Mucopolysaccharidosis Type VI (Maroteaux–Lamy Syndrome)

An autosomal recessive lysosomal disease caused by deficiency of N-acetylgalactosamine-4-sulfatase (arylsulfatase B), encoded by ARSB, with dermatan sulphate accumulation, progressive skeletal dysplasia, valvular disease, corneal clouding, airway obstruction and spinal cord compression, usually with preserved intelligence.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and historical milestones

Mucopolysaccharidosis type VI was described as a distinct entity in 1963 by Pierre Maroteaux, Maurice Lamy and colleagues, who recognised normal intelligence and urinary mucopolysaccharide excretion consisting predominantly of “chondroitin sulphate B”, now termed dermatan sulphate, in patients with somatic features resembling those of Hurler syndrome; the title of the original article, published in Presse Médicale, described “a new dysostosis with urinary excretion of chondroitin sulphate B” [8, 21]. The fibroblast cross-correction studies of Fratantoni, Hall and Neufeld in 1968 showed that cells from patients with different mucopolysaccharidoses (MPS) corrected one another through secreted factors, leading to the identification of a “Maroteaux–Lamy corrective factor” and, later, of the recombinant enzymes used therapeutically, whose uptake depends on the mannose-6-phosphate marker [8, 22].

In 1974, the groups of Matalon and O'Brien demonstrated that the defect lay in N-acetylgalactosamine-4-sulfatase, an enzyme initially identified using artificial substrates as arylsulfatase B [8]. The gene was mapped to the 5q13-q14 region by Litjens and colleagues in 1989, and human complementary DNA was cloned by Schuchman and colleagues in 1990; its current location is 5q14.1 [6, 8, 23]. The first bone marrow transplant in a patient with MPS VI was published by Krivit and colleagues in 1984, and galsulfase, a recombinant human enzyme, was approved by the Food and Drug Administration (FDA) in 2005 and by the European Commission in 2006 [14, 15, 24].

1.2. Nomenclature and reclassifications

In the historical classification of MPS, types V and VIII ceased to be used (type V corresponded to the current Scheie form of MPS I), so the numbering jumps from type IV to type VI [22]. The designation “MPS VIA, Maroteaux-Lamy A” still appears in atlases of skeletal dysplasias and is historical [2]. The Maroteaux eponym is associated with several skeletal dysplasias unrelated to MPS VI, including acromesomelic dysplasia, Maroteaux type (ORPHA:40; NPR2), spondyloepimetaphyseal dysplasia, Maroteaux type (ORPHA:263482; TRPV4), brachyolmia, Maroteaux type (ORPHA:93302), Maroteaux–Malamut syndrome, or acrodysostosis (ORPHA:950), Maroteaux–Verloes–Stanescu metaphyseal anadysplasia (ORPHA:1040) and Maroteaux–Le Merrer–Bensahel carpotarsal osteochondromatosis (ORPHA:2767); literature and coding searches must distinguish these entities [10].

1.3. Definition of the entity and phenotypic continuum

MPS VI is defined by biallelic N-acetylgalactosamine-4-sulfatase deficiency, with lysosomal accumulation of dermatan sulphate and chondroitin-4-sulphate and increased urinary dermatan sulphate excretion [1, 6]. Presentation forms a continuum: at one extreme, the rapidly progressive form, with onset from birth or in the early years, urinary GAGs usually above 100 µg/mg creatinine, severe dysostosis multiplex and death in the second or third decade in the pre-ERT era; at the other, the slowly progressive form, with later diagnosis, urinary GAGs usually below 100 µg/mg creatinine, mild dysostosis and survival into the fourth or fifth decade, with an intermediate form recognised between the two [1, 5, 6]. Orphanet codes the rapidly and slowly progressive forms separately under the main entity ORPHA:583 [3, 4, 10]. Unlike severe MPS I, severe MPS II, MPS III and MPS VII, MPS VI does not accumulate heparan sulphate, which probably explains the usual preservation of intellectual development [1, 9].

2. Molecular Genetics and Pathophysiology

2.1. The ARSB gene and N-acetylgalactosamine-4-sulfatase

The ARSB gene is located at 5q14.1; the MANE Select reference transcript is NM_000046.5, which encodes protein NP_000037.2 [6, 7]. The human enzyme is a monomeric protein of 533 amino acids, including a 46-amino-acid signal peptide, with considerable homology to the other sulfatases; the feline enzyme, by contrast, is homodimeric [8]. Biosynthesis and processing follow the lysosomal hydrolase pathway: the protein is glycosylated, receives mannose-6-phosphate residues that target it to the lysosome through the mannose-6-phosphate receptor, and undergoes maturation proteolysis [8]. Sulfatase activity depends on formylglycine-generating enzyme (FGE), encoded by SUMF1; FGE deficiency causes simultaneous deficiency of 17 sulfatases, including all lysosomal sulfatases, and therefore reproduces arylsulfatase B deficiency alongside that of other sulfatases [9, 25].

The enzyme removes the 4-sulphate group from the non-reducing terminal N-acetylgalactosamine-4-sulphate residues of dermatan sulphate and chondroitin-4-sulphate, an obligatory step in the degradation of these two glycosaminoglycans [1, 6, 8]. Chondroitin sulphate is degraded by hyaluronidase into sulphated tetrasaccharides and trisaccharides, which accumulate with the undigested terminal residue; chondroitin sulphate therefore contributes to joint disease but does not appear in relevant amounts in urine, which contains mainly dermatan sulphate [1, 8]. The enzyme also has UDP-N-acetylgalactosamine-4-sulphate sulphohydrolase activity [8].

2.2. Tissue and physiological mechanisms

Dermatan sulphate is abundant in the skin, tendons, ligaments, blood vessels, airways, cornea and heart valves, explaining the distribution of manifestations [6, 9]. Lysosomal accumulation produces cellular engorgement and dysfunction; secondary mechanisms include altered cell signalling, altered biomechanical properties of the matrix and activation of inflammatory pathways affecting the growth plate, osteoclasts and osteoblasts [1, 9]. In animal models, GAGs stimulate the inflammatory response of articular chondrocytes through signalling resembling that of lipopolysaccharide, and preclinical work links accumulated dermatan sulphate to tumour necrosis factor (TNF)-mediated inflammation and chondrocyte apoptosis, providing the rationale for immunomodulation trials [1, 5, 6]. Valvular disease is more frequent in MPS that accumulate dermatan sulphate (I, II, VI and VII), as this is the most abundant GAG in valves; hernias result from connective tissue weakness and increased intra-abdominal pressure due to organomegaly; cervical spinal cord compression results from dural thickening (cervical pachymeningitis), ligamentous thickening at the craniocervical junction, odontoid hypoplasia and bony stenosis [8, 9]. The absence of heparan sulphate accumulation probably explains the absence of primary neurodegeneration [1].

2.3. Inheritance and relationship between residual activity and phenotype

Inheritance is autosomal recessive; sibships with several affected children born to healthy parents and parental consanguinity have been described [8]. Manifestations arise only with severe deficiency, generally below 10% of the lower limit of normal, and severity is greatest in patients with no detectable activity; heterozygous carriers have no clinical manifestations [1]. Residual activity above approximately 20% of normal is compatible with a normal phenotype [8]. In the feline model, leucocyte activities between 0.3% and 2% of normal span the entire severity spectrum, and approximately 1% is sufficient to prevent skeletal disease in cats [1]. In the Brazilian series of 28 patients reported by Azevedo and colleagues (2004), manifestations did not correlate significantly with urinary GAGs or measured enzyme activity [8, 26]. Conversely, in the cross-sectional survey of 121 untreated patients (Swiedler and colleagues, 2005), urinary GAGs above 200 µg/mg creatinine were associated with advanced disease (height of 80–120 cm, low weight, reduced endurance, impaired pulmonary function and reduced joint range of motion), and survival beyond 20 years was rare with values above 100 µg/mg [1, 27].

2.4. Variant spectrum

In June 2009, the Human Gene Mutation Database recorded 133 ARSB variants: 100 missense or nonsense variants, 9 splicing variants, 18 small deletions, 3 small insertions, 1 indel and 2 large deletions [1]. Analysis of 105 patients (approximately 10% of the worldwide MPS VI population at the time) identified 83 different causal variants, 62 of them novel (38 missense, 5 nonsense, 11 deletions, 1 insertion and 7 splicing variants), as well as 4 polymorphisms, with a large proportion of private variants [28]. Among 45 missense variants at CpG dinucleotides, the vast majority were restricted to a small number of families [8, 29]. Southern blot analysis of 17 patients showed no deletions or rearrangements, and most were compound heterozygotes [8]. Alleles with two or three variants in cis exist, complicating interpretation [1]. An inversion with breakpoints in ARSB was detected only by whole-genome sequencing, and complex structural and splicing variants were functionally characterised in a Russian registry with a view to personalised antisense therapy, at the preclinical stage [30, 31].

The variants below were normalised using VariantValidator (GRCh38, MANE Select), and their classification was consulted in ClinVar on 10 October 2026; conversions derive from these tools rather than manual calculation [7, 32].

Three historical designations were not normalised because no verifiable correspondence was available: the single-base deletion “ΔG238”, described in homozygosity in a severely affected patient by Garrido and colleagues (2007); the “L266P” variant, which Nyhan's atlas associates with mild disease together with p.Cys405Tyr; and the 23-base-pair deletion in exon 8, written as “1533del23” in the 2010 review and “c.1534del23” in the case reported by Andrade and colleagues (2022), which reportedly accounted for 23% of alleles in Brazilian patients and was also found in Portuguese patients, at an unknown frequency [1, 8, 36, 37]. These designations remain in quotation marks as historical nomenclature and should not be transferred to reports without confirmation in ClinVar or VariantValidator.

2.5. Genotype–phenotype correlations

Genotype–phenotype correlation is difficult because many variants are private, most patients are compound heterozygotes and some alleles carry more than one variant [1, 9]. Nevertheless, Karageorgos and colleagues observed a clear correlation between genotype and urinary GAGs, which can be used to anticipate the clinical course [28]. p.C117R, “ΔG238”, p.G144R, p.C521Y, the “T1285” insertion, p.L321P and, in homozygosity, p.D54N, p.L98Q and p.I223V are associated with rapidly progressive disease; p.L72R and p.R315Q, the latter frequently in cis with p.S384N, are associated with intermediate or severe phenotypes [1]. p.Y210C or p.C405Y in compound heterozygosity (GAGs < 100 µg/mg creatinine), homozygosity for p.R152W or p.C192R, and the combinations p.D83Y, p.H430R and p.R434I are associated with an attenuated phenotype [1]. Patients over 20 years of age with an “attenuated” genotype may have poor exercise endurance, so treatment decisions should not be based on genotype alone [1].

2.6. Pseudodeficiency and polymorphisms

The p.T212I variant confers pseudodeficiency activity: reduced enzyme activity in vitro, with a normal phenotype and normal urinary GAGs [1]. The p.S384N variant (c.1151G>A) is a non-pathogenic polymorphism, functionally characterised by Garrido and colleagues (2008), and its presence alone does not support the diagnosis, which has implications for newborn screening and prenatal diagnosis [1, 38]. For these reasons, low enzyme activity in an asymptomatic individual with normal urinary GAGs requires molecular investigation and integrated interpretation before the disease is diagnosed.

2.7. Allelic diseases and modifiers

The sources consulted do not describe ARSB allelic diseases distinct from MPS VI; the gradation between rapidly and slowly progressive forms is allelic within the same entity [1, 6]. A polymorphism on the same allele as a pathogenic variant may modify progression, and complex alleles with several variants in cis have been documented [1]. Arylsulfatase B deficiency also occurs, as part of a broader defect, in multiple sulfatase deficiency caused by SUMF1 variants, which is a distinct genetic entity [9, 11].

3. Clinical Spectrum and Manifestations by System

3.1. Natural history: rapidly progressive form

In the rapidly progressive form, signs appear before 2–3 years of age; macrocephaly or a prominent chest may be present at birth, and noisy breathing begins in early childhood [1, 8]. The first consultation often takes place at 2–3 years because of growth failure, and skeletal deformities and MPS facial features, recognisable but subtler than in Hurler syndrome, are already present at that age [8]. Growth slows after the first year and stops at 3–4 years, with adult height usually below 120 cm; Nyhan's atlas reports, for the classic phenotype, a final height of 107–138 cm reached at 6–8 years [1, 8]. Unlike most MPS, in which a gain in height and weight during the first 2–3 years precedes the fall-off of the curve, in MPS VI and MPS IVA the inflection of the height curve is early [13]. Mobility is impaired by around 10 years, puberty is absent or delayed, and after 10 years severe airway obstruction requiring tracheostomy, valvular disease warranting replacement, hip disease, claw hand with carpal tunnel syndrome, kyphoscoliosis and cervical stenosis with spinal cord compression accumulate [1]. In the pre-ERT era, death often occurred from cardiac or respiratory failure in the second or third decade, usually before 30 years [1, 6, 8].

