the risk of fatal dysrhythmias, and intubation is performed with cervical precautions [1]. Perioperative spinal cord injury distant from the surgical site, with paraplegia, has been described in the MPS, associated with low mean arterial pressure, compromised spinal circulation, duration and positioning; prevention rests on careful positioning, monitoring of motor and somatosensory evoked potentials and avoidance of hypotension [26]. Anaesthetic risk also complicates valve surgery [102]. A 12-year-old child with MPS VII died during anaesthesia for dental treatment [19].

The 2025 French PNDS expands on the anaesthetic risk of the MPS [18]. Upper airway problems (macroglossia, large tonsils and adenoids, limited mouth opening with difficult mask ventilation) add to those of the lower airway (diffuse narrowing of the tracheobronchial tree, tracheal stenoses and tortuosity, tracheomalacia), and moving the neck in rotation, flexion or extension requires caution because of high cervical stenosis, possible C1–C2 instability and odontoid hypoplasia. Operations in the prone position expose the patient to abdominal compression, limited chest expansion, compression of the inferior vena cava and displacement of the tube, which should lie below any stenosis. According to the PNDS, perioperative events occur in 25% of patients with MPS, mainly upper airway obstruction, laryngospasm, stridor and reintubation, respiratory and ventilation problems and, more rarely, cardiocirculatory problems; events are more frequent without specific treatment, increase with age, are more likely in adults and in MPS I and II than in MPS III, and tracheal stenoses are a major risk for intubation and ventilation complications [18]. This figure comes from a Hamburg and Rostock series (2002–2016) and is measured per anaesthetic, not per patient: in 67 children with MPS or mucolipidosis undergoing 269 anaesthetics, at least one adverse event occurred in 25.6% of anaesthetics; the risk was greater in MPS I (odds ratio, OR 8.0) and II (OR 8.8) than in MPS III, and direct laryngoscopy was associated with more airway problems than indirect techniques (estimated rates of 47.8% and 10.1%) [146]. Direct laryngoscopy is riskier than indirect; the technique with the lowest risk and fewest conversions is fibreoptic intubation through a laryngeal mask, and repeated attempts at direct laryngoscopy, which promote inflammation, should be avoided [18]. Extubation may be difficult and requires monitoring in intensive care, because of the risk of upper airway obstruction and pulmonary, laryngeal or lingual oedema, even at a distance; prolonged non-invasive ventilation may be necessary [18]. Emergency tracheotomy, sometimes necessary in severe forms with acute obstruction, is made difficult by the short neck and is complicated by secondary stenosis, granulomas and difficult decannulation; a tracheal stent in very tight stenoses risks displacement and inflammatory granuloma and is decided case by case [18].

Before any general anaesthetic, the PNDS requires a checklist (Table 7.9) and that the purpose of the anaesthetic be questioned (follow-up examination in an agitated child or necessary surgery), along with the urgency, the possibility of grouping several procedures under a single anaesthetic without prolonging it excessively, the alternatives (locoregional anaesthesia for carpal tunnel, dental care under conscious sedation) and the need for long-term venous access [18]. The patient and caregivers should be informed of the risks, including that of failed extubation, with possible involvement of the palliative care team. A multidisciplinary team meeting (anaesthetists, metabolic disease specialists, neurologists, ENT, intensivists, neurosurgeons, pulmonologists, palliative care) precedes any planned anaesthetic and should be considered in adolescence to anticipate urgent surgery; planned surgery takes place in a reference centre with an experienced anaesthetist and ENT surgeon, and the CETMPS-GP and G2M have drafted an emergency protocol (Table 4.1) [18].

Table 7.9. Checklist before general anaesthesia in an MPS according to the 2025 French PNDS.

Source: [18].

7.12. Hydrops, the newborn and very early treatment

Treatment of NIHF follows the obstetric recommendations of Table 5.3 [22]. In a newborn of 30+1 weeks with severe hydrops and refractory ascites, ventilation and inhaled nitric oxide, the ascites was treated with prednisone, octreotide and factor XIII concentrate, cord blood exome sequencing identified compound heterozygosity in GUSB at 4 months, ERT was started, the ascites resolved and the child was discharged at 5 months [119]. In a fetus with NIHF diagnosed at 20 weeks by exome and amniotic fluid biochemistry, birth occurred at 36+5 weeks, vestronidase alfa was started on day 20 of life with a fall in urinary GAGs and HSCT was planned [122]. Dubot’s patient started ERT at 4 months and underwent HSCT at 13 months (section 10) [86]. These approaches come from case reports and are not routine. In utero fetal ERT is being studied in the PEARL trial, without published results for MPS VII [144]. The youngest patient included in the trials was 5 months old [24].

7.13. Specific therapies in the class of MPS

Intravenous ERT was approved first for MPS I and then for MPS II, IVA, VI and VII; the pivotal trials and follow-up showed improvement in walking, joint mobility and pulmonary function, reduction of the liver and spleen, an effect on growth and possibly on survival, with significant residual burden despite prolonged treatment [26]. Sibling studies show a more favourable course when ERT begins before irreversible changes [26]. Alloantibodies develop in most patients, and interference with efficacy has been demonstrated in MPS I and II, but not in others [26]. In MPS heart disease, ERT has beneficial effects on the myocardium and limited data suggest valvular stabilisation or regression, and HSCT makes hypertrophy regress but has little effect on existing valve lesions [102].

Table 7.10. Approved disease-modifying therapies in the class of MPS, with the dose given in the 2025 French PNDS.

Sources: [7, 18, 26, 64, 147].

According to the PNDS, laronidase improves 6-minute walk distance, forced vital capacity, sleep apnoea, visceromegaly, cardiomyopathy and GAG excretion; idursulfase improves the walk test, liver and spleen volume, the frequency of respiratory infections and GAGs; elosulfase alfa improves the walk test, forced vital capacity and GAGs; and galsulfase improves the 12-minute walk test, GAGs, respiratory function and growth before puberty [18]. Laronidase and idursulfase do not cross the blood–brain barrier and do not halt neurological involvement [18]. The PNDS dates the first ERTs to 2003 (MPS I), 2006 (MPS VI), 2007 (MPS II), 2014 (MPS IV) and 2019 (MPS VII); the date for MPS VII does not coincide with the European marketing authorisation, of 23 August 2018 [18, 24].

The FDA approval of tividenofusp alfa (Avlayah®) on 24 March 2026, for the neurological manifestations of MPS II in paediatric patients weighing at least 5 kg before advanced neurological damage, is an accelerated approval based on the reduction of heparan sulphate in cerebrospinal fluid (CSF); the label dose is 15 mg/kg weekly intravenously, over about 4 hours after titration, not in combination with other ERTs, and the label carries a boxed warning for hypersensitivity and anaphylaxis [147]. It is the first regulatory use of CSF heparan sulphate as a surrogate endpoint in the MPS, a topic discussed at a Reagan-Udall Foundation workshop with the FDA in February 2024 and in a 2026 review that includes the severe forms of MPS VII among the neuronopathic MPS [61, 148]. For MPS VII, there is no CNS-directed therapy approved or in a registered human trial [144].

The PNDS lists as therapies under study ex vivo gene therapy with autologous haematopoietic stem cells in MPS IH, with favourable preliminary results, the same approach in MPS IIA, IIIA and IIIB, in vivo gene therapy in MPS IIIA and IIIB and chimeric ERTs that cross the blood–brain barrier in MPS IIA [18]. The first is an ex vivo gene-addition therapy: the patient’s own haematopoietic stem cells are transduced with a lentiviral vector encoding α-L-iduronidase and reinfused after myeloablative conditioning, so that the haematopoietic progeny produce the enzyme in excess and deliver it to tissues, including the CNS [149]. In the Milan phase 1/2 trial (NCT03488394), eight children with MPS IH without a suitable allogeneic donor and with a developmental or intelligence quotient above 70 were treated at a mean age of 1.9 ± 0.5 years; with median follow-up of 2.10 years, all had rapid and sustained engraftment of the corrected cells and supraphysiological blood α-L-iduronidase activity in the first month, urinary GAGs normalised at 12 months in four of five evaluable children, the enzyme became detectable in the CSF, with local GAG clearance, and cognitive performance, motor milestones, brain and spinal MRI, joint stiffness and growth remained stable or improved; the safety profile was similar to that of autologous haematopoietic cell transplantation [149]. With median follow-up of 3.78 years, growth remained on the World Health Organization reference curves, with height gain greater than that of an external cohort treated with allogeneic HSCT, joint mobility normalised earlier and completely, acetabular dysplasia indices decreased and the spinal MRI score stabilised; the authors consider longer follow-up necessary [150]. A randomised phase 3 trial comparing this therapy (OTL-203) with allogeneic HSCT (NCT06149403) enrolled 41 patients and was active, not recruiting, at the last registry update, in December 2025 [151]. For MPS VII there is no registered human gene therapy trial (section 7.15).

7.14. Treatment of MPS IX, MPS X and MPS-plus syndrome

In MPS IX, no ERT or HSCT has been described, and treatment is symptomatic for the arthropathy [7]. Recombinant human hyaluronidase (Hylenex®) is approved only as an adjuvant for drug dispersion and absorption and for subcutaneous hydration and is not an ERT [7]. In MPS X there is no specific treatment or registered trial, and management is orthopaedic [68]. In MPS-plus syndrome, ERT has no rationale, because no enzyme is deficient; treatment is haematological, renal, cardiac, respiratory and developmental support, with palliative care, and secondary haemophagocytic lymphohistiocytosis is treated with corticosteroids, as in the Italian child on very prolonged corticosteroid therapy [99, 114]. Bortezomib, eliglustat, genistein, ambroxol and triclabendazole partially corrected trafficking in cells, without any testing in patients [91, 99, 100].

7.15. Developments in the last 12 months

Table 7.11. Developments between October 2025 and October 2026, with level of evidence.

In 2024 a preclinical study with a self-complementary adeno-associated virus (AAV) vector for corneal clouding in MPS VII was published [153]. A ClinicalTrials.gov search in October 2026 found no human gene therapy trials for MPS VII, which does not demonstrate that no programmes are in development [144].

7.16. Pregnancy and lactation

There are no data on pregnancy in women with MPS VII in the sources consulted. As for vestronidase alfa, there are no data in pregnant women: in female rats and rabbits there were no developmental effects up to 1.6 and 10 times human exposure, but in the pre- and postnatal study in female rats there was an increase in stillbirths at exposures below human exposure (2 mg/kg, 0.01 times the human area under the curve), of uncertain clinical relevance [23]. The European SmPC considers it preferable, as a precaution, to avoid use in pregnancy, unless the benefit to the mother outweighs the theoretical risk to the fetus, and the PCDT recommends not starting ERT during pregnancy [21, 24]. The current Brazilian package leaflet classifies alfavestronidase in category B (use in pregnancy only under medical guidance) and makes use during lactation dependent on medical assessment, without the pre- and postnatal study in female rats that appears in the American label [23, 139]. No systemic exposure of the infant through milk is expected, and breastfeeding during treatment is acceptable if the benefit outweighs the theoretical risk [21, 24]. In a pregnant woman with MPS, the airway, spine and heart issues of section 7.11 apply to obstetric anaesthesia.

