Mucopolysaccharidosis type X

Mendelian MONDO:0030524 Pathograph 18 Show in embeddings browser Mucopolysaccharidosis Lysosomal Storage Disorder

Mucopolysaccharidosis type X (MPS X, MPS 10) is an autosomal recessive lysosomal storage disorder caused by biallelic loss-of-function variants in ARSK, which encodes the lysosomal sulfatase arylsulfatase K (also called glucuronate 2-sulfatase, GDS). ARSK removes the 2-O-sulfate group from 2-sulfoglucuronate, an obligate step in the stepwise exolytic degradation of heparan sulfate, dermatan sulfate, and chondroitin sulfate. It is the most recently defined mucopolysaccharidosis: the human phenotype was first delineated in 2022, more than twenty years after the previous new MPS subtype. MPS X is the mildest and most narrowly skeletal of the mucopolysaccharidoses. Affected individuals present in mid-childhood with hip and knee pain, a waddling gait, and progressive hip dysplasia, and are typically first diagnosed with bilateral Legg-Calve-Perthes disease, spondyloepiphyseal dysplasia, or multiple epiphyseal dysplasia rather than with a storage disorder. Metaphyseal striation of the long bones is the most consistent radiographic clue. Coarse facial features, short stature, and mild cardiac and ophthalmological involvement are variable and emerge late; classical dysostosis multiplex, hepatosplenomegaly, hearing loss, and cognitive impairment are characteristically absent. The biochemical signal is correspondingly weak - routine dimethylmethylene blue urinary glycosaminoglycan screening is frequently normal, and only sensitive LC-MS/MS disaccharide quantification reveals the modest dermatan sulfate elevation. MPS X is therefore a mucopolysaccharidosis that the standard MPS diagnostic pathway systematically misses, and it is likely underdiagnosed among children carrying a skeletal-dysplasia label. No disease-modifying therapy exists; management is orthopaedic, analgesic, and surveillance-based.

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1
Mappings
1
Inheritance
5
Pathophys.
24
Phenotypes
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Gaps
18
Pathograph
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Genes
2
Medical Actions
3
Differentials
1
Models
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Classifications

Lysosomal Storage
mucopolysaccharidosis
ICIMD (Inherited Metabolic Disorders)
glycosaminoglycan degradation
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Mappings

MONDO
MONDO:0030524 mucopolysaccharidosis, type 10
skos:exactMatch MONDO
MONDO:0030524 is the MPS type 10 concept (OMIM:619698, ORPHA:662216, MEDGEN:1794274), corresponding exactly to the ARSK-deficiency disorder described here.
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Inheritance

1
Autosomal recessive inheritance HP:0000007
MPS X is autosomal recessive. Every reported family has had homozygous ARSK variants with heterozygous, unaffected parents; the two founding families were consanguineous, and homozygosity mapping contributed to gene identification in both.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34916232 SUPPORT Human Clinical
"we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively."
Homozygous ARSK variants in affected children of two consanguineous families establish autosomal recessive inheritance.
PMID:35959767 SUPPORT Human Clinical
"Both children were homozygous, and both parents heterozygous, for a predicted stop variant in ARSK"
Affected homozygous siblings with unaffected heterozygous parents is the direct segregation demonstration of autosomal recessive inheritance.
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Discussions and Knowledge Gaps

1
Why does the Arsk-knockout mouse accumulate the predicted GAG metabolites yet develop no skeletal disease, when skeletal disease is essentially the entire human phenotype?
HUMAN MODEL MISMATCH OPEN mpsx_mouse_skeletal_mismatch
Attached to
pathophysiology#Chondro-osseous storage and epiphyseal-metaphyseal dysplasia
The mismatch is not a failure of the model to reproduce a subtle feature; it is close to an inversion. The mouse has the biochemistry without the skeletal pathology and a behavioural phenotype instead, while humans have the skeletal pathology with normal cognition. Because the storage burden in MPS X is small in both species, the human skeletal phenotype is unlikely to be a simple dose effect of accumulated substrate. A more plausible reading is that glucuronate-2-O-sulfation is differentially abundant on the specific chondroitin and dermatan sulfate chains that carry load in the human growth plate and epiphysis, so the same enzymatic block has a tissue-specific consequence in humans that it does not have in mice. Resolving this matters practically: the mouse is the only available model, and it lacks the outcome an enzyme replacement therapy would need to move.
Proposed experiments
Compare glucuronate-2-O-sulfation abundance in human and murine growth-plate GAGs
exp_mpsx_species_sulfation_comparison
Quantify the fraction of chondroitin, dermatan, and heparan sulfate chains bearing 2-O-sulfated glucuronate in human versus murine epiphyseal and growth-plate cartilage by LC-MS/MS disaccharide analysis, to test whether differential substrate abundance in the relevant tissue explains the species divergence.
Would support
pathophysiology#Chondro-osseous storage and epiphyseal-metaphyseal dysplasia
Supporting outcome
  • Human growth-plate and epiphyseal cartilage carries a substantially higher fraction of 2-O-sulfated glucuronate than the murine equivalent, matching the tissue distribution of human disease.
Refuting outcome
  • The modification is present at comparable abundance in both species' cartilage, indicating that the species difference lies downstream of substrate abundance, in how chondrocytes tolerate the stalled fragments rather than in how many are produced.
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Pathophysiology

