Mucopolysaccharidosis Type I (Hurler, Hurler–Scheie, Scheie) and Mucopolysaccharidosis Type II (Hunter)

Alpha-L-iduronidase (IDUA) and iduronate-2-sulfatase (IDS) deficiency: two lysosomal disorders involving dermatan and heparan sulphate, with a continuous severity spectrum, treated with haematopoietic transplantation, enzyme replacement therapy and, since 2026, an enzyme that crosses the blood–brain barrier.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Mucopolysaccharidoses (MPS) are lysosomal storage disorders in which deficiency of a hydrolase interrupts the sequential degradation of glycosaminoglycans. The Atlas by Nyhan and colleagues emphasises that these disorders provided an early demonstration that complex dysmorphic changes can arise from a single gene defect with a biochemical consequence, and that attenuated forms may remain undiagnosed for years; the implications of this delay became more serious with the advent of therapies whose effects are predominantly preventive [29]. The current classification distinguishes seven clinical types and eleven enzyme deficiencies; Saudubray's textbook additionally includes MPS X due to arylsulfatase K deficiency and multiple sulfatase deficiency [4, 29]. MPS I and II share the same accumulated substrates, dermatan sulphate and heparan sulphate, and much of their somatic phenotype, but differ in their gene, inheritance, corneal involvement and therapeutic options, which warrants their joint discussion with separate subsections.

The history of MPS II began in 1917, when Charles Hunter, a Canadian physician, described two brothers with the disorder that now bears his name [9, 25]. In 1919, Gertrud Hurler described the form that became the prototype of MPS; Scheie, Hambrick and Barness described a “forme fruste” of Hurler disease in 1962, and Stevenson and colleagues delineated the intermediate Hurler–Scheie form in 1976 [2, 8, 30]. McKusick classified Hurler syndrome as MPS I and proposed that the Hurler and Scheie phenotypes represented homozygosity for different alleles, with compound heterozygotes having an intermediate phenotype; subsequent molecular findings showed that some intermediate phenotypes result from homozygosity for specific variants [30].

The decisive advance came from cell biology. Using fibroblasts cultured with sulphur-35-labelled sulphate, Fratantoni, Hall and Neufeld showed that patients' cells accumulated the label without turning it over, and that mixing Hurler and Hunter cells normalised the kinetics in both: each cell line secreted the factor missing from the other [9, 29]. Scheie cells were not corrected by the Hurler factor, demonstrating that the two disorders were allelic [29, 30]. The Hurler corrective factor was identified as alpha-L-iduronidase in 1972 and the Hunter factor as iduronate sulfatase in 1973 [8, 9]. By showing that an enzyme secreted by one cell can be taken up by another through the mannose-6-phosphate receptor, these observations established the basis for both haematopoietic transplantation and enzyme replacement therapy (ERT) [29].

The first haematopoietic cell transplantation for an MPS disorder was performed in the United Kingdom in a patient with a Hurler phenotype; the review by Kubaski and colleagues dates the first procedure to 1980 [4, 31]. Laronidase was approved in the United States and European Union in 2003, and idursulfase in the United States in 2006 and European Union in 2007 [12, 13, 15, 16]. Neither intravenous enzyme crosses the blood–brain barrier in sufficient quantities, leaving neurological disease in severe MPS I and neuronopathic MPS II without pharmacological treatment [4]. Transplantation became the treatment of choice for severe MPS I diagnosed early, but its role in MPS II remains disputed [14, 25].

Developments in 2025–2026 changed this situation. In March 2026, the FDA granted accelerated approval to tividenofusp alfa-eknm, an I2S fused to a transferrin receptor-binding domain, for the neurological manifestations of MPS II; the MPS II gene therapy RGX-121 received a complete response letter and is under clinical hold; and the autologous gene therapy OTL-203 for Hurler syndrome completed recruitment for a phase 3 trial comparing it with allogeneic transplantation [17, 32–34]. Meanwhile, newborn screening for both disorders, included in the US recommended uniform panel, shifted diagnosis into the presymptomatic period and brought enzyme pseudodeficiency to the forefront [20, 35]. These developments are integrated with the foundational evidence from textbooks, GeneReviews and published guidance.

2. Molecular Genetics and Pathophysiology

2.1. Dermatan and heparan sulphate degradation pathway

GAGs are linear polysaccharides comprising repeating disaccharide units, covalently linked to core proteins to form extracellular matrix and cell-surface proteoglycans; their heterogeneity in mass, composition and degree of sulphation relates to distinct biological functions and the tissue distribution of the signs of each MPS disorder [4]. Lysosomal degradation of dermatan and heparan sulphate is sequential: each enzyme removes a residue or sulphate group from the non-reducing end, and failure of one step prevents all subsequent steps [29]. I2S removes sulphate from position 2 of iduronic acid and acts before alpha-L-iduronidase, which hydrolyses the terminal, already desulphated iduronic acid residue; deficiency of either enzyme therefore causes accumulation of the same two GAGs and their urinary excretion [8, 9]. In MPS I, dermatan and heparan sulphate are excreted in an approximate 2:1 ratio, whereas in MPS II the amounts are approximately equal [8, 9].

2.2. IDUA: structure, variants and genotype–phenotype correlation

The IDUA gene lies at 4p16.3, contains 14 exons spanning approximately 19 kb, and has a 13 kb intron between exons 2 and 3; its complementary DNA encodes a 653-amino-acid protein, a monomer of approximately 70 kDa after signal peptide removal, with six potential N-glycosylation sites, which acquires mannose-6-phosphate for lysosomal targeting [1, 8]. The D4S111 locus, linked to Huntington disease, proved to be the IDUA gene itself [8]. GeneReviews states that IDUA contains an overlapping transcript encoding a putative sulphate transporter (SLC26A6), without known human pathogenic variants [1]. The mechanism is loss of function; ClinGen classifies the IDUA–MPS I relationship as definitive, and its lysosomal disease expert panel has published gene-specific ACMG/AMP (American College of Medical Genetics and Genomics / Association for Molecular Pathology) specifications and submitted classifications of 131 variants to ClinVar [36, 37].

Sequencing identifies both causative variants in 97% of 556 patients in the international MPS I registry; deletions of one or more exons or the entire gene are rare, and GeneReviews records whole-gene and exon 1–2 and 14 deletions, one identified as maternal mosaicism [1]. The Brazilian PCDT cites Sanger detection rates of 95%–97% in two series and approximately 250 reported variants [23]. The nonsense variants p.Trp402Ter and p.Gln70Ter, neither producing detectable functional protein, account for more than half of alleles in patients of European origin [1, 8]. In the international registry, 68% (257/380) of patients with severe MPS I had two variants predicted to be severely disruptive, and 95.6% (151/158) of those with attenuated disease had at least one missense variant, presumably allowing some residual activity [1]. Any combination of two “severe” variants produces severe disease [1]. Using the same registry, Kubaski and colleagues add that genotypes p.[Trp402*];[Trp402*], p.[Trp402*];[Gln70*] and p.[Gln70*];[Gln70*] account for 51% of genotypes in severe patients, but more than 50% of patients have unique genotypes, and p.[Pro533Arg];[Pro533Arg] was found in seven severe and 17 attenuated patients, preventing phenotype prediction from genotype alone in a substantial proportion of cases [31]. Residual activity measured with artificial substrates does not distinguish phenotypes; fibroblast studies suggest that approximately 0.13% of normal activity may suffice for a mild phenotype [1].

Table 1 presents IDUA variants of clinical or population relevance. Numbering was confirmed using VariantValidator against the MANE Select transcript NM_000203.5 (the same numbering as NM_000203.3 used in GeneReviews), and classifications of the most frequent variants were checked in ClinVar [7, 38].

Table 1. Selected IDUA variants (NM_000203.5; NP_000194.2)

The textbooks describe additional alleles in specific populations: a deletion/insertion in exon 6 in a Libyan Jewish patient, stop codons at Tyr64 and Gln310, and threonine→proline substitution at codon 366 and glycine→arginine substitution at codon 409 in Arab and Druze patients in Israel [8]. The former corresponds to NM_000203.5:c.1096A>C p.(Thr366Pro), classified as pathogenic in ClinVar; for the latter, the Atlas does not give the nucleotide change, and in ClinVar p.(Gly409Arg) results from two distinct variants: NM_000203.5:c.1225G>C, benign/likely benign in isolation and pathogenic in the complex allele NM_000203.3:c.[1225G>C;1962A>T], and NM_000203.5:c.1225G>A, with conflicting classifications [7, 8, 38].

2.3. IDUA pseudodeficiency

Pseudodeficiency denotes reduced or undetectable IDUA activity with artificial substrates, without altered GAG metabolism when sulphur-35-labelled GAGs are used [1]. It is the principal interpretative pitfall in MPS I: GeneReviews therefore requires simultaneous demonstration of deficient enzyme activity and increased urinary GAGs for biochemical diagnosis, and prenatal diagnosis has shifted from enzymatic to molecular methods [1]. Its relevance has grown with newborn screening. In California, 65% of 524 variants identified in screen-positive newborns were known pseudodeficiency alleles, 25% were variants of uncertain significance and 10% were pathogenic; in Missouri, 71 of 133 positive screens represented pseudodeficiency [11, 40]. In a study of 65,309 biobank participants, 1803 adults homozygous for pseudodeficiency alleles did not differ from controls in clinically relevant outcomes [41]. The variant c.250G>A (p.Gly84Ser), found in homozygosity in three children screened in Michigan and California without signs of MPS I up to age 3.5 years, was proposed as a possible pseudodeficiency allele, particularly in people of South Asian ancestry; the article does not specify the reference transcript [42]. Classification as pseudodeficiency therefore requires biochemical GAG findings and follow-up, and cannot be inferred from low enzyme activity alone.

2.4. IDS, the IDSP1 pseudogene and females with MPS II

The IDS gene lies at Xq28, has nine exons spanning approximately 24 kb and encodes a 550-amino-acid polypeptide that removes sulphate from position 2 of iduronic acid [9]. Approximately 25 kb telomeric to IDS lies the pseudogene IDSP1 (also called IDS2); homologous regions promote unequal recombination, complex rearrangements, a recurrent gene–pseudogene inversion and large deletions [3]. Table 2 summarises the yield of each method. Point variants cluster at CpG dinucleotides, suggesting independent origins in different families; the Arg468 variant produced mild disease in a North American patient (p.Arg468Trp) and severe disease in a Japanese patient, while other substitutions at this codon (Gln, Leu, Gly) were associated with severe disease [9]. VariantValidator normalisation against NM_000202.8 confirms p.Arg468Trp as c.1402C>T and p.Arg468Gln as c.1403G>A [7].

Table 2. Molecular tests in MPS II and their yields

Genotype–phenotype correlation is limited. The variant c.1122C>T, synonymous at protein level (p.(Gly374=) according to VariantValidator) but creating a new donor site in exon 8 with loss of 20 amino acids, is associated predominantly with the non-neuronopathic form [3, 7]. Gene deletions and complex rearrangements, present in approximately 17% of patients, are invariably associated with a neuronopathic phenotype; contiguous Xq28 deletions may add atypical signs such as ptosis and seizures [3]. In a Dutch cohort, very low or cell-type-specific residual activity was sufficient to prevent the neuronal phenotype, and genotype was considered a good predictor [3]. The panel led by Gaviglio reports more than 700 described variants, without highly recurrent variants, most private to a family, and estimates that approximately 15% of cases result from chromosome-level changes, half of them the recurrent rearrangement with the pseudogene [26]. The screening report by Ream and colleagues states that approximately 60% of patients have a private variant [20].

MPS II affects almost exclusively boys. Female cases are explained by X;autosome translocation with a breakpoint in the gene and inactivation of the normal X, non-random inactivation of the normal X (including one member of a dizygotic twin pair), complete or partial X monosomy and, in one case, homozygosity for a point variant [9, 24, 43]. In the Hunter Outcome Survey (HOS), 15 female patients represented 1.1% of the cohort; median ages at first symptom and diagnosis were 1.8 and 3.1 years, 8 of 14 (57.1%) had cognitive impairment at their last visit, two had X-chromosome abnormalities, and somatic burden was similar to that in males [44]. In two opposite-sex sibling pairs with the same missense variant, only the sisters had cognitive impairment [44]. I2S activity is unreliable for identifying heterozygotes because X-inactivation may be non-random [3].