The 2025 French PNDS, for the MPS as a whole, records few data and reports pregnancies carried to term in women with moderate forms of MPS I, IV and VI, with variable tolerance of the physiological changes of pregnancy, such as increased cardiac output and weight [18]. It recommends a preconception consultation with the MPS specialist and an obstetrician familiar with these diseases, to review the disease, arrange cardiovascular assessment and imaging, adapt treatments, including analgesics, provide genetic counselling and discuss maternal and fetal risks, mode of delivery and arrangements for the baby’s arrival; caesarean section is recommended in most cases, the postpartum period requires enhanced monitoring and, in certain cases, pregnancy is advised against because of the risk of serious complications [18]. The maternity unit is chosen according to maternal symptoms, the risk of prematurity and the obstetrician’s experience with the MPS, and the anaesthetic consultation should be early, with assessment of intubation difficulty [18]. As for ERT, data in pregnancy are scarce but reassuring; the PNDS proposes, if possible, stopping it in the 1st trimester and resuming it if the maternal clinical condition requires it, considers transfer into milk very low and advises against breastfeeding when there is a risk of maternal osteoporosis; combined oral oestrogen–progestogen contraception or an intrauterine device is possible and is decided case by case [18]. These recommendations diverge from those for vestronidase alfa: the European SmPC prefers to avoid use in pregnancy unless the maternal benefit outweighs the risk, the PCDT recommends not starting ERT during pregnancy without providing for interruption in the 1st trimester, and the SmPC and the PCDT accept breastfeeding if the benefit outweighs the risk, without the PNDS restriction related to osteoporosis [18, 21, 24]. The PNDS recommendations are class recommendations and are not based on MPS VII data. In patients due to undergo transplantation, fertility preservation should be offered before HSCT (section 7.9) [18].

7.17. Transition to adulthood

There are no transition programmes specific to MPS VII; the 2025 French PNDS defines transition for the MPS as a whole [18]. Patients who reach adulthood retain orthopaedic (hip prosthesis, spinal surgery), cardiac, ophthalmological and hearing needs and, frequently, dependence in activities of daily living, as in the adults described in France and the United Kingdom and in the patient followed until 37 years [48, 89, 109]. The European SmPC does not establish safety or efficacy above 65 years [24]. Continuity between paediatric and adult centres, maintenance of ERT and of the surveillance in Table 11.2 and access to a MetabERN lysosomal disease centre are the elements that the sources for the class identify for this phase [25, 26].

According to the PNDS, transition should be anticipated, organised and guided by clinical status as much as by legal age, preferably with a first joint consultation of the paediatrician and the adult physician, at which a summary document is handed over and follow-up arrangements are defined [18]. Assessment in adults is the same as in paediatrics, with attention to laryngotracheal manifestations (malacia, stenosis, compression), often minimally or not at all symptomatic at rest and whose detection is essential before any intubation: at transition, cervicothoracic CT with study of the trachea and pulmonary function tests with measurement of maximal inspiratory pressure and the sniff nasal inspiratory test are proposed [18]. The cervical junction should be assessed before any intubation, because the risk of spinal cord compression exists in almost all types of MPS and persists in adults regardless of treatment, owing to odontoid hypoplasia, hypertrophy of the posterior ligaments or meninges or disc disease [18]. Cardiological follow-up is at least annual in adults, to detect valvular disease, sometimes isolated, aortic root dilatation and dysrhythmias, and sleep apnoea should be looked for, especially if there is arterial hypertension; ophthalmological (corneal clouding, glaucoma, retinopathy), hearing and peripheral neurological (radiculopathy, carpal tunnel) surveillance is maintained [18]. Transition covers all those involved, including transplant physicians and paediatric and adult palliative care teams, the arrangements for continuing ERT (day hospital, hospital-at-home, home nursing) and information on anaesthetic risk, with prior contact with the reference team before an anaesthetic; the general practitioner has a central role here, and the G2M filière provides transition guides [18].

7.18. Agents and situations to avoid

Without cervical fusion, activities with a risk of cervical injury, such as gymnastics, and cervical hyperextension during intubation or accidentally should be avoided [1, 21, 104]. Vestronidase alfa should not be infused during acute febrile or respiratory illness, and the infusion line should not be flushed, to avoid a bolus of enzyme [23, 24]. Unnecessary general anaesthetics and perioperative hypotension should be avoided [21, 26]. Recombinant hyaluronidase should not be presented as a treatment for MPS IX [7].

7.19. Breaking the diagnosis, information, therapeutic education and palliative care

The 2025 French PNDS entrusts the breaking of the diagnosis to a specialist from a reference or competence centre, who explains the prognosis, the possible treatments, their objectives and limitations and the follow-up, at least annual, ensures contact with the general practitioner, provides information on patient organisations and may hand over the emergency card [18]. In particularly severe forms, a joint consultation with a palliative care team may be proposed early, to optimise symptomatic treatment, support the family and build a life plan, possibly with hospital-at-home [18]. Information for the patient and family covers the disease and warning signs, treatments and their adverse effects, planning holidays and travel abroad several weeks or months ahead in order to adapt ERT, routine examinations, adherence, the genetics clinic, including for the extended family, influenza and pneumococcal vaccines, special follow-up in pregnancy, coordination with local professionals and patient organisations [18].

Therapeutic education is distinct from simple information or preventive advice. The French programme Enzy-moi, developed by experts with the patient organisation Vaincre les Maladies Lysosomales and funded by the Directorate-General for Healthcare Provision, is intended for patients over 12 years and caregivers of patients of any age with a lysosomal disease, treated or not with ERT; it offers up to 10 workshops, mostly remote and in groups of up to 4 people, after a shared educational diagnosis, on the disease, ERT, the place of treatment (hospital or home), the organisation of infusions, combining treatment with school, work and family, surveillance, unforeseen situations and travel, with enrolment by the patient or the physician through the G2M filière [18].

The palliative approach is not limited to the end of life and can be integrated early, in parallel with ERT or a trial [18]. The meeting with the palliative care team may take place at diagnosis or at a turning point: a new distressing symptom, doubt about surgery or about continuing ERT, the level of treatment in a decompensation, deterioration in general condition or family exhaustion. With therapeutic progress, death now occurs more often in adulthood than in childhood. Advance discussion of management in severe decompensations, the drafting of advance directives by the adult patient, the choice of place of residence and respite for caregivers are part of the care plan, guided by quality of life, beneficence, non-maleficence and respect for autonomy, in order to avoid both therapeutic obstinacy and loss of opportunity; decisions on limitation of treatment follow the collegial procedure laid down in the French Claeys-Leonetti law, and bereavement support draws on professional, institutional and voluntary resources [18].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

MPS VII, MPS IX, MPS X and MPS-plus syndrome are autosomal recessive. At conception, each sibling of a proband has a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier; carriers are asymptomatic and are not at risk of disease [1, 21]. All children of an affected individual are obligate carriers, and each sibling of the parents of a proband has a 50% chance of being a carrier [1]. In MPS II, X-linked, a carrier mother transmits the disease to 50% of her sons and carrier status to 50% of her daughters [115]. In NIHF due to lysosomal disease diagnosed by exome, all variants were inherited, and hydrops recurred in 75% (15/20) of families with information; in an Indian series, 36% of recurrent NIHF were lysosomal diseases [70, 132]. Recurrence of hydrops in a family should therefore lead to targeted metabolic and genetic investigation.

Table 8.1. Recurrence risks by scenario.

8.2. Cascade testing, carriers and minors

Testing of at-risk siblings, of any age, is recommended in order to start ERT and preventive measures early [1]. Carrier detection requires prior identification of the familial variants, because carriers’ enzyme activity is low-normal or slightly deficient and overlaps with that of pseudodeficiency alleles [1, 83]. The ideal time to assess risk and discuss prenatal diagnosis or PGT is before pregnancy, and counselling should be offered to young adults who are affected, carriers or at risk; partners of carriers and of affected individuals should be tested, especially if they share Mexican, Japanese or Brazilian ancestry [1]. In probands without a molecular diagnosis, DNA should be stored [1]. Carrier testing in minors without immediate medical implications is not specifically addressed in the sources consulted. Testing of siblings at risk of being affected is justified by the medical benefit of early treatment [1]. In the European survey, 6 of 12 families had not been offered genetic counselling [106]. In France, informing relatives has been a legal obligation since decree No. 2013-527 of 20 June 2013: it falls to the parents or the adult patient, with the support of the geneticist or genetic counsellor, who offers relatives a consultation; the 2025 PNDS recommends constructing the family tree in all families, extending it in MPS II to identify possible female carriers and testing relatives by direct analysis of the familial variant [18].

8.3. Prenatal diagnosis and preimplantation genetic testing

With both familial variants known, prenatal diagnosis by chorionic villus sampling or amniocentesis and PGT are possible, and clinical exome sequencing has proved useful in prenatal diagnosis, counselling and PGT in families with MPS VII [1, 128]. Enzymatic diagnosis on villi or amniocytes requires prior knowledge of the enzyme status and, ideally, the genotype of the parents, because of interference from pseudodeficiency [83, 96]. The decision on the use of prenatal testing is personal, and perspectives on its use differ [1]. In pregnancies with NIHF, counselling should be individualised and include all options, including termination, in line with SMFM recommendation 4 [22]. In MPS-plus syndrome, increased prenasal thickness in the 2nd trimester and placental biopsy allowed early prenatal diagnosis in a family of known carriers [117]. When the proband dies without a diagnosis, preservation of tissue and DNA and genomic autopsy allow the variants to be identified and chorionic villus sampling, amniocentesis or PGT to be offered in subsequent pregnancies, as in the Japanese couple with two hydropic pregnancies described in 2026 [107]. The 2025 French PNDS performs prenatal diagnosis by molecular biology when the variants of the index case and of both parents have been identified, or possibly by enzyme study, by chorionic villus sampling between 11 and 13 weeks of gestation or by amniocentesis from 15–16 weeks; in MPS II, determination of fetal sex in maternal blood from 9 weeks avoids the invasive procedure in carriers of a female fetus; if the fetus is affected, termination of pregnancy for medical reasons may be carried out at the request of the couple or the mother, with a multidisciplinary prenatal diagnosis centre, and preimplantation diagnosis is among the options to be presented [18].