5
ARSK glucuronate 2-sulfatase deficiency
Biallelic loss-of-function variants in ARSK abolish or severely reduce the activity of arylsulfatase K, the lysosomal sulfatase that removes the 2-O-sulfate group from 2-sulfoglucuronate. Reported variants act through two distinct routes to the same end point. Nonsense alleles (p.Leu187Ter, p.Tyr417Ter) yield no detectable protein, consistent with nonsense-mediated decay. Missense alleles are catalytically dead while remaining stably expressed: p.Arg84Cys disrupts the conserved sulfatase signature 80-CCPSR-84 that is required to convert the active-site cysteine to formylglycine, and p.Ser356Tyr abolishes activity within the sulfatase domain without destabilizing the protein. Because sulfatases show high substrate specificity and no functional redundancy, no other human sulfatase compensates for the lost step. Term-binding note: the molecular function below is bound to GO:0008484 (sulfuric ester hydrolase activity), a broad parent, deliberately. GO has no term for glucuronate 2-O-sulfatase (glucuronate 2-sulfatase, GDS) activity, and no sibling sulfatase term fits - ARSK is specific for the 2-O-sulfate of 2-sulfoglucuronate and does not share substrates with the other lysosomal sulfatases. Binding a narrower but wrong term would misstate the enzymology, so the accurate parent is preferred over a manufactured match. A GO term request for the specific activity is the way to improve this.
ARSK hgnc:25239 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ARSK (hgnc:25239). hgnc:25239 is a gene from the HUGO Gene Nomenclature Committee.
glucuronate 2-O-sulfatase activity GO:0008484 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves glucuronate 2-O-sulfatase activity, annotated with sulfuric ester hydrolase activity (GO:0008484), qualified as loss of function. GO:0008484 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
lysosome GO:0005764 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosome (GO:0005764). GO:0005764 is a cellular component from the Gene Ontology.
Downstream
Lysosomal accumulation of 2-O-sulfoglucuronate-capped GAG fragments With the 2-O-desulfation step blocked, exolytic degradation stalls at every chain terminus bearing a 2-O-sulfated glucuronate, and the partially degraded fragments accumulate in the lysosome.
Show evidence (4 references)
PMID:34916232 SUPPORT Human Clinical
"Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate."
Defines the enzymatic step that is lost in MPS X: lysosomal removal of the 2-O-sulfate from 2-sulfoglucuronate during glycosaminoglycan degradation.
PMID:34916232 SUPPORT In Vitro
"Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by..."
Functional proof that the two founding variants cause loss of ARSK activity, by absent protein and by loss of catalytic activity respectively.
PMID:34916232 SUPPORT In Vitro
"The arginine at amino acid position 84 in ARSK is part of the highly conserved sulfatase signature 80-CCPSR-84"
Locates the p.Arg84Cys missense lesion in the sulfatase signature motif, explaining why a stably expressed protein is catalytically inactive.
+ 1 more reference
Lysosomal accumulation of 2-O-sulfoglucuronate-capped GAG fragments
Partially degraded heparan sulfate, dermatan sulfate, and chondroitin sulfate fragments terminating in 2-O-sulfoglucuronate accumulate in lysosomes. This is the GAG-accumulation hub of the mps_gag_storage module, but the storage burden is far smaller than in the other mucopolysaccharidoses and is engaged in a highly restricted way. Glucuronate-2-O-sulfation is an uncommon modification rather than a backbone-defining one, so only the minority of chains carrying it are blocked; the bulk of heparan, dermatan, and chondroitin sulfate is still catabolized normally. The module's heparan-sulfate neuronopathic arm and its keratan-sulfate skeletal arm are therefore not engaged - keratan sulfate is not an ARSK substrate, and no reported patient has CNS disease. Only the dermatan-sulfate connective-tissue arm is engaged, and even that partially: dermatan sulfate is the one GAG species reproducibly elevated in patient urine, and the downstream disease is confined to chondro-osseous and cardiac connective tissue rather than the generalized visceral storage of MPS I or VI.
glycosaminoglycan catabolic process GO:0006027 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycosaminoglycan catabolic process (GO:0006027). GO:0006027 is a biological process from the Gene Ontology. ↓ DECREASED dermatan sulfate proteoglycan catabolic process GO:0030209 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dermatan sulfate proteoglycan catabolic process (GO:0030209). GO:0030209 is a biological process from the Gene Ontology. ↓ DECREASED chondroitin sulfate proteoglycan catabolic process GO:0030207 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chondroitin sulfate proteoglycan catabolic process (GO:0030207). GO:0030207 is a biological process from the Gene Ontology. ↓ DECREASED heparan sulfate proteoglycan catabolic process GO:0030200 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased heparan sulfate proteoglycan catabolic process (GO:0030200). GO:0030200 is a biological process from the Gene Ontology. ↓ DECREASED
lysosome GO:0005764 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosome (GO:0005764). GO:0005764 is a cellular component from the Gene Ontology.
Animal models
Arsk knockout mouse Mouse recapitulates Complete loss of glucuronate desulfation with organ-specific accumulation of heparan and chondroitin sulfate metabolites bearing 2-O-sulfated glucuronate at their non-reducing ends, which is precisely the predicted biochemical lesion.
Downstream
Chondro-osseous storage and epiphyseal-metaphyseal dysplasia Storage in cartilage and bone-forming tissue disturbs epiphyseal and metaphyseal development, producing the skeletal disease that dominates MPS X. The intermediate steps between fragment accumulation and disturbed endochondral ossification have not been worked out in this disorder, so the link is annotated as indirect.
Cardiac valve storage involvement Dermatan-sulfate-biased storage in valvular connective tissue produces the mild, late cardiac findings of MPS X.
Ocular connective-tissue involvement Dermatan-sulfate-biased storage in ocular connective tissue produces the lens and vitreous opacity reported in the index family.
Show evidence (3 references)
PMID:34916232 SUPPORT Human Clinical
"Glucuronate-2-O-sulfation occurs in HS, DS and CS and, during degradation, is selectively removed by ARSK"
Establishes which GAG species carry the ARSK-dependent modification, and hence which are stalled when the enzyme is lost.
PMID:34916232 SUPPORT Human Clinical
"Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS."
Dermatan sulfate is the GAG species measurably elevated in patients, supporting the restricted, dermatan-biased character of the storage.
PMID:40742107 SUPPORT INDIRECT Human Clinical
"Biochemical analyses reveal variable dermatan sulfate (DS) excretion in urine, with some patients showing increased DS, while others had normal urinary glycosaminoglycans (GAGs), suggesting that a normal GAG profile does not exclude this condition."
Identifies dermatan sulfate as the affected species. Marked INDIRECT because the quote reports urinary excretion, from which lysosomal storage follows only by inference, and because it simultaneously establishes that the signal is inconsistent and can be undetectable by routine assays - the qualification this node depends on.
Chondro-osseous storage and epiphyseal-metaphyseal dysplasia
The dominant and near-universal disease arm of MPS X. Cartilage and bone-forming tissue develop an epiphyseal, metaphyseal, and vertebral dysplasia that presents clinically as hip and knee pain with a waddling gait in mid-childhood, and radiographically as metaphyseal striation of the long bones, platyspondyly with anterior vertebral beaking, delayed carpal ossification, small epiphyses, and inferior tapering of the ilia with a poorly formed acetabulum. Two features of its natural history distinguish it from the other mucopolysaccharidoses: the vertebral changes regress with time rather than progressing, while the hip dysplasia progresses in every reported patient, so the hip rather than the spine is the long-term burden. The picture is close enough to spondyloepiphyseal dysplasia, multiple epiphyseal dysplasia, and bilateral Legg-Calve-Perthes disease that every published patient carried one of those labels before sequencing.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
endochondral ossification GO:0001958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal endochondral ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology. ⚠ ABNORMAL
hip joint UBERON:0001486 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in hip joint (UBERON:0001486). UBERON:0001486 is an anatomical location from the Uberon multi-species anatomy ontology. epiphysis UBERON:0001437 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in epiphysis (UBERON:0001437). UBERON:0001437 is an anatomical location from the Uberon multi-species anatomy ontology. vertebra UBERON:0002412 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in vertebra (UBERON:0002412). UBERON:0002412 is an anatomical location from the Uberon multi-species anatomy ontology. growth plate cartilage UBERON:0004129 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in growth plate cartilage (UBERON:0004129). UBERON:0004129 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Arsk knockout mouse Mouse fails to recapitulate The mouse does not develop the skeletal disease that defines human MPS X. This is a substantive negative result rather than a gap: it means the mouse cannot serve as a preclinical efficacy model for the outcome that matters clinically, and any enzyme replacement therapy programme would need a different readout or a different species.
Downstream
Hip dysplasia Progressive acetabular and femoral head dysplasia is the dominant skeletal burden.
Avascular necrosis of the capital femoral epiphysis Femoral head involvement presents as a Legg-Calve-Perthes-like osteonecrosis, usually bilateral.
Metaphyseal striations Vertical metaphyseal striation of the long bones is the consistent radiographic marker.
Platyspondyly Vertebral body flattening with anterior beaking and irregular endplates.
Arthralgia Hip, knee, and back pain is the usual presenting complaint.
Waddling gait Hip disease produces the waddling gait that typically brings the child to attention.
Delayed ossification of carpal bones Carpal bones are unossified or small for age.
Disproportionate short-trunk short stature Vertebral involvement produces short-trunk disproportion, but only in older patients; younger children are of normal stature and proportion.
Show evidence (3 references)
PMID:38634625 SUPPORT Human Clinical
"Remarkably, all patients showed metaphyseal striation of the long bones, a crucial diagnostic clue to identify ARSK-related MPS type 10."
Identifies metaphyseal striation as the consistent radiographic marker of the chondro-osseous arm across an independent patient series.
PMID:38634625 SUPPORT Human Clinical
"Interestingly, vertebral involvement regressed during follow-up. On the other hand, hip dysplasia progressed in all patients."
Supports the divergent natural history annotated here: regressing vertebral disease with progressive hip disease.
PMID:38634625 SUPPORT Human Clinical
"While typical dysostosis multiplex findings were not observed, mild platyspondyly with anterior beaking of some vertebral bodies, irregular vertebral endplates, wide ribs, inferior tapering of the ilea with a poorly developed acetabulum, irregularity of the central part of the femoral head,..."
Enumerates the skeletal findings and states explicitly that classic dysostosis multiplex is absent, which is the discriminating feature of this node relative to the other mucopolysaccharidoses.
Cardiac valve storage involvement
A mild and late arm of the disease, found only on deliberate targeted assessment after the genetic diagnosis is made. Reported findings are an aortic or mitral murmur, valve thickening with regurgitation, mild aortic valve stenosis, and mild left ventricular hypertrophy suggesting early storage cardiomyopathy. Curated separately from the ocular arm below because the two have different evidence: the later series that found normal eye examinations throughout did not report absent cardiac involvement, so a single bundled node would leave it ambiguous which half its refuting evidence applied to.
cardiac valve UBERON:0000946 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cardiac valve (UBERON:0000946). UBERON:0000946 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Abnormal mitral valve morphology Valve leaflet thickening with regurgitation.
Aortic valve stenosis Mild aortic valve stenosis on echocardiography.
Show evidence (2 references)
PMID:34916232 SUPPORT DIRECT Human Clinical
"Heart abnormalities in S1 and S2 included cardiac murmur (aortic or mitral), valve disease, thickened leaflets and regurgitation."
Documents the valvular connective-tissue involvement that defines this node.
PMID:34916232 SUPPORT DIRECT Human Clinical
"Mild aortic valve stenosis and mild left ventricular hypertrophy were noted in cardiac ultrasound in S1 and S2."
Documents the stenotic and ventricular findings of this node on echocardiography.
Ocular connective-tissue involvement
The most variable arm of the disease, and the one with directly conflicting evidence. The index family showed mild lens and vitreous opacity, with loss of the retinal interdigitation zone temporal to the macula on optical coherence tomography in one patient. Two independent later series reported normal eye examinations throughout. This arm is therefore genuinely inconsistent between kindreds rather than merely under-ascertained, which is why it is recorded with both supporting and refuting evidence rather than being asserted or dropped. It remains the basis for offering ophthalmological surveillance once MPS X is diagnosed.
eye UBERON:0000970 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in eye (UBERON:0000970). UBERON:0000970 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Abnormal lens morphology Mild lens and vitreous opacity found on slit-lamp examination.
Show evidence (2 references)
PMID:34916232 SUPPORT DIRECT Human Clinical
"reverse phenotyping revealed mild opacity of the lens and vitreous body"
Documents the ocular finding in the index family.
PMID:38634625 REFUTE DIRECT Human Clinical
"All patients showed normal intelligence, normal hearing and eye examinations, and none had organomegaly."
Cuts directly against this node: an independent series found normal eye examinations in every patient. Now that the ocular arm is its own node, this REFUTE is unambiguous about what it refutes.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Mucopolysaccharidosis type X Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