2.5. From lysosomal accumulation to tissue damage

GAG accumulation alone does not explain the phenotype. GeneReviews describes a mechanism encompassing the direct cellular effect of storage, activation of inflammatory pathways, changes in extracellular matrix composition and function, interference with other lysosomal and endosomal pathways, cell signalling and autophagy [1]. In growth cartilage, intracellular and extracellular deposition of GAGs and fragments alters cellular communication and biomechanical properties and activates inflammatory pathways affecting chondrocytes, osteoclasts and osteoblasts, producing dysostosis multiplex [4]. Heart valves are rich in dermatan sulphate, explaining the predominance of valvular disease in MPS disorders accumulating this GAG (I, II, VI and VII); coronary lesions result from diffuse myointimal proliferation, and immunohistochemical studies of coronary arteries in MPS I patients showed overactivity of transforming growth factor beta signalling [4, 8, 45]. In the central nervous system (CNS), heparan sulphate accumulation is associated with neurodegeneration, present in severe MPS I and II and in MPS VII; the Atlas describes secondary ganglioside accumulation, neuronal zebra bodies and meningeal thickening favouring communicating hydrocephalus and spinal cord compression [4, 8]. This distribution has direct therapeutic implications: intravenous enzyme, taken up by peripheral tissues through the mannose-6-phosphate receptor, does not reach brain parenchyma, whereas cells derived from the haematopoietic graft can cross the barrier, differentiate into microglia and secrete enzyme in the nervous system [24, 31].

3. Clinical Spectrum and System-Specific Manifestations

3.1. From eponyms to a continuum: classification

The classical division of MPS I into Hurler, Hurler–Scheie and Scheie has no measurable biochemical correlate, and the presentations overlap; GeneReviews and Saudubray's textbook prefer severe (neuronopathic) and attenuated (non-neuronopathic) MPS I, because this distinction determines treatment selection [1, 4]. An operational criterion proposed by GeneReviews classifies disease as attenuated in a child with normal development at 24 months and moderate somatic involvement [1]. MPS II follows the same approach: a neuronopathic form with cognitive deterioration and a non-neuronopathic form with little or no CNS involvement; European recommendations acknowledge that the dichotomy simplifies a continuum and that evolving signs are a better indicator than a cross-sectional assessment [3, 24]. Saudubray's textbook adds an intermediate MPS II group, with cognitive impairment stable over decades [4].

Phenotype distribution depends on the source. In the international MPS I registry in 2011, 57% of 891 patients were classified as Hurler, 23.5% as Hurler–Scheie and 10% as Scheie, with the ascertainment bias inherent in registries [1]. Smith states that at least 80% of patients lie at the severe end, whereas the Brazilian PCDT cites Latin American data in which the attenuated phenotype predominates and Hurler syndrome accounts for 31% of diagnosed cases [2, 23]. In MPS II, the neuronopathic phenotype appears approximately twice as frequent as the attenuated phenotype; the North American screening report estimates approximately 60% severe forms, and Orphanet gives 60–80% [3, 6, 20].

3.2. Severe MPS I (Hurler syndrome)

Newborns appear normal. The first manifestations are non-specific: inguinal or umbilical hernias, chronic rhinitis, otitis and recurrent respiratory infections before age 1 year; many patients first present to a surgeon for hernia repair [1, 8]. Growth in the first year may be faster than usual; registry data show deviation from the median from 6 months and height below the third percentile by 4 years, while linear growth stops around 3 years [1, 2]. Thoracolumbar gibbus becomes clinically evident within the first 10 months and has been described at 6 months; Saudubray's textbook reports thoracolumbar kyphosis already present at birth [1, 4]. Mean age at diagnosis is approximately 10 months, and most are diagnosed before 18 months [1]. The French PNDS places diagnosis between 4 and 18 months, prompted mainly by hernias, thoracolumbar gibbus, joint stiffness, macrocephaly and ear, nose and throat infections or chronic respiratory congestion [10].

Facial features coarsen during the first two years: macrocephaly with scaphocephaly, frontal bossing, depressed nasal bridge, anteverted nares, thick lips and tongue, gingival and alveolar ridge hypertrophy, small spaced teeth and hypertrichosis [1, 2, 8]. Ground-glass corneal clouding occurs in all MPS I patients; open-angle glaucoma, retinal degeneration with night blindness, and optic nerve compression and atrophy also occur [1, 8]. Mixed hearing loss results from otitis, Eustachian tube dysfunction, ossicular dysostosis, tympanic scarring and eighth cranial nerve injury [1]. GAG infiltration of the upper airway (tonsils, adenoids, epiglottis, vocal cords and narrowed trachea) causes noisy breathing, hoarseness and obstructive sleep apnoea [1, 2].

Cardiac involvement occurs in all patients with the severe form and is detected by echocardiography well before clinical manifestations; valve thickening predominantly causes mitral regurgitation, accompanied by aortic regurgitation and stenosis, cardiomyopathy, coronary disease (which angiography may underestimate), arrhythmia and sudden death [1, 8]. A small subgroup has fatal endocardial fibroelastosis in the first year [1, 8]. Smith describes systemic hypertension, central or due to coarctation [2]. Hepatosplenomegaly may be massive without liver dysfunction; diarrhoea alternates with constipation [1].

Developmental delay becomes evident around 18 months, followed by a plateau and decline; reanalysis of untreated patients showed measurable month-by-month loss of developmental quotient [1]. Intellectual function peaks between 2 and 4 years, and behaviour is typically placid, unlike MPS II and III; seizures are rare [1, 8]. High-pressure communicating hydrocephalus is frequent and may accelerate cognitive decline [1]. Without treatment, death from cardiorespiratory failure occurs in the first decade, and the Atlas describes poor tolerance of anaesthesia as a contributor to mortality [1, 8].

3.3. Attenuated MPS I (Hurler–Scheie and Scheie)

Onset is usually between 3 and 10 years, but recognition is often delayed; in Hurler–Scheie, symptoms arise between 3 and 8 years and survival to 20–30 years is common, whereas in Scheie symptoms appear in the second and third decades, with normal or nearly normal life expectancy [1, 2, 4]. The Brazilian PCDT describes Scheie onset between 5 and 15 years [23]. According to the French PNDS, the first signs of Scheie appear after age 5 years and diagnosis is usually made in the second and sometimes the third decade, in the presence of disabling polyarticular stiffness, carpal tunnel syndrome, corneal clouding, deafness and sometimes valvular disease or spinal cord compression; in Hurler–Scheie, moderate intellectual disability may be present [10]. Joint disease is the main source of disability: stiffness, claw hands, trigger fingers, genu valgum, pes cavus and pain; in the international registry, more than 85% of attenuated patients had dysostosis, predominantly vertebral and femoral, and carpal tunnel syndrome arose at a median age of 9 years and 11 months in 138 patients [1, 30]. Median nerve compression is often asymptomatic until advanced stages, warranting nerve conduction studies [1].

Corneal clouding occurred in approximately 82% of children with attenuated disease, at a median age of 9.1 years, and significant cardiac involvement in approximately 88%, at a median age of 11.7 years; among 78 patients, 40% had one valve affected and 60% two or more [1]. Aortic valve disease is more frequent in the attenuated than the severe form [1]. Cervical pachymeningitis from dural thickening causes insidious myelopathy, sometimes presenting only as reduced exercise tolerance until irreversible injury develops, and is more common in Hurler–Scheie [1, 30]. Hernias were recorded in approximately 65% of patients [1]. Development may be normal, but learning difficulties and psychiatric manifestations arise, including psychosis reported in Scheie [1, 30]. Pregnancy has been reported in Hurler–Scheie [30].

Table 3. MPS I: frequency of findings by phenotype (dependent on patient age)

Source: GeneReviews, Table 2 [1].

3.4. Neuronopathic and non-neuronopathic MPS II

In MPS II, infants identified by newborn screening are asymptomatic and have no radiological abnormalities [3]. Signs appear between 18 months and 4 years in the neuronopathic form and approximately two years later in the attenuated form; in HOS, mean age at first symptoms was 1.5 and 2.2 years, respectively, with diagnosis following a diagnostic odyssey [3, 26]. Macrocephaly is universal; children are initially taller than their peers, many above the 50th percentile and some above the 97th percentile in early childhood, but by age 8 years height is below the third percentile [3, 24]. Smith gives an adult height of 120–150 cm in the severe form and an attenuated form without CNS involvement in 18% of male patients [43].

Two findings distinguish MPS II from MPS I. The cornea usually remains clear, although subtle lesions may be visible on slit-lamp examination; and nodular or “pebbly”, sometimes ivory-coloured skin lesions arise over the scapular region, arms and thighs and are considered pathognomonic [3, 9]. Extensive Mongolian spots (extensive dermal melanocytosis) are described [4, 9]. Approximately 20% of patients have optic disc swelling without intracranial hypertension, due to scleral thickening, and approximately 11% have optic atrophy; retinopathy is more frequent in the neuronopathic form, and ERT does not halt ocular progression [3].

Airway infiltration progresses relentlessly: macroglossia, tonsillar and adenoidal hypertrophy, temporomandibular ankylosis, tracheomalacia and tracheal collapse culminate in sleep apnoea, positive-pressure ventilation and sometimes tracheostomy [3, 24]. Cardiac disease affects the majority: 82% have cardiovascular signs or symptoms and 62% a murmur, in decreasing frequency mitral, aortic, tricuspid and pulmonary; cardiomyopathy, hypertension and arrhythmia occur in fewer than 10% [3]. The Atlas describes sudden death from complete atrioventricular block [9]. Cervical spinal stenosis may compress the cord; in a cohort of 32 patients, 20% had severe stenosis or mild compression [3].

Behaviour in children with the neuronopathic form contrasts with Hurler syndrome: hyperactivity, impulsivity, aggression, perseverative chewing, pica and severe sleep disturbances, described in the Atlas between ages 2 and 6 years [3, 9]. Regression usually occurs between 6 and 8 years, and death in the first or second decade [3]. The French PNDS designates the two forms MPS IIA (neurodegenerative) and MPS IIB (without neurodegeneration): in IIA, diagnosis is made between 18 months and 4 years, behavioural disturbances are marked from the first year, neurological deterioration occurs between 6 and 10 years, with a picture close to that of MPS III and possible epilepsy, and the ivory-coloured nodules are located over the sacral region, buttocks and upper limbs; in IIB there may be moderate, stable intellectual disability, visceral and osteoarticular involvement may be as severe as in IIA, and there are no corneal opacities [10]. In a Taiwanese series cited in the Atlas, mean age at death was 13 years in the severe form and 23 years in the mild form; according to GeneReviews, citing the same group, respiratory (56%) and cardiac (18%) failure were the predominant causes of death in the non-neuronopathic form [3, 9]. HOS estimates ages at death without treatment of 6–23 years in the neuronopathic form and 5–45 years in the non-neuronopathic form, with survival into the sixth decade in attenuated forms [9, 26].

Table 4. MPS II: frequency of findings in HOS (patients younger than 10 years unless indicated)

Source: GeneReviews, Tables 2 and 3, adapted from Lau et al. 2023 [3].

3.5. Shared system-specific manifestations

The skeleton is the most consistently affected system. Dysostosis multiplex comprises macrocephaly with a J-shaped sella turcica, a thick calvarium, broad paddle-shaped ribs, broad clavicles, ovoid vertebrae with anterior beaking and posterior notching, iliac hypoplasia with femoral head dysplasia and coxa valga, poorly modelled diaphyses and proximally tapered metacarpals with bullet-shaped phalanges [8, 46]. These changes are specific to defective degradation of complex carbohydrates but not to the type of disorder; at 2 months, the spine and pelvis of an infant with MPS I may appear normal [46]. In attenuated disease, as in the 15-year-old Scheie case illustrated in the skeletal dysplasia atlas, diaphyseal modelling may be preserved, with contractures and small carpal bones predominating [46].

The heart is affected in all MPS disorders, particularly rapidly progressive forms; the mitral valve is more affected than the aortic valve, regurgitation predominates over stenosis, and early coronary disease is more common in MPS I and II [45]. Surgical treatment of valvular disease is complicated by anaesthetic and spinal cord injury risks [45]. Saudubray's textbook highlights spinal cord compression remote from the operative site during prolonged surgery, possibly due to hypotension and impaired spinal cord circulation, warranting intraoperative neurophysiological monitoring [4]. The Brazilian genetic syndromes manual summarises the same system-specific manifestations and adds dental abnormalities (anterior open bite, high-arched palate and delayed eruption) [47].