3.2. Natural history: slowly progressive and intermediate forms

In the slowly progressive form, symptoms develop later and diagnosis usually occurs after 5 years, sometimes in the second or third decade; complications may be concentrated in a single system and prompt hip, valve, corneal or cervical decompression surgery [1]. These patients tend to have a height above 140 cm and urinary GAGs below 100 µg/mg creatinine, and usually survive into the third decade or beyond, or into the fourth or fifth decade according to other sources [1, 6]. Some mild forms present with hip dysplasia resembling Legg–Calvé–Perthes disease, sometimes only in adulthood, while others are discovered in adolescence or adulthood because of thoracic kyphosis, growth retardation or valvular disease [8, 23]. The spectrum includes paucisymptomatic presentations mistaken for skeletal dysplasias, and the number of diagnoses in adults has increased [9]. In an extreme case, a 44-year-old woman with 5% arylsulfatase B activity, mild dermatan sulphaturia, normal stature, 1 cm hepatomegaly, mild photophobia and mild hearing loss was identified through leucocyte inclusions [1]. The intermediate form shares features of both extremes, and higher urinary GAGs are associated with more rapid progression [5].

3.3. Musculoskeletal system

The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease [1, 9]. The typical appearance combines a short trunk, prominent abdomen, lumbar lordosis, progressive lumbar kyphosis and anterior sternal protrusion, pectus carinatum and thoracolumbar gibbus [1, 8]. Joint stiffness progresses to flexion contractures of the fingers, elbows and knees; genu valgum and semiflexion of the knees produce a characteristic crouched posture, the hand assumes the claw configuration of MPS, and the volar subcutaneous tissue of the second to fourth fingers may thicken as in Dupuytren contractures [8]. The hip is involved in all patients from an early age, first in the ilium and acetabulum and then in the femoral head, with an unpredictable final shape; failure of ossification of the lateral acetabular roof, failure of medial proximal femoral epiphyseal growth and coxa valga lead to subluxation or dislocation [5, 9]. In early-onset forms, a complex craniosynostosis with exorbitism has been described, contributing to the cranial deformities that prompt diagnosis before 2 years [13]. The radiological findings of dysostosis multiplex are described in subsection 5.4.

3.4. Cardiovascular system

Valvular disease is the dominant cardiac manifestation, and valve anatomy and function are abnormal in essentially all affected individuals [5, 6]. In the Brazilian series of 28 patients, 74% had an abnormal electrocardiogram and most had valve abnormalities, with mitral involvement in 96%, tricuspid involvement in 71% and aortic involvement in 43% [1, 8, 26]. The mitral and aortic valves become thickened, sometimes calcified and stenotic; an aortic stenosis murmur is frequent, but regurgitation predominates, and the mitral valve is affected more frequently than the aortic valve [8, 23]. Valvular disease worsens with age even in slowly progressive forms [1]. Hypertrophy and diastolic dysfunction, late-stage left ventricular dilatation and dysfunction, conduction abnormalities progressing to high-grade atrioventricular block through infiltration of the conduction system, premature coronary disease due to diffuse intimal proliferation, which may be silent, left ventricular apical aneurysms and, as unusual infant presentations, acute cardiomyopathy at 5 months and endocardial fibroelastosis at 9 months have been described [1, 5, 8, 23]. Arterial hypertension occurs in approximately 20% of patients with MPS I, and the 2010 review recommends considering it in MPS VI as well [1]. Heart failure was the most frequent cause of death in the untreated classic form [1, 8].

3.5. Airway, lungs and sleep

Upper airway obstruction results from cranial abnormalities, a short neck, macroglossia, adenotonsillar hypertrophy and supraglottic GAG deposition; the lower airway may show tracheobronchomalacia, while restrictive lung disease results from short stature, chest deformity and organomegaly [5]. Snoring, obstructive sleep apnoea, thick rhinorrhoea, recurrent sinusitis and otitis media, and reduced pulmonary function are common [1, 6]. Some patients have died from pulmonary infection, and respiratory impairment is among the most relevant causes of mortality [8, 39].

3.6. Eye

Corneal clouding results from GAG accumulation in keratocytes; it is detectable early by slit-lamp examination, becomes clinically apparent as clouding, is denser at the periphery and may reduce vision [8, 9]. A series cited in the 2010 review reports corneal clouding in 95% and glaucoma in 50% of patients [1]. The thickened cornea falsely elevates measured intraocular pressure; glaucoma may be angle-closure, due to iridociliary cysts, or open-angle, due to trabecular GAG deposition [1]. The optic disc is abnormal, with mild to moderate oedema, in approximately 50%; optic atrophy occurs in 15%, retinopathy is rare (night blindness), and high hypermetropia is frequent [1, 5]. Optic atrophy with blindness may result from chronic intracranial hypertension [9, 37].

3.7. Ear, nose and throat, and oral cavity

Hearing loss is a regular finding and is mixed, conductive and sensorineural, partly related to recurrent otitis media; it may mimic developmental delay [1, 5, 8]. Macroglossia, tongue protrusion, gingival hypertrophy, a high-arched palate, anterior open bite, spaced teeth and delayed tooth eruption are frequent; mandibular height is reduced, and teeth may be displaced towards the lower border, with roots almost perforating the cortex [1, 8, 39].

3.8. Nervous system

Intelligence is usually normal [8, 9]. Two families with intellectual disability, possibly of another aetiology, have been described, and a French centre reported intellectual disability in 4 of 6 patients; in a Turkish series of 14 children, 6 had mild cognitive impairment, an atypical finding [1, 8, 40]. Neurological complications are mainly mechanical [6]. Communicating hydrocephalus due to pachymeningeal thickening may require ventricular shunting; intracranial hypertension may cause neither headache nor vomiting and may present with papilloedema and rapid visual deterioration, and a ventriculoperitoneal shunt may prevent optic atrophy [1, 8]. Cervical myelopathy results from atlantoaxial subluxation, cervical dural thickening with insidious compression and spastic paraplegia, vertebral body abnormalities with kyphoscoliosis, and ligamentum flavum hypertrophy with diffuse compression and spastic tetraparesis [8]. Compression presents insidiously, with loss of endurance before signs of paralysis, and persists during ERT [9, 14]. Carpal tunnel syndrome is frequent and often atypical because the child does not report numbness; it may present with nocturnal pain or a habit of biting or shaking the fingers [5, 41]. In one patient, absence of secondary sexual characteristics and marked dwarfism suggested anterior pituitary involvement [8]. Even without neurodegeneration, sensory deficits and motor limitation may impair learning and autonomy; neuropsychological assessment, whose interpretation is hampered by communication limitations, should be performed by professionals experienced in these diseases [13].

3.9. Abdomen, skin and other features

Hepatomegaly is a regular finding after 6 years, and splenomegaly occurs in approximately half of patients; some have episodic diarrhoea [8]. Hepatosplenomegaly is minimal or absent in slowly progressive phenotypes [9]. Umbilical and inguinal hernias are frequent and recurrent and may require surgical repair in the early years [8, 9]. The skin may appear taut, and hirsutism or hypertrichosis is common [1, 8]. Extensive Mongolian spots are a classic cutaneous sign of MPS I, II and VI [13]. Prenatal presentation with fetal ascites was described in a Brazilian infant with rapidly progressive cardiac disease (see section 10) [35].

3.10. Treated disease versus natural history

The preceding descriptions refer mainly to natural history. During galsulfase treatment, trial and surveillance data show improvement in endurance, pulmonary function and growth in subgroups, and lower observed mortality than in untreated patients, but corneal clouding, skeletal dysplasia, valvular disease and spinal cord compression continue to progress or occur, even when treatment starts in the first year of life [42–46]. Figures are detailed in sections 7 and 11.

4. Clinical Recognition and Warning Signs

4.1. When to suspect the disease, by age

In the prenatal period, fetal ascites or hydrops without an infectious or immunological cause should include MPS VI in the differential diagnosis, alongside MPS I, IVA and VII [35]. In infants, thoracolumbar gibbus, recurrent umbilical or inguinal hernias, macrocephaly, noisy breathing, recurrent respiratory infections, a mitral or aortic murmur and unexplained cardiomyopathy are reasons for investigation [1, 8, 35]. An inguinal hernia in a term-born infant should prompt a search for other signs of MPS; in the most severe forms of the group, onset may be prenatal, with polyhydramnios or fetoplacental anasarca [13]. Between 2 and 5 years, slowing growth with coarse facial features, joint stiffness, claw hands and corneal clouding in a child with normal cognitive development is the most frequent presentation; the EPAR summary states that the disease is usually diagnosed between 1 and 5 years [8, 15]. The French PNDS places diagnosis of the severe forms usually before 2 years, in the presence of slowing growth velocity, skeletal and cranial deformities, corneal clouding, coarse facial features and upper airway obstruction [13]. In older children, adolescents and adults, hip dysplasia resembling Legg–Calvé–Perthes disease, otherwise unexplained mitral or aortic valvular disease, bilateral carpal tunnel syndrome in childhood and corneal clouding should prompt consideration of a slowly progressive form [8, 23, 41].

4.2. Suggestive associations

The combination of corneal clouding, dysostosis multiplex and normal intelligence distinguishes MPS VI from severe MPS I and MPS II [2, 9]. Metabolic causes of visible corneal clouding from late childhood to adulthood include MPS I, MPS VI, MPS IV, cystinosis and lecithin–cholesterol acyltransferase deficiency, among others; in MPS II the cornea is usually clear, correcting an outdated list in the Oxford Desk Reference that includes MPS II [1, 41, 47]. Carpal tunnel syndrome in a child points towards MPS VI or mucolipidosis type III [41]. Metachromatic cytoplasmic inclusions in 90–100% of granulocytes (Alder granules) and up to 50% of lymphocytes are more prominent in MPS VI than in any other MPS and may be the first clue on a blood smear [1, 8]. In the Oxford Desk Reference table of non-lethal skeletal dysplasias, MPS VI (ARSB) appears among the storage diseases with valgus deformity, contractures and pointed metacarpals, without associated intellectual disability, unlike severe MPS I, II and III [48].

4.3. Warning signs and emergencies

Urgent signs include loss of strength, loss of exercise endurance, difficulty rising, gait changes, spasticity, hyperreflexia with clonus or a Babinski sign, and urinary retention or incontinence due to a neurogenic bladder, suggesting cervical spinal cord compression and requiring magnetic resonance imaging (MRI) and neurosurgical assessment [14, 16, 37]. Rapid visual deterioration, papilloedema or a visual field defect suggest intracranial hypertension due to communicating hydrocephalus [1]. Dyspnoea, orthopnoea and oedema suggest heart failure due to valvular disease; syncope, unexplained falls or dizziness in an older patient require prolonged electrocardiographic recording [5]. Snoring with morning headaches suggests obstructive sleep apnoea and hypoventilation [5]. Any anaesthesia or sedation constitutes a risk setting requiring specialist planning (subsection 7.12) [5, 9].

The emergency certificate of the G2M filière (October 2023), annexed to the French PNDS and common to all MPS, stresses that no disease-specific test or treatment is urgent and that the ERT infusion never is, and may be postponed or cancelled; management is symptomatic and takes into account the risks specific to MPS [13]. In a patient with an implantable port and fever, catheter infection should be excluded (full blood count, C-reactive protein, procalcitonin, blood cultures drawn from the port and from a peripheral vein) and, if suspected, antistaphylococcal antibiotic therapy should be started according to the local protocol, for example intravenous vancomycin with a loading dose of 15 mg/kg over 60 minutes followed by 45 mg/kg/day by continuous infusion, with or without intravenous gentamicin 8 mg/kg/day as a single 30-minute administration and an antibiotic lock of the catheter (the certificate does not state a maximum dose; serum concentration monitoring and adjustments follow the local protocol); given the valvular disease, endocarditis should be sought [13]. In the presence of acute respiratory signs, the oral cavity and oropharynx are examined (with the otorhinolaryngologist, if necessary) and blood gases and a chest radiograph are requested; topical corticosteroid sprays or short courses of systemic corticosteroids reduce inflammation and oedema of the upper airway, antibiotic therapy is frequent, and some patients with repeated decompensations receive alternating antibiotic therapy [13]. Acute cardiac symptoms require an electrocardiogram (with or without Holter monitoring), troponin, echocardiography and a cardiology opinion [13]. Vomiting, headache, increasing head circumference or balance disturbances suggest hydrocephalus or, in a patient with a ventriculoperitoneal shunt, valve obstruction; recent urinary symptoms, a pyramidal syndrome, motor or sensory deficit and pain suggest high spinal cord compression, from C1–C2 instability, or low compression, from thoracolumbar kyphoscoliosis; both situations require an urgent neurosurgical opinion [13]. The certificate also notes that these patients are difficult to intubate, ventilate and extubate, that in an emergency intubation is performed under endoscopic guidance, with tracheostomy discussed, if possible with an otorhinolaryngologist and in an experienced centre, and that cervical mobilisation must be cautious because of the risk of permanent paraplegia; some patients in palliative care have a transfer form for the emergency medical service setting out the agreed care plan [13].