24
Cardiovascular 3
Abnormal mitral valve morphology OCCASIONAL HP:0001633 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thickened valve leaflets with regurgitation, annotated with Abnormal mitral valve morphology (HP:0001633). HP:0001633 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"Heart abnormalities in S1 and S2 included cardiac murmur (aortic or mitral), valve disease, thickened leaflets and regurgitation."
Documents valve thickening and regurgitation.
Aortic valve stenosis OCCASIONAL HP:0001650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild aortic valve stenosis, annotated with Aortic valve stenosis (HP:0001650), qualified as severity mild. HP:0001650 is a phenotype from the Human Phenotype Ontology.
Severity: MILD
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"Mild aortic valve stenosis and mild left ventricular hypertrophy were noted in cardiac ultrasound in S1 and S2."
Documents mild aortic stenosis and ventricular hypertrophy.
Hepatosplenomegaly Absent EXCLUDED HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
Show evidence (2 references)
PMID:40742107 SUPPORT DIRECT Human Clinical
"None demonstrated hepatosplenomegaly, neurological deficits, or cognitive impairment."
Review across all ten reported patients states the absence of hepatosplenomegaly directly.
PMID:38634625 SUPPORT DIRECT Human Clinical
"All patients showed normal intelligence, normal hearing and eye examinations, and none had organomegaly."
An independent series independently reports absent organomegaly.
Ear 1
Hearing Impairment Absent EXCLUDED HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
Show evidence (2 references)
PMID:34916232 SUPPORT DIRECT Human Clinical
"Auditory tests revealed normal results in S1 and S2 at the age of 16 years and 14 years, respectively."
Formal audiometry was normal in both index patients tested.
PMID:38634625 SUPPORT DIRECT Human Clinical
"All patients showed normal intelligence, normal hearing and eye examinations, and none had organomegaly."
An independent series reports normal hearing throughout.
Eye 1
Abnormal lens morphology OCCASIONAL HP:0000517 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild lens and vitreous opacity, annotated with Abnormal lens morphology (HP:0000517), qualified as severity mild. HP:0000517 is a phenotype from the Human Phenotype Ontology.
Severity: MILD
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"reverse phenotyping revealed mild opacity of the lens and vitreous body"
Documents the lens and vitreous opacity.
Head and Neck 3
Thickened calvaria HP:0002684 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thickened calvaria (HP:0002684). HP:0002684 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
Documents thickened calvaria in all four index patients.
Coarse facial features OCCASIONAL HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild coarse facial features, annotated with Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34916232 SUPPORT Human Clinical
"The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex."
Reports coarse facial features among the MPS features of the index patients.
PMID:35959767 SUPPORT INDIRECT Human Clinical
"at age 9 years 5 months and at 11 years, respectively, they did not have coarse facial features or short stature, and were not disproportionate"
Reports absent coarse facies in two affected siblings who were younger than the index cases. The claim curated here is not that any given patient has coarse facies but that the feature is occasional and age-dependent, and a report of its absence in younger children supports that claim - so the direction is SUPPORT, marked INDIRECT because the age dependence is an inference from the contrast with the older index patients rather than something this quote states.
Enamel hypoplasia OCCASIONAL HP:0006297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypomineralized dental enamel, annotated with Enamel hypoplasia (HP:0006297). HP:0006297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35959767 SUPPORT Human Clinical
"Both children have slightly hypomineralized enamel on their permanent teeth."
Documents the enamel defect in both affected siblings of one family.
Limbs 4
Avascular necrosis of the capital femoral epiphysis HP:0005743 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral Legg-Calve-Perthes-like femoral head osteonecrosis, annotated with Avascular necrosis of the capital femoral epiphysis (HP:0005743). HP:0005743 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35959767 SUPPORT Human Clinical
"Bilateral LCPD should result in considering the possibility of MPS type X as well as other MPS subtypes"
Establishes bilateral Legg-Calve-Perthes disease as an MPS X presentation and a diagnostic prompt.
Metaphyseal striations VERY_FREQUENT HP:0031367 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vertical metaphyseal striations of the long bones, annotated with Metaphyseal striations (HP:0031367). HP:0031367 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38634625 SUPPORT Human Clinical
"Remarkably, all patients showed metaphyseal striation of the long bones, a crucial diagnostic clue to identify ARSK-related MPS type 10."
Supports both the near-universal frequency and the diagnostic value.
Delayed ossification of carpal bones HP:0001216 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed and defective carpal ossification, annotated with Delayed ossification of carpal bones (HP:0001216). HP:0001216 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35959767 SUPPORT Human Clinical
"Radiological changes were not present in the hand of Individual 1 at age 2 years, but at age 8 years 5 months several carpal bones were either not ossified or small for his age."
Documents defective carpal ossification and its emergence during childhood rather than at birth.
Genu valgum HP:0002857 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genu valgum (HP:0002857). HP:0002857 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"coarse facial features, short trunk disproportionate short stature and short neck, genua valga, and hip pain were noticed at the end of the first decade"
Documents genua valga among the presenting features.
Musculoskeletal 8
Hip dysplasia VERY_FREQUENT HP:0001385 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hip dysplasia with acetabular hypoplasia, annotated with Hip dysplasia (HP:0001385), qualified as course progressive. HP:0001385 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:40742107 SUPPORT Human Clinical
"The affected individuals usually present with progressive hip joint abnormalities."
Review of all reported patients establishes progressive hip involvement as the usual presentation.
PMID:38634625 SUPPORT Human Clinical
"Interestingly, vertebral involvement regressed during follow-up. On the other hand, hip dysplasia progressed in all patients."
Directly supports the progressive clinical course annotated here.
Platyspondyly HP:0000926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Platyspondyly with anterior vertebral beaking, annotated with Platyspondyly (HP:0000926). HP:0000926 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
Documents platyspondyly with anterior beaking in all four index patients.
Anterior beaking of lower thoracic vertebrae HP:0004607 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anterior inferior beaking of the thoracolumbar vertebrae, annotated with Anterior beaking of lower thoracic vertebrae (HP:0004607). HP:0004607 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
Documents anterior inferior vertebral beaking in all four index patients.
Small epiphyses HP:0010585 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small epiphyses (HP:0010585). HP:0010585 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
Documents small epiphyses in all four index patients.
Broad ribs HP:0000885 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad oar-shaped ribs, annotated with Broad ribs (HP:0000885). HP:0000885 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
Documents rib and clavicular broadening in all four index patients.
Hypoplastic iliac wing HP:0002866 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inferior tapering of the ilia, annotated with Hypoplastic iliac wing (HP:0002866). HP:0002866 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40742107 SUPPORT Human Clinical
"Radiographically, platyspondyly, inferior tapering of the ilea with acetabular hypoplasia, irregularity of the central part of the femoral head, and metaphyseal striation of the long bones characterize this condition."
Review across all reported patients confirms inferior iliac tapering with acetabular hypoplasia as a characteristic finding.
Joint hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypermobile interphalangeal finger joints, annotated with Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35959767 SUPPORT Human Clinical
"Both children had hypermobile interphalangeal finger joints, which is also a feature of MPS type IV"
Documents interphalangeal hypermobility and explicitly aligns it with the MPS IV joint phenotype rather than the stiffness of MPS I/II/VI.
Dysostosis Multiplex Absent EXCLUDED HP:0000943 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Dysostosis multiplex (HP:0000943). HP:0000943 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
Show evidence (1 reference)
PMID:38634625 SUPPORT DIRECT Human Clinical
"While typical dysostosis multiplex findings were not observed, mild platyspondyly with anterior beaking of some vertebral bodies, irregular vertebral endplates, wide ribs, inferior tapering of the ilea with a poorly developed acetabulum, irregularity of the central part of the femoral head,..."
States outright that typical dysostosis multiplex was not observed, and enumerates the narrower skeletal findings that appear in its place.
Nervous System 2
Waddling gait HP:0002515 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Waddling gait (HP:0002515). HP:0002515 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38634625 SUPPORT Human Clinical
"The patients' initial complaints were hip or knee pain and a waddling gait."
Establishes waddling gait as a presenting feature.
Intellectual Disability Absent EXCLUDED HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
Show evidence (2 references)
PMID:40742107 SUPPORT DIRECT Human Clinical
"None demonstrated hepatosplenomegaly, neurological deficits, or cognitive impairment."
States the absence of cognitive impairment across all reported patients.
PMID:34916232 SUPPORT INDIRECT Human Clinical
"All four subjects of this study had normal behaviour and attended a regular school"
Normal schooling in the index family. Marked INDIRECT because attendance at a regular school implies rather than measures normal intellect.
Constitutional 1
Arthralgia HP:0002829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hip, knee and back pain, annotated with Arthralgia (HP:0002829), qualified as course progressive. HP:0002829 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:38634625 SUPPORT Human Clinical
"The patients' initial complaints were hip or knee pain and a waddling gait."
Establishes joint pain as the presenting symptom of MPS X.
Growth 1
Disproportionate short-trunk short stature OCCASIONAL HP:0003521 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short-trunk disproportionate short stature, annotated with Disproportionate short-trunk short stature (HP:0003521). HP:0003521 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"coarse facial features, short trunk disproportionate short stature and short neck, genua valga, and hip pain were noticed at the end of the first decade"
Documents short-trunk disproportionate short stature and its end-of-first-decade onset.
🧬

Genetic Associations

1
ARSK pathogenic variants (Causative)
Gene: ARSK hgnc:25239 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ARSK (hgnc:25239). hgnc:25239 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (3 references)
PMID:35959767 SUPPORT Human Clinical
"Both children were homozygous, and both parents heterozygous, for a predicted stop variant in ARSK"
Documents the nonsense allele and its segregation.
PMID:38292179 SUPPORT Human Clinical
"we identified a novel homozygous missense germline variant, c.1067C>A (p.S356Y), in the ARSK gene"
Documents the p.Ser356Tyr missense allele.
PMID:34916232 SUPPORT Human Clinical
"In gnomAD, this variant is listed with a total allele frequency of 0.002129% (6/281810 alleles)."
Documents the population rarity of the founding allele, supporting the rarity annotated in features.
💊

Medical Actions

2
Supportive orthopaedic and analgesic care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
No disease-modifying therapy exists for MPS X. There is no approved or investigational enzyme replacement therapy, no substrate reduction therapy, and no reported use of hematopoietic stem cell transplantation. Management is orthopaedic care for progressive hip dysplasia and femoral head osteonecrosis, analgesia for joint pain, and physiotherapy. Because the disease is chondro-osseous and the reported burden is pain and disability rather than organ failure, the authors of the fourth-patient report explicitly identify enzyme replacement therapy development as the unmet need.
Show evidence (1 reference)
PMID:38292179 SUPPORT Human Clinical
"It will be very important to develop enzyme replacement therapy and potentially other treatments, given the pain and disability associated with this disorder."
States that no disease-modifying therapy is available and identifies enzyme replacement therapy as the unmet need.
Cardiac, ophthalmological and audiological surveillance
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Once ARSK-related MPS is molecularly confirmed, targeted surveillance is warranted even in an asymptomatic child, because the cardiac and ocular involvement documented in the index family was found only on deliberate reverse phenotyping and was clinically silent. Surveillance also substantiates genetic counselling for the family.
Show evidence (1 reference)
PMID:35959767 SUPPORT Human Clinical
"The diagnosis of MPS type X allows for tailored cardiac, ophthalmologic and audiological surveillance, and can inform genetic counseling."
States the clinical utility of the diagnosis, which is surveillance and counselling rather than treatment.
🔬