The 2025 French PNDS sets out the warning signs common to the MPS in a way that is useful for the attending physician [10]. In growth, accelerated height and weight gain in the first two or three years is followed by a fall-off in the height curve; the head circumference curve shows progressive macrocephaly or, in the presence of craniosynostosis (described in MPS I, II and VII), stagnation. In the skeleton, thoracolumbar kyphosis is highly suggestive, the chest tends towards pectus excavatum in MPS I, claw hand due to camptodactyly is typical of MPS I and II, and carpal tunnel syndrome (or, more rarely, ulnar tunnel syndrome) in a child is highly suggestive; radiographs show platyspondyly, coxa valga, flat acetabular roofs, dysostosis multiplex and tapered metacarpals. In the skin, extensive Mongolian spots are classic in MPS I, II and VI, and in MPS II there may be a grained “orange-peel” appearance over the shoulder blades or thighs. An inguinal hernia in a non-premature infant should prompt a search for other signs of MPS, and inguinal and umbilical hernias characteristically recur after repair. In the mouth, delayed eruption, enamel anomalies, limited mouth opening, gingival hypertrophy and dental cysts or abscesses are suggestive without being exclusive. In the heart, aortic and mitral valve involvement, almost constant in MPS I and II, may be accompanied by hypertrophic cardiomyopathy, systemic hypertension and, more rarely, coronary disease and pulmonary arterial hypertension. In the nervous system, in addition to delay and regression, the PNDS lists autism spectrum disorders and sleep disturbances, hydrocephalus and progressive multilevel spinal cord compression, which may reveal the disease in adulthood. Absence of facial dysmorphism does not exclude the diagnosis in moderate forms, and the most severe forms may begin prenatally with polyhydramnios or fetoplacental hydrops. In most patients, multiple disability develops progressively, becoming profound multiple disability when there is neurodegeneration [10].

4. Clinical Recognition and Warning Signs

Recognition depends on combining signs that are individually commonplace. In early infancy, inguinal or umbilical hernia (particularly recurrent), persistent rhinorrhoea without infection, recurrent otitis, noisy breathing and macrocephaly should prompt examination for gibbus, restricted hip mobility and hepatomegaly [1, 2, 8]. Later, finger contractures without inflammatory signs, claw hands, childhood carpal tunnel syndrome, corneal clouding or a valvular murmur in a short child suffice to request urinary GAG testing [1, 39]. The Oxford Desk Reference summarises the approach to coarse facial features: when clinical suspicion of Hurler syndrome is strong, proceed directly to enzymatic and molecular confirmation; when uncertain, include urinary metabolic screening for mucopolysaccharides and oligosaccharides, assessment for vacuolated lymphocytes, skeletal radiographs and echocardiography [48, 49]. Childhood corneal clouding should suggest MPS I, IV, VI and VII, but not MPS III, and is rare in MPS II [47, 49].

Attenuated forms are the most difficult to recognise. The Atlas describes patients with joint pain and stiffness referred to rheumatology or dermatology, and Scheie diagnoses made only in adulthood [30]. GeneReviews recommends including attenuated MPS I in the differential diagnosis of juvenile idiopathic arthritis because its arthropathy is non-inflammatory [1]. In a published report discussed in section 10, a boy whose hip dysplasia was treated as Legg–Calvé–Perthes disease and whose short stature was followed in endocrinology was diagnosed only at age 17 years [39]. The authors cite one series in which approximately 20% of 60 attenuated MPS I patients experienced delays of 5 years or more, consulting 4 to 5 specialists, and another in which 18 patients with symptoms at 18 months had a mean age at biochemical diagnosis of 75 months; registry data showed no reduction in time to diagnosis up to 2017 [1, 39]. Smith's Recognizable Patterns, in the MPS III chapter, cites a study in which time to diagnosis and diagnostic delay in MPS I and MPS III did not change between 1988 and 2017, despite efforts to publicise the presenting signs and symptoms, and concludes that newborn screening is the best way to ensure early diagnosis [50]. Endocrinologists have a particular opportunity: a hand radiograph for bone age may reveal typical bullet-shaped phalanges [39].

Table 5. Warning signs and immediate action

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Urinary glycosaminoglycans

Quantitative urinary GAG measurement (for example, the dimethylmethylene blue method) and two-dimensional electrophoresis were the traditional first step; tandem mass spectrometry (MS/MS) methods have shown greater sensitivity and are now considered the screening standard [4]. No method identifies the deficient enzyme: an abnormal result indicates probable MPS, and the dermatan and heparan sulphate pattern is shared by MPS I, II and VII [1, 23]. Both lose sensitivity in dilute urine, and qualitative spot tests have false positives and negatives [1, 29]. The Brazilian manual considers toluidine blue testing obsolete [47]. A negative result does not exclude disease when clinical findings are suggestive [45]. The French PNDS stresses that, in moderate forms and especially in adults, urinary GAGs may be only slightly raised or not raised at all, and requires quantitative and qualitative GAG analysis, enzyme activities and sequencing to be performed in a reference medical biology laboratory; in France there are six, in Lyon, Paris (Necker), Rouen, Toulouse, Grenoble and Lille, and the Lyon, Necker and Rouen laboratories also sequence SUMF1, HYAL1, ARSK, ARSG, VPS33A and VPS16, in addition to the genes of the classical MPS, which Toulouse also sequences [10].

5.2. Enzyme assays and diagnostic criteria

In MPS I, IDUA activity can be measured in leucocytes, plasma, fibroblasts or dried blood spots on filter paper; all patients have absent or very low activity by standard methods, but the value does not predict phenotype [1]. Because of pseudodeficiency, GeneReviews establishes diagnosis through suggestive clinical and laboratory findings AND deficient IDUA activity AND increased urinary GAGs, or two pathogenic or likely pathogenic variants in trans [1]. The 2025 Brazilian PCDT translates these principles into operational criteria: IDUA activity below 10% of the lower reference limit (plasma, fibroblasts or leucocytes), with normal activity of a reference enzyme in the same sample using the same method, and increased urinary GAGs; or activity below 10% (including dried blood spots) with biallelic pathogenic variants [23]. The same protocol cites 88% agreement between dried blood spot activity and other tissues, and considerable loss of activity after 21 days of sample storage [23].

In MPS II, diagnosis in a boy is established by absent or reduced I2S activity in leucocytes, fibroblasts or plasma, provided at least one other sulfatase has normal activity; without this step, multiple sulfatase deficiency may be mistaken for MPS II [3, 24]. European recommendations consider dried blood spot measurement valuable: it requires no heparin, uses little blood and is stable for several days at room temperature [24]. Their diagnostic algorithm is available in Figure 2 of Scarpa et al. 2011 [24]. The Brazilian PCDT requires I2S activity below 10% of the lower limit with another sulfatase normal and increased urinary GAGs, or a recognised pathogenic variant [27]. Diagnosis in a female is molecular [3]. The French PNDS agrees with these principles: biochemical confirmation is performed in leucocytes (dried blood spot on filter paper or leucocyte pellet), with serum or plasma as an alternative in MPS I and II, and fibroblasts, cultured amniocytes or chorionic villi in other situations; activity measured with synthetic substrates does not distinguish severe from attenuated forms; and any deficiency of one sulfatase requires measurement of a second sulfatase to exclude multiple sulfatase deficiency [10].

5.3. Molecular tests, limitations and reporting

In MPS I, start with IDUA sequencing (or an MPS panel), followed by deletion/duplication analysis when one or no variant is found; in MPS II, sequencing should be complemented by dosage analysis and methods targeting the inversion and rearrangements with IDSP1, which sequencing, including exome and genome sequencing, may miss [1, 3]. The proportion of variants detectable by a method is not the test's clinical sensitivity: a negative result in a patient with confirmed enzyme deficiency does not exclude MPS II and requires further molecular investigation [3, 36]. Two IDUA variants of uncertain significance, or one pathogenic and one uncertain variant, neither establish nor exclude diagnosis [1]. Reports should specify gene, versioned transcript (NM_000203.5 for IDUA; NM_000202.8 for IDS), HGVS nomenclature, zygosity, ACMG/AMP classification and methodological limitations; historical designations (W402X, Q70X, 704ins5) should accompany normalised nomenclature when used in the literature [7, 37]. In MPS I, parental testing is necessary to confirm phase; apparent homozygosity when only one parent is a carrier requires consideration of a de novo variant or uniparental isodisomy [1]. The French PNDS offers molecular testing to all patients, because in some cases it predicts severity, and considers parental testing essential to confirm segregation and to prepare for possible prenatal diagnosis [10].

5.4. Practical algorithm

Symptomatic patients follow the sequence: clinical suspicion → urinary GAGs (quantitative, preferably MS/MS) → enzymes in leucocytes or plasma (IDUA; I2S with another sulfatase) → molecular testing to confirm diagnosis, predict phenotype and enable counselling [1, 3, 4]. Newborn screening reverses the order: dried blood spot enzyme → second-tier dried blood spot GAGs or molecular testing → confirmatory leucocyte or plasma enzyme and urinary GAGs → genotype [1, 26]. In MPS I, determining the likely phenotype at diagnosis is critical because it defines the indication for transplantation; the European consensus recommends genotyping all patients, developmental assessment by a neuropsychologist experienced in MPS and team-based decision-making [14]. After diagnosis, GeneReviews recommends a skeletal survey, ophthalmological assessment (acuity, intraocular pressure, slit lamp, electroretinography and visual fields), echocardiography, hearing and otorhinolaryngological assessment with a sleep study, brain magnetic resonance imaging, assessment of spinal cord and carpal tunnel involvement, and developmental evaluation [1].

The French PNDS describes a more detailed baseline assessment, common to the MPS and adapted to the type, at the end of which the individual treatment decision is made (Table 5A) [10]. Two practical details have consequences: dynamic flexion–extension radiographs of the cervical spine are performed only after cervical spinal MRI, because of the risk of canal narrowing, and the lower-radiation EOS system should be preferred when available [10].

Table 5A. Baseline assessment according to the 2025 French PNDS

Source: [10].

5.5. Newborn screening

The US Secretary of Health recommended inclusion of MPS I in the RUSP in February 2016 and approved MPS II on 2 August 2022, following the advisory committee's recommendation in February that year [18–20]. In December 2025, 45 of 54 US programmes screened for MPS I [35]. Outside the United States, Taiwan has screened for both disorders since August 2015 and north-eastern Italy for MPS I since 2015 [51, 52]. The US advisory committee was disbanded in March 2025, and the HRSA (Health Resources and Services Administration) pages are now archived [53].

First-tier testing measures dried blood spot enzyme activity using MS/MS or fluorimetry [26]. Enzyme-only MPS I screening performed inadequately because of pseudodeficiency and other causes of low activity; second-tier dried blood spot GAGs or molecular testing substantially reduced false positives [26]. For MPS II, Gaviglio and colleagues' panel recommends following activity below the cut-off with dried blood spot GAG measurement by MS/MS (internal heparan and dermatan sulphate disaccharides or the endogenous non-reducing-end oligosaccharide biomarker), before referral; confirmation includes plasma or leucocyte I2S, urinary GAGs and a second sulfatase [26]. I2S pseudodeficiency is more frequent than the disease [26]. An international Delphi consensus involving 21 experts from 8 countries on evaluation of MPS II screen-positive newborns was published in 2025; only its abstract was consulted for this article [19].

Table 6. Newborn screening programme performance (published data)

Second-tier GAG testing was evaluated at scale: in Ontario, among 384,144 newborns, 166 samples with low IDUA activity were analysed, and all newborns with pseudodeficiency or carrier status had normal GAGs, leading the authors to favour this method over second-tier molecular testing [61]. In a survey of 32 US programmes, those using second-tier GAGs reported 48% severe cases versus 29% in programmes without this tier, and similar proportions of attenuated disease (13% and 14%) [35]. These figures must be interpreted with each programme's denominators and methods; they are not directly comparable, and incidence estimates from small programmes have very wide intervals.

Screening raises specific issues. Newborns with uncertain genotypes or pseudodeficiency need clinical and biochemical follow-up; the lack of robust enzyme–GAG–phenotype correlations requires genotype to guide transplantation decisions, and positive results should be communicated promptly and empathetically with written information [26, 31]. In the evidence-review model underlying inclusion of MPS II, screening the 3.6 million annual US newborns would produce approximately 480 positives, 59 cases and 322 false positives, versus approximately 24 cases detected clinically [20]. The consulted sources contained no description of MPS I or II newborn screening programmes in Portugal or Brazil; Brazil is mentioned among countries with MPS I pilot studies [31].

5.6. Prenatal diagnosis

When familial variants are known, prenatal and preimplantation diagnosis should be molecular [1, 3]. In MPS I, enzyme measurement in amniocytes or chorionic villi has been abandoned because of pseudodeficiency and the scarcity of experienced laboratories; the Atlas recalls that activity in villi is normally so low that extreme care is required [1, 8]. In MPS II, prenatal enzyme diagnosis requires karyotyping or sex determination because female fetuses may have low activity; European recommendations allow measurement of I2S and GAGs in amniocytes, villi or cord blood when the mother is an obligate carrier without an identified variant [9, 24]. The French PNDS prefers molecular testing when the variants of the index case and of both parents have been identified, while accepting enzyme testing; sampling is by chorionic villus biopsy between 11 and 13 weeks of gestation or by amniocentesis from 15–16 weeks, and in MPS II fetal sex determination in maternal blood, possible from 9 weeks, avoids the invasive procedure when the fetus is female [10]. In France, termination of pregnancy for medical reasons, at the request of the couple or the woman, is decided with a multidisciplinary prenatal diagnosis centre, and preimplantation genetic testing is among the options to be presented at the genetics clinic [10].