4.4. Newborn screening

The sources consulted do not describe newborn screening programmes for MPS VI in Portugal or Brazil. High-throughput assays using tandem mass spectrometry (MS/MS) or fluorimetry on dried blood spots allow multiplex screening for MPS I, II and VI, and some regional programmes screen mainly for MPS I (USA, Taiwan, northern Italy) [9]. Taiwan's national programme, launched in August 2015, screened 587,158 newborns for MPS VI up to 31 March 2025 using enzyme measurement by liquid chromatography and MS/MS, followed by urinary GAGs, leucocyte enzyme testing and genetic analysis; the published abstract describes 7 cases of MPS I, 14 of MPS II and 10 of MPS IVA and does not report confirmed cases of MPS VI, and the mean age at MPS diagnosis fell from 4.3 to 0.2 years [49]. The French prospective LysoNeo study screened 100,000 newborns for 13 lysosomal diseases between March 2021 and November 2024, with 75 first-line positives (0.075%), 14 recalled infants and 8 confirmed diagnoses; the abstract does not provide a separate breakdown for MPS VI [50]. In the USA, the Early Check and ScreenPlus research studies include MPS panels [51]. The international consensus considers that newborn screening, where available, would facilitate early diagnosis and intervention, and the Monte Santo study advocates community newborn screening in that founder population [5, 33]. The existence of pseudodeficiency (p.T212I) and the p.S384N polymorphism requires molecular and biochemical confirmation of any positive screen [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The accepted diagnosis rests on demonstrating arylsulfatase B activity below 10% of the lower limit of normal, measured in isolated leucocytes or cultured fibroblasts in an accredited laboratory, in a patient with a compatible phenotype, and demonstrating normal activity of at least one other sulfatase to exclude multiple sulfatase deficiency; the molecular alternative or complement is identification of two biallelic pathogenic ARSB variants [1, 5, 6]. Elevated urinary GAGs and increased dermatan sulphate support the diagnosis but are not sufficient in isolation [5, 6]. Supporting findings are urinary dermatan sulphate without chondroitin sulphate, heparan sulphate, keratan sulphate or hyaluronan by chromatography or electrophoresis, and intermediate activity in both parents [1]. Multiple sulfatase deficiency is diagnosed by low activity of two or more sulfatases [6, 11].

5.2. Urinary glycosaminoglycans

Total urinary GAGs were traditionally measured using dimethylmethylene blue (DMB) with two-dimensional electrophoresis; MS/MS methods have greater sensitivity and are now the reference for urinary screening, quantifying specific GAGs such as dermatan sulphate and oligosaccharides [5, 9]. Urinary spot tests are unreliable, with false positives and false negatives, and the toluidine blue test has fallen out of use [22, 39]. Total urinary GAGs may be normal in patients with dermatan sulphaturia and a mild phenotype, so a normal total urinary screen does not exclude MPS VI [8, 23]. The French PNDS stresses the same limitation in moderate forms, especially in adults, in whom urinary GAGs may be only slightly raised or not raised at all, and recommends that the analyses be performed in a reference medical biology laboratory [13]. GAGs are physiologically elevated in newborns and decline during the first year, and interpretation requires age-specific reference values, preferably from the same laboratory [1, 5]. Values reported in studies use µg/mg creatinine; the 100 µg/mg threshold approximately separates slowly and rapidly progressive forms, and the 200 µg/mg threshold was used in growth studies and the surveillance programme to define rapidly progressive disease [1, 52, 53]. During ERT, GAGs fall significantly 2–3 months after initiation [1].

5.3. Enzyme assay

Arylsulfatase B activity is measured in leucocytes, fibroblasts or plasma; leucocytes or plasma establish the final diagnosis, and measurement on filter paper may accelerate initial diagnosis [9, 39]. The French PNDS indicates leucocytes (dried blood spot on filter paper or leucocyte pellet) as the reference matrix, with fibroblasts, cultured amniocytes and chorionic villi as alternatives, and reserves serum or plasma for MPS I, II, IIIB and VII, not including MPS VI (subsection 7.20); activity measured with synthetic substrates does not distinguish severe from attenuated forms [13]. In any sulfatase deficiency, at least one other sulfatase should be measured to exclude multiple sulfatase deficiency (Austin disease) [1, 9, 13]. The main limitation of the assay is pseudodeficiency (p.T212I), which produces low activity with a normal phenotype and normal GAGs [1]. Heterozygosity may result in intermediate activity, but carrier testing and prenatal diagnosis are preferably performed by molecular analysis when the familial variants are known [1, 8].

5.4. Imaging and other supporting investigations

Radiological assessment for dysostosis multiplex is an effective MPS screening method, although it is not specific: it also occurs in generalised GM1 gangliosidosis and mucolipidoses [2, 22]. In MPS VI, the classic hand may be indistinguishable from the Hurler hand, and some diaphyses show constriction resembling that in Morquio syndrome [8]. Findings include macrocephaly, a thickened ground-glass calvarium, sclerotic mastoids and an enlarged J-shaped or omega-shaped sella turcica; broad paddle-shaped ribs, narrowed near the vertebrae; broad clavicles; immature oval vertebral bodies, with a wedge-shaped L1 and anterior beaking or hypoplasia of T12–L1 producing the gibbus; a sometimes markedly hypoplastic odontoid; small, constricted iliac bodies with flared wings, hypoplastic acetabula with oblique roofs, dysplastic femoral heads with irregular ossification resembling Legg–Calvé–Perthes disease, and coxa valga; short, thickened long bones, bowed radii and ulnae, metaphyseal constriction and oval metaphyseal radiolucencies due to cartilage islands; short, broad metacarpals with proximal tapering [2, 8, 9]. Neutral-position spinal MRI is the reference investigation for spinal cord compression, with flexion and extension MRI when neutral MRI shows no significant compression [5, 16]. The peripheral blood smear shows the Alder inclusions already described, and biopsies show lysosomal inclusions in Kupffer cells, hepatocytes, platelets, conjunctiva, cornea and skin, as well as fibroblasts with large clear juxtanuclear inclusions [8].

5.5. Genetic testing

ARSB sequencing, either alone or within a lysosomal disease or skeletal dysplasia panel, confirms the diagnosis, enables carrier testing and prenatal and preimplantation diagnosis, and provides limited prognostic information [1, 9]. The French PNDS recommends that molecular testing be systematically offered and considers parental testing indispensable, as it establishes allele segregation, confirms the diagnosis on a molecular basis and is a prerequisite for prenatal diagnosis [13]. Sequencing may fail to identify the variant or may find a previously undescribed variant whose classification requires functional and segregation data [28, 39]. Exon sequencing and panels may miss balanced structural variants, such as the inversion with breakpoints in ARSB detected only by whole-genome sequencing, and complex splicing variants [30, 31]. As large deletions have been described, copy-number analysis complements sequencing when only one variant is found [1]. The presence of p.S384N, a non-pathogenic polymorphism, or p.T212I, a pseudodeficiency allele, should not be interpreted as diagnostic [1, 38]. ClinVar classification may differ from the historical description: p.Gly137Val, associated with an intermediate phenotype in homozygosity, remains of uncertain significance in ClinVar with a single submitter [1, 32]. A report should state the gene, transcript with version (NM_000046.5), complementary DNA and protein HGVS nomenclature, zygosity, phase (cis or trans, confirmed by parental testing), classification according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, and correlation with the enzyme result. A negative molecular result does not exclude the disease when the biochemistry is diagnostic.

5.6. Practical algorithm

5.7. Prenatal and preimplantation diagnosis

Prenatal diagnosis is performed by measuring arylsulfatase B activity in chorionic villi or cultured amniocytes and, when the familial variants are known, by molecular analysis of the same samples [1, 23, 39]. The Brazilian textbook of genetic syndromes also mentions enzyme measurement in cord blood in the third trimester, an option not described by the other sources consulted [39]. Preimplantation genetic testing requires known familial variants. The presence of p.S384N or p.T212I in a parent should be known before enzyme-based prenatal diagnosis to avoid misinterpretation [1].

5.8. Initial multisystem assessment

The French PNDS details the initial assessment that establishes severity and underpins the treatment decision, and prefers the EOS system for radiographs because of the lower radiation dose [13].

This set overlaps with the baseline assessment of the international consensus (step 5 of subsection 5.6), with three additions: the sequence requiring cervical MRI before dynamic radiographs, systematic electrophysiological study of the median nerve and the list of second-line cardiac investigations [5, 13].

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differential diagnoses

MPS I is the closest differential diagnosis because it shares the facial features, dysostosis, corneal clouding, valvular disease and spinal cord compression; differentiation relies on the absence of cognitive impairment in MPS VI, which, however, is also absent in attenuated MPS I, so the decision rests on GAG fractionation (almost 100% dermatan sulphate in MPS VI, heparan sulphate and dermatan sulphate in MPS I) and enzyme measurement [1, 9]. Attenuated MPS VII may resemble MPS I, II and VI [9]. MPS IVA is distinguished by ligamentous laxity, in contrast to the joint stiffness of MPS VI [1].

Multiple sulfatase deficiency is the differential diagnosis that must be excluded in any arylsulfatase B deficiency, because FGE deficiency suppresses the activity of 17 sulfatases; progressive psychomotor delay is always present, ichthyosis is frequent and urinary GAGs may be normal, requiring measurement of several sulfatases or SUMF1 analysis [9, 25]. The Saudi variant of multiple sulfatase deficiency presents with severe early-onset dysostosis multiplex resembling that of Maroteaux–Lamy and Morquio syndromes, with corneal clouding in 6 of 8 patients, and is distinguished by neurodegeneration and ichthyosis [25].

Mucolipidoses II and III share dysostosis and, in type III, carpal tunnel syndrome and contractures, but ML II has serum lysosomal hydrolases 10–20 times above normal with deficiency in fibroblasts, and sialidosis and mucolipidoses III and IV do not increase urinary GAGs [1, 8]. In slowly progressive forms presenting late, the differential shifts towards skeletal dysplasias and Legg–Calvé–Perthes disease, and a normal total urinary screen should not end the investigation [8, 9].

7. Treatments and Risk Management Strategies

7.1. Guidelines and general principles

The reference guideline is the international consensus of Akyol and colleagues (2019), developed in parallel for MPS IVA and VI by a steering committee of 26 professionals and 3 patient representatives, with a systematic review following PRISMA, Oxford levels of evidence and a two-round modified Delphi process involving 197 physicians from 35 clinical disciplines in 25 countries; the abstract reports 93 statements and the results section 94, an internal discrepancy in the article [5]. The overall AGREE II rating was 5.3 out of 7; the work was funded by BioMarin, the galsulfase marketing authorisation holder, which according to the authors had no role in the content; diagnosis and validation of outcome instruments were outside the scope, and statements are grade D (expert opinion) unless otherwise indicated [5]. This guideline methodologically supersedes the expert-opinion-based guidance of Giugliani, Harmatz and Wraith (2007) and is complemented by the multinational consensus on spinal cord compression of Solanki and colleagues (2012) [5, 16, 54]. The committee planned a review after 5 years; no formal update was identified up to 10 October 2026, which does not exclude its existence [5]. There is also a Saudi consensus for MPS IVA and VI (2024), obtained by Delphi with 7 geneticists, whose abstract covers screening, diagnosis, ERT and local data generation, and an Asia-Pacific regional survey (2012) documenting highly variable access to diagnosis and treatment [55, 56]. Brazil's Ministry of Health published a Clinical Protocol and Therapeutic Guidelines (PCDT) for MPS VI, whose text was not consulted [6, 57].

In France, the French National Diagnosis and Care Protocol (PNDS) “Mucopolysaccharidoses” of the Haute Autorité de Santé (HAS), dated January 2025, covers MPS I, II, III, IVA and IVB, VI, VII and IX; it was drawn up according to the 2012 HAS method, through critical analysis of the literature, by a group coordinated by the Reference Centre for Lysosomal Diseases and the CETMPS-GP committee, with the G2M filière and review by readers distinct from the authors, including patient organisations; most members declare links with the pharmaceutical industry, which took no part in drafting or review [13]. It is an expert consensus document without grading of recommendations, which adopts for transplantation the 2022 recommendations of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire; divergences from the other sources are collected in subsection 7.20 [13].