8.4. Germline mosaicism and special situations

Post-zygotic mosaicism in a parent is one of the explanations for finding a single parental variant, and germline mosaicism has been described in MPS II [1, 62]. The possibility of pseudodeficiency in healthy relatives should be explained, because low enzyme activity in a healthy sibling or parent does not equate to disease, as shown by the asymptomatic adult woman described in 2026 [84, 96]. Oocyte donation does not eliminate the risk of recessive disease, as in the fetus with NIHF conceived by in vitro fertilisation with a donor, in whom duo exome sequencing identified two GUSB variants [122].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency of MPS VII by region

The estimates of the frequency of MPS VII measure different things and are not directly comparable (Table 9.1). All result from clinical ascertainment and are probably underestimates, because perinatal presentations with hydrops and neonatal death may never be diagnosed [13, 19].

Table 9.1. Estimates of the frequency of MPS VII.

The INFARMED report cites a prevalence between 1:250,000 and 1:2,000,000 and 150–200 cases diagnosed in developed countries [104]. The HAS cites 0.02 to 0.29/100,000 live births and estimates about twenty patients in France, by expert opinion [72]. Estimation from population exomes and genomes (ExAC and gnomAD) produced maximum MPS prevalences of 0.46 to 7.1/100,000, higher than those published, which may reflect underdiagnosis or in silico overestimation [155].

9.2. Epidemiology of the class

The incidence of the MPS as a whole has been estimated at 1:25,000 births [102] and between 1.9 and 4.5/100,000 in another source [115]. In the USA, between 1995 and 2015, the overall incidence was 0.98/100,000 live births, with 0.26 for each of MPS I, II and III, 0.14 for IV, 0.04 for VI and 0.027 for VII [15]. In Brazil, the birth prevalence of the MPS as a whole was 1.25/100,000 (1994–2015; 4.62 adjusted) [16] and 1.57/100,000 (1994–2018) in a reference laboratory with 1652 patients, MPS II being the most common (0.48/100,000; 0.94 in boys) and MPS VI the most common in the Northeast [156]. In Japan the prevalence was 1.53/100,000 and in Switzerland 1.56/100,000; relatively high prevalences have been described in Germany, Northern Ireland, Portugal and the Netherlands [154]. In an update covering 189 publications from 33 countries, the overall frequency of the MPS was highest in Saudi Arabia, followed by Portugal, Brazil, the Netherlands and Australia [157]. In Portugal, the birth prevalence of 29 lysosomal diseases was 25/100,000 live births, twice that of Australia and the Netherlands, with mucolipidoses II and III the most frequent; the abstract of the study does not separate out MPS VII [158]. The most frequent MPS varies by region: MPS I and III in most countries, MPS VI in the United Arab Emirates and Turkey, MPS II in Brazil and MPS II and VI in Ceará [26, 115, 156]. The frequencies by type according to the core sources (per 100,000) are: MPS I 1.2; MPS II 1.0; MPS IIIA 1; MPS IIIB 0.5; MPS IIIC 0.067; MPS IIID 0.1; MPS IVA 0.37; MPS VI 0.23; multiple sulfatase deficiency 0.071 [28]. The OMIM entries bring together other regional studies, each with its own period and method of ascertainment. In the Netherlands, birth prevalence was 1.19/100,000 for MPS I (25% of diagnosed MPS), 1.16/100,000 for MPS IIIA and 0.67/100,000 for MPS II (1.30 per 100,000 boys) [32, 36]. In Western Australia (1969–1996, several ascertainment sources), the approximate incidences were 1:107,000 live births for MPS IH, 1:58,000 for MPS III overall (5 cases of type A, 5 of B and 1 of C), 1:320,000 for MPS II (1:165,000 boys), 1:320,000 for MPS VI and 1:640,000 for MPS IVA [32, 35, 38, 40, 42]. In British Columbia (1952–1986), MPS II reached 1:110,950 male live births, MPS IH 1:144,274, MPS IVA 1:216,412 and MPS IIIA 1:324,617 live births [32, 35, 36, 40]. In Taiwan (1984–2004), the combined incidence was 2.04/100,000, with MPS II accounting for 52% of cases (1.07/100,000), and MPS IVA was estimated at about 1:300,000 live births in Italy [35, 40]. The birth prevalence of MPS IIIC was estimated at 0.07/100,000 in Australia, 0.12/100,000 in Portugal and 0.21/100,000 in the Netherlands [38]. The 2025 French PNDS estimates the cumulative incidence of the MPS at 1:25,000 to 1:30,000 births and gives, without period or ascertainment method, 1:100,000 births for MPS I, 1:80,000 boys for MPS II, 1:147,000 for MPS III (with type A the most frequent in France), 1:300,000 for MPS IVA and 1:600,000 for MPS VI; it notes that MPS VII is very rare, diagnosed mainly in the prenatal period, with few living patients in France, and that no case of MPS IX has been diagnosed in the country [18]. The expression “few living patients” contrasts with the twenty or so patients estimated by the HAS in 2020 as the target population for vestronidase alfa; the two figures come from documents with different purposes and neither is presented as a prevalence [18, 72].

9.3. Founder populations and diversity

MPS VII is pan-ethnic [19]. In the Montaño survey, 62% of patients were Caucasian, 18% white Hispanic, 9% Black and 7% Asian, and the countries most represented were Brazil (27%), the USA (20%), Germany (18%) and Argentina (11%) [19]. In the monitoring programme, 46% were white, 14% Black, 11% American Indian or Alaska Native, 9% Asian and 40% Hispanic [74]. The populations with founder variants are Brazil (p.Leu176Phe, of probable European origin), Mexico (complex allele p.[(Pro408Ser;Pro415Leu)]) and Japan (p.Ala619Val) [73, 81, 85]. In the other MPS, the OMIM entries document several regionally distributed alleles, presented here in the historical notation of those entries. In MPS I, the nonsense variants W402X (= NM_000203.5:c.1205G>A p.(Trp402Ter)) and Q70X (= NM_000203.5:c.208C>T p.(Gln70Ter)) of IDUA account for between 24% (Italy) and 84% (Scandinavia) of European alleles; in Scandinavia Q70X predominates (62%) and in the rest of Europe W402X (48%). P533R (= NM_000203.5:c.1598C>G p.(Pro533Arg)) is concentrated in Sicily, and in Japan the severe 704ins5 and the mild R89Q (= NM_000203.5:c.266G>A p.(Arg89Gln)) predominate, without W402X or Q70X [32, 33]. In MPS IIIC, R344C (= NM_152419.3:c.1030C>T p.(Arg344Cys)) and S518F (= NM_152419.3:c.1553C>T p.(Ser518Phe)) of HGSNAT account for 22% and 29.3% of Dutch alleles [38]. In MPS IIIB, R234C (= NM_000263.4:c.700C>T p.(Arg234Cys)) of NAGLU is a founder in the Iberian Peninsula, and MPS IIIB predominates in central-eastern Greece [37]. In MPS IVA, G340D (= NM_000512.5:c.1019G>A p.(Gly340Asp)) of GALNS showed a founder effect in central-eastern China [40]. MPS-plus syndrome is concentrated in the Yakut population, with cases in Turkey and Italy [56, 67, 114]. MPS IX has been described in the family of the index patient and in a consanguineous family from the Middle East, and MPS X in consanguineous families and in series from several countries [20, 54, 65, 66].

9.4. Portugal and Brazil

The Iberian MPS VII cohort, with 9 patients from Spain and Portugal, was described by Spanish and Portuguese authors [105]. The international monitoring programme includes the Centro Hospitalar do Porto and the Hospital de Clínicas de Porto Alegre as centres [74, 144]. In Portugal, vestronidase alfa has been funded for hospital use in the National Health Service (SNS) since 2022 [104]. In Brazil, most patients live in the Northeast, the p.Leu176Phe variant is almost universal, diagnosis occurred at a mean of 5 years and treatment is provided by the SUS according to the PCDT [21, 81]. In the class, a study of 11 Portuguese patients with MPS IIIB, which OMIM cites as the most frequent MPS in Portugal, found NAGLU R234C (historical notation, = NM_000263.4:c.700C>T p.(Arg234Cys)) in 32% of alleles, on a haplotype shared with Spanish patients that indicates a single and relatively recent origin in the Iberian Peninsula [37]. In Brazil, testing for 10 known IDUA variants in 24 patients with MPS I defined only 54% of alleles, which shows the low frequency of the common European alleles in this population [32].

9.5. Special populations

Pregnant women with MPS VII and pregnant women on ERT have no specific data (section 7.16). Patients over 65 years and those with renal or hepatic impairment have not been studied [24]. Patients with severe intellectual disability cannot perform many of the functional tests used to measure the response to ERT, such as spirometry, which limits the application of response criteria [52, 74].

9.6. Reference networks and patient organisations

MetabERN is the European Reference Network for hereditary metabolic disorders, including lysosomal diseases [25]. Patient organisations include the MPS Society in the United Kingdom, the National MPS Society in the USA and the Canadian MPS Society [1, 159, 160]. In Brazil, Rede MPS Brasil, a diagnostic and research network, and Instituto Vidas Raras, a patient organisation whose database was used in the Brazilian epidemiological study, are the resources cited [16, 115, 161]. In France, the patient organisation Vaincre les Maladies Lysosomales took part as a stakeholder in the HAS reassessment of vestronidase alfa [72]; recognised as being of public utility, it welcomes all people with a lysosomal disease, and the 2025 PNDS also refers to the MPS Society [18]. The sources consulted did not confirm the address of a Portuguese organisation for patients with lysosomal diseases. Orphanet information on MPS VII and MPS IX is in the ORPHA:584 and ORPHA:67041 records [2, 3].

In France, the organisation of care described in the 2025 PNDS rests on the rare disease reference centres, accredited from 2004: the CRML, coordinated by the Hôpital Armand-Trousseau (Paris), with constituent and competence centres, the Reference Centre for Inherited Metabolic Diseases, coordinated in Marseille, and the Reference Centre for Constitutional Bone Diseases, linked to the G2M health filière, accredited in 2014 and again in 2019 [18]. The Committee for the Evaluation of Treatment of Lysosomal Diseases (CETL) and its subgroup CETMPS-GP may be consulted by any physician about a patient with MPS and help to harmonise practice; the multidisciplinary team meetings take place on a digital platform (Skemeet) and cover diagnostic strategy, validation of the diagnosis, the indication for or discontinuation of a specific treatment and collegial palliative decisions [18]. Dedicated multidisciplinary consultations, lasting half a day to two days, are held 1 to 2 times a year, and the reference medical biology laboratories are in Lyon, Paris-Necker, Rouen, Toulouse, Grenoble and Lille [18]. The national RaDiCo-MPS cohort, sponsored by the National Institute of Health and Medical Research (INSERM), registers patients with all types of MPS in order to learn about the epidemiology, natural history, benefit of treatments and socio-economic data, with the consent of the patient or legal representatives [18].