6. Differential Diagnosis

The main differential comprises other disorders with dysostosis multiplex and abnormal GAG or oligosaccharide excretion. Clinical distinction between MPS I and II is often impossible in a young child with severe disease: corneas, inheritance, skin lesions and behaviour provide clues, but the decisive test is enzymatic [3, 4].

Table 7. Differential diagnosis of MPS I and II

The Brazilian manual adds causes of increased urinary GAG excretion outside MPS, including Marfan syndrome, rheumatoid arthritis, lupus, psoriasis, urticaria pigmentosa and active scleroderma, reinforcing that elevated GAGs are a screening finding rather than a diagnosis [47].

The summary table of the 2025 French PNDS helps to order the differential diagnosis between the classical types by the relative intensity of each manifestation [10]. MPS I and VI share prominent orthopaedic involvement, joint contractures, and frequent corneal opacities and valvular disease; MPS II has the same visceral, cardiac and ear, nose and throat profile, but without corneal opacities, and only form IIA has neurodegeneration; in MPS III, neurodegeneration and behavioural disturbances predominate, with subtle or late facial features and organomegaly; in MPS IV, joint hyperlaxity, pectus carinatum, “beaked” T12, L1 or L2 vertebrae and the risk of acute occipito-atlanto-axial spinal cord compression contrast with the stiffness of the other forms; and MPS VII presents mainly in the prenatal period with fetoplacental hydrops. The same document stresses that MPS IVA and VI tend to show early growth deceleration, rather than the accelerated height gain in the first years typical of MPS I and II [10].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no curative treatment [1, 27]. Management combines three layers: deficiency-directed treatment (HCT, conventional ERT, blood–brain barrier-crossing enzymes and investigational gene therapies), multidisciplinary symptomatic care and scheduled surveillance [1, 3, 4]. The team should include orthopaedics, neurology and neurosurgery, otorhinolaryngology, cardiology, physiotherapy and rehabilitation, ophthalmology, metabolic paediatrics, internal medicine and clinical genetics, with follow-up in specialist centres [4]. Age at treatment initiation most strongly influences the outcome of any therapy: studies of siblings treated at different ages show better outcomes when treatment begins before irreversible damage [1, 4, 20]. Pain is frequent and requires specific management [4].

The 2025 French PNDS sets three management goals (improving or slowing multisystem progression, improving quality of life and social, educational or occupational integration, and informing and supporting the patient and family) and requires the baseline assessment and follow-up to be coordinated by a hospital physician at a reference or competence centre for inherited metabolic diseases, lysosomal diseases or constitutional bone diseases [10]. The coordinator is, in children, the paediatrician, paediatric neurologist or physical and rehabilitation medicine physician and, in adults, the internist, rheumatologist, neurologist or physiatrist; around this physician, depending on the organ involvement, are anaesthesia, laboratory medicine, cardiology, orthopaedic and visceral surgery, gastroenterology, genetics, haematology, pain medicine, palliative care, neurosurgery, neurology, dentistry and stomatology, otorhinolaryngology, ophthalmology, respiratory medicine, psychiatry, radiology and rheumatology, as well as genetic counsellors, nurses, physiotherapists, occupational therapists, neuropsychologists, speech and language therapists, psychomotor therapists, orthotists and prosthetists, psychologists and social workers [10]. Hospital at home is described as frequent support, both for the weekly infusions and for symptoms and family support in the place of residence. The choice of specific treatment depends on the MPS type, phenotype, age and neurological status, and every initial prescription of ERT must be validated case by case, by a multidisciplinary team, by experts from a reference or competence centre; for the PNDS, ERT is not a systematic treatment [10].

7.2. Haematopoietic cell transplantation in severe MPS I

HCT is standard treatment for severe MPS I and the only treatment shown to alter the natural history of neurocognitive disease [1]. Its mechanism combines replacement of recipient macrophages by donor cells, enzyme transfer through cell contact and plasma, and nervous system repopulation by donor-derived microglia; the latter takes approximately one year, explaining the lag between engraftment and cognitive stabilisation [14, 31].

Indications have become more precise. The 2009 international guideline used age (2 years or younger versus older than 2 years), predicted phenotype and developmental quotient to balance HCT risk against ERT, which is low-risk but does not cross the blood–brain barrier [21]. The 2011 European consensus, developed through a modified Delphi process with eight metabolic paediatricians and seven transplant specialists, reached nine statements with unanimous agreement (Table 8) [14]. GeneReviews generally recommends HCT before age 2 years, only in carefully selected children with prior assessment and counselling and provision for long-term follow-up; adults have not undergone transplantation [1]. The 2025 Brazilian PCDT defines eligibility for related or unrelated myeloablative allogeneic HCT as MPS I children up to 3 years with age-appropriate neuropsychomotor development on neurological assessment, excludes homozygous related donors and assesses heterozygotes individually [23]. These age differences (2, 2.5 and 3 years) reflect different sources and settings rather than a biological boundary: the European consensus stresses that phenotyping and the team matter more than a rigid cut-off [14].

The 2025 French PNDS adopts the 2022 recommendations of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) [10]. Transplantation is recommended for every child with MPS I-H, as early as possible, before 24 to 30 months and before any cognitive regression assessed by an experienced neuropsychologist; the other indications (MPS I-HS, MPS II, IV, VI and VII) are discussed case by case, when diagnosis is early, at a multidisciplinary team meeting with transplant physicians, paediatric neurologists and metabolic disease specialists, and there is no indication in MPS III. The recommended myeloablative conditioning combines busulfan and fludarabine. Donor choice depends on urgency and non-carrier status: first line, a non-heterozygous HLA-identical sibling; second, an 8/8 or 7/8 matched cord blood unit, preferred for its rapid availability, more complete chimerism and higher post-transplant enzyme activity, at the cost of a higher risk of rejection and autoimmune cytopenias; third, a 10/10 matched unrelated volunteer donor. Because the risk of rejection or graft failure is higher in these non-malignant diseases, the graft should be cell-rich [10].

Regarding ERT around transplantation, the PNDS recommends starting it as soon as MPS I-H is diagnosed, because it reduces morbidity and mortality and ear, nose and throat obstruction, and states that the development of anti-enzyme antibodies is not related to engraftment [10]. After transplantation, ERT is continued until there is complete donor chimerism, normal or near-normal enzyme activity and normal urinary GAGs, which occurs on average 3 to 6 months later [10]. Follow-up is shared between the transplant team and the reference team, with regular enzyme assays and chimerism. The PNDS acknowledges that the morbidity and mortality of the procedure are not negligible (toxicity and graft failure) and that skeletal, ocular, cardiac and sometimes ear, nose and throat and neurological manifestations may progress despite successful transplantation [10].

Table 8. European consensus on ERT and HCT at MPS I diagnosis (de Ru et al. 2011)

Source: [14].

Outcomes have improved over the decades. The Brazilian PCDT cites survival rising from 49% at 2 years in a 1996 study to 77% at 3 years and 86% at 5 years, and a 2015 series of 62 MPS I patients (56 Hurler) with overall survival of 95.2%, event-free survival of 90.3%, acute graft-versus-host disease in 13.3% and chronic disease in 14.8% [23]. The Atlas cites overall survival of 74% at 5 years in 258 children receiving various cell sources after myeloablative conditioning [8]. Experienced centres report survival with engraftment of approximately 90%, attributed to implementation of European Society for Blood and Marrow Transplantation guidance, unrelated cord blood use, busulfan therapeutic monitoring and a short diagnosis-to-transplant interval [14, 31]. Aldenhoven and colleagues' multicentre study of 217 successfully engrafted patients, with median follow-up age 9.2 years, showed considerable residual burden and identified preserved cognitive function and younger age at transplantation as predictors of better cognitive outcomes; normal IDUA activity after HCT (non-carrier donors and complete chimerism) predicted better outcomes in most organs [62]. In a Duke series (2017–2023) of children identified by newborn screening, nine underwent transplantation at a median age of 5.2 months; eight were alive with normal IDUA, and one died from autoimmune haemolytic anaemia on day +139 [63].

HCT reduces facial infiltration and hepatosplenomegaly, improves hearing, prevents or stabilises hydrocephalus, and stabilises myocardial function with regression of hypertrophy [1, 23]. Its effect on valves, corneas and skeleton is limited: dysostosis and corneal clouding progress, and longer survival brings hip and knee pain and stiffness, carpal tunnel syndrome, spinal cord compression and progressive thoracolumbar kyphosis [1, 45]. In children transplanted before substantial delay, usually between 12 and 18 months, cognitive decline appears to slow; deficits established before HCT are not reversed [1]. Prolonged ERT after HCT was studied in ten patients, with possible growth benefits in the youngest; in its preliminary statements, the European consensus found no evidence of benefit from ERT after successful HCT [1, 14].

7.3. Laronidase (Aldurazyme®)

Laronidase is recombinant human alpha-L-iduronidase produced in Chinese hamster ovary cells, taken up through the mannose-6-phosphate receptor [23, 29]. In the phase 1/2 trial published in 2001, ten patients aged 5–22 years treated weekly for 52 weeks normalised liver volume in eight cases by 26 weeks, increased height and weight growth velocity by 85% and 131% in the six prepubertal patients, reduced apnoea and hypopnoea episodes by 61% and urinary GAGs by 63% [64]. The randomised, double-blind pivotal trial included 45 patients (1 Hurler, 37 Hurler–Scheie and 7 Scheie, aged 6–43 years) treated with 100 U/kg (0.58 mg/kg) or placebo for 26 weeks [12, 65]. The publication reports mean improvement of 5.6 percentage points in predicted forced vital capacity (FVC; p=0.009) and 38.1 m in the 6-minute walk test (6MWT; p=0.066 in the primary test, p=0.039 by analysis of covariance) [65]. The US label gives the FVC difference as a mean of 4 and median of 2 points (95% confidence interval [CI] 0.4–7; p=0.02, Wilcoxon test) and the 6MWT difference as a mean of 38 m (p=0.07) [12]. The differences between sources reflect different statistical analyses of the same trial; neither supports describing the walking effect as statistically robust. Extension and real-world studies show sustained urinary GAG reduction (usual response within 12 weeks), normalisation of liver and spleen volumes, stabilisation (not improvement) of respiratory function, increased shoulder range in the first two years, and improved mobility and quality of life [1]. The Brazilian PCDT cites shoulder flexion gains of 17°–33.5° and urinary GAG reduction of at least 50% from the fourth week; the 2019 Cochrane review found a 54% reduction from baseline with laronidase versus placebo at 26 weeks [23].

Laronidase does not cross the blood–brain barrier and does not alter corneal disease, valvular progression, large-joint and hand arthropathy or vertebral disease with cord compression; carpal tunnel syndrome continues to develop [1, 8]. In sibling series, earlier initiation was associated with better outcomes [1]. In European practice and the Brazilian PCDT, ERT is also used before HCT to improve clinical status without interfering with engraftment [14, 23].

Table 9. Laronidase: dosing and label information (USA and EU)

Sources: [12, 13]. The 2025 French PNDS recommends 100 U/kg weekly intravenously, in children and adults, for non-neurological manifestations, with no maximum dose defined, the same dose as the European SmPC (equivalent to the 0.58 mg/kg of the US label), and lists as demonstrated benefits 6MWT distance, FVC, sleep apnoea, visceromegaly, cardiomyopathy and urinary GAG excretion, with no effect on the central nervous system [10]. The Brazilian PCDT uses 0.58 mg/kg weekly over 3–4 hours and does not recommend 1.2 mg/kg fortnightly, despite studies with favourable outcomes, because evidence is scarce [23].

Infusion-associated reactions were the most frequent adverse effect: in the controlled trial, flushing (23%), fever, headache and rash; in children up to 5 years, infusion reactions occurred in 35% (7 of 20) [12]. Management follows the label: for mild to moderate reactions, stop for 15–30 minutes or reduce the rate by 25–50%; for severe reactions, stop and treat, considering reintroduction with premedication and a reduced rate [12]. Inhibitory antibodies correlated with a higher dermatan/chondroitin sulphate ratio and the severity of sleep-disordered breathing, and the PCDT recommends testing neutralising antibodies when GAGs do not fall and desensitisation protocols for IgE-mediated reactions [23, 31].