The consensus general principles, all grade D, are diagnosis in infancy as a critical factor (98% agreement), an initial consultation with a physician experienced in MPS immediately after diagnosis (97%), ongoing psychosocial support with referral to the national patient organisation (94%), baseline multisystem assessment within days of diagnosis (88%), regular multisystem monitoring, at least annually (100%), timely interventions to prevent irreversible damage (99%), a multidisciplinary team (99%), advance coordination of procedures to combine operations and reduce the number of anaesthetics (93%), informed decision-making with the patient and family (100%), surgery by teams experienced in MPS at centres with intensive care facilities (99%), and pain management as an integral part of care (100%) [5]. The most serious surgical complications occur in advanced disease, so indicated procedures, particularly airway procedures, should be performed as early as possible [5]. Multidisciplinary symptomatic care at specialist centres is the most relevant aspect of management, and pain, which is very frequent, should be addressed directly [9].

7.2. Enzyme replacement therapy with galsulfase

Galsulfase (Naglazyme®, BioMarin) is recombinant human N-acetylgalactosamine-4-sulfatase, taken up by cells through the mannose-6-phosphate receptor [14]. It is the only specific therapy licensed for MPS VI [5, 6]. The consensus recommends starting long-term intravenous ERT with galsulfase 1 mg/kg/week as soon as possible after confirmed diagnosis (grade B; 89% agreement), taking into account the patient's condition, disease burden and prognosis at diagnosis [5]. The French PNDS retains the dose of 1 mg/kg/week, specifies that ERT be started at a reference or competence centre and that each initial prescription be validated case by case, on a multidisciplinary basis, by experts from an accredited centre, and lists as demonstrated benefits of galsulfase the 12-minute walk test distance, urinary GAG excretion, respiratory function and growth in prepubertal patients [13]. The 2011 American College of Medical Genetics review of presymptomatic patients with lysosomal diseases likewise recommends initiating ERT as soon as the diagnosis is confirmed [8, 58]. Galsulfase does not reach the central nervous system or, to a relevant extent, the cornea and articular cartilage, which are poorly vascularised sites [1, 8].

Saudubray's textbook lists the same intravenous dose of 1 mg/kg per week [59]. In open-label studies, two infants received 2 mg/kg per week for 105 and 81 weeks, and the phase 4 infant study compared 1 and 2 mg/kg; the 2 mg/kg dose is experimental and does not correspond to the authorised posology [14, 60]. The European summary of product characteristics (SmPC) states that total doses administered at about twice the recommended rate caused no apparent adverse events, and that in the four infants under 1 year the 2 mg/kg/week dose had a safety profile similar to that of 1 mg/kg/week [15].

7.3. Galsulfase safety and management of adverse effects

The US label carries a boxed warning on hypersensitivity reactions, including anaphylaxis, which may occur at initiation or after prolonged therapy; infusion should begin in a setting with monitoring and resuscitation equipment, and a severe reaction requires stopping the infusion and immediate treatment, including adrenaline (adrenaline) [14]. Despite premedication, 33 of 59 patients (56%) treated in five studies had infusion-associated reactions, some severe (laryngeal oedema, apnoea, fever, urticaria, respiratory distress, angioedema, anaphylactoid reaction), with onset between week 1 and week 146; 23 of the 33 (70%) had recurrent reactions, and neither predisposing factors nor an association between severity and antibody titre were identified [5, 14]. Reactions are managed by reducing the rate or temporarily interrupting the infusion and administering antihistamines, antipyretics and, sometimes, corticosteroids; subsequent infusions use slower rates, additional prophylactic antihistamines and, after severe reactions, prophylactic corticosteroids [5, 14]. If anaphylaxis is suspected, the consensus recommends hospital admission [5]. The French PNDS adds that the risk of reaction is highest between the 6th and 15th infusions but persists after months or years of treatment, and increases with intercurrent infection, especially respiratory, and with a history of allergy, situations that require clinical assessment before infusion; premedication may include antihistamines, corticosteroids, antipyretics and/or nebulised β2 agonists [13].

Sleep apnoea is frequent, and antihistamines may increase apnoeic episodes; the US label calls for assessment of airway patency before initiation, availability of oxygen or continuous positive airway pressure (CPAP) during infusion, and postponement of infusion in the event of acute febrile or respiratory illness, while the consensus recommends a non-sedating antihistamine [5, 14]. The 2010 review notes that diphenhydramine may cause severe apnoea [1]. Patients weighing 20 kg or less, those with acute respiratory disease, or those with impaired cardiac or respiratory function are at risk of acute cardiorespiratory failure due to volume overload, requiring reduced volume and rate and prolonged observation [14]. Immune-complex (type III) reactions have been described, including membranous glomerulonephritis with glomerular deposits of galsulfase–immunoglobulin immune complexes, and rare thrombocytopenia; affected patients were successfully rechallenged under surveillance [14]. Cervical spinal cord compression with myelopathy, a complication of natural history, continues to occur during galsulfase treatment, with postmarketing reports of onset or worsening requiring decompression [14].

In the controlled trial, adverse reactions affecting at least two more patients in the active group (19 patients) than in the placebo group (20) were abdominal pain (47% versus 35%), ear pain (42% versus 20%), arthralgia (42% versus 25%), pain (32% versus 5%), conjunctivitis, dyspnoea, rash and chills (21% each versus 0–10%), and chest pain (16% versus 5%) [14]. In open-label studies, with a mean exposure of 138 weeks at 1 mg/kg, no patient discontinued because of adverse effects, and the most frequent reactions (≥ 10%) were rash, pain, urticaria, fever, pruritus, chills, headache, nausea, vomiting, abdominal pain and dyspnoea [14]. Anti-galsulfase IgG antibodies developed in 53 of 54 patients (98%) within 4–8 weeks, and neutralising antibodies in 4 of 16 (25%), with no clinically relevant effect identified on reactions, urinary GAGs or endurance [14]. Alloantibodies interfere with efficacy in MPS I and II, but such interference has not been established in MPS VI [9]. Pharmacokinetics in 13 patients showed a median half-life of 9 minutes at week 1 and 26 minutes at week 24, with considerable variability; the urinary GAG response to dose changes is unknown, and the relationship between GAGs and clinical response is not established [14].

According to the French PNDS, anti-enzyme antibodies are frequent and their titre does not correlate with the walk test or urinary GAGs, but neutralising antibodies may reduce the benefit; measurement is considered in the event of repeated reactions or unexpected loss of efficacy, after contacting the marketing authorisation holder's laboratory [13]. Annex 6 of the PNDS proposes a stepwise approach to infusion reactions [13]:

Source: Annex 6 of the PNDS, which reproduces the 2016 French recommendations on anaphylaxis in emergency medicine, including the Sampson criteria [13].

To prevent recurrences, the PNDS escalates premedication [13]:

Hydroxyzine and dexchlorpheniramine are sedating antihistamines, in contrast with the international consensus preference for non-sedating antihistamines and the US label warning about worsening of apnoea (subsection 7.20) [5, 13, 14].

7.4. Infusion organisation and venous access

Initial infusions should take place under the guidance of a clinician experienced in metabolic diseases, at a centre able to manage reactions and anaphylaxis [5]. Home infusion may be considered where available, through shared decision-making, with careful selection, good venous access and a written reaction management plan; the 2010 review reserved it for less severely affected patients with no previous reactions [1, 5]. A totally implantable venous access device may be considered, with information about the risks of infection and thrombosis; endocarditis prophylaxis in the presence of valvular disease and a catheter should be discussed with the cardiologist [1, 5]. In the French PNDS, the first infusions are given in hospital, in a setting with resuscitation equipment, via a peripheral vein or an implantable port; a port is weighed on a benefit–risk basis when there is significant valvular disease or a prosthetic valve, and its replacement may become necessary with growth and the age of the device [13]. After hospital initiation and under defined conditions, infusion may be transferred to the home, through hospital-at-home services or service providers, according to the therapeutic use protocol of each enzyme [13]. Holidays, travel and periods of study or work abroad should be prepared weeks or months in advance to adapt the infusion schedule, and an infusion may be cancelled or postponed when circumstances prevent its administration [13].

7.5. Comparative regulatory status

The centralised European authorisation covers Portugal; the sources consulted do not describe funding arrangements in Portugal or access through Brazil's Unified Health System (SUS), whose PCDT was not read [15, 57]. The searches performed did not identify galsulfase biosimilars in 2025–2026, a finding that does not demonstrate their non-existence.

7.6. Galsulfase clinical trials and long-term studies

The clinical programme for the recombinant human enzyme (rhASB, subsequently galsulfase) included a phase 1/2 study, an open-label phase 2 study, the pivotal placebo-controlled phase 3 trial ASB-03-05 (NCT00067470) with the open-label extension ASB-03-06 (NCT00104234), and the phase 4 infant study ASB-008 (NCT00299000) [60–62].

The EPAR summary describes the same trial with 39 patients and a gain of 109 m versus 18 m with placebo, whereas the US label, which analyses 19 patients in the placebo group (one withdrew after week 4), gives 26 m; the difference probably results from the population analysed [14, 15]. In the phase 2 study, pulmonary function improved without growth in 3 of 6 patients, shoulder range of motion increased, and pain and stiffness improved by at least 50% at week 24 [64].

The limitations of this evidence are explicit: there is a single controlled trial, lasting 24 weeks and including 39 patients, whose secondary stair-climbing outcome did not reach significance, and the Cochrane review rates the certainty of evidence for clinical outcomes as very low, with unclear risk of bias because randomisation and allocation concealment were not described [65, 67]. Trial patients were aged 5–29 years and mostly had severe disease; there are no controlled data in infants or adults over 29 years [14]. Long-term studies are open-label, without a contemporary control group, with losses to follow-up and small numbers of patients with paired data, and improvements in pulmonary function in children are partly attributable to growth [5, 43]. Indirect comparison of results between studies with different populations and ages at initiation is not justified.

7.7. Long-term data and mortality during ERT

In the 10-year resurvey of patients from the 2001–2002 survey (NCT01387854), with clinical data for 59 patients and survival data for 117, mean ERT duration was 6.8 years (standard deviation 2.2); height increased by 20.4 cm in the group aged 4–7 years at baseline and by 16.8 cm in the group aged 8–12 years, forced vital capacity (FVC) increased by 68% and forced expiratory volume in one second (FEV1) by 55% in those under 13 years, and the 6MWT increased by 65.7 m (standard deviation 100.6), without significant improvement or worsening in cardiac parameters [42]. Observed mortality was 50% (7 of 14) in untreated patients and 16.5% (17 of 103) in treated patients, with an unadjusted hazard ratio of 0.24 (95% CI 0.10–0.59); this is a non-randomised, unadjusted comparison subject to selection bias [42].

In the Clinical Surveillance Program (CSP; NCT00214773), between 30/06/2005 and 01/05/2020, 221 participants were included in the final analysis, 212 of whom received ERT, with a median exposure of 11.7 years; urinary GAGs fell by 59.7% after a mean of 8.0 years (n = 84; p < 0.0001), the 6MWT increased by 42.3 m (standard error 21.81) after 7.0 years (n = 35; p = 0.0610), FEV1 increased by 0.36 L after 6.5 years (n = 24; p = 0.0014) and FVC by 0.52 L after 6.3 years (n = 25; p = 0.0013), with gains concentrated in patients under 18 years at baseline, stabilisation in older patients and no new safety signals [43]. An earlier CSP subanalysis compared patients with pretreatment GAGs < 100 µg/mg (n = 39) and ≥ 200 µg/mg (n = 68): the 6MWT increased by 49 m and 42 m, without an impact on cardiac function and with largely unchanged pulmonary function [53]. In the analysis of 56 clinical study patients, FVC increased by 17% and FEV1 by 11% at 96 weeks, and maximum voluntary ventilation by approximately 15% as early as 24 weeks [68]. In 141 patients who started galsulfase by 18 years, compared with untreated MPS VI growth charts, height Z-score increased in patients with baseline GAGs > 200 µg/mg who started between 0 and 15 years, with no increase when starting at 15–18 years or with GAGs ≤ 200 µg/mg, and the greatest benefit occurred when starting by 6 years [52, 69].

7.8. Early initiation and limitations of ERT

In two Australian siblings, the younger started rhASB 1 mg/kg/week at 8 weeks and the older at 3.6 years; after 3.6 years, the younger had no scoliosis and retained preserved joints, valves and facial morphology, whereas the older had improved joint mobility and valvular disease and stable scoliosis; both had progression of corneal opacity and skeletal abnormalities [70]. In two Japanese siblings, the sister treated from 6 weeks had, after at least 36 months, an almost complete absence of short stature, facial dysmorphism, hepatosplenomegaly, hearing loss, corneal opacity and dysostosis multiplex, with preserved cardiac function and mobility, whereas the brother treated from 5.6 years had improved shoulder function and hearing without changes in skeletal deformity or height [71]. In the three infants from ASB-008 followed for 7.9–10.5 years, skeletal dysplasia, already present at baseline, progressed, corneal opacity progressed in all, valvular disease followed a variable course, and liver size normalised in two; two had a 6MWT normal for age and height [44]. In a Brazilian resurvey of 34 patients with rapidly progressive disease who started galsulfase before 5 years, with approximately 10 years of ERT and 4 deaths, growth velocity improved, puberty was normal in all survivors, and pneumonias and hospital admissions decreased, but valve disease progressed and spinal cord compression was frequent [45]. In a 10-year prospective US study, the 9 MPS VI patients treated with ERT and/or HSCT had declining height Z-scores, adult height of 128 ± 15 cm and contractures in all [46]. In a Turkish series of 14 children starting at 2.8–15.8 years, endurance improved in most after 1.9–3.2 years, without prevention of valvular, ocular, auditory or skeletal progression [40].