The PNDS also describes social support in France [18]. Long-term condition No. 17 exempts the patient from co-payment for disease-related expenses, but requires basic and supplementary cover; transport to a centre more than 150 km away is reimbursed on prior request stamped by the centre, which must be the one closest to home. Parents may obtain 5 days of leave when the diagnosis is announced, parental presence leave compensated by the family allowance fund, up to 310 days over a maximum period of 3 years, not exceeding 22 days per month, and compensated carer’s leave of up to 3 months (66 days or 132 half-days), which can be split and renewed up to 1 year; family solidarity leave is unpaid. The departmental centre for persons with disabilities (MDPH) awards the compensation benefits (education allowance for a child with a disability, allowance for an adult with a disability and disability compensation benefit), the mobility inclusion card (invalidity entry from 80% incapacity; parking entry if walking distance is limited) and recognition as a worker with a disability, which allows the workplace to be adapted. Schooling takes place, whenever possible, in the local school, with a personalised schooling plan, a classroom assistant, adapted timetable and materials and extra time in examinations; before 6 years, early medico-social action centres support the child without prior referral by the MDPH, and thereafter home-based special education and care services or medico-educational institutions, institutions for motor education and institutions for children with multiple disabilities. In adults, work may be in an ordinary setting with adaptation, in an adapted company or in a sheltered work establishment, and patients without autonomy may be referred to residential homes, day care or specialised care homes [18].

10. Illustrative Clinical Case

Dubot and colleagues described in 2019, in Toulouse, the first patient with MPS VII treated with ERT before 6 months of age and the first treated with ERT followed by HSCT [86]. He was the first child of non-consanguineous parents, born after a normal pregnancy and delivery, without hydrops, weighing 2680 g, with a length of 44 cm and head circumference of 34 cm. At birth he had lymphoedema, coarse facies, talipes equinovarus and mild hepatosplenomegaly, with thrombocytopenia; the blood film showed lymphocytes with Alder-type cytoplasmic inclusions (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC6861985/figure/ijms-20-05345-f001/). At 10 days of life there were traces of dermatan sulphate in the urine, and β-glucuronidase activity was below 1% of control in leucocytes and plasma (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC6861985/figure/ijms-20-05345-f002/).

Sanger sequencing identified three missense variants in exon 3 of GUSB (NM_000181.4): c.526C>T p.(Leu176Phe), inherited from the father, and c.422A>C p.(Glu141Ala) and c.424C>T p.(His142Tyr), in cis on the maternal allele. On expression in HEK293T cells, the double maternal allele retained 45% of normal activity, each maternal variant alone 83% and 73%, and p.(Leu176Phe) 59% [86].

As vestronidase alfa was not yet available in France, the patient received it on a compassionate-use basis, at a dose of 4 mg/kg every 2 weeks, from 4 to 18 months. The dysmorphism improved, the hepatomegaly disappeared and the spleen decreased in size, without normalising; urinary heparan sulphate and chondroitin and dermatan sulphate decreased between weeks 2 and 12 (Figure 4: https://pmc.ncbi.nlm.nih.gov/articles/PMC6861985/figure/ijms-20-05345-f004/), without adverse effects. The clubfoot was corrected by the Ponseti method. At 1 year he had global hypotonia and slight motor delay, and auditory evoked potentials showed partial bilateral deafness until 2 years [86].

At 13 months he underwent unrelated cord blood HSCT with 6/6 HLA matching, with 100% donor chimerism at 30 days and at 2 years. The post-transplant course was complicated by severe cutaneous and intestinal graft-versus-host disease, treated with ciclosporin, corticosteroids and infliximab, severe anorexia with enteral nutrition, slowing of growth from −1 to −2 SD, transient psychomotor stagnation and partial hypothyroidism treated with levothyroxine. At 4 years, growth was stable at −2 SD, without hepatosplenomegaly, with normal auditory potentials, normal language and psychomotor development and normal schooling; the family declined neuropsychological testing. After transplantation, leucocyte β-glucuronidase activity normalised, but plasma activity remained very low, and urinary GAGs normalised, which raised the question of continuing ERT after HSCT [86].

The case illustrates the value of the blood film in neonatal diagnosis, the need to establish the phase of variants when there are two on the same allele and the early biochemical and visceral response to ERT. The sequence of ERT followed by HSCT is not a standardised approach: the Brazilian PCDT does not recommend HSCT, INFARMED does not consider it standard treatment, and GeneReviews only allows it to be considered before irreversible damage [1, 21, 104]. The figure images were not inspected visually; the description follows the legends and text of the article.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The prognosis depends on the form of presentation. In the fetal and neonatal form, death may occur in utero or in the first 6 months, and the patients in the neonatal group of the Montaño survey who survived gestation mostly died in early childhood [19, 48]. By contrast, 13 of 23 patients with a history of NIHF survived childhood with a mild to intermediate course until the end of adolescence, and NIHF does not predict severity in survivors [19, 103]. In the analysis of 53 published patients, the median survival of those diagnosed postnatally reached 360 months (30 years), and residual activity >1.4% in fibroblasts and urinary GAGs <602% of normal were associated with longer survival [94]. The causes of death are respiratory complications, dysrhythmias and cardiac arrest, renal failure, aspiration and, in older children, neurodegenerative complications; survival beyond 30 years is exceptional, and the longest-known survivor at the time of Nyhan’s atlas died at 37 years, although a French patient with an attenuated form lived to 52 [19, 48, 104, 109]. In NIHF in general, survival of live-born infants is 36–68%, with neurological impairment in up to 48%, and NIHF due to inborn errors of metabolism is among those at highest risk [22].

The functional prognosis is limited: 57% of the patients in the survey walked unaided and more than 40% lose independent walking over the course of the disease [19, 104]. ERT does not modify the neurocognitive prognosis and does not reverse established skeletal lesions; its effect on final height and survival has not been established [1, 24, 26]. In the class of MPS, early diagnosis improves the prognosis, and very early treatment suggests prevention or delay of heart disease [102, 115]. In MPS-plus syndrome, usual survival does not exceed the 2nd year, with the exception of the juvenile form [59, 91]. In MPS IX and MPS X, the course in adulthood is unknown; in MPS X, hip dysplasia progresses and vertebral changes may regress [7, 66].

11.2. Initial assessment after diagnosis

Table 11.1. Recommended assessments after the diagnosis of MPS VII.

11.3. Surveillance

Table 11.2. Surveillance of MPS VII.

Surveillance is individualised, because the spectrum is broad, and serves to follow existing manifestations, the response to treatment and the appearance of new manifestations [1]. Functional tests require cooperation, and some patients are unable to perform them [74]. The sources diverge on several intervals: brain MRI is periodic in the PCDT (every 2–3 years) and only with warning signs in the 2025 French PNDS; spinal MRI is annual in childhood in GeneReviews and every 1–3 years from 2 years in the PNDS; polysomnography is guided by the clinical picture in GeneReviews and periodic in the PNDS; the walk test is six-monthly in the PCDT and annual in the PNDS; dental care is six-monthly to annual in GeneReviews and annual in the PNDS; and the PNDS sets no interval for urinary GAGs or routine tests for MPS VII, unlike GeneReviews and the PCDT [1, 18, 21]. In patients on vestronidase alfa, the intervals linked to the response to ERT follow the PCDT, and those of the PNDS serve as reference for the multisystem surveillance common to the class.

12. Summary and Concluding Remarks

The mucopolysaccharidoses are lysosomal diseases caused by deficiency of one of the enzymes of sequential GAG degradation, with a multisystem, progressive phenotype in which the type of GAG accumulated determines organ involvement: heparan sulphate is associated with cognitive impairment, dermatan sulphate with valvular disease and keratan sulphate with spondyloepiphyseal dysplasia. The class now comprises types I to IX and type X, and MPS-plus syndrome due to VPS33A, without enzyme deficiency, extends it to defects of endosomal trafficking.

MPS VII, caused by biallelic GUSB variants, is ultra-rare and is distinguished by the frequency of non-immune hydrops fetalis, present in 30–50% of patients and the most frequent lysosomal cause of NIHF in prenatal exome series. The spectrum ranges from fetal death to attenuated adult forms, and hydrops does not predict severity in survivors. Diagnosis combines urinary GAGs, which may be only slightly abnormal, β-glucuronidase activity and genotype, with exclusion of the pseudodeficiency allele c.454G>A p.(Asp152Asn) and of multiple sulfatase deficiency. In pregnancies with hydrops, fetal exome or genome sequencing, combined with amniotic fluid biochemistry, allows diagnosis and counselling on the 25% recurrence risk.

Vestronidase alfa, at a dose of 4 mg/kg every 2 weeks, reduces urinary GAGs and may improve walking and growth, but the evidence comes from few patients, with very low certainty for clinical outcomes, and the treatment does not act on the CNS. The European indication is limited to non-neurological manifestations, and access varies between countries: funded in Portugal and Brazil, not reimbursed in France. HSCT has heterogeneous results and an indication that diverges between sources. Management rests on multidisciplinary care, surveillance of the cervical spine, airway and heart and specialised preparation for anaesthesia. In France, the 2025 MPS PNDS places MPS VII within the national organisation for lysosomal diseases, proposes periodic surveillance common to the class and allows HSCT to be discussed case by case, without recommending vestronidase alfa, which is not reimbursed.

MPS IX is an arthropathy due to hyaluronidase deficiency, described in four patients, which is confused with juvenile idiopathic arthritis. MPS X is a skeletal dysplasia with hip predominance and metaphyseal striation, without visceromegaly or intellectual disability. MPS-plus syndrome is a severe disease of infancy with renal and haematopoietic involvement, concentrated in the Yakut population. None of these three entities has a specific treatment.