7.4. Idursulfase (Elaprase®)

Idursulfase is recombinant I2S produced in a human fibrosarcoma cell line (HT-1080) [27]. The pivotal phase 2/3 trial included 96 patients aged 5–31 years, randomised to placebo, idursulfase 0.5 mg/kg weekly or 0.5 mg/kg fortnightly for 53 weeks; the composite endpoint (6MWT and predicted FVC) was met (p=0.0049 weekly; p=0.0416 fortnightly), with a 37 m 6MWT increase (p=0.013), a non-significant 2.7% increase in predicted FVC (p=0.065) and a 160 mL increase in absolute FVC (p=0.001) in the weekly arm [66]. The US label, using adjusted analysis, reports a 35 m 6MWT difference and non-significant changes in predicted FVC [15]. European recommendations add approximately 25% reductions in liver and spleen volume, reduced urinary GAGs, gains of approximately 12° and 15° in shoulder abduction and flexion at 36 months, and improved disability indices [24]. In HOS, survival was higher in treated than untreated patients; in a British cohort receiving ten years of ERT cited by GeneReviews, initiation before age 8 years was associated with better predicted FVC at 16 years (median 69% versus 48%; p=0.045) [3]. Idursulfase does not cross the blood–brain barrier and is not expected to affect the CNS, although neuronopathic patients benefit in somatic manifestations [3, 16].

Table 10. Idursulfase: dosing and label information (USA and EU)

Sources: [15, 16, 27]. The 2025 French PNDS recommends 0.5 mg/kg weekly intravenously, in children and adults, with no maximum dose defined, consistent with both labels, and lists as demonstrated benefits the 6MWT, reduction in spleen and liver volume, fewer respiratory infections and a fall in urinary GAGs, stressing that the enzyme does not cross the blood–brain barrier and that, in MPS IIA, neurological, cognitive and behavioural disturbances continue to worsen [10].

In trials, 15% of patients (16 of 108) had hypersensitivity reactions involving at least two systems, in 0.3% of infusions [15]. In the trial in children up to 7 years, those with a complete deletion, large rearrangement, nonsense, frameshift or splicing variant had more hypersensitivity reactions (73% versus 42%), more severe reactions (60% versus 17%) and antibodies in all 15 cases, compared with 3 of 12 with missense variants [15]. The label does not suggest routine premedication; GeneReviews describes diphenhydramine and paracetamol (or ibuprofen) one hour beforehand when reactions persist despite rate reduction, and a regimen of corticosteroid 24 and 8 hours beforehand, antihistamine and intravenous methylprednisolone after severe reactions [3]. European recommendations request observation for at least 24 hours after moderate to severe reactions, discourage substantial infusion shortening and propose a 12–18-month trial period in all phenotypes, followed by shared decision-making [24]. IgG antibodies developed in 46.9% of patients and neutralising antibodies in 22 of 94; the latter were associated with smaller absolute FVC gains [24, 66].

The French PNDS describes the practical arrangements for laronidase and idursulfase together [10]. ERT is initiated at a reference or competence centre and the first infusions are given in hospital, through a peripheral vein or a totally implanted catheter; the decision to implant a catheter weighs the infectious risk in the presence of significant valvular disease or a prosthetic valve, and replacement of the device may become necessary with growth and device age. Infusion requires a setting with resuscitation equipment, because of the risk of infusion-associated reactions, sometimes severe, including anaphylactic shock; after hospital initiation, and under defined conditions, it may move to the home, through hospital at home or service providers, according to the therapeutic use protocol of each medicine [10]. The manifestations to recognise are headache, fever, erythema, flushing, urticaria, pruritus, oedema, vomiting, abdominal pain, diarrhoea, malaise, hypotension or hypertension, tachycardia, dyspnoea, bronchospasm, angioedema and shock. The risk is higher during an intercurrent infection, especially respiratory, and in patients with a history of allergy, which requires assessment of the patient before infusion; it is concentrated between the 6th and 15th infusions, but may arise after months or years of treatment [10]. Anti-enzyme antibodies are frequent and their titre does not correlate with the 6MWT or urinary GAGs; only some neutralising antibodies reduce benefit, and their measurement, requested through the laboratory that markets the enzyme, is reserved for repeated reactions or unexpected loss of efficacy [10]. The management of reactions and the premedication proposed in annex 6 of the PNDS are summarised in Table 10A; the anaphylaxis section refers to the 2016 French emergency medicine recommendations [10].

Table 10A. ERT infusion-associated reactions: management and premedication according to the 2025 French PNDS

Source: annex 6 of the PNDS [10]. The annex also includes nebulised adrenaline, outside the marketing authorisation (minimum 0.1 mg/kg and maximum 5 mg in children; 2–5 mg in adults; in normal saline up to 5 mL, repeatable at 20 minutes). The French regimen differs from the labels: the European SmPC for laronidase recommends premedication, but the US idursulfase label does not suggest routine premedication (Table 14A) [13, 15].

The 2020 ACMG Delphi resource recommends ERT for all patients with severe or genotype-predicted severe MPS II before signs or symptoms, and all symptomatic patients; it does not recommend ERT in asymptomatic attenuated patients, allows home infusions with early disease, controlled reactions and a stable environment, recommends discontinuation only for uncontrollable allergic reactions, and reached no consensus on HCT or intrathecal ERT [25]. The Brazilian PCDT restricts idursulfase to patients without neurological regression [27].

7.5. Tividenofusp alfa-eknm (Avlayah®): the first blood–brain barrier-crossing enzyme

Tividenofusp alfa is an I2S fusion protein with a modified Fc domain binding the transferrin receptor, designed to cross the blood–brain barrier by receptor-mediated transcytosis while retaining peripheral activity [3, 67]. In the phase 1/2 trial (NCT04251026), 47 boys up to 18 years received weekly infusions for 24 weeks followed by extensions; all experienced at least one adverse event, predominantly infusion reactions, with fever, urticaria and vomiting in more than 40% despite premedication, and three had serious treatment-related adverse events without discontinuation [67]. Cerebrospinal fluid (CSF) and urinary heparan sulphate fell approximately 91% and 88% at 24 weeks; reductions persisted through week 153, adaptive behaviour stabilised or improved, and liver volume normalised or remained normal [67]. The FDA granted accelerated approval (biologics licence application, BLA, 761485; approval date 24/03/2026 in the FDA approved-drug database, sponsor announcement 25/03/2026), based on CSF heparan sulphate reduction; continued approval depends on confirmation of clinical benefit [17, 68–70]. The confirmatory double-blind phase 2/3 COMPASS trial (NCT05371613) compares the drug with idursulfase (2:1) in 65 patients, with primary endpoints of CSF heparan sulphate at 24 weeks and Vineland-3 at 96 weeks [71]. In Europe, it has only European Medicines Agency (EMA) PRIME (Priority Medicines) designation and is not authorised outside the United States [69, 70].

Table 11. Tividenofusp alfa-eknm: US label information (version dated 20/03/2026)

Source: [17]. GeneReviews revised in April 2026 gives “30 mg/kg” weekly; the label sets maintenance at 15 mg/kg and describes 30 mg/kg as twice the approved dose, without additional heparan sulphate reduction, so label dosing takes precedence [3, 17].

7.6. Transplantation in MPS II

Sources disagree. The 2011 European recommendations considered that transplantation does not preserve neurological function once deterioration has occurred, and benefits did not appear to outweigh risks when ERT was available; many centres stopped offering it, although the literature was biased by late transplantation [24]. ACMG reached no consensus [25]. The screening evidence report cites mortality up to 8%, more recent evidence of benefit in selected patients and a non-significant trend towards better independence in 18 transplanted severe patients versus 29 receiving ERT, with “early” transplantation defined as before age 5 years [20]. GeneReviews describes HCT as primary treatment for the neuronopathic form in China, because of limited ERT access, and in Japan, and considers it an option if performed early [3]. The Brazilian PCDT allows HCT for severe disease with neurological regression, preferably up to age 3 years, as the only treatment available in the Sistema Único de Saúde (SUS, Unified Health System) potentially capable of neurological benefit [27]. Saudubray's textbook classifies it as indicated in young neuronopathic patients with a good donor [4]. The 2025 French PNDS places MPS II among the indications to be discussed case by case, only with early diagnosis and at a multidisciplinary team meeting, and includes in its bibliography the Lyon series of boys with Hunter syndrome who underwent transplantation and were followed for 7 to 17 years [10]. Decisions therefore require assessment at an experienced centre and now also consider the availability of a blood–brain barrier-crossing enzyme in the United States and ongoing trials [26].

7.7. Regulatory status and access

Table 12. Comparative regulatory status (consulted 6 October 2026)

Sources: [12, 13, 15–17, 23, 27, 32, 33, 70, 72, 73]. Authorisation does not guarantee marketing or reimbursement in each country. ANVISA registration and access in Portugal (INFARMED) were not verified in the consulted sources; both conventional enzymes have centralised EU authorisation.

7.8. Clinical trials and interpretation

Table 13. Pivotal trials and reference studies

The laronidase trial recruited predominantly attenuated patients, and the idursulfase trial patients older than 5 years without cognitive impairment, limiting extrapolation to infants and neuronopathic forms; endpoints (6MWT, FVC) have limited utility for following young children or those with cognitive impairment, as the ACMG panel itself acknowledges [25, 65]. Evidence for blood–brain barrier-crossing enzymes rests on a biomarker (CSF heparan sulphate) and single-arm studies; US approval is accelerated, and confirmation of clinical benefit depends on ongoing trials [17, 75]. Biomarker reductions cannot be compared across products because trials used different methods, doses and populations. The negative intrathecal trial and RGX-121's course show that a biomarker effect guarantees neither approval nor demonstrated clinical benefit [32, 74].

7.9. Developments in 2025–2026 and emerging therapies

MPS II. Beyond US approval of tividenofusp alfa (phase 1/2 article published January 2026; recruitment of the neuronopathic cohort in COMPASS complete), RGX-121 (AAV9 carrying IDS, administered intracisternally or intraventricularly) followed this course, known only from sponsor announcements to the US Securities and Exchange Commission (SEC): FDA acceptance of the application in May 2025 through an accelerated pathway; partial clinical hold in January 2026 because of similarity to RGX-111 after an intraventricular tumour in a participant receiving the latter, with lifting announced in May; complete response letter on 7 February 2026 due to concerns about neuronopathic disease criteria, comparability of the natural history control and validity of the CSF D2S6 biomarker; and another hold on 24 August 2026 after asymptomatic findings (small nodules or cystic masses) on spinal MRI in five participants treated 3–6 years earlier, without expectation of resubmission in the near term [32, 33]. RGX-121 clinical results have not been published in a journal; the February 2024 announcement reports achievement of the primary endpoint at 16 weeks (p=0.00016) [32]. Pabinafusp alfa is in the global phase 3 STARLIGHT trial (86 patients, primary completion expected October 2027) [77]. In Japan, intracerebroventricular idursulfase beta (up to 30 mg every 4 weeks) reduced CSF heparan sulphate by 72.3% in a 5-year study of six patients; a 2026 post-marketing study of 37 patients showed developmental progression aligned with healthy controls only when treatment started before age 3 years, with device-related infections in two patients [73, 78]. An intrathecal idursulfase substudy in nine children younger than 3 years was published in 2026 [79]. Other programmes include verenafusp alfa (approved in Russia according to Gaviglio's panel), autologous gene therapy with IDS fused to ApoEII (Manchester, phase 1/2) and fetal ERT (PEARL trial) [26, 80]. In vivo genome editing with zinc-finger nucleases (SB-913) had a favourable safety profile but no sustained blood enzyme expression [81].

MPS I. OTL-203 (autologous haematopoietic stem cells transduced with a lentiviral IDUA vector after myeloablative conditioning) was tested in eight Hurler children (mean age 1.9 years): rapid engraftment, supraphysiological IDUA activity in the first month, detectable CSF IDUA, normal urinary GAGs at 12 months in four of five evaluable patients, stable cognitive performance and normal growth [76]. Retrospective comparisons with external transplanted cohorts suggest better growth and joint mobility, resolution of corneal clouding in 3 of 8 and no carpal tunnel surgery (0/8 versus 7/9 after allogeneic HCT), but the authors themselves call for prospective studies [82, 83]. The phase 3 trial comparing OTL-203 with allogeneic HCT (NCT06149403; 41 patients aged 28 days to 30 months; primary endpoint event-free survival at 2 years) has completed recruitment, with primary completion expected in 2028 [34]. RGX-111 (intracisternal AAV9) is on hold after an intraventricular tumour with vector integration near the proto-oncogene PLAG1 in a participant treated four years earlier, without established causality; a 2026 single-case report describes a 20-month-old child treated without HCT, with normal brain imaging and continued acquisition of skills, but whether this was the same patient is unknown [32, 84]. Lepunafusp alfa (JR-171, IDUA fused to an anti-transferrin receptor antibody) showed reduced CSF heparan sulphate in a phase 1/2 study of 18 patients, and the company is seeking partners [72, 85]. ISP-001 (autologous B lymphocytes modified to secrete IDUA, without conditioning) is in phase 1 in adults with attenuated disease; a 2026 poster, not peer reviewed, describes urinary GAG normalisation in two patients alongside ERT [86]. Other approaches mentioned in the sources, without demonstrated clinical utility, include stop-codon readthrough (chloramphenicol, ataluren), chaperones, substrate reduction, adalimumab and pentosan polysulphate [1, 8, 31].