Biochemical Markers

2
Urinary dermatan sulfate (Elevated)
Context: The biochemical hallmark of MPS X, and the one that most distinguishes it from the other mucopolysaccharidoses in practice: it is small enough to be missed. Sensitive LC-MS/MS disaccharide quantification shows a threefold to fourfold elevation of dermatan-sulfate-derived disaccharides, with heparan and keratan sulfate generally normal. Routine dimethylmethylene blue total-GAG screening, by contrast, is normal or only borderline in most patients, and thin-layer chromatography shows a normal GAG profile. A normal urinary GAG screen therefore does not exclude MPS X - the practical consequence is that this diagnosis is reached by sequencing, not by biochemistry, and the biochemistry serves to confirm it afterwards.
Show evidence (4 references)
PMID:34916232 SUPPORT Human Clinical
"Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS."
Establishes the dermatan sulfate elevation detectable by LC-MS/MS.
PMID:34916232 SUPPORT Human Clinical
"showed a threefold and fourfold elevation of specific DS-derived disaccharides in a morning urine sample, respectively"
Quantifies the magnitude of the dermatan sulfate elevation on LC-MS/MS.
PMID:40742107 SUPPORT Human Clinical
"Biochemical analyses reveal variable dermatan sulfate (DS) excretion in urine, with some patients showing increased DS, while others had normal urinary glycosaminoglycans (GAGs), suggesting that a normal GAG profile does not exclude this condition."
Supports both the dermatan sulfate signal and, critically, that its absence does not exclude the diagnosis.
+ 1 more reference
Lysosomal enzyme activities for the established MPS subtypes (Normal)
Context: Normal, by design of the diagnostic workup. Because the skeletal picture suggests MPS IVA or IVB, patients are routinely assayed for galactosamine-6-sulfatase and beta-galactosidase, and in the index family a full panel of GAG-degrading lysosomal hydrolases was measured in fibroblasts. All were normal. There is no clinically available ARSK enzyme assay; the published functional assays use a synthetic 2-sulfoglucuronate disaccharide substrate in a research setting.
Show evidence (1 reference)
PMID:35959767 SUPPORT Human Clinical
"Morquio disease, MPS type IVA, was suspected, but both children had normal serum levels of galactose‐6‐sulfatase and beta‐galactosidase."
Documents the normal MPS IV enzyme assays that leave the diagnosis to sequencing.
🔬

Diagnosis

2
Exome or genome sequencing in undiagnosed skeletal dysplasia
The route by which every published MPS X patient was diagnosed. Children are referred with a skeletal-dysplasia phenotype, targeted skeletal gene panels and known-MPS-gene analysis are negative, and exome sequencing identifies biallelic ARSK variants. In the index family, homozygosity mapping in a consanguineous pedigree narrowed the search; in the Norwegian family the diagnosis was reached only after re-interpreting the exome data under a corrected assumption about which parent was affected.
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"Targeted variant analysis of known MPS-associated genes in the exome data set of S1 did not reveal pathogenic or likely pathogenic variants in GALNS, GLB1, GNS, GUSB, HYAL1, IDUA, ARSB, HGSNAT, NAGLU, SGSH and IDS."
Shows that the established MPS gene set is negative, which is why MPS X requires unbiased sequencing to reach.
LC-MS/MS urinary glycosaminoglycan disaccharide quantification
The confirmatory biochemical test, and the only one that reliably detects the MPS X signal. Enzymatic digestion followed by LC-MS/MS quantification of heparan, dermatan, and keratan sulfate disaccharides shows the dermatan sulfate elevation that dimethylmethylene blue screening misses. It should be used specifically when MPS is suspected on skeletal grounds and routine screening is normal.
Show evidence (1 reference)
PMID:40742107 SUPPORT Human Clinical
"Biochemical analyses reveal variable dermatan sulfate (DS) excretion in urine, with some patients showing increased DS, while others had normal urinary glycosaminoglycans (GAGs), suggesting that a normal GAG profile does not exclude this condition."
Establishes both the value of sensitive disaccharide quantification and the limits of routine total-GAG screening.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Ten patients from six families had been reported as of the 2025 review, with a median age at presentation of 9.5 years. The true frequency is unknown and probably understated: the phenotype is mild, routine urinary GAG screening is often normal, and the skeletal picture is readily absorbed into a spondyloepiphyseal-dysplasia or Legg-Calve-Perthes label. gnomAD carries roughly 386 unique ARSK missense, in-frame, and truncating variants, over 95 percent of them below an allele frequency of 1 in 10,000, which is consistent with a low but non-zero incidence.
Show evidence (1 reference)
PMID:40742107 SUPPORT Human Clinical
"To date, 10 ARSK-related MPS10 patients from six families have been reported, with a median age at presentation of 9.5 years."
Supports the reported case count and typical age at presentation.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Mucopolysaccharidosis type X:

Morquio syndrome MONDO:0018938
Overlapping Features MPS IVA and IVB are the differential that has been actively pursued in essentially every reported MPS X patient, because the short-trunk skeletal phenotype, platyspondyly, joint hypermobility, and enamel defects all overlap. Normal galactosamine-6-sulfatase and beta-galactosidase activity excludes MPS IV and leaves MPS X reachable only by sequencing.
Distinguishing Features
  • Normal GALNS and GLB1 enzyme activity excludes Morquio syndrome.
  • Metaphyseal striation of the long bones favors MPS X.
  • Progressive femoral head osteonecrosis with a Legg-Calve-Perthes appearance favors MPS X.
  • Corneal clouding and marked keratan sulfate excretion favor Morquio syndrome.
Show evidence (1 reference)
PMID:35959767 SUPPORT Human Clinical
"Morquio disease, MPS type IVA, was suspected, but both children had normal serum levels of galactose‐6‐sulfatase and beta‐galactosidase."
A worked instance of MPS IV being suspected and excluded enzymatically before MPS X was found.
Legg-Calve-Perthes disease
Overlapping Features Bilateral Legg-Calve-Perthes disease is the single most common misclassification of MPS X. Idiopathic Legg-Calve-Perthes disease is usually unilateral; bilateral disease, particularly with metaphyseal striation, vertebral changes, or delayed carpal ossification, should prompt consideration of a mucopolysaccharidosis including MPS X.
Distinguishing Features
  • Bilaterality favors a storage or dysplasia diagnosis over idiopathic Legg-Calve-Perthes disease.
  • Metaphyseal striation, platyspondyly, and delayed carpal ossification are extrinsic to Legg-Calve-Perthes disease.
Show evidence (1 reference)
PMID:35959767 SUPPORT Human Clinical
"Bilateral LCPD should result in considering the possibility of MPS type X as well as other MPS subtypes"
Directly states the discriminating rule annotated here.
Spondyloepiphyseal dysplasia
Overlapping Features The radiographic label most often applied to MPS X before molecular diagnosis, on the basis of platyspondyly with small epiphyses. Multiple epiphyseal dysplasia and Meyer dysplasia have also been proposed in reported patients. None of these is excluded radiographically; the discriminator is the finding of biallelic ARSK variants.
Distinguishing Features
  • Metaphyseal striation of the long bones is atypical for spondyloepiphyseal dysplasia and favors MPS X.
  • Elevated urinary dermatan sulfate on LC-MS/MS favors MPS X.
  • Biallelic ARSK variants are definitive.
Show evidence (1 reference)
PMID:34916232 SUPPORT Human Clinical
"In both families, parents were consanguineous and had two affected children with skeletal dysplasia, resembling spondyloepiphysial dysplasia."
Documents that the presenting radiographic impression in both founding families was spondyloepiphyseal dysplasia.
🐁

Animal Models

1
Arsk knockout mouse
The constitutive Arsk-knockout mouse established the biochemical consequence of ARSK loss two years before any human patient was described, and it is the reason ARSK was already a candidate MPS gene when the first families were sequenced. It reproduces the biochemistry faithfully and the disease poorly.
Species
Mouse
Genotype
Constitutive Arsk knockout
Publication
PMID:32856704
Pathograph links
Lysosomal accumulation of 2-O-sulfoglucuronate-capped GAG fragments recapitulates fidelity: high Complete loss of glucuronate desulfation with organ-specific accumulation of heparan and chondroitin sulfate metabolites bearing 2-O-sulfated glucuronate at their non-reducing ends, which is precisely the predicted biochemical lesion.
Readouts
Non-reducing-end 2-O-sulfated glucuronate GAG metabolites in tissue
Direction: INCREASED
Interpretation: Direct biochemical readout of the blocked degradation step in the storage node.
Show evidence (1 reference)
PMID:32856704 SUPPORT Model Organism
"Arsk-deficient mice show, in an organ-specific manner, a moderate accumulation of HS and CS metabolites characterized by 2-O-sulfated glucuronate moieties at their non-reducing ends."
Reports the measured accumulation of the expected metabolites.
Show evidence (1 reference)
PMID:32856704 SUPPORT Model Organism
"Recently, we identified and characterized the lysosomal enzyme arylsulfatase K (Arsk) exhibiting glucuronate-2-sulfatase activity as needed for the degradation of heparan sulfate (HS), chondroitin sulfate (CS) and dermatan sulfate (DS)."
Establishes that the mouse model targets the same enzymatic step that is lost in human MPS X, making it informative for the storage node.
Chondro-osseous storage and epiphyseal-metaphyseal dysplasia fails to recapitulate fidelity: low The mouse does not develop the skeletal disease that defines human MPS X. This is a substantive negative result rather than a gap: it means the mouse cannot serve as a preclinical efficacy model for the outcome that matters clinically, and any enzyme replacement therapy programme would need a different readout or a different species.
Limitations: No bone abnormalities or prominent lysosomal storage pathology develop, despite complete loss of glucuronate desulfation and measurable metabolite accumulation. The mouse phenotype is limited to behavioural changes, which is close to the inverse of the human picture, where skeletal disease is universal and cognition is normal. The species divergence most likely reflects differences in glucuronate-2-O-sulfation abundance or in the growth-plate load carried by the affected chains; it has not been resolved experimentally.
Show evidence (1 reference)
PMID:32856704 SUPPORT Model Organism
"Pathophysiological studies reflect a rather mild phenotype including behavioral changes. Interestingly, no prominent lysosomal storage pathology like bone abnormalities were detected."
States explicitly that bone abnormalities are absent in the knockout, which is the failure to recapitulate annotated here.
{ }