13. References

1. Sun A, Wang R. Mucopolysaccharidosis Type VII. 2024 Jan 4. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK598990/
2. Orphanet. Mucopolysaccharidosis type 7 (ORPHA:584). Available from: https://www.orpha.net/en/disease/detail/584
3. Orphanet. Hyaluronidase deficiency (ORPHA:67041). Available from: https://www.orpha.net/en/disease/detail/67041
4. Lipiński P, Różdżyńska-Świątkowska A, Wiśniewska K, Rusecka J, Ługowska A, Żuber Z, et al. Mucopolysaccharidoses-What Clinicians Need to Know: A Clinical, Biochemical, and Molecular Overview. Biomolecules. 2025;15(10):1448. doi:10.3390/biom15101448. PMID:41154677. PMCID: PMC12562998.
5. National Center for Biotechnology Information. Gene [Internet]: GUSB (Gene ID 2990), HYAL1 (3373), VPS33A (65082), ARSK (153642). Bethesda (MD): NLM. Available from: https://www.ncbi.nlm.nih.gov/gene/2990
6. OMIM® Online Mendelian Inheritance in Man. *611499 BETA-GLUCURONIDASE; GUSB. Johns Hopkins University; last edited 01/03/2022. https://omim.org/entry/611499. Accessed 28 October 2026.
7. GeneGuidance. HYAL1 — gene record.
8. OMIM® Online Mendelian Inheritance in Man. #601492 MUCOPOLYSACCHARIDOSIS, TYPE IX; MPS9. Johns Hopkins University; last edited 24/09/2022. https://omim.org/entry/601492. Accessed 28 October 2026.
9. OMIM® Online Mendelian Inheritance in Man. #253220 MUCOPOLYSACCHARIDOSIS, TYPE VII; MPS7. Johns Hopkins University; last edited 14/12/2023. https://omim.org/entry/253220. Accessed 28 October 2026.
10. OMIM® Online Mendelian Inheritance in Man. *607071 HYALURONOGLUCOSAMINIDASE 1; HYAL1. Johns Hopkins University; last edited 01/03/2022. https://omim.org/entry/607071. Accessed 28 October 2026.
11. ClinGen. Gene-disease validity: GUSB – mucopolysaccharidosis type 7 (MONDO:0009662), autosomal recessive, Definitive (5 Jul 2022). Available from: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aae0c8bd-5ff2-48a1-90e9-9038dcb44bc3-2022-07-05T160000.000Z
12. Fink SP, Triggs-Raine B. Genetic Deficiencies of Hyaluronan Degradation. Cells. 2024;13(14):1203. doi:10.3390/cells13141203. PMID:39056785. PMCID: PMC11275217.
13. GeneGuidance. GUSB — gene record (accessed 26/09/2026).
14. Grant CL, López-Valdez J, Marsden D, Ezgü F. Mucopolysaccharidosis type VII (Sly syndrome) - What do we know?. Mol Genet Metab. 2024;141(3):108145. doi:10.1016/j.ymgme.2024.108145. PMID:38301529.
15. Puckett Y, Mallorga-Hernández A, Montaño AM. Epidemiology of mucopolysaccharidoses (MPS) in United States: challenges and opportunities. Orphanet J Rare Dis. 2021;16(1):241. doi:10.1186/s13023-021-01880-8. PMID:34051828. PMCID: PMC8164808.
16. Federhen A, Pasqualim G, de Freitas TF, Gonzalez EA, Trapp F, Matte U, et al. Estimated birth prevalence of mucopolysaccharidoses in Brazil. Am J Med Genet A. 2020;182(3):469-483. doi:10.1002/ajmg.a.61456. PMID:31926052.
17. Kiykim E, Barut K, Cansever MS, Zeybek CA, Zubarioglu T, Aydin A, et al. Screening Mucopolysaccharidosis Type IX in Patients with Juvenile Idiopathic Arthritis. JIMD Rep. 2016;25:21-24. doi:10.1007/8904_2015_467. PMID:26122630. PMCID: PMC5059191.
18. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Mucopolysaccharidoses. Centre de Référence des Maladies Lysosomales; Comité d'Evaluation du Traitement des Mucopolysaccharidoses et Glycoprotéinoses; Filière de santé maladies rares G2M. Saint-Denis La Plaine: HAS; 2025 Jan 21. Available from: https://www.has-sante.fr/jcms/p_3579099
19. Montaño AM, Lock-Hock N, Steiner RD, Graham BH, Szlago M, Greenstein R, et al. Clinical course of sly syndrome (mucopolysaccharidosis type VII). J Med Genet. 2016;53(6):403-18. doi:10.1136/jmedgenet-2015-103322. PMID:26908836. PMCID: PMC4893087.
20. Imundo L, Leduc CA, Guha S, Brown M, Perino G, Gushulak L, et al. A complete deficiency of Hyaluronoglucosaminidase 1 (HYAL1) presenting as familial juvenile idiopathic arthritis. J Inherit Metab Dis. 2011;34(5):1013-22. doi:10.1007/s10545-011-9343-3. PMID:21559944.
21. Brasil. Ministério da Saúde. Portaria Conjunta SAES/SCTIE n.º 8, de 21 de maio de 2021. Aprova o Protocolo Clínico e Diretrizes Terapêuticas da Mucopolissacaridose do Tipo VII. Brasília: Ministério da Saúde; 2021. Available from: https://www.gov.br/conitec/pt-br/midias/protocolos/20210531_pcdt_mps_vii.pdf
22. Society for Maternal‐Fetal Medicine (SMFM), Sparks TN, Norton ME, SMFM Publications Committee. Society for Maternal-Fetal Medicine Consult Series #75: Evaluation and management of non-immune hydrops fetalis. Pregnancy (Hoboken). 2026;2(2):e70208. doi:10.1002/pmf2.70208. PMID:42596935. PMCID: PMC13344273.
23. Ultragenyx Pharmaceutical Inc. MEPSEVII (vestronidase alfa-vjbk) injection, for intravenous use. Prescribing information. BLA 761047. Silver Spring (MD): U.S. Food and Drug Administration; SPL version 17, effective 2025 Nov 18. Available from: https://api.fda.gov/drug/label.json?search=openfda.generic_name:vestronidase (DailyMed set id 925d4e21-fd98-474d-a34d-a0b3558ed750).
24. European Medicines Agency. Mepsevii (vestronidase alfa): EPAR – product information (summary of product characteristics, annexes). EMEA/H/C/004438. Amsterdam: EMA; first authorised 2018 Aug 23; renewal 2023 Jul 28; latest procedure N/0000358430 (2026 Jul 08). Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/mepsevii
25. European Reference Network for Hereditary Metabolic Disorders (MetabERN). Available from: https://metab.ern-net.eu/
26. Jones S, Wijburg FA. Glycosaminoglycans and Oligosaccharides Disorders: Glycosaminoglycans Synthesis Defects, Mucopolysaccharidoses, Oligosaccharidoses and Sialic Acid Disorders. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 41, section 41.2 Mucopolysaccharidoses.
27. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Introduction to mucopolysaccharidoses. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 555–557.
28. GeneGuidance. IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, GLB1, ARSB, SUMF1 — gene records.
29. Orphanet. Mucopolysaccharidosis (ORPHA:79213, group). Available from: https://www.orpha.net/en/disease/detail/79213
30. Orphanet. Mucopolysaccharidosis type 10 (ORPHA:662216). Available from: https://www.orpha.net/en/disease/detail/662216
31. Orphanet. Mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders (ORPHA:505248). Available from: https://www.orpha.net/en/disease/detail/505248
32. OMIM® Online Mendelian Inheritance in Man. #607014 HURLER SYNDROME. Johns Hopkins University; last edited 28/03/2023. https://omim.org/entry/607014. Accessed 28 October 2026.
33. OMIM® Online Mendelian Inheritance in Man. #607015 HURLER-SCHEIE SYNDROME. Johns Hopkins University; last edited 09/07/2016. https://omim.org/entry/607015. Accessed 28 October 2026.
34. OMIM® Online Mendelian Inheritance in Man. #607016 SCHEIE SYNDROME. Johns Hopkins University; last edited 23/03/2023. https://omim.org/entry/607016. Accessed 28 October 2026.
35. OMIM® Online Mendelian Inheritance in Man. #309900 MUCOPOLYSACCHARIDOSIS, TYPE II; MPS2. Johns Hopkins University; last edited 16/02/2026. https://omim.org/entry/309900. Accessed 28 October 2026.
36. OMIM® Online Mendelian Inheritance in Man. #252900 MUCOPOLYSACCHARIDOSIS, TYPE IIIA; MPS3A. Johns Hopkins University; last edited 17/02/2022. https://omim.org/entry/252900. Accessed 28 October 2026.
37. OMIM® Online Mendelian Inheritance in Man. #252920 MUCOPOLYSACCHARIDOSIS, TYPE IIIB; MPS3B. Johns Hopkins University; last edited 14/02/2024. https://omim.org/entry/252920. Accessed 28 October 2026.
38. OMIM® Online Mendelian Inheritance in Man. #252930 MUCOPOLYSACCHARIDOSIS, TYPE IIIC; MPS3C. Johns Hopkins University; last edited 13/06/2022. https://omim.org/entry/252930. Accessed 28 October 2026.
39. OMIM® Online Mendelian Inheritance in Man. #252940 MUCOPOLYSACCHARIDOSIS, TYPE IIID; MPS3D. Johns Hopkins University; last edited 14/02/2024. https://omim.org/entry/252940. Accessed 28 October 2026.
40. OMIM® Online Mendelian Inheritance in Man. #253000 MUCOPOLYSACCHARIDOSIS, TYPE IVA; MPS4A. Johns Hopkins University; last edited 17/06/2022. https://omim.org/entry/253000. Accessed 28 October 2026.
41. OMIM® Online Mendelian Inheritance in Man. #253010 MUCOPOLYSACCHARIDOSIS, TYPE IVB; MPS4B. Johns Hopkins University; last edited 12/05/2021. https://omim.org/entry/253010. Accessed 28 October 2026.
42. OMIM® Online Mendelian Inheritance in Man. #253200 MUCOPOLYSACCHARIDOSIS, TYPE VI; MPS6. Johns Hopkins University; last edited 17/07/2025. https://omim.org/entry/253200. Accessed 28 October 2026.
43. OMIM® Online Mendelian Inheritance in Man. #619698 MUCOPOLYSACCHARIDOSIS, TYPE X; MPS10. Johns Hopkins University; last edited 03/04/2026. https://omim.org/entry/619698. Accessed 28 October 2026.
44. OMIM® Online Mendelian Inheritance in Man. #617303 MUCOPOLYSACCHARIDOSIS-PLUS SYNDROME; MPSPS. Johns Hopkins University; last edited 17/11/2020. https://omim.org/entry/617303. Accessed 28 October 2026.
45. OMIM® Online Mendelian Inheritance in Man. #272200 MULTIPLE SULFATASE DEFICIENCY; MSD. Johns Hopkins University; last edited 18/02/2025. https://omim.org/entry/272200. Accessed 28 October 2026.