The French PNDS, written before the US approval of tividenofusp alfa, is limited to validated treatments and mentions, as research, ex vivo gene therapy with autologous stem cells in the Hurler form (promising preliminary results), the same approach under study in MPS IIA, and trials of chimeric enzymes that cross the blood–brain barrier in MPS IIA; it recommends that follow-up visits also be used to assess the possibility of offering a therapeutic trial [10].

7.10. Supportive treatment and system-specific risk management

Anaesthesia and airway. This is the highest-risk procedure: upper airway obstruction, narrow trachea, thick vocal cords, temporomandibular ankylosis, cervical instability and cardiorespiratory disease [1, 3, 4]. Sources recommend anaesthesia in experienced centres with intensive care, prior assessment by an anaesthetist, otorhinolaryngologist and cardiologist, a sleep study, flexible nasendoscopy and airway computed tomography, smaller endotracheal tubes, fibreoptic intubation or a laryngeal mask, careful positioning without cervical hyperextension, regional anaesthesia when possible and prolonged post-extubation observation, because laryngeal oedema has been reported up to 27 hours later [1, 3, 24]. During prolonged surgery, motor and somatosensory evoked-potential monitoring and prevention of hypotension are recommended [4]. Sleep apnoea is treated with adenotonsillectomy, continuous positive airway pressure (CPAP), oxygen and, as a last resort, tracheostomy; tongue surgery is not indicated [1, 24].

The French PNDS quantifies and organises this risk [10]. At least one perioperative event occurs in approximately 25% of patients with MPS (upper airway obstruction, laryngospasm, stridor, reintubation, ventilatory problems and, more rarely, cardiocirculatory problems); events are more frequent without specific treatment than with ERT or transplantation, increase with age, are more frequent in adults than in children and in MPS I and II than in MPS III, and tracheal stenoses are the main factor in difficult intubation and ventilation. Direct laryngoscopy carries more risk than indirect laryngoscopy, and the technique with the lowest risk and lowest conversion rate is fibreoptic intubation through a laryngeal mask; repeated attempts at direct laryngoscopy, which promote inflammation, should be avoided. Extubation may be difficult and the patient should remain in intensive care, because laryngeal, lingual or pulmonary oedema and obstruction may arise later. Emergency tracheotomy, sometimes necessary in acute obstruction in severe forms, is technically difficult (short neck) and exposes the patient to secondary stenosis, granulomas and difficult decannulation; tracheal stenting has been attempted in very tight stenoses, with a risk of migration and granuloma, and is discussed only case by case. During positioning, cervical rotation and flexion–extension require caution because of high cervical stenosis, possible C1–C2 instability and odontoid hypoplasia; the prone position (craniocervical junction or spinal surgery) adds abdominal compression, limited chest expansion, compression of the inferior vena cava and a risk of tube displacement, and the tube must lie below any stenosis [10].

Before any general anaesthesia, the PNDS requires a checklist: ear, nose and throat assessment with nasal fibreoptic endoscopy (need for an ear, nose and throat procedure or awake laryngotracheobronchial endoscopy); anaesthetic assessment (Mallampati score, mouth opening, thyromental distance, cervical mobility and venous access); tracheal CT (narrowing, tortuosity); polysomnography or polygraphy; echocardiogram less than 1 year old; and, if possible, cervicothoracolumbar spinal MRI with a neurosurgical opinion [10]. The indication should be questioned: what the goal is (a follow-up examination in an agitated child or necessary surgery), whether it is urgent, whether procedures can be combined without unduly prolonging anaesthesia, whether there are alternatives (regional anaesthesia for carpal tunnel release, sedation for dental care) and whether long-term venous access needs to be placed. The patient and carers should be informed of the risks, including extubation failure, with the palliative care team able to take part in this discussion; a multidisciplinary meeting (anaesthesia, metabolic diseases, neurology, otorhinolaryngology, intensive care, neurosurgery, respiratory medicine, palliative care) is needed before any planned anaesthesia and should be considered in adolescence to anticipate a surgical emergency; planned surgery is performed at a reference centre, with an experienced anaesthetist and otorhinolaryngologist; and the G2M filière and the CETMPS-GP group have drawn up an emergency protocol [10].

Surgery by area according to the PNDS. The document lists the procedures that arise over a lifetime: in otorhinolaryngology, adenoidectomy, tonsillectomy, tympanostomy tubes, tympanoplasty and tracheotomy; in ophthalmology, corneal transplantation and glaucoma and cataract surgery; in dentistry, dental care and extractions under endocarditis prophylaxis, excision of follicular cysts and surgical correction of limited mouth opening; in neurosurgery, shunting for hydrocephalus and spinal cord decompression with arthrodesis; in orthopaedics, median and sometimes ulnar nerve decompression, trigger finger surgery, surgery for thoracolumbar kyphoscoliosis and cervical stenosis or instability, hip surgery (including custom-made prostheses), genu valgum and hallux valgus; and in visceral surgery, repair of inguinal and umbilical hernias, gastrostomy and central venous catheter placement [10].

Spine and orthopaedics. The 2019 international consensus on thoracolumbar kyphosis in MPS I (16 unanimously agreed statements) defines the objective as correction and prevention of progression with good neurological and biomechanical outcomes; surgery, when indicated, is generally performed between 5 and 13 years in units with multimodal neurophysiological monitoring, after whole-spine and brain MRI; decisions should not rest solely on the curve angle, low developmental quotient is not a contraindication, bracing may delay surgery in flexible curves and may be used for 3–6 months postoperatively, and instrumentation at least two levels above and below dysplastic segments appears appropriate [22]. Cervical myelopathy should be investigated and operated on early in attenuated and transplanted patients [1]. Early physiotherapy preserves joint range; hip and knee replacement and correction of alignment may be needed [1, 24]. Experience with growth hormone in MPS II is very limited, and it is not standard treatment [24].

Carpal tunnel syndrome. Because typical symptoms are absent, nerve conduction studies are recommended (annually during the first 10 years in MPS I; from approximately 2 years in MPS II), with early decompression, which may require repetition [1, 3].

Nervous system. High-pressure communicating hydrocephalus is treated with a ventriculoperitoneal shunt, predominantly palliative in severe MPS I; lumbar puncture opening pressure is the preferred assessment method [1]. Seizures are treated with low-dose monotherapy; sleep problems may respond to melatonin and may reflect frontal non-convulsive status epilepticus; pain, hydrocephalus, seizures and sleep disorders should be excluded before treating behavioural disturbances [3, 24].

Heart. Regular echocardiography, electrocardiography and Holter monitoring when indicated; early valve replacement in MPS I when needed, with success reported in Scheie and Hurler–Scheie; standard hypertension and arrhythmia treatment [1, 24, 30]. Sources disagree on endocarditis prophylaxis: MPS I GeneReviews advises it in patients with cardiac abnormalities, whereas European MPS II recommendations note that NICE no longer recommends it [1, 24]; the 2025 French PNDS keeps prophylactic antibiotic therapy, notably for endocarditis, among the non-specific treatments, and provides for dental care and extractions under this prophylaxis [10]. The same document requests BNP or NT-proBNP and troponin measurement, cardiac MRI, coronary angiography and Holter ECG or ambulatory blood pressure monitoring only when findings justify them, and antiarrhythmic, antihypertensive and heart failure treatment according to general rules [10].

Eyes, ears and teeth. Peaked caps and sunglasses reduce glare; corneal transplantation is successful in attenuated disease, although the graft may cloud again and retinal and optic nerve disease limit vision; ventilation tubes, hearing aids and active treatment of otitis; six-monthly dental assessment in MPS II [1, 3, 30]. The French PNDS recommends two pairs of glasses, one with normal lenses and another with filter lenses for the photophobia of corneal opacities, low-vision aids when needed, orthoptics for ocular motility disorders, medical treatment of glaucoma and other anterior chamber lesions, hearing aids complemented by speech and language therapy, adapted toothbrushes and orthodontic treatment [10].

Pain and general medical treatments. The French PNDS lists therapeutic classes and recalls that each medicine is used within its authorisation; in low-weight adults, dosages are adjusted to body size and, in obese patients, to the ideal weight corresponding to a normal body mass index for height [10]. Nociceptive pain, mainly osteoarticular, follows the classical three-step analgesic ladder, with weight-adjusted doses, and may benefit from injections; neuropathic pain is treated with antidepressants, mainly tricyclics, and antiepileptic drugs, mainly gabapentin [10]. As topical alternatives without systemic effects, the PNDS describes two compounded preparations: amitriptyline 10% cream, applied twice daily to the painful area (for example, carpal tunnel pain in a patient unsuitable for surgery), and baclofen cream, two to three times daily, for musculoskeletal pain [10]. The list also includes bronchodilators, treatment of hyperactivity, behaviour and mood (neuroleptics, antidepressants and methylphenidate, the latter off-label before age 6 years), corticosteroids and anti-inflammatory drugs, antiepileptic drugs, curative antibiotic therapy, treatment of gastro-oesophageal reflux and bowel disturbances, treatment of sleep disorders, oral nutritional supplements and vitamins according to nutritional assessment, hormonal treatments and transplant-specific treatments; influenza and pneumococcal vaccines are added to the national immunisation schedule [10].

Rehabilitation and assistive devices. The PNDS includes physical and rehabilitation medicine, motor and respiratory physiotherapy, psychological support, speech and language therapy (oral and written language, orofacial re-education), psychomotor therapy and occupational therapy; mechanical ventilation, oxygen therapy and secretion suction; enteral feeding; orthoses, prostheses and braces; and walking frames, wheelchairs, adjustable beds and other assistive devices for functional limitations [10].

Information for the patient and family. Information should cover the disease, the warning signs that require medical attention, the treatments and their adverse effects, the schedule of investigations, the need for adherence and annual follow-up, vaccinations, the specific follow-up of a pregnancy, coordination with local physicians and professionals, patient associations and the systematic offer of a genetics clinic appointment, including for the extended family [10]. Holidays, travel abroad and placements or studies abroad should be planned weeks or months in advance, to adapt ERT infusions [10].

7.11. Criteria for ERT initiation and discontinuation

Table 14. Discontinuation criteria in the consulted guidance

Sources: [10, 14, 23–25, 27]. Brazilian criteria are public-system access rules and do not constitute evidence of absence of benefit. The PNDS places the decision to continue or stop ERT within a global reflection on the appropriate level of care, notably in the face of life-threatening decompensations or intercurrent complications, weighing the benefit, risk and burden of treatment, and supports the patient and family in a decision they often experience as difficult [10].

Table 14A. Divergences between the 2025 French PNDS and the other guidance cited

Source: [10] and the sources indicated in each row.

7.12. Pregnancy, breastfeeding and transition

According to the European SmPC, laronidase should not be used during pregnancy unless necessary, whereas the US label states that data from more than 30 pregnant women (MPS I registry pregnancy subregistry, reports and pharmacovigilance) identified no drug-associated risk [12, 13]; the Brazilian PCDT cites a report of continuation during pregnancy and breastfeeding with favourable outcomes, recommends against initiating ERT during pregnancy, particularly in the first trimester, and leaves the decision to the physician and patient [13, 23]. Pregnant women with MPS I require frequent assessment and monitoring of cardiorespiratory and spinal cord function [1]. For idursulfase, the European SmPC prefers avoidance during pregnancy as a precaution, and the Brazilian PCDT does not recommend it in pregnant or breastfeeding women; spermatogenesis data are unavailable, and European recommendations advise men with MPS II to continue ERT when seeking conception [16, 24, 27]. The tividenofusp alfa label has no pregnancy data and does not establish safety and efficacy below 5 kg [17]. Transition to adult care should be planned, ideally with joint paediatric and internal medicine consultations, because no standardised MPS II transition processes exist [3].