In summary, ERT improves endurance, pulmonary function and growth in subgroups, and early initiation produces better results in sibling studies, but does not prevent corneal clouding, skeletal dysplasia, valvular progression or spinal cord compression [5, 9, 44]. The consensus considers that initiation before 12 years may prevent progression of valve abnormalities, with an equivocal effect on cardiac outcomes, and that initiation before 16 years improves growth velocity [5]. Limited cardiac data suggest valvular stabilisation or regression, possibly attenuated by late initiation, and cases with very early initiation suggest prevention or substantial delay of cardiac disease [23].

7.9. Monitoring the response to ERT

Before initiation and regularly thereafter, assessment should cover urinary GAGs or dermatan sulphate, endurance (6MWT or, if walking is limited, the adapted 25-foot walk test), upper limb function, respiratory function when age permits, growth, pain, activities of daily living and quality of life [5]. Urinary GAGs are measured before galsulfase and every 6 months (grade C) as a pharmacodynamic marker [5, 6]. Benefit is not uniform and should be assessed individually [5]. The French PNDS provides for discontinuation of ERT when the expected benefits are no longer achieved, when the severity of the lesions justifies it or when the risk of infusion becomes excessive, for example in the presence of reactions poorly controlled by antihistamines and corticosteroids; the decision is collegial, taken at a multidisciplinary team meeting of the CETMPS-GP with the palliative care team, and forms part of the reflection on the appropriate level of care and on the balance between benefits, risks and burden [13].

7.10. Haematopoietic stem cell transplantation

The first bone marrow transplant in MPS VI, published by Krivit and colleagues in 1984, was performed in a 13-year-old girl with normal intelligence, advanced heart failure and obstructive apnoea requiring nocturnal oxygen and tracheostomy; at 24 months, urinary MPS excretion and hepatosplenomegaly had decreased, cardiopulmonary function had normalised and visual acuity had improved, but corneal clouding and dysostosis multiplex persisted [8, 24]. Liver biopsies from transplant recipients showed clearance of stored GAGs in Kupffer cells and hepatocytes, and in the feline model transplantation caused corneal clouding to disappear [8]. In the Center for International Blood and Marrow Transplant Research (CIBMTR) series, 45 patients transplanted between 1982 and 2007, at a median age of 5 years (1–22), had a cumulative incidence of acute graft-versus-host disease of 36% (95% CI 21–53%) at 100 days and survival of 78% (65–89%) at 100 days and 66% (52–79%) at 1 and 3 years; these data are from an era before ERT and current techniques and should not be extrapolated to current mortality [72]. Saudubray's textbook mentions more than 45 reported patients and states that transplantation is usually offered when ERT is unavailable [9]. Transplantation produces regression of myocardial hypertrophy and prevents deterioration of cardiac function, with little or no effect on existing valve lesions [23].

The 2019 consensus considers that HSCT may be an option for patients with a matched family donor, preferably a non-carrier, a well-matched unrelated adult donor or cord blood, weighing morbidity and mortality (grade C; 86%), and only at institutions with a multidisciplinary team experienced in MPS VI (grade D; 91%) [5]. The rationale notes that the risk–benefit balance is less clear than in other MPS because MPS VI lacks the cognitive impairment that justifies transplantation in severe MPS I, and that a comparative study of HSCT and ERT is lacking [5]. Transplant recipients should be assessed before and at least annually afterwards for endurance, cardiorespiratory function, height and weight, with orthopaedic, ophthalmological, otorhinolaryngological, neurological and endocrinological assessments [5]. In a single-centre Turkish series, 17 children transplanted between 2021 and 2023 with myeloablative conditioning, a median of 6 years after diagnosis, all engrafted with normal enzyme activity and improved their 6MWT at 9 months; the authors advocate offering transplantation as a “less expensive and permanent” option, a position in tension with the consensus, in a study with short follow-up and no ERT comparison [73]. A study of galsulfase for 2 years after allogeneic HSCT (NCT02156674) ended with a single patient [74]. Two boys aged 7 and 8 years with graft failure after transplantation were maintained on ERT [1].

The French PNDS, which follows the 2022 recommendations of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire, reserves HSCT in MPS VI for case-by-case discussion, when diagnosis is early, at a multidisciplinary team meeting with the transplant, paediatric neurology and metabolic disease teams [13]. The recommended myeloablative conditioning combines busulfan and fludarabine; the donor of first choice is a non-heterozygous HLA-identical sibling, followed by an 8/8 or 7/8 cord blood unit, preferred for its rapid availability, better chimerism and higher enzyme activity after transplantation, at the cost of a greater risk of rejection and autoimmune cytopenia, and finally a 10/10 unrelated donor; the graft should be cell-rich, because the risk of rejection or graft failure is greater in these non-malignant diseases [13]. Peri-transplant ERT is formally recommended only in severe MPS I, from diagnosis until there is complete donor chimerism, normal or near-normal enzyme activity and normal urinary GAGs (on average 3–6 months after transplantation), with no relationship between anti-enzyme antibodies and engraftment; its application to MPS VI is an extrapolation, with no specific data beyond the interrupted study mentioned above [13, 74]. Follow-up is shared between the transplant team and the reference team, with frequent enzyme assays and chimerism studies at first and annual ones thereafter; before busulfan, fertility preservation should be offered (cryopreservation of ovarian tissue or testicular pulp), and skeletal, ocular, cardiac and sometimes otorhinolaryngological manifestations may continue to progress despite transplantation [13].

7.11. Airway, respiratory function and sleep

The consensus recommends CPAP for obstructive sleep apnoea persisting after tonsillectomy and/or adenoidectomy (grade B; 100%), non-invasive positive-pressure ventilation (NIV) for nocturnal hypoventilation unresponsive to CPAP or daytime hypoventilation with increased PaCO2 or serum bicarbonate (grade B; 94%), and oxygen for apnoea with nocturnal hypoxaemia and mask intolerance (grade B; 83%), with monitoring for hypercapnia after oxygen initiation (grade D; 97%) [5]. Mask fitting is difficult because of facial morphology [5]. Influenza and pneumococcal vaccination are recommended [5]. The French PNDS and the associated emergency certificate recommend the complete vaccination schedule, with influenza, pneumococcal and COVID-19 vaccines; after HSCT, the schedule is decided with the transplant team [13]. Reversal of tracheostomy during ERT has been described [1].

7.12. Anaesthesia and perioperative care

Anaesthesia in MPS VI carries high risk because of difficult mask ventilation and intubation (adenotonsillar hypertrophy, macroglossia, reduced mouth opening, micrognathia, short stiff neck, subglottic narrowing, lower airway deformity), atlantoaxial instability due to odontoid hypoplasia and ligamentous laxity, restrictive lung disease, cardiac disease and risk of spinal cord hypoperfusion; deaths and paralysis have been described in MPS patients [5, 9]. Perioperative or postoperative spinal cord injury may occur remote from the surgical site, owing to low mean arterial pressure with compromised spinal circulation, and is associated with duration and positioning [9].

Source: Akyol and colleagues, 2019 [5].

Practical considerations include cautious, monitored sedative premedication, baseline airway assessment by flexible nasopharyngolaryngoscopy and, where possible, three-dimensional computed tomography (CT) of the trachea, echocardiogram and electrocardiogram, and cervical flexion and extension imaging before anaesthesia, repeated with age [5]. Recommendations include intubation during spontaneous ventilation whenever possible, avoiding neuromuscular blocking agents until the airway is secured, using smaller endotracheal tubes because of intraoperative oedema, maintaining mean arterial pressure with an arterial line and, if safe intubation is impossible, considering elective tracheostomy before prolonged surgery or postponing surgery [5]. Pulling the tongue forwards with forceps or gauze may facilitate laryngeal access in children with MPS VI [5]. Cervical range of motion is assessed with the patient awake immediately before anaesthesia and should not be exceeded under anaesthesia; flexion and extension MRI was considered safe in experienced teams after spinal cord compression had been excluded [5]. Intraoperative corticosteroids for airway oedema are common practice and may be continued for 24 h; extubation takes place in theatre, by an anaesthetist able to reintubate, asking the patient to move all four limbs, and intensive cardiorespiratory monitoring continues for 24–48 h, with NIV and CPAP available [5]. Ultrasound-guided peripheral nerve blocks may avoid general anaesthesia in selected cases [5].

The French PNDS quantifies the risk: it reports perioperative events in 25% of patients with MPS (upper airway obstruction, laryngospasm, stridor, reintubation, ventilatory problems and, more rarely, cardiocirculatory problems), with a higher frequency without specific treatment, a significant increase with age, more difficult intubation in adults than in children and greater risk in MPS I and II than in MPS III; tracheal stenoses are the main risk of intubation and ventilation failure [13]. This figure comes from a Hamburg and Rostock series (2002–2016) and is measured per anaesthetic, not per patient: in 67 children with MPS or mucolipidosis undergoing 269 anaesthetics, at least one adverse event occurred in 25.6% of anaesthetics; the risk was greater in MPS I (odds ratio, OR 8.0) and II (OR 8.8) than in MPS III, and direct laryngoscopy was associated with more airway problems than indirect techniques (estimated rates of 47.8% and 10.1%) [75]. Direct laryngoscopy is associated with more adverse events than indirect laryngoscopy, and the technique with the lowest risk and lowest conversion rate is fibreoptic intubation through a laryngeal mask airway; repeated attempts at direct laryngoscopy, which worsen inflammation, should be avoided [13]. After extubation, the patient remains in intensive care because of the risk of obstruction and of pulmonary, laryngeal or lingual oedema, even late, with possible prolonged NIV; emergency tracheostomy is technically difficult because of the short neck and exposes the patient to secondary stenosis, granulomas and difficulty with decannulation, and a tracheal stent in very tight stenoses, with a risk of migration and granuloma, is decided case by case [13]. The prone position (craniocervical junction or spinal surgery) adds abdominal compression, limitation of chest expansion, compression of the inferior vena cava and a risk of tube displacement, and the tube should lie below any stenosis [13].

Before any general anaesthetic, the PNDS requires a checklist with otorhinolaryngological assessment by nasofibroscopy, anaesthetic assessment (Mallampati, mouth opening, thyromental distance, cervical mobility and venous access), tracheal CT, polysomnography or polygraphy, an echocardiogram less than 1 year old and, if possible, cervicothoracolumbar spinal MRI with a neurosurgical opinion [13]. The purpose of the anaesthetic, its urgency, the possibility of grouping procedures without excessively prolonging the anaesthetic, the alternatives (regional anaesthesia, for example for carpal tunnel release, or awake sedation for dental care) and the need to place long-term venous access at the same time should be questioned [13]. The patient and carers are informed of the risks, including extubation failure, with the palliative care team when relevant; a multidisciplinary meeting precedes every planned anaesthetic and should also be held in adolescence to anticipate surgical emergencies, and planned surgery takes place at a reference centre with an anaesthetist and otorhinolaryngologist experienced with these patients [13].

7.13. Orthopaedic and spinal surgery

Source: Akyol and colleagues, 2019 [5].

Almost all patients have abnormal hip radiographs, so surgery is justified only when symptoms are present; growth modulation is performed as soon as deformity appears or with a tibiofemoral angle above 15°, and the period after ERT initiation may be appropriate [5]. Hip surgery requires prolonged intensive physiotherapy, with the aim of reducing pain and improving mobility rather than restoring range of motion [5]. Spinal surgery is indicated by symptoms (weakness, numbness, paraesthesiae, gait changes) or findings of stenosis, compression, myelomalacia or instability, and its timing should be coordinated with any potential valve replacement, which may require lifelong anticoagulation [5]. The consensus of Solanki and colleagues considers functional assessment and neurological examination the basis of early myelopathy detection, MRI the reference standard, neurophysiological monitoring mandatory in complex spinal and head and neck surgery, and referral to experienced centres essential; surgery may include decompression, stabilisation or both [16]. Laminectomy with removal of the thickened dura improved myelopathy in a classic report [8]. Medical therapies have limited effects on skeletal deformities [5].