46. Jones KL, Jones MC, del Campo M. Mucopolysaccharidosis I H, I H/S, I S. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 642–645.
47. Sly WS, Quinton BA, McAlister WH, Rimoin DL. Beta glucuronidase deficiency: report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis. J Pediatr. 1973;82(2):249-57. doi:10.1016/s0022-3476(73)80162-3. PMID:4265197.
48. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Sly disease/β-glucuronidase deficiency/mucopolysaccharidosis VII. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 608–612.
49. Glaser JH, Sly WS. Beta-glucuronidase deficiency mucopolysaccharidosis: methods for enzymatic diagnosis. J Lab Clin Med. 1973;82(6):969-77. PMID:4202279.
50. Oshima A, Kyle JW, Miller RD, Hoffmann JW, Powell PP, Grubb JH, et al. Cloning, sequencing, and expression of cDNA for human beta-glucuronidase. Proc Natl Acad Sci U S A. 1987;84(3):685-9. doi:10.1073/pnas.84.3.685. PMID:3468507. PMCID: PMC304280.
51. Fox JE, Volpe L, Bullaro J, Kakkis ED, Sly WS. First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient. Mol Genet Metab. 2015;114(2):203-8. doi:10.1016/j.ymgme.2014.10.017. PMID:25468648. PMCID: PMC4360956.
52. Harmatz P, Whitley CB, Wang RY, Bauer M, Song W, Haller C, et al. A novel Blind Start study design to investigate vestronidase alfa for mucopolysaccharidosis VII, an ultra-rare genetic disease. Mol Genet Metab. 2018;123(4):488-494. doi:10.1016/j.ymgme.2018.02.006. PMID:29478819.
53. U.S. Food and Drug Administration. BLA 761047 approval letter: Mepsevii (vestronidase alfa-vjbk). 2017 Nov 15. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761047Orig1s000ltr.pdf
54. Natowicz MR, Short MP, Wang Y, Dickersin GR, Gebhardt MC, Rosenthal DI, et al. Clinical and biochemical manifestations of hyaluronidase deficiency. N Engl J Med. 1996;335(14):1029-33. doi:10.1056/NEJM199610033351405. PMID:8793927.
55. Triggs-Raine B, Salo TJ, Zhang H, Wicklow BA, Natowicz MR. Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX. Proc Natl Acad Sci U S A. 1999;96(11):6296-300. doi:10.1073/pnas.96.11.6296. PMID:10339581. PMCID: PMC26875.
56. Kondo H, Maksimova N, Otomo T, Kato H, Imai A, Asano Y, et al. Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms. Hum Mol Genet. 2017;26(1):173-183. doi:10.1093/hmg/ddw377. PMID:28013294.
57. Verheyen S, Blatterer J, Speicher MR, Bhavani GS, Boons GJ, Ilse MB, et al. Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency. J Med Genet. 2022;59(10):957-964. doi:10.1136/jmedgenet-2021-108061. PMID:34916232. PMCID: PMC9554054.
58. Trabszo C, Ramms B, Chopra P, Lüllmann-Rauch R, Stroobants S, Sproß J, et al. Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate. Biochem J. 2020;477(17):3433-3451. doi:10.1042/BCJ20200546. PMID:32856704. PMCID: PMC8261863.
59. Cyske Z, Gaffke L, Pierzynowska K, Węgrzyn G. Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease?. Int J Mol Sci. 2024;25(17):9570. doi:10.3390/ijms25179570. PMID:39273517. PMCID: PMC11395409.
60. Orphanet. Lysosomal storage disease with skeletal involvement (ORPHA:93448, group). Available from: https://www.orpha.net/en/disease/detail/93448
61. Muenzer J, Dant M, Dickson PI, Ellinwood NM, Fuller M, Giugliani R, et al. Cerebrospinal fluid heparan sulfate as a biomarker for neuronopathic mucopolysaccharidoses: Rationale and regulatory challenges. Mol Genet Metab. 2026;148(2):109911. doi:10.1016/j.ymgme.2026.109911. PMID:41935419.
62. Jones KL, Jones MC, del Campo M. Hunter syndrome (mucopolysaccharidosis II). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 646–649.
63. Jones KL, Jones MC, del Campo M. Sanfilippo syndrome (mucopolysaccharidosis III, types A, B, C and D). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 650–651.
64. Jones KL, Jones MC, del Campo M. Morquio syndrome (mucopolysaccharidosis IV, types A and B). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 652–655.
65. Al Fahdi I, Singh S, Yadavalli K, Chatti K, Bhavani GS, Girisha KM. ARSK-Related Mucopolysaccharidosis Type 10. Am J Med Genet A. 2025;197(12):e64210. doi:10.1002/ajmg.a.64210. PMID:40742107.
66. Uludağ Alkaya D, Taner HE, Yıldırım T, Akpınar E, Tüysüz B. Further characterization of ARSK-related mucopolysaccharidosis type 10. Am J Med Genet A. 2024;194(8):e63635. doi:10.1002/ajmg.a.63635. PMID:38634625.
67. Vasilev F, Sukhomyasova A, Otomo T. Mucopolysaccharidosis-Plus Syndrome. Int J Mol Sci. 2020;21(2):421. doi:10.3390/ijms21020421. PMID:31936524. PMCID: PMC7013929.
68. GeneGuidance. ARSK — gene record.
69. Sofou K, Meier K, Sanderson LE, Kaminski D, Montoliu-Gaya L, Samuelsson E, et al. Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease. EMBO Mol Med. 2021;13(5):e13376. doi:10.15252/emmm.202013376. PMID:33938619. PMCID: PMC8103096.
70. Makhamreh MM, Shivashankar K, Rice SM, Wodoslawsky S, Grant C, McLaren R, et al. Lysosomal storage disorders in nonimmune hydrops fetalis diagnosed by exome sequencing. Orphanet J Rare Dis. 2025;20(1):351. doi:10.1186/s13023-025-03851-9. PMID:40640912. PMCID: PMC12243238.
71. Iyer NS, Gimovsky AC, Ferreira CR, Critchlow E, Al-Kouatly HB. Lysosomal storage disorders as an etiology of nonimmune hydrops fetalis: A systematic review. Clin Genet. 2021;100(5):493-503. doi:10.1111/cge.14005. PMID:34057202. PMCID: PMC12107385.
72. Haute Autorité de Santé, Commission de la Transparence. MEPSEVII (vestronidase alfa) 2 mg/ml, solution à diluer pour perfusion – Réévaluation. Avis définitif du 24 juin 2020 (CT-18299). Saint-Denis: HAS; 2020 [mis en ligne 2020 Jul 01]. Available from: https://www.has-sante.fr/upload/docs/evamed/CT-18299_MEPSEVII_PIC_INS_AvisDef_CT18299.pdf
73. Tomatsu S, Montaño AM, Dung VC, Grubb JH, Sly WS. Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome). Hum Mutat. 2009;30(4):511-9. doi:10.1002/humu.20828. PMID:19224584. PMCID: PMC3048808.
74. Giugliani R, Gonzalez-Meneses A, Scarpa M, Burton B, Wang R, Martins E, et al. Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program. Orphanet J Rare Dis. 2024;19(1):189. doi:10.1186/s13023-024-03176-z. PMID:38715031. PMCID: PMC11077874.
75. Lew V, Pena L, Edwards R, Wang RY. Cardiovascular Histopathology of a 11-Year Old with Mucopolysaccharidosis VII Demonstrates Fibrosis, Macrophage Infiltration, and Arterial Luminal Stenosis. JIMD Rep. 2018;39:31-37. doi:10.1007/8904_2017_43. PMID:28702876. PMCID: PMC5953895.
76. Vervoort R, Gitzelmann R, Bosshard N, Maire I, Liebaers I, Lissens W. Low beta-glucuronidase enzyme activity and mutations in the human beta-glucuronidase gene in mild mucopolysaccharidosis type VII, pseudodeficiency and a heterozygote. Hum Genet. 1998;102(1):69-78. doi:10.1007/s004390050656. PMID:9490302.
77. Vervoort R, Islam MR, Sly WS, Zabot MT, Kleijer WJ, Chabas A, et al. Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII. Am J Hum Genet. 1996;58(3):457-71. PMID:8644704. PMCID: PMC1914559.
78. Sparks TN, Lianoglou BR, Adami RR, Pluym ID, Holliman K, Duffy J, et al. Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis. N Engl J Med. 2020;383(18):1746-1756. doi:10.1056/NEJMoa2023643. PMID:33027564. PMCID: PMC7650529.
79. National Center for Biotechnology Information. ClinVar [Internet]: VCV000000905, 000908, 000893, 001324520, 001324522, 000458510 (GUSB); 000003530, 001342863 (HYAL1); 000374985, 001500222 (VPS33A). Bethesda (MD): NLM. Available from: https://www.ncbi.nlm.nih.gov/clinvar/
80. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. Ferramenta: https://rest.variantvalidator.org (GRCh38, mane_select, consultada 2026-10-27). PMID:28967166. PMCID: PMC5765404.
81. Giugliani R, Barth AL, Dumas MRC, da Silva Franco JF, de Rosso Giuliani L, Grangeiro CHP, et al. Mucopolysaccharidosis VII in Brazil: natural history and clinical findings. Orphanet J Rare Dis. 2021;16(1):238. doi:10.1186/s13023-021-01870-w. PMID:34022924. PMCID: PMC8141134.
82. Orii K, Suzuki Y, Tomatsu S, Orii T, Fukao T. Long-Term Follow-up Posthematopoietic Stem Cell Transplantation in a Japanese Patient with Type-VII Mucopolysaccharidosis. Diagnostics (Basel). 2020;10(2):105. doi:10.3390/diagnostics10020105. PMID:32079065. PMCID: PMC7168249.
83. Vervoort R, Islam MR, Sly W, Chabas A, Wevers R, de Jong J, et al. A pseudodeficiency allele (D152N) of the human beta-glucuronidase gene. Am J Hum Genet. 1995;57(4):798-804. PMID:7573038. PMCID: PMC1801516.
84. Roemer MGM, Chevallier M, van Dijk M, van Kuilenburg ABP, Ter Horst KW, Zant JC. Alder-Reilly Anomaly Leading to Incidental Diagnosis of MPS VII in an Asymptomatic Adult. JIMD Rep. 2026;67(6):e70128. doi:10.1002/jmd2.70128. PMID:42920760. PMCID: PMC13691299.
85. da Costa AJM, de Souza ICN, Feio RH, Viana LKL, Cisz M, Rafaelli CL, et al. Analysis of genomic ancestry and characterization of a new variant in MPS type VII. Orphanet J Rare Dis. 2025;20(1):198. doi:10.1186/s13023-025-03593-8. PMID:40275366. PMCID: PMC12023397.