Source YAML

click to show 
name: Mucopolysaccharidosis type X
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Mucopolysaccharidosis type X (MPS X, MPS 10) is an autosomal recessive
  lysosomal storage disorder caused by biallelic loss-of-function variants in
  ARSK, which encodes the lysosomal sulfatase arylsulfatase K (also called
  glucuronate 2-sulfatase, GDS). ARSK removes the 2-O-sulfate group from
  2-sulfoglucuronate, an obligate step in the stepwise exolytic degradation of
  heparan sulfate, dermatan sulfate, and chondroitin sulfate. It is the most
  recently defined mucopolysaccharidosis: the human phenotype was first
  delineated in 2022, more than twenty years after the previous new MPS subtype.
  MPS X is the mildest and most narrowly skeletal of the mucopolysaccharidoses.
  Affected individuals present in mid-childhood with hip and knee pain, a
  waddling gait, and progressive hip dysplasia, and are typically first
  diagnosed with bilateral Legg-Calve-Perthes disease, spondyloepiphyseal
  dysplasia, or multiple epiphyseal dysplasia rather than with a storage
  disorder. Metaphyseal striation of the long bones is the most consistent
  radiographic clue. Coarse facial features, short stature, and mild cardiac
  and ophthalmological involvement are variable and emerge late; classical
  dysostosis multiplex, hepatosplenomegaly, hearing loss, and cognitive
  impairment are characteristically absent. The biochemical signal is
  correspondingly weak - routine dimethylmethylene blue urinary
  glycosaminoglycan screening is frequently normal, and only sensitive
  LC-MS/MS disaccharide quantification reveals the modest dermatan sulfate
  elevation. MPS X is therefore a mucopolysaccharidosis that the standard MPS
  diagnostic pathway systematically misses, and it is likely underdiagnosed
  among children carrying a skeletal-dysplasia label. No disease-modifying
  therapy exists; management is orthopaedic, analgesic, and surveillance-based.
disease_term:
  preferred_term: Mucopolysaccharidosis type X
  term:
    id: MONDO:0030524
    label: mucopolysaccharidosis, type 10
classifications:
  lysosomal_storage_category:
    classification_value: mucopolysaccharidosis
    notes: >-
      MPS X is a mucopolysaccharidosis: lysosomal accumulation of
      2-O-sulfoglucuronate-capped fragments of heparan sulfate, dermatan
      sulfate, and chondroitin sulfate arising from deficiency of the
      GAG-degrading lysosomal sulfatase ARSK.
  icimd_category:
  - classification_value: glycosaminoglycan_degradation
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Glycosaminoglycan
      degradation" under category "Disorders of complex molecule degradation".
      MPS X postdates the 2021 ICIMD publication, so it is assigned here by
      mechanism rather than by explicit listing - ARSK is a
      glycosaminoglycan-degrading lysosomal sulfatase in exactly the sense that
      places IDS, SGSH, GNS, GALNS, and ARSB in this group.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0030524
      label: mucopolysaccharidosis, type 10
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0030524 is the MPS type 10 concept (OMIM:619698, ORPHA:662216,
      MEDGEN:1794274), corresponding exactly to the ARSK-deficiency disorder
      described here.
parents:
- Mucopolysaccharidosis
- Lysosomal Storage Disorder
synonyms:
- MPS X
- MPS 10
- MPS10
- ARSK-related mucopolysaccharidosis
- arylsulfatase K deficiency
- glucuronate 2-sulfatase deficiency
notes: >-
  Three things make MPS X unusual among the mucopolysaccharidoses and are worth
  keeping in view when reading this entry.

  First, the phenotype is defined largely by its absences. The systemic storage
  burden that dominates MPS I, II, VI, and VII - organomegaly,
  neurodegeneration, corneal clouding, hearing loss, classic dysostosis
  multiplex - is not present. What remains is a chondro-osseous disease of the
  hip and spine. This entry deliberately annotates that restriction rather than
  padding the phenotype list with generic MPS features that the primary reports
  explicitly did not observe.

  Second, MPS X is the counterexample to "MPS is excluded by a normal urine
  GAG". Routine dimethylmethylene blue screening was normal or borderline in
  most reported patients, and in one the standard assay was normal while
  LC-MS/MS on the same patient showed a marked dermatan sulfate elevation. The
  diagnosis in every published case was reached by exome sequencing in a child
  being worked up for skeletal dysplasia, with the biochemistry confirmed
  afterwards.

  Third, the substrate logic is unlike the other MPS types. ARSK acts on
  glucuronate-2-O-sulfate, a rare modification of heparan, dermatan, and
  chondroitin sulfate rather than a backbone-defining one. Blocking its removal
  therefore stalls only the minority of GAG chains that carry the modification,
  which is the most parsimonious explanation for both the mild storage burden
  and the fact that the Arsk-knockout mouse shows measurable HS/CS metabolite
  accumulation with no skeletal pathology at all. The mouse work proposed the
  designation "MPS type IIB" for this entity; the human reports established
  "MPS X", which is the name MONDO, OMIM, and Orphanet carry and which this
  entry uses.

  Nomenclature caution for curators and readers: ARSK (arylsulfatase K, MPS X)
  and ARSG (arylsulfatase G) are adjacent in name and in biology - both are
  lysosomal sulfatases acting on heparan sulfate - but are different diseases.
  ARSG deficiency is MPS IIIE in mouse and Usher syndrome type 4 in humans; see
  the Usher Syndrome Type 4 entry.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    MPS X is autosomal recessive. Every reported family has had homozygous
    ARSK variants with heterozygous, unaffected parents; the two founding
    families were consanguineous, and homozygosity mapping contributed to gene
    identification in both.
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively."
    explanation: >-
      Homozygous ARSK variants in affected children of two consanguineous
      families establish autosomal recessive inheritance.
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both children were homozygous, and both parents heterozygous, for a predicted stop variant in ARSK"
    explanation: >-
      Affected homozygous siblings with unaffected heterozygous parents is the
      direct segregation demonstration of autosomal recessive inheritance.
pathophysiology:
- name: ARSK glucuronate 2-sulfatase deficiency
  conforms_to: "lysosomal_substrate_accumulation#Lysosomal Hydrolase or Cofactor Deficiency"
  biological_scale: MOLECULAR
  description: >-
    Biallelic loss-of-function variants in ARSK abolish or severely reduce the
    activity of arylsulfatase K, the lysosomal sulfatase that removes the
    2-O-sulfate group from 2-sulfoglucuronate. Reported variants act through two
    distinct routes to the same end point. Nonsense alleles (p.Leu187Ter,
    p.Tyr417Ter) yield no detectable protein, consistent with nonsense-mediated
    decay. Missense alleles are catalytically dead while remaining stably
    expressed: p.Arg84Cys disrupts the conserved sulfatase signature 80-CCPSR-84
    that is required to convert the active-site cysteine to formylglycine, and
    p.Ser356Tyr abolishes activity within the sulfatase domain without
    destabilizing the protein. Because sulfatases show high substrate
    specificity and no functional redundancy, no other human sulfatase
    compensates for the lost step.