The 2025 French PNDS devotes a section to fertility and pregnancy, acknowledging that data are scarce [10]. Because transplant conditioning (busulfan) frequently compromises fertility, it recommends offering fertility preservation before transplantation (cryopreservation of ovarian tissue or testicular tissue). Pregnancies carried to term have been described in women with moderate forms of MPS I, IV and VI, but the physiological changes (increased cardiac output, weight gain) are variably tolerated. Every woman of reproductive age considering pregnancy should have a preconception consultation, ideally jointly with the MPS specialist and an obstetrician familiar with these diseases, to review the disease, organise cardiovascular and imaging assessment, adapt treatments (including analgesics), provide genetic counselling and discuss risks, mode of delivery and arrangements after birth; in some cases, pregnancy is advised against because of the risk of serious maternal complications. The maternity unit is chosen according to symptoms and the risk of prematurity, favouring the obstetric team's experience with MPS; the anaesthetic consultation takes place early, with assessment of intubation difficulty; caesarean section is recommended in most cases and the postpartum period requires enhanced monitoring. The few data on ERT in pregnancy are reassuring; if possible, it is interrupted in the first trimester and resumed if the maternal condition requires it. Transfer of the enzyme into milk is very low, but breastfeeding is not recommended when the woman is at risk of osteoporosis. Combined oral contraception or an intrauterine device are possible and are decided case by case [10].

Regarding transition, the PNDS asks for it to be anticipated and organised, considering clinical status as much as legal age, with a first joint consultation between the referring paediatrician and the adult physician and the provision of a summary document [10]. The baseline assessment in the adult service is the same as in paediatrics, with three points of attention: laryngotracheal lesions (malacia, stenosis, compression), often minimally symptomatic at rest, which justify cervicothoracic CT with tracheal assessment and pulmonary function tests with inspiratory measurements (including the sniff test) at the time of transition; assessment of the craniocervical junction before any intubation, because the risk of spinal cord compression persists in adults, with or without specific treatment, owing to odontoid hypoplasia, hypertrophy of the posterior ligaments or meninges, or disc disease; and at least annual cardiological follow-up, looking for valvular disease (which may be isolated), aortic root dilatation and arrhythmias, with screening for sleep apnoea especially if there is systemic hypertension [10]. Ophthalmological (corneal opacities, glaucoma, retinopathy), auditory and peripheral neurological (radiculopathy, carpal tunnel) manifestations continue to be monitored. Transition changes all the contacts, including organ specialists, transplant physicians and the paediatric palliative care team, which hands over to an adult team, and defines where ERT continues (day hospital, hospital at home or home nursing); the patient and carers receive written information on anaesthetic risk, and contact with the reference team before any anaesthesia is encouraged. The G2M filière provides transition guides and booklets [10].

8. Reproductive Options and Family Counselling

8.1. MPS I: autosomal recessive inheritance

Parents of an affected child are obligate heterozygotes, asymptomatic and without disease risk; at each conception, the couple has a 25% probability of an affected child, 50% of an asymptomatic carrier and 25% of an unaffected non-carrier [1]. Parental molecular testing is recommended to confirm heterozygosity and calculate recurrence risk; if only one parent has the variant, consider a de novo variant in the proband or uniparental isodisomy with homozygosity for the carrier parent's variant [1]. Smith emphasises parental testing in homozygosity because of possible uniparental disomy [2]. Maternal mosaicism for an IDUA deletion has been reported as a cause of unexpected recurrence [1]. Affected siblings follow a similar course to the proband, allowing the first child's course to inform counselling [1]. Each sibling of a parent has a 50% probability of being a carrier [1].

Carrier detection is molecular, based on familial variants; leucocyte IDUA activity is unreliable because carrier and non-carrier ranges overlap and pseudodeficiency confounds interpretation [1, 8, 30]. In the general population, when a couple belongs to a population with frequent variants, testing p.Trp402Ter and p.Gln70Ter may be used but does not exclude other variants [1, 87]. People with severe MPS I rarely reproduce, but fertility does not appear affected, and better prognosis after treatment may lead to future pregnancies; all children of an affected person are carriers [1]. Once both variants are identified, prenatal and preimplantation genetic diagnosis are possible; when only one parent has an identified variant, options should be discussed in a formal consultation [1].

8.2. MPS II: X-linked inheritance

The father of an affected boy is not a carrier [3]. The mother is an obligate carrier if more than one family member is affected; in an isolated case, she may be a carrier, the variant may be de novo in the proband, or she may have somatic or gonadal mosaicism [3]. The Brazilian PCDT estimates that approximately one-third of cases without family history result from a new variant, with virtually no recurrence in that family, while the Atlas states that new mutation more often gives rise to the carrier than to the affected boy [9, 27]. If the mother is a carrier, each pregnancy has a 50% probability of transmitting the variant: sons inheriting it are affected and daughters are carriers, usually asymptomatic, although skewed X-inactivation can cause disease [3]. If the mother has a chromosomal rearrangement, risk depends on that rearrangement; if the variant is absent from maternal blood, sibling risk remains slightly above population risk because of possible gonadal mosaicism [3]. An affected man transmits the variant to all daughters and no sons [3]. Maternal aunts and female cousins may be carriers, and the newborn screening panel recommends offering cascade testing, which identified four additional affected relatives in the Illinois and Missouri programmes [3, 26, 59].

Carrier detection is molecular: the familial variant when known; if no affected person is available, sequencing, followed by dosage analysis and then complex rearrangement methods [3]. I2S activity is unreliable in women [3, 43]. Prenatal diagnosis uses molecular testing when the variant is known, or enzyme measurement with fetal sex determination [3, 6, 9]. In MPS II, the French PNDS requests an extended pedigree to identify all potential female carriers, whose status is determined by direct testing for the familial variant [10].

8.3. Assessment of at-risk relatives and shared practice

GeneReviews recommends testing all at-risk siblings, regardless of age, to initiate treatment as early as possible; in an at-risk newborn without prenatal diagnosis, test the familial variant or measure enzyme activity and urinary GAGs alongside newborn screening [1]. In MPS II, I2S measurement and molecular testing of at-risk boys are recommended for the same reason; studies of siblings treated at different ages document the importance of early diagnosis [3]. Ideally, reproductive risks and options are discussed before pregnancy, and counselling should be offered to affected, carrier or at-risk young adults [1, 3]. DNA banking is recommended when molecular diagnosis has not been confirmed [1, 3]. Healthcare professionals may hold different views on prenatal and preimplantation diagnosis, which should be treated as a personal decision [1].

The French PNDS adds the organisation of the communication of the diagnosis [10]. As soon as the diagnosis is established, a disclosure consultation by a specialist from a reference or competence centre explains the disease, the prognosis and the therapeutic options with their goals and limits, the principles of multidisciplinary follow-up (at least annual) and the forms of support; in particularly severe forms, a joint consultation with a palliative care team may be offered early, to optimise symptomatic treatment, support the family and build a life plan that meets family priorities, with hospital at home if needed. The family receives information about patient associations, a link with the attending physician is always established, and an emergency card may be provided. Genetic counselling takes place at a clinical genetics clinic, with a pedigree and an explanation of the mode of inheritance, the recurrence risk and the options for prenatal and preimplantation diagnosis; in France, informing relatives has been a legal obligation since decree no. 2013-527 of 20 June 2013, rests with the parents or the adult patient, and is prepared and supported by the geneticist or genetic counsellor, with a consultation offered to relatives [10].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency: what the numbers measure

Frequency estimates depend on method: clinical ascertainment surveys, voluntary registries and newborn screening programmes measure different things and should not be converted into national prevalence estimates [20, 36]. Table 15 presents values from the consulted sources with their respective nature.

Table 15. Frequency of MPS I and II by source

Three patterns emerge. First, newborn screening identifies more cases than clinical diagnosis: the US model predicted approximately twice as many MPS II cases, and in Taiwan age at diagnosis fell from 4.3 to 0.2 years [20, 51]. Second, MPS II is relatively more frequent in Asian populations and some Jewish communities, and ACMG reports higher frequencies in Ashkenazi Jews [9, 25, 60]. Third, MPS II is the most frequently recorded MPS type in Brazil, and in Ceará MPS II and VI are the most prevalent according to the north-eastern Brazilian manual; the same manual states that Brazilian MPS incidence is unknown [27, 47]. Saudubray's textbook notes that although MPS I and III are the most frequent in most regions, MPS VI predominates in the United Arab Emirates and Turkey [4]. For the MPS as a whole, the French PNDS gives estimates of 1:147,000 births for MPS III (with type A predominating in France), 1:300,000 for MPS IVA and 1:600,000 for MPS VI, states that MPS VII is 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; the figure of 1:80,000 boys for MPS II is higher than the GeneReviews and Orphanet estimates and is not accompanied by its source (Table 14A) [10].

9.2. Founder variants and specific populations

The variants p.Trp402Ter and p.Gln70Ter predominate in people of European ancestry, with p.Gln70Ter more frequent in Russia and p.Trp402Ter in the United Kingdom and Australasia [1]. The variant p.Pro533Arg is the only MPS I variant found in Morocco and is frequent in Italy and Brazil; p.Gly51Asp and p.Ala327Pro are relevant in Italy [1, 30]. In Japan, p.Arg89Gln and c.613_617dup predominate, and p.Trp402Ter and p.Gln70Ter may be absent [1]. In Brazil, p.Trp402Ter and p.Pro533Arg are most frequent, while p.Gln70Ter and p.Arg89Gln are rare [23]. In Israel, multiple variants have been described within a small geographical area among Druze and Muslim Arab patients, and a specific variant in a Libyan Jewish patient [8]. Parental consanguinity is frequently reported in MPS I, and the Hurler–Scheie phenotype in consanguineous families results from homozygosity for unique alleles [8, 30]. Latin American data cited by the PCDT suggest a higher proportion of attenuated MPS I than in global registries, potentially reflecting both the variant spectrum and diagnostic access [23].

9.3. Portugal and Brazil

No epidemiological data or MPS I and II newborn screening programmes in Portugal were found in the consulted sources; absence from these sources does not establish absence of publications. In Brazil, the Ministry of Health's 2025 clinical protocols define diagnostic criteria, access to laronidase and idursulfase, and HCT eligibility in SUS; in 2010, the international MPS I registry included 82 Brazilian patients among 891 [23, 27]. According to trial registries, Brazil participates in studies of several emerging therapies (RGX-111, RGX-121, lepunafusp alfa, pabinafusp alfa, tividenofusp alfa) [80].

9.4. Reference networks and patient organisations

In Europe, the relevant reference network is MetabERN (European Reference Network for Hereditary Metabolic Disorders), of which one of the MPS II GeneReviews authors is a coordinator [3, 28]. GeneReviews lists the Canadian MPS Society, UK MPS Society, US National MPS Society and, for MPS II, the National Organization for Rare Disorders; the HRSA state screening page remains accessible as an archive [1, 3]. Orphanet lists hundreds of specialist centres, patient organisations and national protocols, including the 2025 French protocol (PNDS), common to all MPS [5, 6, 10].

In France, the organisation described in the 2025 PNDS rests on rare disease reference centres accredited since 2004: the Centre de Référence des Maladies Lysosomales (CRML), coordinated at the Hôpital Armand Trousseau (AP-HP, Paris), with constituent centres in Paris (Necker-Enfants Malades, Beaujon, Pitié-Salpêtrière, Diaconesses Croix Saint-Simon), Rouen and Garches and regional competence centres, and the Centre de Référence des Maladies Héréditaires du Métabolisme, coordinated in Marseille (La Timone), with constituent and competence centres in almost all university hospitals [10]. The centres belong to the G2M health filière (inherited metabolic diseases), accredited in 2014 and again in 2019, and to the Comité d'Évaluation du Traitement des Maladies Lysosomales (CETL), whose subgroup for MPS and glycoproteinoses (CETMPS-GP) can be consulted by any physician about a patient with suspected or diagnosed MPS, harmonises practices and issues collegial opinions, including on starting and stopping treatment. Multidisciplinary clinics dedicated to lysosomal diseases bring together specialists and investigations over half a day to two days, once or twice a year, and multidisciplinary team meetings take place on a digital platform, including the collegial palliative decision meetings provided for by the Claeys-Leonetti law. GAGs, enzyme activities and sequencing are performed in six reference laboratories (Lyon, Paris-Necker, Rouen, Toulouse, Grenoble and Lille) [10]. The national RaDiCo-MPS cohort, sponsored by INSERM, collects, with consent, data on epidemiology, natural history, treatment benefit and social costs for all MPS [10]. The Enzy-moi therapeutic education programme is aimed at patients over 12 years of age and at carers of patients of any age with a lysosomal disease, whether or not treated with intravenous ERT, and offers up to ten sessions, remote or in person, after a shared educational diagnosis; enrolment is through the G2M filière website, which also provides the emergency card [10]. This card, credit-card sized and sometimes bilingual, is completed by the physician at the reference or competence centre and contains the contact details of the family, physicians and centre, emergency recommendations and useful links [10]. The associations indicated are Vaincre les Maladies Lysosomales (VML), recognised as being of public utility and open to all lysosomal diseases, and the international MPS Society [10].