86. Dubot P, Sabourdy F, Plat G, Jubert C, Cancès C, Broué P, et al. First Report of a Patient with MPS Type VII, Due to Novel Mutations in GUSB, Who Underwent Enzyme Replacement and Then Hematopoietic Stem Cell Transplantation. Int J Mol Sci. 2019;20(21):5345. doi:10.3390/ijms20215345. PMID:31661765. PMCID: PMC6861985.
87. Lee CL, Chuang CK, Hsu CH, Chiu HC, Tu RY, Lo YT, et al. The first mucopolysaccharidosis type VII in a Taiwanese girl: A case report and review of the literature. J Formos Med Assoc. 2022;121(3):712-717. doi:10.1016/j.jfma.2021.07.024. PMID:34420841.
88. Lee CL, Chuang CK, Chiu HC, Chang YH, Tu YR, Lo YT, et al. Enzyme Replacement Therapy in Mucopolysaccharidosis Type VII: A Three-Year Clinical Outcome Study of the First Taiwanese Case. Diagnostics (Basel). 2025;15(4):464. doi:10.3390/diagnostics15040464. PMID:40002615. PMCID: PMC11854746.
89. Oldham A, Oxborrow NJ, Woolfson P, Jenkins P, Gadepalli C, Ashworth J, et al. MPS VII - Extending the classical phenotype. Mol Genet Metab Rep. 2022;33:100922. doi:10.1016/j.ymgmr.2022.100922. PMID:36299251. PMCID: PMC9589197.
90. Dursun A, Yalnizoglu D, Gerdan OF, Yucel-Yilmaz D, Sagiroglu MS, Yuksel B, et al. A probable new syndrome with the storage disease phenotype caused by the VPS33A gene mutation. Clin Dysmorphol. 2017;26(1):1-12. doi:10.1097/MCD.0000000000000149. PMID:27547915.
91. Pavlova EV, Lev D, Michelson M, Yosovich K, Michaeli HG, Bright NA, et al. Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A. Hum Mutat. 2022;43(12):2265-2278. doi:10.1002/humu.24479. PMID:36153662. PMCID: PMC10091966.
92. Cyske Z, Rintz E, Narajczyk M, Świątek N, Gaffke L, Pierzynowska K, et al. Cellular and molecular changes in mucopolysaccharidosis-plus syndrome caused by a homozygous c.599G > C (p.Arg200Pro) variant of the VPS33A gene. J Appl Genet. 2026;67(3):683-699. doi:10.1007/s13353-025-00997-x. PMID:40758165. PMCID: PMC13534158.
93. Bilal M, Fakhar M, Eid T, Helmi N, Rafeeq M, Gul M, et al. Structural dynamics and stability analysis of a novel ARSK variant confirms its role in MPS type X pathogenesis. Glycoconj J. 2026;43(1):28. doi:10.1007/s10719-026-10226-0. PMID:42517956.
94. Zielonka M, Garbade SF, Kölker S, Hoffmann GF, Ries M. Quantitative clinical characteristics of 53 patients with MPS VII: a cross-sectional analysis. Genet Med. 2017;19(9):983-988. doi:10.1038/gim.2017.10. PMID:28383542.
95. Van Dorpe J, Moerman P, Pecceu A, Van den Steen P, Fryns JP. Non-immune hydrops fetalis caused by beta-glucuronidase deficiency (mucopolysaccharidosis VII). Study of a family with 3 affected siblings. Genet Couns. 1996;7(2):105-12. PMID:8831129.
96. Chabas A, Giros ML, Guardiola A. Low beta-glucuronidase activity in a healthy member of a family with mucopolysaccharidosis VII. J Inherit Metab Dis. 1991;14(6):908-14. doi:10.1007/BF01800472. PMID:1779649.
97. Montaño AM, Różdżyńska-Świątkowska A, Jurecka A, Ramirez AN, Zhang L, Marsden D, et al. Growth patterns in patients with mucopolysaccharidosis VII. Mol Genet Metab Rep. 2023;36:100987. doi:10.1016/j.ymgmr.2023.100987. PMID:37415957. PMCID: PMC10320588.
98. Martin DC, Atmuri V, Hemming RJ, Farley J, Mort JS, Byers S, et al. A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis. Hum Mol Genet. 2008;17(13):1904-15. doi:10.1093/hmg/ddn088. PMID:18344557.
99. GeneGuidance. VPS33A — gene record.
100. Pavlova EV, Shatunov A, Wartosch L, Moskvina AI, Nikolaeva LE, Bright NA, et al. The lysosomal disease caused by mutant VPS33A. Hum Mol Genet. 2019;28(15):2514-2530. doi:10.1093/hmg/ddz077. PMID:31070736. PMCID: PMC6644154.
101. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 44, Disorders of Cellular Trafficking (tables with VPS33A).
102. Linhart A. Metabolic cardiomyopathy. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 158–159.
103. Jones KL, Jones MC, del Campo M. Mucopolysaccharidosis VII (Sly syndrome, β-glucuronidase deficiency). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 656–657.
104. INFARMED, Direção de Avaliação das Tecnologias de Saúde. Relatório público de avaliação: Mepsevii (vestronidase alfa). Tratamento das manifestações não neurológicas da mucopolissacaridose VII (MPS VII; síndrome de Sly). Avaliação do financiamento ao abrigo do Decreto-Lei n.º 97/2015. Lisboa: INFARMED, I.P.; 2022 Jul 1 (funding granted on 16/06/2022). Available from: https://extranet.infarmed.pt/INFOMED-fo/
105. Gónzalez-Meneses A, Pineda M, Bandeira A, Janeiro P, Ruiz MÁ, Diogo L, et al. Description of the molecular and clinical characteristics of the mucopolysaccharidosis type VII Iberian cohort. Orphanet J Rare Dis. 2021;16(1):445. doi:10.1186/s13023-021-02063-1. PMID:34686181. PMCID: PMC8532367.
106. Morrison A, Oussoren E, Friedel T, Cruz J, Yilmaz N. Pathway to diagnosis and burden of illness in mucopolysaccharidosis type VII - a European caregiver survey. Orphanet J Rare Dis. 2019;14(1):254. doi:10.1186/s13023-019-1233-z. PMID:31727109. PMCID: PMC6854616.
107. Okuno T, Ikawa M, Yuasa M, Muramoto A, Fu L, Matsumoto N, et al. Genomic autopsy in neonatal-onset mucopolysaccharidosis type VII: Key for diagnosis and future planning. Pediatr Int. 2026;68(1):e70299. doi:10.1111/ped.70299. PMID:41492846. PMCID: PMC12771064.
108. Kamihara Y, Ozawa K, Muromoto J, Sugibayashi R, Wada S, Shibata Y, et al. Clinical features of fetal hydrothorax associated with mucopolysaccharidosis-VII. J Obstet Gynaecol Res. 2023;49(10):2538-2543. doi:10.1111/jog.15744. PMID:37469021.
109. Guffon N, Froissart R, Fouilhoux A. A rare late progression form of Sly syndrome mucopolysaccharidosis. JIMD Rep. 2019;49(1):1-6. doi:10.1002/jmd2.12039. PMID:31497474. PMCID: PMC6718110.
110. Marek J, Kuchynka P, Mikulenka V, Palecek T, Sikora J, Hulkova H, et al. Combined valve replacement and aortocoronary bypass in an adult mucopolysaccharidosis type VII patient. Cardiovasc Pathol. 2021;50:107297. doi:10.1016/j.carpath.2020.107297. PMID:33045360.
111. Lau HA, Viskochil D, Tanpaiboon P, Lopez AG, Martins E, Taylor J, et al. Long-term efficacy and safety of vestronidase alfa enzyme replacement therapy in pediatric subjects < 5 years with mucopolysaccharidosis VII. Mol Genet Metab. 2022;136(1):28-37. doi:10.1016/j.ymgme.2022.03.002. PMID:35331634.
112. Tüysüz B, Güneş N, Yıldırım T, Karakaş H, Kasap B, Onur H, et al. Diagnostic Yield of Genetic Disorders in Children with Hip Dysplasia Mimicking Bilateral Legg-Calvé-Perthes Disease. Diagnostics (Basel). 2026;16(14):2293. doi:10.3390/diagnostics16142293. PMID:42510156. PMCID: PMC13409581.
113. Sofronova V, Iwata R, Moriya T, Loskutova K, Gurinova E, Chernova M, et al. Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome. Int J Mol Sci. 2022;23(10):5851. doi:10.3390/ijms23105851. PMID:35628659. PMCID: PMC9145135.
114. Faraguna MC, Musto F, Crescitelli V, Iascone M, Spaccini L, Tonduti D, et al. Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child. Genes (Basel). 2022;13(3):442. doi:10.3390/genes13030442. PMID:35327996. PMCID: PMC8951474.
115. Ferreira AFP, Ribeiro HPB, Ribeiro EM. Mucopolissacaridoses. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 306–309.
116. Al-Kouatly HB, Felder L, Makhamreh MM, Kass SL, Vora NL, Berghella V, et al. Lysosomal storage disease spectrum in nonimmune hydrops fetalis: a retrospective case control study. Prenat Diagn. 2020;40(6):738-745. doi:10.1002/pd.5678. PMID:32134517. PMCID: PMC7260084.
117. Sofronova V, Gotovtseva L, Danilova A, Sukhomyasova A, Moriwaki T, Terawaki S, et al. Prenatal Diagnosis of Mucopolysaccharidosis-Plus Syndrome (MPSPS). Genes (Basel). 2023;14(8):1581. doi:10.3390/genes14081581. PMID:37628632. PMCID: PMC10454871.
118. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, Clinical Approach to Inborn Errors of Metabolism in Paediatrics, sections 1.2.1–1.2.2 and 1.3.5.5.
119. Fukui K, Amari S, Yotani N, Kosaki R, Hata K, Kosuga M, et al. A Neonate with Mucopolysaccharidosis Type VII with Intractable Ascites. AJP Rep. 2023;13(1):e25-e28. doi:10.1055/a-2028-7784. PMID:36936745. PMCID: PMC10019997.
120. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Dysostosis multiplex. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 109–116.
121. Abecia Martínez EI, Puente Prieto J, Delgado Fernández JL, Martínez Castillón J, Nagore González C, Ferrando Lamana L. Mucopolysaccharidoses type VII (Sly syndrome): New uncertain pathogenic variants in GUSB gene. Rev Esp Patol. 2025;58(3):100814. doi:10.1016/j.patol.2025.100814. PMID:39983349.
122. Chandler NJ, Ramachandran V, Beesley C, Otigbah C, Davison J, Ashraf T. Prenatal diagnosis of mucopolysaccharidosis type VII facilitating treatment in neonatal period. Prenat Diagn. 2023;43(12):1567-1569. doi:10.1002/pd.6455. PMID:37964423.
123. Firth HV, Hurst JA. Oedema—increased nuchal translucency, cystic hygroma, and hydrops. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 768–769.
124. Society for Maternal-Fetal Medicine (SMFM), Norton ME, Chauhan SP, Dashe JS. Society for maternal-fetal medicine (SMFM) clinical guideline #7: nonimmune hydrops fetalis. Am J Obstet Gynecol. 2015;212(2):127-39. doi:10.1016/j.ajog.2014.12.018. PMID:25557883.