    Term-binding note: the molecular function below is bound to GO:0008484
    (sulfuric ester hydrolase activity), a broad parent, deliberately. GO has no
    term for glucuronate 2-O-sulfatase (glucuronate 2-sulfatase, GDS) activity,
    and no sibling sulfatase term fits - ARSK is specific for the 2-O-sulfate of
    2-sulfoglucuronate and does not share substrates with the other lysosomal
    sulfatases. Binding a narrower but wrong term would misstate the enzymology,
    so the accurate parent is preferred over a manufactured match. A GO term
    request for the specific activity is the way to improve this.
  genes:
  - preferred_term: ARSK
    term:
      id: hgnc:25239
      label: ARSK
  molecular_functions:
  - preferred_term: glucuronate 2-O-sulfatase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0008484
      label: sulfuric ester hydrolase activity
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate."
    explanation: >-
      Defines the enzymatic step that is lost in MPS X: lysosomal removal of the
      2-O-sulfate from 2-sulfoglucuronate during glycosaminoglycan degradation.
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS."
    explanation: >-
      Functional proof that the two founding variants cause loss of ARSK
      activity, by absent protein and by loss of catalytic activity respectively.
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The arginine at amino acid position 84 in ARSK is part of the highly conserved sulfatase signature 80-CCPSR-84"
    explanation: >-
      Locates the p.Arg84Cys missense lesion in the sulfatase signature motif,
      explaining why a stably expressed protein is catalytically inactive.
  - reference: PMID:38292179
    reference_title: "A novel homozygous missense variant in ARSK causes MPS X, a new subtype of mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ARSK-S356Y completely abolished the ARSK enzyme activity compared with the wild-type (ARSK-WT)"
    explanation: >-
      A second, independently identified missense allele is also catalytically
      null, supporting loss of enzyme activity as the shared molecular lesion.
  downstream:
  - target: Lysosomal accumulation of 2-O-sulfoglucuronate-capped GAG fragments
    causal_link_type: DIRECT
    description: >-
      With the 2-O-desulfation step blocked, exolytic degradation stalls at
      every chain terminus bearing a 2-O-sulfated glucuronate, and the partially
      degraded fragments accumulate in the lysosome.
    evidence:
    - reference: PMID:32856704
      reference_title: "Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Arsk-deficient mice show, in an organ-specific manner, a moderate accumulation of HS and CS metabolites characterized by 2-O-sulfated glucuronate moieties at their non-reducing ends."
      explanation: >-
        Directly demonstrates that loss of ARSK causes accumulation of GAG
        metabolites capped by the very modification ARSK removes, establishing
        the causal link from enzyme loss to substrate storage.
- name: Lysosomal accumulation of 2-O-sulfoglucuronate-capped GAG fragments
  conforms_to: "mps_gag_storage#Lysosomal GAG Accumulation"
  biological_scale: CELLULAR
  description: >-
    Partially degraded heparan sulfate, dermatan sulfate, and chondroitin
    sulfate fragments terminating in 2-O-sulfoglucuronate accumulate in
    lysosomes. This is the GAG-accumulation hub of the mps_gag_storage module,
    but the storage burden is far smaller than in the other mucopolysaccharidoses
    and is engaged in a highly restricted way. Glucuronate-2-O-sulfation is an
    uncommon modification rather than a backbone-defining one, so only the
    minority of chains carrying it are blocked; the bulk of heparan, dermatan,
    and chondroitin sulfate is still catabolized normally. The module's
    heparan-sulfate neuronopathic arm and its keratan-sulfate skeletal arm are
    therefore not engaged - keratan sulfate is not an ARSK substrate, and no
    reported patient has CNS disease. Only the dermatan-sulfate
    connective-tissue arm is engaged, and even that partially: dermatan sulfate
    is the one GAG species reproducibly elevated in patient urine, and the
    downstream disease is confined to chondro-osseous and cardiac connective
    tissue rather than the generalized visceral storage of MPS I or VI.
  chemical_entities:
  - preferred_term: dermatan sulfate
    modifier: INCREASED
    term:
      id: CHEBI:18376
      label: dermatan sulfate
  - preferred_term: heparan sulfate
    modifier: INCREASED
    term:
      id: CHEBI:28815
      label: heparan sulfate
  - preferred_term: chondroitin sulfate
    modifier: INCREASED
    term:
      id: CHEBI:37397
      label: chondroitin sulfate
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  biological_processes:
  - preferred_term: glycosaminoglycan catabolic process
    modifier: DECREASED
    term:
      id: GO:0006027
      label: glycosaminoglycan catabolic process
  - preferred_term: dermatan sulfate proteoglycan catabolic process
    modifier: DECREASED
    term:
      id: GO:0030209
      label: dermatan sulfate proteoglycan catabolic process
  - preferred_term: chondroitin sulfate proteoglycan catabolic process
    modifier: DECREASED
    term:
      id: GO:0030207
      label: chondroitin sulfate proteoglycan catabolic process
  - preferred_term: heparan sulfate proteoglycan catabolic process
    modifier: DECREASED
    term:
      id: GO:0030200
      label: heparan sulfate proteoglycan catabolic process
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glucuronate-2-O-sulfation occurs in HS, DS and CS and, during degradation, is selectively removed by ARSK"
    explanation: >-
      Establishes which GAG species carry the ARSK-dependent modification, and
      hence which are stalled when the enzyme is lost.
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS."
    explanation: >-
      Dermatan sulfate is the GAG species measurably elevated in patients,
      supporting the restricted, dermatan-biased character of the storage.
  - reference: PMID:40742107
    reference_title: "ARSK-Related Mucopolysaccharidosis Type 10."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical analyses reveal variable dermatan sulfate (DS) excretion in urine, with some patients showing increased DS, while others had normal urinary glycosaminoglycans (GAGs), suggesting that a normal GAG profile does not exclude this condition."
    explanation: >-
      Identifies dermatan sulfate as the affected species. Marked INDIRECT
      because the quote reports urinary excretion, from which lysosomal storage
      follows only by inference, and because it simultaneously establishes that
      the signal is inconsistent and can be undetectable by routine assays - the
      qualification this node depends on.
  downstream:
  - target: Chondro-osseous storage and epiphyseal-metaphyseal dysplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Storage in cartilage and bone-forming tissue disturbs epiphyseal and
      metaphyseal development, producing the skeletal disease that dominates
      MPS X. The intermediate steps between fragment accumulation and disturbed
      endochondral ossification have not been worked out in this disorder, so
      the link is annotated as indirect.
    evidence:
    - reference: PMID:34916232
      reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
      explanation: >-
        Documents the chondro-osseous consequence of ARSK deficiency as a
        consistent epiphyseal, metaphyseal, and vertebral dysplasia.
  - target: Cardiac valve storage involvement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Dermatan-sulfate-biased storage in valvular connective tissue produces the
      mild, late cardiac findings of MPS X.
    evidence:
    - reference: PMID:34916232
      reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities."
      explanation: >-
        Establishes that cardiac and ocular involvement occurs, and that it is
        subclinical enough to require deliberate targeted assessment.
  - target: Ocular connective-tissue involvement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Dermatan-sulfate-biased storage in ocular connective tissue produces the
      lens and vitreous opacity reported in the index family.
    evidence:
    - reference: PMID:34916232
      reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities."
      explanation: >-
        Establishes that ophthalmological involvement occurs and is subclinical
        enough to require deliberate targeted assessment.
- name: Chondro-osseous storage and epiphyseal-metaphyseal dysplasia
  biological_scale: TISSUE
  description: >-
    The dominant and near-universal disease arm of MPS X. Cartilage and
    bone-forming tissue develop an epiphyseal, metaphyseal, and vertebral
    dysplasia that presents clinically as hip and knee pain with a waddling gait
    in mid-childhood, and radiographically as metaphyseal striation of the long
    bones, platyspondyly with anterior vertebral beaking, delayed carpal
    ossification, small epiphyses, and inferior tapering of the ilia with a
    poorly formed acetabulum. Two features of its natural history distinguish it
    from the other mucopolysaccharidoses: the vertebral changes regress with
    time rather than progressing, while the hip dysplasia progresses in every
    reported patient, so the hip rather than the spine is the long-term burden.
    The picture is close enough to spondyloepiphyseal dysplasia, multiple
    epiphyseal dysplasia, and bilateral Legg-Calve-Perthes disease that every
    published patient carried one of those labels before sequencing.
  locations:
  - preferred_term: hip joint
    term:
      id: UBERON:0001486
      label: hip joint
  - preferred_term: epiphysis
    term:
      id: UBERON:0001437
      label: epiphysis
  - preferred_term: vertebra
    term:
      id: UBERON:0002412
      label: vertebra
  - preferred_term: growth plate cartilage
    term:
      id: UBERON:0004129
      label: growth plate cartilage
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: endochondral ossification
    modifier: ABNORMAL
    term:
      id: GO:0001958
      label: endochondral ossification
  evidence:
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkably, all patients showed metaphyseal striation of the long bones, a crucial diagnostic clue to identify ARSK-related MPS type 10."
    explanation: >-
      Identifies metaphyseal striation as the consistent radiographic marker of
      the chondro-osseous arm across an independent patient series.
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, vertebral involvement regressed during follow-up. On the other hand, hip dysplasia progressed in all patients."
    explanation: >-
      Supports the divergent natural history annotated here: regressing
      vertebral disease with progressive hip disease.
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While typical dysostosis multiplex findings were not observed, mild platyspondyly with anterior beaking of some vertebral bodies, irregular vertebral endplates, wide ribs, inferior tapering of the ilea with a poorly developed acetabulum, irregularity of the central part of the femoral head, delayed ossification of the carpals were noted."
    explanation: >-
      Enumerates the skeletal findings and states explicitly that classic
      dysostosis multiplex is absent, which is the discriminating feature of
      this node relative to the other mucopolysaccharidoses.
  downstream:
  - target: Hip dysplasia
    causal_link_type: DIRECT
    description: Progressive acetabular and femoral head dysplasia is the dominant skeletal burden.
  - target: Avascular necrosis of the capital femoral epiphysis
    causal_link_type: DIRECT
    description: >-
      Femoral head involvement presents as a Legg-Calve-Perthes-like
      osteonecrosis, usually bilateral.
  - target: Metaphyseal striations
    causal_link_type: DIRECT
    description: Vertical metaphyseal striation of the long bones is the consistent radiographic marker.
  - target: Platyspondyly
    causal_link_type: DIRECT