7.14. Hand, eye, heart and otorhinolaryngology

For the hand, the consensus recommends median nerve decompression with tenosynovectomy of all flexors in the carpal canal when there are interphalangeal flexion contractures (claw hand), hand pain or numbness from the thumb to the middle finger and positive nerve conduction studies (grade C; 89%), and release of the A1 and A3 pulleys for trigger finger (grade C; 94%) [5]. Early decompression improves function and pain; numbness of all fingers makes carpal tunnel syndrome unlikely, and pain in the fifth finger suggests more proximal compression, requiring neurophysiological investigation to exclude cervical compression; recurrence is frequent in older patients; weak grip is not an indication for surgery and is treated with splints and occupational therapy [5].

For the eye, corneal transplantation may be considered when significant visual loss is attributable to corneal clouding (grade B; 100%), after retinopathy and optic neuropathy have been excluded as the main causes by electroretinography and visual evoked potentials (VEPs) [5]. Deep anterior lamellar keratoplasty (DALK) is the first approach because it carries a lower rejection risk than penetrating keratoplasty; rejection occurred mainly in younger transplant recipients (13–28 years), recurrence of deposits has rarely been reported, and postoperative care requires prolonged topical treatment and annual assessment of the graft, deposits, astigmatism and optic neuropathy due to intracranial hypertension [5]. Intraocular pressure and pachymetry should be measured before transplantation [5]. Reversal of papilloedema with visual improvement in an 11-year-old patient after 130 weeks of ERT and stabilisation of acuity in 6 patients at 144 weeks have been described [1].

For the heart, the consensus recommends aortic or mitral valve replacement for severe symptomatic stenosis or regurgitation (grade C; 100%) and resection of left ventricular apical aneurysms whenever possible (grade D; 85%), in accordance with European and American guidelines and taking comorbidities into account [5]. The Ross procedure is contraindicated because valve disease is systemic, a small valve annulus may preclude prosthesis implantation, balloon valvuloplasty has no reported success, and transcatheter aortic valve implantation (TAVI) may be appropriate in some patients [5]. Valve surgery is usually performed in adults (reported mean age 30.9 years, range 3–62), and successful aortic and mitral valve replacement is documented; a Brazilian infant underwent mitral valvuloplasty at 11 months (section 10) [8, 35]. Echocardiography should be interpreted by someone familiar with the condition, and the decision requires a joint anaesthetic plan at a referral centre [5].

In otorhinolaryngology, recommendations include tonsillectomy and/or adenoidectomy for upper airway obstruction, recurrent otitis media, snoring or obstructive apnoea, as early as possible after diagnosis (grade C; 91%), tracheostomy for severe obstruction without an alternative or refractory severe apnoea (grade D; 95%), and ventilation tubes for serous or recurrent otitis media (grade D; 96%) [5]. Secondary post-tonsillectomy haemorrhage and difficult intubation are serious risks; polysomnography before tonsillectomy, postoperative admission, preferably to intensive care in the early period, and reassessment of ventilation tubes every 3 months are recommended; uvulopalatopharyngoplasty, mandibular advancement and tongue reduction are experimental [5]. Permanent conductive and sensorineural hearing loss is frequent, and speech and language therapy is indicated when speech is impaired [5].

7.15. Other interventions, rehabilitation and pain

Umbilical and inguinal hernias may require surgical repair in the early years, and communicating hydrocephalus with intracranial hypertension is treated with ventriculoperitoneal shunting [1, 8]. Physiotherapy, occupational therapy and rehabilitation medicine should assess the patient regularly and suggest walking aids and adaptations (93–98%) [5]. Pain is very frequent and should be managed as an integral part of care [5, 9]. Oral health requires at least annual assessment, and endocarditis prophylaxis before dental procedures should be decided with the cardiologist [5]. Ongoing psychosocial support and referral to patient organisations form part of management [5]. The French PNDS adds, for nociceptive osteoarticular pain, the World Health Organization analgesic ladder adjusted for weight and infiltrations; for neuropathic pain, tricyclic antidepressants and antiepileptic drugs, especially gabapentin; and two topical treatments prepared as compounded formulations, without systemic effects: 10% amitriptyline cream twice daily on 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 [13]. The PNDS does not state systemic doses; for gabapentin, the harmonised European SmPC authorises peripheral neuropathic pain only in adults, starting at 900 mg/day in three divided doses (or titration with 300 mg on day 1, 300 mg twice on day 2 and three times on day 3) and increases of 300 mg/day every 2–3 days up to a maximum of 3600 mg/day, with slower titration in low-weight patients; use in children with neuropathic pain is an off-label extrapolation [13, 76]. In low-weight adults, doses are adjusted to body build and, in obese patients, to ideal body weight [13]. The PNDS also lists treatment of glaucoma and other anterior segment diseases, bronchodilators, antiarrhythmic, antihypertensive and heart failure therapy, treatment of gastro-oesophageal reflux, bowel transit and sleep disorders, nutritional and vitamin supplements according to the nutritional assessment, antibiotic prophylaxis of endocarditis and hormonal treatments; there is no specific diet and no disease-specific drug contraindication [13].

Among surgical procedures, the PNDS lists, in addition to those already described, hip arthroplasty with a custom-made prosthesis, correction of genu valgum and hallux valgus, trigger finger surgery, ulnar nerve decompression, surgery for follicular cysts and limited mouth opening, dental extractions in the context of endocarditis prophylaxis, glaucoma and cataract surgery, tympanoplasty, gastrostomy and central catheter placement [13]. Among non-pharmacological measures, it includes physical and rehabilitation medicine, motor and respiratory physiotherapy, psychomotor therapy, occupational therapy, speech and language therapy (including orofacial re-education), orthoptics, hearing aids, two pairs of spectacles (normal lenses and tinted lenses for the photophobia of corneal clouding) and low-vision aids, mechanical ventilation, oxygen and secretion suction, enteral feeding, orthoses and braces, adapted toothbrushes and orthodontics, a walking frame, wheelchair and adjustable bed, as well as psychological support [13].

7.16. Investigational therapies and developments over the last 12 months

Liver-directed gene therapy with the AAV2/8.TBG.hARSB vector was tested in a phase 1/2 trial (NCT03173521; Telethon Institute of Genetics and Medicine, Naples) in 9 patients aged 4 years or older, who stopped ERT and received a single intravenous infusion in three dose cohorts [77, 78]. There were no serious adverse effects attributable to the vector; in the low- and intermediate-dose cohorts, serum ARSB stabilised at approximately 20% of the normal mean, but patients resumed ERT by 14 months because of increased urinary GAGs, while in the high-dose cohort ARSB remained at 30–100% of the normal mean with a modest GAG increase, without a need for ERT or clinical deterioration up to 2 years [77]. Follow-up of the high-dose cohort (6 × 10^12 genomes/kg; 4 patients aged 5–10 years; median 45 months), published in 2025, showed serum ARSB at 38–67% of the reference value, no late safety events or relevant changes in endurance, cardiac or pulmonary function, and resumption of ERT in 1 of the 4 patients because of elevated GAGs [79]. The trial was completed on 16/07/2024, and no phase 3 trial or regulatory application was identified [78, 79]. Level of evidence: published phase 1/2 trial.

Odiparcil, an oral drug that promotes synthesis of soluble drug-bound GAGs excreted in urine, was studied in the phase 2a iMProveS trial (NCT03370653) in patients aged 16 years or older for 26 weeks: 20 enrolled, 13 (65%) completed; it increased total urinary GAGs, chondroitin sulphate and dermatan sulphate in proportion to exposure, with good tolerability and individual signals of improvement in pain, corneal opacity and cardiac, vascular and respiratory function [80]. Inventiva's annual report to the Securities and Exchange Commission (SEC) for the 2024 financial year describes suspension of clinical activity in 2020, the FDA's indication in 2022 that a single 52-week paediatric phase 2/3 trial with 50 patients aged 5–15 years could support a marketing application, the absence of a partner and, in February 2025, the company's exclusive focus on lanifibranor; the programme is on hold [81]. Level of evidence: phase 2a trial and company regulatory report.

Ongoing studies without published results include a phase 1/2 trial of off-label vosoritide (Voxzogo®) for growth deficiency in MPS IVA and VI (NCT05845749; 6 patients aged 5–10 years; 15 µg/kg/day subcutaneously for 96 weeks; active, not recruiting, completion expected in 2029), a phase 1/2 trial of adalimumab versus placebo for pain in MPS I, II and VI (NCT03153319; completion expected in 2027), and the PEARL study of prenatal intrauterine ERT in lysosomal diseases (NCT04532047), whose registry does not explicitly specify MPS VI inclusion [82–84]. Other registrations include the French RaDiCo-MPS cohort, a losartan study in MPS IV and VI in Porto Alegre with unknown status, and a growth hormone study terminated with 2 patients [51]. A 2025 review identifies AAV and CRISPR/Cas9 gene therapy, HSCT combined with gene therapy, substrate reduction, immunomodulation, stop-codon read-through, pharmacological chaperones and cartilage targeting as preclinical approaches [85]. Personalised antisense therapy for ARSB splicing variants is at the preclinical stage [31].

Over the last 12 months (October 2025 to October 2026), relevant publications were the 15-year CSP report, the Turkish HSCT series, the 10-year results of Taiwan's newborn screening programme and the LysoNeo study, and a case of caesarean section under epidural anaesthesia; in the European Union, galsulfase authorisation underwent annual renewal by decision of 12/12/2025, and in the USA the label did not change after 12/09/2024 [14, 15, 43, 49, 50, 73, 86].

7.17. Pregnancy and lactation

Pregnancy may exacerbate MPS VI manifestations, and neurological deterioration during pregnancy has been described [8, 14]. The US label brings together 17 galsulfase-exposed pregnancies from the CSP pregnancy substudy and published cases, with no major birth defects or adverse maternal or fetal outcomes attributable to the drug; in rats and rabbits, doses up to 3 mg/kg/day (approximately 0.5 and 0.97 times the human dose by body surface area) caused no fetal harm [14]. The pregnancy substudy was not found as a separate publication. There are no data on the presence of galsulfase in milk, effects on the infant or milk production, and the decision to breastfeed weighs the benefits of breastfeeding against the mother's treatment needs [14]. At the time of authorisation, the EPAR summary stated that safety and efficacy in pregnant and breastfeeding women remained information awaited [15]. The current European SmPC recommends that galsulfase not be used in pregnancy unless clearly necessary and that breastfeeding be discontinued during treatment, diverging from the US label, which leaves the decision to breastfeed to clinical judgement [14, 15].

Obstetric anaesthesia follows the principles in subsection 7.12: neuraxial techniques require extreme caution but may be considered during pregnancy to avoid general anaesthesia (grade D; 88%) [5]. In a Chinese case published in 2026, a 29-year-old primigravida with very short stature, wheelchair dependence, macroglossia, Mallampati IV and aortic valve disease underwent elective caesarean section at 26 weeks because of progressive lower limb weakness, under ultrasound-guided continuous epidural anaesthesia with incremental lidocaine doses to a T6 sensory level, with rescue general anaesthesia prepared, without complications and with a viable newborn [86].

The French PNDS describes pregnancies carried to term in women with a moderate form of MPS VI and recommends a preconception consultation with the disease specialist and an obstetrician familiar with these situations, to review cardiovascular and imaging status, adjust treatments (including analgesics), provide genetic counselling and discuss the risks and mode of delivery [13]. Caesarean section is usually recommended, the postpartum period requires enhanced monitoring and, in some cases, pregnancy is discouraged because of maternal risk; the maternity unit is chosen for its obstetric expertise in MPS and the risk of prematurity, and the anaesthetic consultation should be early and assess the difficulty of intubation [13]. As for ERT, data are scarce but reassuring: the PNDS proposes interrupting it, if possible, in the first trimester and resuming it if the mother's clinical condition requires; transfer into milk is very low, but breastfeeding is not recommended in women at risk of osteoporosis; combined oral oestrogen–progestogen contraception or an intrauterine device is discussed case by case [13].

7.18. Transition to adulthood

Adult patients continue multisystem monitoring, with the possibility of reducing spinal MRI and spirometry frequency when stable and asymptomatic [5]. No patients over 29 years were included in galsulfase trials, and the CSP showed gains mainly in those under 18 years at baseline and stabilisation in older patients [14, 43]. In adults, hip replacement, valve surgery, corneal transplantation, spinal cord decompression and recurrent carpal tunnel syndrome become more prominent [5]. The case reported by Andrade and colleagues illustrates the potential for employment with preserved intelligence (section 10) [37]. The French PNDS asks that transition be anticipated and adjusted to clinical status, beyond legal age, with a first joint consultation between the paediatrician and the adult physician and a summary document, and that it include the change of all contacts, including from paediatric to adult transplant and palliative care teams, and the definition of the ERT setting [13]. At transition it recommends cervicothoracic CT with tracheal assessment and pulmonary function tests with inspiratory measures (maximal inspiratory pressure and sniff test), because laryngotracheal malacia, stenosis or compression may be minimally symptomatic at rest; assessment of the craniocervical junction before any intubation (odontoid hypoplasia, ligamentous or meningeal hypertrophy, disc disease), since the risk of spinal cord compression persists in adults regardless of treatment; cardiological follow-up at least annually (isolated valvular disease, aortic root dilatation, arrhythmias); and screening for sleep apnoea, especially if there is arterial hypertension [13].