125. Norton ME, Ziffle JV, Lianoglou BR, Hodoglugil U, Devine WP, Sparks TN. Exome sequencing vs targeted gene panels for the evaluation of nonimmune hydrops fetalis. Am J Obstet Gynecol. 2022;226(1):128.e1-128.e11. doi:10.1016/j.ajog.2021.07.014. PMID:34331894. PMCID: PMC8748274.
126. Désilets V, De Bie I, Audibert F. No. 363-Investigation and Management of Non-immune Fetal Hydrops. J Obstet Gynaecol Can. 2018;40(8):1077-1090. doi:10.1016/j.jogc.2017.12.011. PMID:30103882.
127. Gort L, Granell MR, Fernández G, Carreto P, Sanchez A, Coll MJ. Fast protocol for the diagnosis of lysosomal diseases in nonimmune hydrops fetalis. Prenat Diagn. 2012;32(12):1139-42. doi:10.1002/pd.3972. PMID:22991067.
128. Poyatos-Andújar AM, García-Linares S, Carretero P, Ocon O, Fresneda D, Gort L, et al. Prenatal mucopolysaccharidosis VII: A novel pathogenic variant identified in GUSB gene. Clin Case Rep. 2021;9(2):790-795. doi:10.1002/ccr3.3644. PMID:33598246. PMCID: PMC7869334.
129. Bellini C, Hennekam RC, Fulcheri E, Rutigliani M, Morcaldi G, Boccardo F, et al. Etiology of nonimmune hydrops fetalis: a systematic review. Am J Med Genet A. 2009;149A(5):844-51. doi:10.1002/ajmg.a.32655. PMID:19334091.
130. Bellini C, Hennekam RC. Non-immune hydrops fetalis: a short review of etiology and pathophysiology. Am J Med Genet A. 2012;158A(3):597-605. doi:10.1002/ajmg.a.34438. PMID:22302731.
131. Gimovsky AC, Luzi P, Berghella V. Lysosomal storage disease as an etiology of nonimmune hydrops. Am J Obstet Gynecol. 2015;212(3):281-90. doi:10.1016/j.ajog.2014.10.007. PMID:25305402.
132. Sheth J, Mistri M, Shah K, Chaudhary M, Godbole K, Sheth F. Lysosomal Storage Disorders in Nonimmune Hydrops Fetalis (NIHF): An Indian Experience. JIMD Rep. 2017;35:47-52. doi:10.1007/8904_2016_24. PMID:27928775. PMCID: PMC5585095.
133. Burin MG, Scholz AP, Gus R, Sanseverino MT, Fritsh A, Magalhães JA, et al. Investigation of lysosomal storage diseases in nonimmune hydrops fetalis. Prenat Diagn. 2004;24(8):653-7. doi:10.1002/pd.967. PMID:15305357.
134. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Appendix: Differential diagnosis of clinical phenotypes. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 815–828 (lista «Hydrops fetalis», p. 821).
135. Mardy AH, Chetty SP, Norton ME, Sparks TN. A system-based approach to the genetic etiologies of non-immune hydrops fetalis. Prenat Diagn. 2019;39(9):732-750. doi:10.1002/pd.5479. PMID:31087399. PMCID: PMC6699893.
136. Comissão Nacional de Incorporação de Tecnologias no SUS (CONITEC). Vestronidase alfa for mucopolysaccharidosis type VII. Recommendation report no. 540. Brasília: Ministério da Saúde; 2020. Available from: https://www.gov.br/conitec/pt-br/midias/consultas/relatorios/en2020/20210607_report_540_vestronidase_alfa_mucopolysaccharidosis_type_vii.pdf
137. Cadaoas J, Boyle G, Jungles S, Cullen S, Vellard M, Grubb JH, et al. Vestronidase alfa: Recombinant human β-glucuronidase as an enzyme replacement therapy for MPS VII. Mol Genet Metab. 2020;130(1):65-76. doi:10.1016/j.ymgme.2020.02.009. PMID:32192868.
138. INFARMED. Infomed: Mepsevii 2 mg/ml concentrado para solução para perfusão (vestronidase alfa); n.º de registo 5758263. Lisboa: INFARMED, I.P. Available from: https://extranet.infarmed.pt/INFOMED-fo/
139. Ultragenyx Brasil Farmacêutica Ltda. MEPSEVII (alfavestronidase) solução para diluição para infusão 2 mg/ml: bula para profissionais de saúde. Registro MS 1.3964.0001; version approved by ANVISA on 02/12/2025 (file 1551783258; new product registration 15/10/2018, initial inclusion of package leaflet text 24/05/2021). Brasília: ANVISA, Bulário Eletrônico; 2025 [accessed 2026-10-29]. Available from: https://consultas.anvisa.gov.br/#/bulario/q/?nomeProduto=MEPSEVII . Previous version (2021): https://www.ultragenyx.com/wp-content/uploads/2021/08/Mepsevii_BULA-PARA-PROFISSIONAIS.pdf
140. Qi Y, McKeever K, Taylor J, Haller C, Song W, Jones SA, et al. Pharmacokinetic and Pharmacodynamic Modeling to Optimize the Dose of Vestronidase Alfa, an Enzyme Replacement Therapy for Treatment of Patients with Mucopolysaccharidosis Type VII: Results from Three Trials. Clin Pharmacokinet. 2019;58(5):673-683. doi:10.1007/s40262-018-0721-y. PMID:30467742. PMCID: PMC6451706.
141. Agência Nacional de Vigilância Sanitária. Dados abertos: medicamentos registados (DADOS_ABERTOS_MEDICAMENTOS.csv) — MEPSEVII (alfavestronidase), registration 139640001. Brasília: ANVISA. Available from: https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv
142. Jones S, Coker M, López AG, Sniadecki J, Mayhew J, Hensman P, et al. Open-label phase 1/2 study of vestronidase alfa for mucopolysaccharidosis VII. Mol Genet Metab Rep. 2021;28:100774. doi:10.1016/j.ymgmr.2021.100774. PMID:34136357. PMCID: PMC8178115.
143. Wang RY, da Silva Franco JF, López-Valdez J, Martins E, Sutton VR, Whitley CB, et al. The long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis VII. Mol Genet Metab. 2020;129(3):219-227. doi:10.1016/j.ymgme.2020.01.003. PMID:32063397.
144. ClinicalTrials.gov: NCT01856218, NCT02230566, NCT02432144, NCT02418455, NCT03604835, NCT04532047, NCT03775174, NCT02298699, NCT02171104. Bethesda (MD): NLM. Available from: https://clinicaltrials.gov
145. Poswar FO, Henriques Nehm J, Kubaski F, Poletto E, Giugliani R. Diagnosis and Emerging Treatment Strategies for Mucopolysaccharidosis VII (Sly Syndrome). Ther Clin Risk Manag. 2022;18:1143-1155. doi:10.2147/TCRM.S351300. PMID:36578769. PMCID: PMC9791935.
146. Dohrmann T, Muschol NM, Sehner S, Punke MA, Haas SA, Roeher K, et al. Airway management and perioperative adverse events in children with mucopolysaccharidoses and mucolipidoses: a retrospective cohort study. Paediatr Anaesth. 2020;30(2):181-90. doi:10.1111/pan.13787. PMID: 31834659.
147. Denali Therapeutics Inc. AVLAYAH (tividenofusp alfa) injection. Prescribing information. BLA 761485. Silver Spring (MD): U.S. Food and Drug Administration; 2026 (SPL effective 2026 Mar 20; Drugs@FDA approval 2026 Mar 24). Available from: https://api.fda.gov/drug/label.json?search=openfda.generic_name:tividenofusp
148. Muenzer J, Ho C, Lau H, Dant M, Fuller M, Boulos N, et al. Community consensus for Heparan sulfate as a biomarker to support accelerated approval in Neuronopathic Mucopolysaccharidoses. Mol Genet Metab. 2024;142(4):108535. doi:10.1016/j.ymgme.2024.108535. PMID:39018614.
149. Gentner B, Tucci F, Galimberti S, Fumagalli F, De Pellegrin M, Silvani P, et al. Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome. N Engl J Med. 2021;385(21):1929-1940. doi:10.1056/NEJMoa2106596. PMID:34788506.
150. Consiglieri G, Tucci F, De Pellegrin M, Guerrini B, Cattoni A, Risca G, et al. Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome. Sci Transl Med. 2024;16(745):eadi8214. doi:10.1126/scitranslmed.adi8214. PMID:38691622.
151. ClinicalTrials.gov: NCT03488394 (autologous haematopoietic cell gene therapy in MPS IH, phase 1/2) and NCT06149403 (OTL-203 versus allogeneic HSCT in MPS IH, phase 3). Bethesda (MD): NLM. Records accessed 6 November 2026. Available from: https://clinicaltrials.gov
152. Shan L, He Q, Zhang W, Zheng X, Zhao J, Yang P, et al. CRISPR/Cas9-mediated promoterless gene targeting reduces lysosome storage in MPS VII mice. Sci China Life Sci. 2025;68(9):2697-2706. doi:10.1007/s11427-024-2915-x. PMID:40614014.
153. Venkatakrishnan J, Yuan Y, Zhang J, Yu Y, Hu YC, Kao WW. Self-complementary AAV vector therapy for treating corneal cloudiness of mucopolysaccharidosis type VII (MPS VII). Ocul Surf. 2024;32:39-47. doi:10.1016/j.jtos.2024.01.002. PMID:38218582.
154. Khan SA, Peracha H, Ballhausen D, Wiesbauer A, Rohrbach M, Gautschi M, et al. Epidemiology of mucopolysaccharidoses. Mol Genet Metab. 2017;121(3):227-240. doi:10.1016/j.ymgme.2017.05.016. PMID:28595941. PMCID: PMC5653283.
155. Borges P, Pasqualim G, Giugliani R, Vairo F, Matte U. Estimated prevalence of mucopolysaccharidoses from population-based exomes and genomes. Orphanet J Rare Dis. 2020;15(1):324. doi:10.1186/s13023-020-01608-0. PMID:33208168. PMCID: PMC7672855.
156. Josahkian JA, Trapp FB, Burin MG, Michelin-Tirelli K, Magalhães APPS, Sebastião FM, et al. Updated birth prevalence and relative frequency of mucopolysaccharidoses across Brazilian regions. Genet Mol Biol. 2021;44(1):e20200138. doi:10.1590/1678-4685-GMB-2020-0138. PMID:33503199. PMCID: PMC7839630.
157. Çelik B, Tomatsu SC, Tomatsu S, Khan SA. Epidemiology of Mucopolysaccharidoses Update. Diagnostics (Basel). 2021;11(2):273. doi:10.3390/diagnostics11020273. PMID:33578874. PMCID: PMC7916572.
158. Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H, et al. Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet. 2004;12(2):87-92. doi:10.1038/sj.ejhg.5201044. PMID:14685153.
159. MPS Society (Society for Mucopolysaccharide Diseases, Reino Unido). Available from: https://mpssociety.org.uk/
160. National MPS Society (EUA). Available from: https://mpssociety.org/
161. Instituto Vidas Raras (Brasil). Available from: https://www.vidasraras.org.br/