The PNDS also describes French social protection, useful as a point of comparison with other systems [10]. The MPS are covered by long-term condition ALD 17 (inherited metabolic diseases requiring prolonged specialised treatment), with 100% coverage of related care, and transport to a centre more than 150 km away is reimbursed upon approved prior request, provided it is the centre closest to home. Parents of minors may benefit from five days' leave when a severe form of neurological disease is disclosed, from paid parental presence leave (up to 310 days over a 3-year period, not exceeding 22 days per month, divisible into half days) and from paid carer's leave (up to 3 months, or 66 days, renewable up to one year); family solidarity leave at the end of life is unpaid. Disability compensation includes allowances for children and adults with disabilities, the compensation benefit, the mobility inclusion card from 80% disability and recognition of disabled worker status, which allows adaptation of the workstation. Schooling takes place, in principle, at the local school, with a personalised schooling plan, a classroom assistant, extra time in examinations and adapted equipment; before age 6 years, an early medico-social action centre can support the child without a prior decision by the disability commission; when mainstream school is no longer possible, the child is directed to medico-educational or motor education institutes or to establishments for children with profound multiple disabilities. In adulthood, work may be in a mainstream setting, in an adapted company or in a work-support establishment, and non-autonomous patients may be directed to residential homes or specialised medical facilities [10]. Brazilian and Portuguese patient organisations were not verified in an official source during this review and are therefore not named.

10. Illustrative Clinical Case

10.1. Attenuated MPS I diagnosed at 17 years after a decade in endocrinology

In 2018, Martins and colleagues described a boy who developed hip pain at age 5 years and was diagnosed by an orthopaedist with bilateral Legg–Calvé–Perthes disease, without investigation for juvenile idiopathic arthritis [39]. Between 5 and 7 years he had recurrent upper respiratory infections and several admissions for wheezing. He was referred to paediatric endocrinology at 7 years for short stature; height remained more than 2 standard deviations below the median and growth velocity below the third percentile before any treatment [39]. He received leuprorelin acetate (3.75 mg monthly) from 13 to 16 years and growth hormone (0.1 IU/kg/day) from 14 to 18 years despite no diagnosis of growth hormone deficiency; he reached 159 cm at 20 years [39]. He had sleep apnoea during adolescence; at 17 years and 9 months, a respiratory physician suspected MPS and referred him to a metabolic disease centre, where moderate joint contractures, mild facial dysmorphism, scoliosis and an umbilical hernia were found; height was 154 cm (z score −2.94), weight 43.7 kg and head circumference 56.5 cm [39]. Dried blood spot alpha-iduronidase activity was 0.62 μmol/L/h (reference 2.5–16.7), and genetic testing identified two pathogenic missense variants, c.1148G>A (p.Arg383His) and c.1598C>G (p.Pro533Arg); he started weekly laronidase 0.58 mg/kg at 18 years [39]. Both variants were normalised against NM_000203.5 in VariantValidator and are classified in ClinVar as pathogenic with expert-panel review [7, 38]. The article's figures show the longitudinal growth curve with treatment periods, growth velocity and an MPS I diagnostic algorithm starting from short stature [39].

The case brings together almost all the warning signs in section 4 (hip dysplasia interpreted as Perthes, respiratory infections, apnoea, contractures, hernia and short stature), showing how each specialist saw only part of the presentation. It also shows that dried blood spot diagnosis was used as an initial test; under GeneReviews criteria, confirmation here rested on the biallelic genotype [1, 39]. Growth hormone and pubertal suppression used in this patient are not MPS I treatments and should not be interpreted as recommendations; the authors, two employed by Sanofi Genzyme and others declaring support from the same company, use the case to advocate greater endocrinologist awareness [39].

10.2. Neuronopathic MPS II in two brothers with the same genotype and divergent courses

In 2021, Tomita and colleagues described two Japanese brothers with the IDS variant they call G140V, normalised in VariantValidator as NM_000202.8:c.419G>T, p.(Gly140Val), and classified as pathogenic in ClinVar [7, 38, 88]. The older brother, born weighing 3860 g, had prenatal left hydronephrosis, a right hydrocele and a left inguinal hernia repaired at 2 months; he was diagnosed at 2 years and 4 months and immediately started weekly idursulfase, which he continued at publication [88]. He walked at 20 months, spoke his first words at 2 years, had language delay and mild ventriculomegaly with cerebral atrophy at 2 years and 4 months, concentration difficulties and motor and cognitive impairment at 2 years and 8 months, and a Kyoto scale developmental quotient of 53 at 4 years [88]. His younger brother was diagnosed prenatally, had undetectable plasma I2S on day 5, an inguinal hernia and mild hepatomegaly at 1 month, received idursulfase from 1 month to 1 year and 11 months, and then entered the phase 2/3 pabinafusp alfa trial (2 mg/kg weekly for approximately 2 years) [88]. He walked at 10 months, spoke single words at 1 year, achieved a developmental quotient of 104 at 3 years and 11 months, and had no somatic MPS II signs at the time of the report; CSF heparan sulphate fell from 5480 ng/mL to 2040 ng/mL at week 25 and 1920 ng/mL at week 52 (63.3% reduction) [88]. The figures show developmental trajectories compared with natural history and the CSF heparan sulphate distribution in the trial's 28 patients [88].

The case illustrates three points. First, the value of presymptomatic diagnosis: the younger brother started ERT at 1 month, and this report cannot separate the effect of age at initiation from switching to a blood–brain barrier-crossing enzyme, although the authors attribute divergence to both factors [88]. Second, the same genotype in an identical family setting allows comparison of trajectories, making such sibling pairs a foundation of the argument for newborn screening [20]. Third, critical appraisal is necessary: several authors belong to the company developing pabinafusp alfa, follow-up is short and one sibling pair cannot replace a controlled trial; the global phase 3 trial remains ongoing [77, 88].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Without treatment, severe MPS I causes death in the first decade from cardiorespiratory failure; attenuated MPS I ranges from death in the second or third decade to normal life expectancy with joint, ocular and cardiac disability [1, 4]. In neuronopathic MPS II, death occurs in the first or second decade, while survival into adulthood is common in the non-neuronopathic form; the Atlas records survival to 87 years but also second-decade deaths in mild forms from cardiac disease, pulmonary infection or airway obstruction [3, 9]. Treatment has changed these figures: HCT increases survival in severe MPS I and better preserves cognition when performed early with normal enzyme activity after engraftment, but considerable residual skeletal, ocular and valvular burden remains [1, 62]. In MPS II, HOS patients treated with idursulfase survived longer than untreated patients; long-term data for blood–brain barrier-crossing enzymes are not yet available [3, 17].

11.2. Surveillance

The 2009 international guideline recommends complete initial evaluation and monitoring every 6–12 months, with individualised specialist assessments; European MPS II recommendations request physical, biochemical and behavioural assessment after diagnosis and at least every 6–12 months in an experienced centre [21, 24]. Tables 16 and 17 summarise GeneReviews intervals; follow-up after HCT follows the transplant centre's protocol [23].

Table 16. MPS I: recommended surveillance

Source: GeneReviews, Table 7 [1]. The Brazilian PCDT adds complete anthropometry, liver size measurement, adolescent Tanner staging, sleep study, visceral imaging volumes as needed, and skull, spine including cervical spine, chest, hip and hand radiographs, avoiding excessive radiation exposure [23].

Table 17. MPS II: recommended surveillance

Source: GeneReviews, Table 8 [3]. The ACMG panel recommends monitoring ERT response through liver and spleen examination, lung function tests when reliable, urinary GAGs, antibodies in the presence of infusion reactions and neuropsychological assessment, and questions the utility of 6MWT and routine annual cervical MRI [25]. For tividenofusp alfa, the label adds haemoglobin before initiation and at 3 months, and creatinine and urinary protein/creatinine ratio monitoring [17].

The 2025 French PNDS proposes its own schedule, common to the MPS and differentiated by type and by whether specific treatment is given (Table 17A) [10]. The follow-up visit repeats the baseline assessment and looks for complications of the disease and of treatment; without complications or specific treatment, it is annual; with ERT or after transplantation, it is quarterly in the first year and then every 6 to 12 months, according to progress. At each visit, quality of life and pain are assessed with dedicated scales, and investigations are brought forward in the presence of functional complaints or before planned surgery. The PNDS acknowledges that recommendations vary between countries; the main divergences from GeneReviews and the other guidance are shown in Table 14A [10].

Table 17A. MPS I and II: follow-up investigations according to the 2025 French PNDS

11.3. Quality of life, transition and palliative care

The disorder imposes considerable emotional, social and financial burdens on caregivers and affects siblings; psychosocial support from diagnosis, liaison with patient organisations and ongoing assessment of palliative care and home nursing needs are recommended [3, 26]. Transition to adult medicine should be planned because treated patients now live longer with skeletal, cardiac and respiratory complications requiring adult teams experienced in metabolic diseases [1, 3].

The 2025 French PNDS insists that palliative care is not limited to the end of life: a palliative approach, justified by the vulnerability and uncertainty of certain situations, may begin early, in parallel with specific treatment or a therapeutic trial, and aims at the patient's quality of life and support for parents and carers within a patient-centred care plan [10]. Contact with the palliative care team may occur at diagnosis or at a turning point: a distressing symptom, doubt about surgery or about continuing ERT, definition of the level of care in a decompensation or intercurrent complication, deterioration in general condition or family exhaustion. The place of living (return to or remaining at home, or institutional care) and respite for carers are central issues. With therapeutic progress, death now occurs more often in adulthood than in childhood; the approach to life-threatening decompensations may be discussed with the patient and family at their own pace, sometimes with advance directives written by the adult patient, and decisions should be guided by quality of life, beneficence, non-maleficence and respect for autonomy, avoiding both unreasonable obstinacy and loss of opportunity. After death, relatives should be supported in bereavement with professional, institutional and voluntary-sector resources [10].

12. Summary and Final Considerations

MPS I and II are lysosomal deficiencies accumulating dermatan and heparan sulphate and producing a shared somatic presentation (coarse facial features, dysostosis multiplex, hepatosplenomegaly, valvular disease, airway obstruction, deafness, carpal tunnel syndrome and spinal cord compression), with a neurological component in severe forms. They differ in inheritance (autosomal recessive in MPS I, X-linked in MPS II), corneas (clouded in MPS I, usually clear in MPS II), skin lesions and behaviour. Diagnosis combines urinary GAGs, enzyme activity (in MPS II with a normal second sulfatase) and genotype; IDUA pseudodeficiency requires confirmation of GAG accumulation, and the IDSP1 pseudogene necessitates complex rearrangement methods when sequencing is negative. Genetic reports should use NM_000203.5 and NM_000202.8 and retain historical designations only as synonyms.

In severe MPS I, early haematopoietic cell transplantation, ideally before 2–2.5 years and substantial cognitive impairment, with a non-carrier donor and complete chimerism, remains standard treatment; laronidase treats somatic manifestations, is used before transplantation and treats attenuated forms. In MPS II, idursulfase treats somatic manifestations; transplantation lacks consensus; and since March 2026 the United States has had a blood–brain barrier-crossing enzyme, granted accelerated approval based on a biomarker, titrated to 15 mg/kg weekly and associated with risks of anaphylaxis, anaemia and nephropathy. Gene therapies are progressing unevenly: OTL-203 has completed recruitment of a phase 3 trial against transplantation, whereas RGX-121 and RGX-111 are on hold.

Newborn screening, implemented in the United States, Taiwan and regions of Italy, shifts diagnosis into the presymptomatic period but requires second-tier GAG testing, careful interpretation of pseudodeficiency and uncertain variants, and capacity for rapid transplantation or enzyme decisions. Follow-up is multidisciplinary and lifelong in reference centres, with particular attention to anaesthesia, spine, heart and airway. The 2025 French PNDS converges in essence with European, North American and Brazilian guidance and adds a pre-anaesthetic checklist, a stepwise premedication regimen for infusions and a schedule of investigations by MPS type, with intervals of 1 to 3 years for spinal MRI and nerve conduction. The principal gaps are the absence of Portuguese epidemiological data in the consulted sources, lack of controlled comparisons between options in neuronopathic MPS II, and lack of long-term data for new therapies.

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