The PNDS integrates palliative care from diagnosis in severe forms, in parallel with specific treatment or a trial, or at turning points (distressing symptoms, a surgical decision, continuation of ERT, level of care in a decompensation, deterioration of general condition, family exhaustion), with attention to the place of residence and respite for carers; with therapeutic progress, death now occurs more often in adulthood, which leads to discussing with the patient the approach to serious complications and, sometimes, drafting advance directives, and to supporting relatives in bereavement [13].

7.19. Agents and situations to avoid

Sedating antihistamines, such as diphenhydramine, may worsen apnoea, and the consensus favours non-sedating antihistamines for premedication [1, 5]. Sedative premedication before anaesthesia is used cautiously and with monitoring [5]. Cervical hyperextension, intraoperative hypotension and volume overload during infusion in patients weighing 20 kg or less should be avoided [5, 14]. Oxygen without monitoring for hypercapnia in patients with hypoventilation is discouraged [5]. Galsulfase infusion should be postponed in the event of acute febrile or respiratory illness [14].

7.20. Divergences between sources

The EPAR summary lists hypersensitivity as a contraindication, whereas the US label has no contraindications [14, 15]. The US label recommends an antihistamine with or without an antipyretic without specifying the type and warns about apnoea, whereas the consensus explicitly recommends a non-sedating antihistamine and considers the evidence for the need for premedication limited [5, 14]. Regarding HSCT, the consensus considers the risk–benefit balance less clear (grades C and D), and Saudubray's textbook reserves it for unavailability of ERT, whereas the 2025 Turkish series advocates offering it as a permanent alternative [5, 9, 73]. Cardiac assessment is annual in the consensus, extendable to 2–3 years if normal, and every 1–2 years in the 2010 review [1, 5]. The 2017 Oxford Desk Reference describes ERT for MPS VI as “under trial”, a statement outdated since 2005 [14, 87].

The 2025 French PNDS diverges on other points. For premedication, it proposes hydroxyzine and treats reactions with dexchlorpheniramine, both sedating antihistamines, whereas the consensus prefers non-sedating antihistamines and the US label warns about apnoea; in a patient with obstructive apnoea, the choice of antihistamine should weigh this risk [5, 13, 14]. For surveillance intervals, the PNDS is less frequent than the consensus for spinal MRI and electroneuromyography (1–3 years after 2 years of age, versus annual), respiratory function (1–3 years, versus annual until the end of growth), audiometry (1–2 years, versus annual), urinary GAGs (six-monthly only in the first year of treatment and annual thereafter, versus six-monthly) and ophthalmology (annual, versus six-monthly if possible), and more frequent for polysomnography (1–3 years, versus 3 years); for the heart it proposes 1–2 years in children and at least annually in adults, versus annual, extendable to 2–3 years if normal [5, 13]. For the functional outcome, the PNDS uses the 6-minute walk test in follow-up, although the benefit of galsulfase was demonstrated with the 12-minute test [13, 65]. For HSCT, the PNDS explicitly ranks donors (non-heterozygous sibling, cord blood, 10/10 unrelated donor), whereas the consensus lists them without hierarchy [5, 13]. In pregnancy and lactation, the PNDS proposes interrupting ERT in the first trimester if possible and discourages breastfeeding only if there is a risk of osteoporosis, an intermediate position between the European SmPC (do not use unless clearly necessary; discontinue breastfeeding) and the US label (no recommendation to interrupt) [13–15]. For the enzyme assay, the PNDS does not include MPS VI among the diseases in which serum or plasma serve as the matrix, unlike Saudubray's textbook and the Brazilian textbook of genetic syndromes; leucocytes are the matrix common to all sources [9, 13, 39]. Finally, the PNDS gene table attributes “arylsulfatase A” and the location 5q11-q13 to MPS VI, typographical errors contradicted by the document's own summary and laboratory annex, which state arylsulfatase B; the current location of ARSB is 5q14.1 [6, 13].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

MPS VI is autosomal recessive: each pregnancy of a couple in which both partners are carriers has a 25% probability of an affected child, 50% of an asymptomatic carrier child and 25% of a non-carrier child [9, 39]. Each healthy sibling of a patient has a 2/3 probability of being a carrier. Children of a patient are, at minimum, obligate carriers; their risk of having the disease depends on the probability that the other parent is a carrier, which increases with consanguinity and in founder populations, such as Monte Santo, where 41.5% of tested unaffected relatives were heterozygotes [33]. Carriers have no clinical manifestations [1]. The sources consulted do not describe germline mosaicism or de novo variants in MPS VI. Parental testing confirms variant phase and avoids interpreting a variant on one allele with a deletion on the other as homozygosity.

8.2. Carrier testing and cascade testing

Genetic testing is available for confirmation and carrier detection, for counselling and family planning purposes [9]. Heterozygosity may produce intermediate arylsulfatase B activity, but molecular testing for familial variants is the method of choice for cascade testing [1, 8]. Siblings of a patient should be assessed biochemically even without symptoms, because early ERT initiation improves outcomes, as sibling studies show [9, 70, 71]. In populations with a high carrier frequency, such as the Monte Santo and Ceará communities, authors advocate community newborn screening, education and genetic counselling [33, 34]. The presence of p.S384N or p.T212I should be interpreted in light of their non-pathogenic nature [1]. In France, informing relatives about a serious genetic disease has been a legal obligation since decree no. 2013-527 of 20 June 2013: it falls to the parents or the adult patient, with explanation and support from the geneticist or genetic counsellor and an offer of a genetics clinic appointment for relatives; with the variants known, heterozygosity in relatives is established by direct testing [13].

8.3. Prenatal and preimplantation diagnosis

Prenatal diagnosis is performed by molecular testing for familial variants or enzyme measurement in chorionic villi or cultured amniocytes (subsection 5.7) [1, 23]. The French PNDS prefers molecular testing when the variants of the index case and of both parents have been identified, leaving enzyme testing as an alternative; chorionic villus sampling is performed between 11 and 13 weeks of gestation and amniocentesis from 15–16 weeks, and termination of pregnancy for medical reasons, at the request of the couple or the woman, is decided with a multidisciplinary prenatal diagnosis centre [13]. Preimplantation genetic testing is an alternative for couples with known variants who wish to avoid termination of pregnancy. The ultrasound finding of fetal ascites or non-immune hydrops in a couple without a previous diagnosis may justify investigation for lysosomal diseases, including MPS VI [35]. Diagnosis at birth by dried blood spot allows ERT initiation in the first weeks in an affected sibling [1, 70].

8.4. Counselling

Counselling should address the severity spectrum, unpredictability of genotype–phenotype correlation, benefits and limitations of ERT and HSCT, burden of weekly infusions and multisystem surveillance, and anaesthetic risks [1, 5]. Carrier testing in asymptomatic minors should generally wait until the individual can decide, unlike diagnostic testing of siblings at risk of disease, which has immediate clinical benefit. A woman with MPS VI considering pregnancy should be informed of the risk of worsening manifestations and the experience limited to 17 galsulfase-exposed pregnancies [14]. Referral to patient organisations forms part of counselling (94% agreement in the consensus) [5]. The French PNDS specifies that the diagnosis be disclosed at a dedicated consultation by a specialist from a reference or competence centre, with information on prognosis, the goals and limitations of treatments and at least annual reassessment, support from the time of disclosure, information on patient organisations, systematic liaison with the attending physician and provision of an emergency card; in particularly severe forms, a palliative care team may be involved early, to support the family and build a life plan [13]. Information for the patient also covers warning signs, treatment adherence, vaccination, the need for specific follow-up in pregnancy and the systematic offer of a genetics clinic appointment, including for the extended family [13].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Birth prevalence and what each figure measures

All available data are birth prevalence estimates obtained by clinical or laboratory case ascertainment, not population prevalence studies, and underestimate the true frequency, particularly of slowly progressive forms; there is no worldwide estimate or centralised registry in the USA [1, 6].

Source: table 1 of Valayannopoulos and colleagues (2010), compiling the studies listed [1, 12].

The relative frequency of MPS VI among MPS varies from 2–4% in Scandinavia and 3% in the Netherlands to 16% in Portugal and 18.5% in Brazil [1]. The cumulative incidence of all MPS in Germany was approximately 3.53/100,000, and a general estimate cited in the cardiogenetics textbook is 1 in 25,000 newborns for all MPS combined [12, 23]. The French PNDS estimates the incidence of MPS VI at 1 in 600,000 births and that of all MPS combined at 1 in 25,000 to 1 in 30,000, without stating the period or the ascertainment method [13]. MPS I and MPS III are the most frequent MPS in most populations, except in the United Arab Emirates and Turkey, where MPS VI is the most frequent [9].

9.2. Europe and populations of Turkish origin

In Germany, birth prevalence among patients of Turkish origin was approximately 10 times higher than in the non-Turkish population (1 in 43,261 versus 1 in 432,610), a difference attributed to consanguinity, and the proportion of patients of Turkish origin was also high in MPS IIIB and IVA [1, 12]. In Turkey, a series of 14 treated children and a series of 17 transplanted children document the clinical frequency of the disease, but the sources consulted do not identify a specific Turkish founder variant [40, 73]. The European Reference Network for Hereditary Metabolic Disorders, MetabERN, includes lysosomal diseases and coordinates referral centres in the European Union [17]. The French national organisation is described in subsection 9.8.

9.3. Portugal

The study by Pinto and colleagues (2004) identified 16 MPS VI patients in Portugal between 1982 and 1999 and estimated a birth prevalence of 0.42/100,000 (1 in 238,095) for northern Portugal, with MPS VI accounting for 16% of MPS, one of the highest proportions in Europe [1, 6]. The 23-base-pair deletion in exon 8 (“1533del23”), frequent in Brazil, was also found in Portuguese patients, at an unknown frequency [1]. The sources consulted do not describe current data on access to ERT in Portugal.

9.4. Brazil and founder populations of the Northeast

At the national reference laboratory in Porto Alegre, 1652 MPS patients were diagnosed between 1982 and 2019; birth prevalence of all MPS was 1.57/100,000 (1994–2018), MPS II was the most common nationally, and MPS VI was the most frequent in the Northeast and second most frequent in the North and Central-West, differences attributed to founder effect, endogamy and consanguinity; the abstract consulted does not give MPS VI-specific prevalence [88]. The Brazilian textbook of genetic syndromes states that MPS incidence in Brazil is unknown and that MPS II and VI are the most prevalent in Ceará [39].

In Monte Santo, a rural, isolated municipality in inland Bahia, with large families, community endogamy and high parental consanguinity (α = 0.00483), 13 patients (9 alive and 4 deceased) were confirmed in 11 kindreds, all homozygous for the founder variant c.533A>T p.(His178Leu), and the families identified another 33 deceased individuals with the same phenotype [33]. Among 236 unaffected relatives tested, 20.8% of alleles were mutant and 41.5% of individuals were heterozygotes; these figures refer to relatives, not the general population [33]. An incidence approaching 1 in 5000 live births in Monte Santo is cited indirectly in a case report, without confirmation in the primary source consulted [37]. In Ceará, in a series of 76 MPS patients, 13 had MPS VI and were children of consanguineous marriages in small neighbouring towns; 10 of them, from at least 7 families, were homozygous for c.1143-8T>G, a variant previously described only in Iberian and South American patients [34]. In the 2004 series of 28 Brazilian patients, the “1533del23” deletion accounted for 23% of alleles [1, 26]. The sources consulted do not document an MPS VI cluster in other northeastern states. Rede MPS Brasil, based at the Federal University of Rio Grande do Sul, organises national laboratory diagnosis [20, 88].

9.5. Middle East, Asia and other regions

The 2024 Saudi consensus presumes above-average prevalence in Saudi Arabia because of high consanguinity, and Nyhan's atlas illustrates the disease using Saudi patients [8, 55]. In the Asia-Pacific region, a survey of 13 physicians from 8 countries or regions brought together 22 patients, approximately 80% with the rapidly progressive form, with wide variation in access to diagnosis, treatment and financial coverage [56]. In Taiwan, newborn screening of 587,158 infants identified no MPS VI cases in the published abstract, consistent with the estimated rarity of 1 in 833,000 [1, 49].

9.6. Special populations

In children weighing 20 kg or less, infusion volume should be reduced [14]. Adults with slowly progressive forms may be diagnosed late in orthopaedic, cardiology or ophthalmology clinics, and patients over 29 years were not studied in trials [8, 14]. Pregnant women require specialist anaesthetic planning (subsection 7.17) [5, 86]. The frequency of the disease in consanguineous and endogamous communities justifies targeted screening and counselling strategies [33, 34].