    description: Vertebral body flattening with anterior beaking and irregular endplates.
  - target: Arthralgia
    causal_link_type: DIRECT
    description: Hip, knee, and back pain is the usual presenting complaint.
  - target: Waddling gait
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Hip disease produces the waddling gait that typically brings the child to attention.
  - target: Delayed ossification of carpal bones
    causal_link_type: DIRECT
    description: Carpal bones are unossified or small for age.
  - target: Disproportionate short-trunk short stature
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Vertebral involvement produces short-trunk disproportion, but only in
      older patients; younger children are of normal stature and proportion.
- name: Cardiac valve storage involvement
  biological_scale: TISSUE
  description: >-
    A mild and late arm of the disease, found only on deliberate targeted
    assessment after the genetic diagnosis is made. Reported findings are an
    aortic or mitral murmur, valve thickening with regurgitation, mild aortic
    valve stenosis, and mild left ventricular hypertrophy suggesting early
    storage cardiomyopathy. Curated separately from the ocular arm below because
    the two have different evidence: the later series that found normal eye
    examinations throughout did not report absent cardiac involvement, so a
    single bundled node would leave it ambiguous which half its refuting
    evidence applied to.
  locations:
  - preferred_term: cardiac valve
    term:
      id: UBERON:0000946
      label: cardiac valve
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heart abnormalities in S1 and S2 included cardiac murmur (aortic or mitral), valve disease, thickened leaflets and regurgitation."
    explanation: >-
      Documents the valvular connective-tissue involvement that defines this node.
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild aortic valve stenosis and mild left ventricular hypertrophy were noted in cardiac ultrasound in S1 and S2."
    explanation: >-
      Documents the stenotic and ventricular findings of this node on
      echocardiography.
  downstream:
  - target: Abnormal mitral valve morphology
    causal_link_type: DIRECT
    description: Valve leaflet thickening with regurgitation.
  - target: Aortic valve stenosis
    causal_link_type: DIRECT
    description: Mild aortic valve stenosis on echocardiography.
- name: Ocular connective-tissue involvement
  biological_scale: TISSUE
  description: >-
    The most variable arm of the disease, and the one with directly conflicting
    evidence. The index family showed mild lens and vitreous opacity, with loss
    of the retinal interdigitation zone temporal to the macula on optical
    coherence tomography in one patient. Two independent later series reported
    normal eye examinations throughout. This arm is therefore genuinely
    inconsistent between kindreds rather than merely under-ascertained, which is
    why it is recorded with both supporting and refuting evidence rather than
    being asserted or dropped. It remains the basis for offering
    ophthalmological surveillance once MPS X is diagnosed.
  locations:
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "reverse phenotyping revealed mild opacity of the lens and vitreous body"
    explanation: Documents the ocular finding in the index family.
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed normal intelligence, normal hearing and eye examinations, and none had organomegaly."
    explanation: >-
      Cuts directly against this node: an independent series found normal eye
      examinations in every patient. Now that the ocular arm is its own node,
      this REFUTE is unambiguous about what it refutes.
  downstream:
  - target: Abnormal lens morphology
    causal_link_type: DIRECT
    description: Mild lens and vitreous opacity found on slit-lamp examination.
phenotypes:
- name: Arthralgia
  category: Musculoskeletal
  description: >-
    Hip, knee, thigh, leg, and back pain is the usual presenting complaint,
    typically beginning between 7 and 11 years of age and severe enough to limit
    walking distance in some patients.
  phenotype_term:
    preferred_term: Hip, knee and back pain
    term:
      id: HP:0002829
      label: Arthralgia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients' initial complaints were hip or knee pain and a waddling gait."
    explanation: Establishes joint pain as the presenting symptom of MPS X.
- name: Waddling gait
  category: Musculoskeletal
  description: >-
    A waddling gait, reflecting hip disease, is present from toddlerhood in some
    patients and is one of the two features that most consistently bring
    affected children to medical attention.
  phenotype_term:
    preferred_term: Waddling gait
    term:
      id: HP:0002515
      label: Waddling gait
  evidence:
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients' initial complaints were hip or knee pain and a waddling gait."
    explanation: Establishes waddling gait as a presenting feature.
- name: Hip dysplasia
  category: Musculoskeletal
  description: >-
    Progressive hip dysplasia with acetabular hypoplasia and inferior tapering
    of the ilia. Unlike the vertebral changes, hip disease worsened over
    follow-up in every patient in whom it was tracked, making it the principal
    long-term morbidity of MPS X.
  phenotype_term:
    preferred_term: Hip dysplasia with acetabular hypoplasia
    term:
      id: HP:0001385
      label: Hip dysplasia
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40742107
    reference_title: "ARSK-Related Mucopolysaccharidosis Type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals usually present with progressive hip joint abnormalities."
    explanation: >-
      Review of all reported patients establishes progressive hip involvement as
      the usual presentation.
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, vertebral involvement regressed during follow-up. On the other hand, hip dysplasia progressed in all patients."
    explanation: Directly supports the progressive clinical course annotated here.
- name: Avascular necrosis of the capital femoral epiphysis
  category: Musculoskeletal
  description: >-
    Femoral head osteonecrosis, generally bilateral, radiographically
    indistinguishable from Legg-Calve-Perthes disease. Several reported patients
    carried a bilateral Legg-Calve-Perthes diagnosis for years before ARSK
    sequencing; bilateral disease is the clue that should prompt consideration
    of a mucopolysaccharidosis.
  phenotype_term:
    preferred_term: Bilateral Legg-Calve-Perthes-like femoral head osteonecrosis
    term:
      id: HP:0005743
      label: Avascular necrosis of the capital femoral epiphysis
  evidence:
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral LCPD should result in considering the possibility of MPS type X as well as other MPS subtypes"
    explanation: >-
      Establishes bilateral Legg-Calve-Perthes disease as an MPS X presentation
      and a diagnostic prompt.
- name: Metaphyseal striations
  category: Skeletal
  description: >-
    Vertical striation of the metaphyses of the long bones, particularly the
    distal femur and tibia. This is the single most consistent radiographic
    finding in MPS X and is present at younger ages than the vertebral or
    facial changes.
  phenotype_term:
    preferred_term: Vertical metaphyseal striations of the long bones
    term:
      id: HP:0031367
      label: Metaphyseal striations
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkably, all patients showed metaphyseal striation of the long bones, a crucial diagnostic clue to identify ARSK-related MPS type 10."
    explanation: Supports both the near-universal frequency and the diagnostic value.
- name: Platyspondyly
  category: Skeletal
  description: >-
    Flattened, broad vertebral bodies with anterior inferior beaking of the
    thoracolumbar spine, irregular endplates, and posterior endplate scalloping.
    Notably, vertebral involvement regressed on follow-up in one series rather
    than progressing.
  phenotype_term:
    preferred_term: Platyspondyly with anterior vertebral beaking
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
    explanation: Documents platyspondyly with anterior beaking in all four index patients.
- name: Anterior beaking of lower thoracic vertebrae
  category: Skeletal
  description: >-
    Anterior inferior beaking of the thoracolumbar vertebral bodies, one of the
    features that makes MPS X radiographically resemble a storage disorder
    despite the absence of classic dysostosis multiplex.
  phenotype_term:
    preferred_term: Anterior inferior beaking of the thoracolumbar vertebrae
    term:
      id: HP:0004607
      label: Anterior beaking of lower thoracic vertebrae
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
    explanation: Documents anterior inferior vertebral beaking in all four index patients.
- name: Delayed ossification of carpal bones
  category: Skeletal
  description: >-
    Carpal bones unossified or small for age, with retarded bone age. This is
    an early finding: one sibling had a normal wrist radiograph at age 2 years
    and defective carpal ossification by age 9.
  phenotype_term:
    preferred_term: Delayed and defective carpal ossification
    term:
      id: HP:0001216
      label: Delayed ossification of carpal bones
  evidence:
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiological changes were not present in the hand of Individual 1 at age 2 years, but at age 8 years 5 months several carpal bones were either not ossified or small for his age."
    explanation: >-
      Documents defective carpal ossification and its emergence during
      childhood rather than at birth.
- name: Small epiphyses
  category: Skeletal
  description: >-
    Small epiphyses at the lower ends of radius and ulna and elsewhere, part of
    the epiphyseal dysplasia that leads to a multiple-epiphyseal-dysplasia or
    spondyloepiphyseal-dysplasia label before molecular diagnosis.
  phenotype_term:
    preferred_term: Small epiphyses
    term:
      id: HP:0010585
      label: Small epiphyses
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
    explanation: Documents small epiphyses in all four index patients.
- name: Thickened calvaria
  category: Skeletal
  description: Mild calvarial thickening on lateral skull radiographs.
  phenotype_term:
    preferred_term: Thickened calvaria
    term:
      id: HP:0002684
      label: Thickened calvaria
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
    explanation: Documents thickened calvaria in all four index patients.
- name: Broad ribs
  category: Skeletal
  description: Broad, oar-shaped ribs and broadened clavicles.
  phenotype_term:
    preferred_term: Broad oar-shaped ribs
    term:
      id: HP:0000885
      label: Broad ribs
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main radiological abnormalities in all four subjects were thickened calvaria, platyspondyly, anterior inferior beaking of the thoracolumbar vertebrae, broadening of clavicles and ribs, narrowing of lower parts of iliac bones, small epiphyses, metaphysial striae, and hypoplastic carpal bones"
    explanation: Documents rib and clavicular broadening in all four index patients.
- name: Hypoplastic iliac wing
  category: Skeletal
  description: >-
    Narrowing and inferior tapering of the lower iliac bones with a poorly
    developed acetabulum, contributing to the progressive hip dysplasia.
  phenotype_term:
    preferred_term: Inferior tapering of the ilia
    term:
      id: HP:0002866
      label: Hypoplastic iliac wing
  evidence:
  - reference: PMID:40742107
    reference_title: "ARSK-Related Mucopolysaccharidosis Type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographically, platyspondyly, inferior tapering of the ilea with acetabular hypoplasia, irregularity of the central part of the femoral head, and metaphyseal striation of the long bones characterize this condition."
    explanation: >-
      Review across all reported patients confirms inferior iliac tapering with