9.7. Patient organisations

The consensus recommends referral to the national MPS society or patient organisation [5]. Examples include the Society for Mucopolysaccharide Diseases in the United Kingdom, the National MPS Society in the USA, and Rede MPS Brasil, the national MPS diagnostic network [18–20]. In France, the association Vaincre les Maladies Lysosomales (VML), recognised as being of public utility, covers all lysosomal storage diseases, took part in drafting the PNDS and sits on the scientific committee of the RaDiCo-MPS cohort; the MPS Society is the international organisation indicated in the same document [13].

9.8. Organisation of care in France

Lysosomal diseases have had accredited reference centres in France since 2004; the 2025 PNDS describes the Reference Centre for Lysosomal Diseases (CRML), coordinated at Hôpital Armand Trousseau (AP-HP, Paris), with constituent and competence centres, the Reference Centre for Inherited Metabolic Diseases, coordinated in Marseille, with 8 constituent centres and 18 competence centres, and the Reference Centre for Constitutional Bone Diseases, all linked to the G2M health filière, accredited in 2014 and renewed in 2019 [13]. The CETMPS-GP committee, a subgroup of the Committee for the Evaluation of Lysosomal Therapies (CETL), may be consulted by any physician about a patient with suspected or diagnosed MPS, validates treatment indications and discontinuations and holds multidisciplinary team meetings on a digital platform [13]. Dedicated multidisciplinary clinics bring together specialists and investigations over half a day to two days, once or twice a year, coordinated by a hospital physician, often supported by hospital-at-home services for infusions and by community–hospital networks that include the school [13].

Biochemical diagnosis is performed in reference medical biology laboratories: Lyon, Necker (Paris), Rouen, Toulouse and Grenoble measure urinary GAGs and MPS enzyme activities, including arylsulfatase B, and Lille measures arylsulfatase B and β-galactosidase; the first four sequence ARSB and the other MPS genes, and Lyon, Necker and Rouen also include SUMF1, for multiple sulfatase deficiency [13]. The national RaDiCo-MPS cohort, sponsored by the Institut National de la Santé et de la Recherche Médicale (INSERM), collects, with consent, epidemiological, natural history, treatment benefit and socioeconomic data on all MPS [13]. The Enzy-moi therapeutic education programme of the G2M filière is intended for patients over 12 years and for carers of patients of any age with a lysosomal disease, whether or not treated with intravenous ERT, and offers up to 10 sessions in groups of no more than 4 people, mostly remote, on the disease, ERT, the infusion setting, balancing school, work and family, surveillance, unforeseen situations and travel; enrolment is through the filière website, followed by a shared educational diagnosis [13].

On the social side, MPS entitles patients to 100% coverage of disease-related expenses under the long-term condition ALD 17, without replacing basic and supplementary insurance; transport to a reference or competence centre more than 150 km away is reimbursed with prior approval; parents may take parental presence leave with a daily allowance (up to 310 days over a 3-year period, at most 22 per month) and carers may take carer's leave (up to 3 months, or 66 days, divisible and renewable up to one year) [13]. The Maison Départementale des Personnes Handicapées awards disability compensation benefits (AEEH, AAH, PCH), the mobility-inclusion card with a disability rate of 80% or more, recognition of disabled worker status and educational and medico-social placements (personalised schooling plan, classroom assistant, CAMSP before 6 years, SESSAD, IME, IEM and, in adults, ESAT, FAM or MAS), whose response times of several months require anticipation [13].

10. Illustrative Clinical Case

10.1. Prenatal presentation and rapidly progressive cardiac disease in a Brazilian infant

Honjo and colleagues (2020) described a boy, the only child of a healthy, non-consanguineous Brazilian couple, whose second-trimester ultrasound showed fetal ascites and bilateral hydrocele, with negative infectious serology [35]. He was born at term by caesarean section weighing 3400 g (58th percentile), measuring 48 cm (20th percentile), with a head circumference of 35.5 cm (79th percentile), hydrocele, diastasis recti, unilateral clubfoot, mildly coarse facial features and no visceromegaly; echocardiography on day four showed only a patent foramen ovale, and radiographs at 1 month showed mildly deformed proximal metacarpals and thickening of provisional cartilage [35]. Figure 1 of the article, consulted on the figure page, shows the newborn, lumbar gibbus at 6 months and a low nasal bridge with mildly coarse facial features at 8 months (https://pmc.ncbi.nlm.nih.gov/articles/PMC7031867/figure/Fig1/) [35].

At 6 months he had a lumbar mass progressing since 2 months (gibbus), recurrent respiratory infections and two admissions for wheezing; fetal ascites initially prompted suspicion of MPS VII [35]. Urinary GAGs were 402 µg/mg creatinine (age-specific reference 133–460), with dermatan sulphate excretion, a value within the age-specific reference interval illustrating the limitations of total GAGs in infancy; leucocyte arylsulfatase B activity was deficient, with another normal sulfatase, and ARSB analysis showed c.944G>A p.(Arg315Gln) and c.1143-1G>C in trans, the latter frequent in Spanish and Argentinian patients [35].

At 7 months respiratory distress developed, and echocardiography showed mild tricuspid regurgitation and a thickened mitral valve with posterior leaflet prolapse and moderate-to-severe regurgitation, treated with furosemide, captopril and spironolactone; at 9 months decompensation required intensive care admission, dobutamine and dopamine followed by carvedilol, with left atrial and ventricular dilatation (diastolic diameter 50.7 mm; ejection fraction 78.9%) and severe mitral regurgitation [35]. At 10 months he developed congestive heart failure and was discharged on furosemide, captopril, spironolactone, carvedilol, digoxin, acetylsalicylic acid and domperidone, then readmitted for hypoxaemia and hepatomegaly requiring bilevel non-invasive ventilation [35]. Figures 2 to 4 of the article document the dilated left ventricle in M-mode, the mitral regurgitant jet in the apical 4-chamber view and Doppler evidence of severe regurgitation; they were described from the captions in the full text (https://pmc.ncbi.nlm.nih.gov/articles/PMC7031867/) [35].

At 11 months he underwent mitral valvuloplasty, with quadrangular resection of the P2 segment and annuloplasty using a bovine pericardial patch (figure 5 of the article, described from its caption), and began weekly galsulfase 1 month later [35]. On the last echocardiogram described, mitral regurgitation was mild, and urinary GAGs were 246 µg/mg creatinine (reference under 2 years: 79–256); at 2.5 years growth had improved and there was mild motor delay, with sitting achieved at 18 months and walking at 23 months [35]. The parents consented to publication of the data and images [35].

10.2. Lessons from the case

The authors consider this the first MPS VI case with a prenatal manifestation of fetal ascites and propose including MPS VI, alongside MPS I, IVA and VII, in the differential diagnosis of fetal hydrops or ascites; this was the second MPS patient to undergo successful mitral valvuloplasty [35]. In the authors' literature review, valve surgery in MPS VI generally occurred in adults (mean age 30.9 years), and mortality from left-sided valve surgery was 20%, an indirectly attributed figure [35]. Valve surgery in the first year of life and initiation of ERT only after surgery reflect the circumstances of the case and do not constitute routine practice; the consensus recommends starting galsulfase as soon as the diagnosis is confirmed and indicates valve replacement for severe symptomatic disease, decided at a referral centre [5].

10.3. Complementary case: 15 years of ERT initiated in adolescence

Andrade and colleagues (2022) described a 29-year-old Brazilian man, born to non-consanguineous parents, whose older brother with a similar phenotype died in 1995, aged 6 years, from respiratory complications without ERT [37]. Diagnosis was made at 2.5 years, with urinary GAGs of 235 µg/mg creatinine (normal 13–45) and leucocyte arylsulfatase B of 6 nmol/h/mg protein (normal 72–176), with normal α-iduronidase and iduronate sulfatase; the genotype included paternally inherited c.944G>A p.(Arg315Gln) and a maternally inherited 23-base-pair deletion in exon 8, written as “c.1534del23” [37]. Before ERT he had growth failure, contractures, coarse facial features, valvular disease, conductive hearing loss and, owing to chronic intracranial hypertension with hydrocephalus, bilateral optic atrophy with irreversible blindness; he could neither stand nor walk [37]. He entered the phase 3 trial in October 2003, aged 13 years, and continued galsulfase 1 mg/kg/week for more than 15 years, becoming able to walk without support, with improved hearing and clinical stability [37]. At 28 years he had height below the 3rd percentile, claw hands, an umbilical hernia, hepatosplenomegaly, 3+ hyperreflexia, unsustained clonus and a Babinski sign, pyramidal signs warning of myelopathy, and multiple nerve compressions consistent with carpal tunnel syndrome on electromyography; he graduated in Law and is employed, without intellectual disability [37]. The article has no clinical figures.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In natural history, the rapidly progressive form led to death, mainly from cardiac or respiratory failure, in the second or third decade, whereas the slowly progressive form allowed survival into the third decade or beyond, or into the fourth or fifth decade according to other sources [1, 6, 8]. Urinary GAGs above 100 µg/mg creatinine are a negative prognostic sign in untreated patients [1, 27]. Prognosis depends on age at onset, rate of progression, age at ERT initiation and quality of care [1]. During ERT, observed mortality in the 10-year resurvey was 16.5% in treated patients versus 50% in untreated patients, in a non-randomised comparison [42]. Osteoarticular disease, corneal clouding, valvular disease and spinal cord compression persist or progress even with ERT initiated in the first year, and mean adult height in treated patients in a US cohort was 128 ± 15 cm [44–46]. Early diagnosis improves prognosis, and respiratory disorders are among the most relevant causes of mortality [39].

11.2. Surveillance

The 2010 review proposed cardiac assessment every 1–2 years, an interval close to the extendable annual interval of the 2019 consensus, which takes precedence [1, 5]. Imaging should minimise radiation and be requested when useful, and MRI may require sedation or general anaesthesia, with the risks described in subsection 7.12 [5]. Radiological signs alone are insufficient to indicate preventive spinal surgery [5]. The divergences between the consensus intervals and those of the French PNDS are discussed in subsection 7.20; the PNDS recommends bringing investigations forward in the presence of functional complaints or before planned surgery and weighing the benefit–risk balance when MRI requires general anaesthesia [13].

12. Summary and Final Considerations

MPS VI is an autosomal recessive lysosomal disease caused by biallelic ARSB variants, which reduce N-acetylgalactosamine-4-sulfatase activity and lead to accumulation of dermatan sulphate and chondroitin-4-sulphate in connective tissues, heart valves, the cornea and meninges. Presentation forms a continuum between a rapidly progressive form, with onset in the early years, marked short stature and death in the second or third decade without treatment, and a slowly progressive form, which may manifest only in adulthood through hip disease, valvular disease or corneal clouding. Intelligence is usually preserved, and neurological complications are mechanical: cervical spinal cord compression, communicating hydrocephalus and optic atrophy.

Diagnosis requires demonstration of arylsulfatase B activity below 10% of the lower limit of normal in leucocytes or fibroblasts, with another normal sulfatase to exclude multiple sulfatase deficiency, and is confirmed by identifying two pathogenic ARSB variants, described on transcript NM_000046.5. Total urinary GAGs may be normal, p.T212I pseudodeficiency and the p.S384N polymorphism may be misleading, and structural variants may escape exon sequencing.

Galsulfase, 1 mg/kg weekly intravenously in children and adults (with no maximum dose defined in the labels), is the only licensed specific therapy, authorised in the USA in 2005 and in the European Union in 2006, and should be started immediately after diagnosis; it improves endurance, pulmonary function and growth in subgroups, but does not prevent corneal, skeletal or valve disease or spinal cord compression, and controlled evidence is limited to one 24-week trial with 39 patients. HSCT is a selected option whose risk–benefit balance relative to ERT remains to be defined. Management rests on a multidisciplinary team that follows the surveillance intervals of the 2019 consensus, intervenes early in the airway, spine, hip, hand, heart and eye, and plans every anaesthetic as a high-risk procedure. The 2025 French PNDS confirms the label dose of 1 mg/kg/week, proposes longer intervals for some surveillance investigations and adds a stepwise protocol for infusion reactions, a pre-anaesthetic checklist and a national organisation with collegial validation of treatment indications.

The epidemiology is characterised by birth prevalence estimates ranging from approximately 1 in 43,000 to 1 in 1.5 million, a high proportion among MPS in Portugal and Brazil, and founder populations in northeastern Brazil, with c.533A>T in Monte Santo and c.1143-8T>G in Ceará. Hepatic gene therapy showed sustained enzyme expression in high-dose patients in a phase 1/2 trial, with no ongoing phase 3 trial, and multiplex newborn screening, already in use in Taiwan, may bring forward diagnosis and treatment initiation.

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