      acetabular hypoplasia as a characteristic finding.
- name: Coarse facial features
  category: Craniofacial
  description: >-
    Mild coarse facial features with midface retrusion and full lips. Age
    dependent and not present in younger patients: two siblings aged 9 and 11
    years had no coarse facies, while the older index patients did.
  phenotype_term:
    preferred_term: Mild coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex."
    explanation: Reports coarse facial features among the MPS features of the index patients.
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "at age 9 years 5 months and at 11 years, respectively, they did not have coarse facial features or short stature, and were not disproportionate"
    explanation: >-
      Reports absent coarse facies in two affected siblings who were younger
      than the index cases. The claim curated here is not that any given patient
      has coarse facies but that the feature is occasional and age-dependent,
      and a report of its absence in younger children supports that claim - so
      the direction is SUPPORT, marked INDIRECT because the age dependence is an
      inference from the contrast with the older index patients rather than
      something this quote states.
- name: Disproportionate short-trunk short stature
  category: Growth
  description: >-
    Short-trunk disproportionate short stature with a short neck and relative
    macrocephaly, noticed at the end of the first decade. As with coarse facies,
    this is age dependent and absent in younger children.
  phenotype_term:
    preferred_term: Short-trunk disproportionate short stature
    term:
      id: HP:0003521
      label: Disproportionate short-trunk short stature
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "coarse facial features, short trunk disproportionate short stature and short neck, genua valga, and hip pain were noticed at the end of the first decade"
    explanation: >-
      Documents short-trunk disproportionate short stature and its
      end-of-first-decade onset.
- name: Genu valgum
  category: Musculoskeletal
  description: Knock-knee deformity, reported in the index family and variably thereafter.
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "coarse facial features, short trunk disproportionate short stature and short neck, genua valga, and hip pain were noticed at the end of the first decade"
    explanation: Documents genua valga among the presenting features.
- name: Joint hypermobility
  category: Musculoskeletal
  description: >-
    Hypermobile interphalangeal finger joints. Worth noting because joint
    stiffness and contracture, not hypermobility, is the classic
    mucopolysaccharidosis joint phenotype; MPS X shares this reversal with
    MPS IV.
  phenotype_term:
    preferred_term: Hypermobile interphalangeal finger joints
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both children had hypermobile interphalangeal finger joints, which is also a feature of MPS type IV"
    explanation: >-
      Documents interphalangeal hypermobility and explicitly aligns it with the
      MPS IV joint phenotype rather than the stiffness of MPS I/II/VI.
- name: Enamel hypoplasia
  category: Dental
  description: >-
    Hypomineralized enamel on the permanent teeth, with enamel pitting and
    extractions in one reported sibling. Proposed as a feature of MPS X by
    analogy with MPS IV; documented in one family so far.
  phenotype_term:
    preferred_term: Hypomineralized dental enamel
    term:
      id: HP:0006297
      label: Enamel hypoplasia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both children have slightly hypomineralized enamel on their permanent teeth."
    explanation: Documents the enamel defect in both affected siblings of one family.
- name: Abnormal mitral valve morphology
  category: Cardiovascular
  description: >-
    Valve leaflet thickening with regurgitation and an aortic or mitral murmur,
    found on targeted echocardiography after molecular diagnosis.
  phenotype_term:
    preferred_term: Thickened valve leaflets with regurgitation
    term:
      id: HP:0001633
      label: Abnormal mitral valve morphology
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heart abnormalities in S1 and S2 included cardiac murmur (aortic or mitral), valve disease, thickened leaflets and regurgitation."
    explanation: Documents valve thickening and regurgitation.
- name: Aortic valve stenosis
  category: Cardiovascular
  description: >-
    Mild aortic valve stenosis with mild left ventricular hypertrophy suggesting
    early storage cardiomyopathy.
  phenotype_term:
    preferred_term: Mild aortic valve stenosis
    term:
      id: HP:0001650
      label: Aortic valve stenosis
    severity: MILD
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild aortic valve stenosis and mild left ventricular hypertrophy were noted in cardiac ultrasound in S1 and S2."
    explanation: Documents mild aortic stenosis and ventricular hypertrophy.
- name: Abnormal lens morphology
  category: Ophthalmologic
  description: >-
    Mild lens and vitreous opacity, with loss of the retinal interdigitation
    zone temporal to the macula on optical coherence tomography in one patient.
    Absent in two later series, so this is a variable rather than defining
    feature.
  phenotype_term:
    preferred_term: Mild lens and vitreous opacity
    term:
      id: HP:0000517
      label: Abnormal lens morphology
    severity: MILD
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reverse phenotyping revealed mild opacity of the lens and vitreous body"
    explanation: Documents the lens and vitreous opacity.
- name: Dysostosis Multiplex Absent
  category: Skeletal
  frequency: EXCLUDED
  diagnostic: true
  description: >-
    The defining exclusion of MPS X, and the reason it is not recognised as a
    mucopolysaccharidosis at the bedside. Dysostosis multiplex is the skeletal
    hallmark shared by MPS I, II, IV, VI, and VII; it is explicitly absent in
    MPS X. What is present instead is a narrower epiphyseal-metaphyseal
    dysplasia - metaphyseal striation, platyspondyly with anterior beaking,
    delayed carpal ossification - which reads as a primary skeletal dysplasia
    rather than as storage. This exclusion is why every published patient
    carried a spondyloepiphyseal-dysplasia, multiple-epiphyseal-dysplasia, or
    Legg-Calve-Perthes label before sequencing, and it is why MPS X is admitted
    to the Mucopolysaccharidoses grouping through the joint operands of the
    membership criterion rather than through the classic hallmarks.
  phenotype_term:
    preferred_term: Dysostosis multiplex
    term:
      id: HP:0000943
      label: Dysostosis multiplex
    modifier: ABSENT
  evidence:
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "While typical dysostosis multiplex findings were not observed, mild platyspondyly with anterior beaking of some vertebral bodies, irregular vertebral endplates, wide ribs, inferior tapering of the ilea with a poorly developed acetabulum, irregularity of the central part of the femoral head, delayed ossification of the carpals were noted."
    explanation: >-
      States outright that typical dysostosis multiplex was not observed, and
      enumerates the narrower skeletal findings that appear in its place.
- name: Hepatosplenomegaly Absent
  category: Gastrointestinal
  frequency: EXCLUDED
  diagnostic: true
  description: >-
    Organomegaly is absent in every reported MPS X patient. This separates MPS X
    from the visceral-storage mucopolysaccharidoses (MPS I, II, VI, VII), in
    which hepatosplenomegaly is an early and near-universal finding, and it is
    consistent with the small overall storage burden that follows from ARSK
    acting on an uncommon GAG modification rather than a backbone feature.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
    modifier: ABSENT
  evidence:
  - reference: PMID:40742107
    reference_title: "ARSK-Related Mucopolysaccharidosis Type 10."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "None demonstrated hepatosplenomegaly, neurological deficits, or cognitive impairment."
    explanation: >-
      Review across all ten reported patients states the absence of
      hepatosplenomegaly directly.
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed normal intelligence, normal hearing and eye examinations, and none had organomegaly."
    explanation: >-
      An independent series independently reports absent organomegaly.
- name: Intellectual Disability Absent
  category: Neurologic
  frequency: EXCLUDED
  diagnostic: true
  description: >-
    Cognition is normal in MPS X. All four index patients attended regular
    school, two at A level, and no neurological deficit or cognitive impairment
    has been reported in any of the ten published patients. This is the
    mechanistic expectation rather than a surprise: the CNS-toxic
    mucopolysaccharidoses are the heparan-sulfate storers, and although heparan
    sulfate carries the ARSK-dependent modification, the fraction of chains
    stalled is too small to produce a neuronopathic burden. It also means MPS X
    sits with MPS IV, MPS VI, and MPS IX rather than with MPS I, II, III, or VII
    on the neuronopathic axis.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
    modifier: ABSENT
  evidence:
  - reference: PMID:40742107
    reference_title: "ARSK-Related Mucopolysaccharidosis Type 10."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "None demonstrated hepatosplenomegaly, neurological deficits, or cognitive impairment."
    explanation: >-
      States the absence of cognitive impairment across all reported patients.
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four subjects of this study had normal behaviour and attended a regular school"
    explanation: >-
      Normal schooling in the index family. Marked INDIRECT because attendance
      at a regular school implies rather than measures normal intellect.
- name: Hearing Impairment Absent
  category: Otologic
  frequency: EXCLUDED
  description: >-
    Hearing is normal in MPS X, on formal audiometry in the index family and on
    clinical examination in a later series. Worth recording as an exclusion
    because hearing loss is common enough across the other mucopolysaccharidoses
    to be part of their standard surveillance protocols, and its absence here
    contributes to the mild, narrowly skeletal character of the disease.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
    modifier: ABSENT
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Auditory tests revealed normal results in S1 and S2 at the age of 16 years and 14 years, respectively."
    explanation: Formal audiometry was normal in both index patients tested.
  - reference: PMID:38634625
    reference_title: "Further characterization of ARSK-related mucopolysaccharidosis type 10."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed normal intelligence, normal hearing and eye examinations, and none had organomegaly."
    explanation: An independent series reports normal hearing throughout.
biochemical:
- name: Urinary dermatan sulfate
  presence: Elevated
  context: >-
    The biochemical hallmark of MPS X, and the one that most distinguishes it
    from the other mucopolysaccharidoses in practice: it is small enough to be
    missed. Sensitive LC-MS/MS disaccharide quantification shows a threefold to
    fourfold elevation of dermatan-sulfate-derived disaccharides, with heparan
    and keratan sulfate generally normal. Routine dimethylmethylene blue
    total-GAG screening, by contrast, is normal or only borderline in most
    patients, and thin-layer chromatography shows a normal GAG profile. A normal
    urinary GAG screen therefore does not exclude MPS X - the practical
    consequence is that this diagnosis is reached by sequencing, not by
    biochemistry, and the biochemistry serves to confirm it afterwards.
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS."
    explanation: Establishes the dermatan sulfate elevation detectable by LC-MS/MS.
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed a threefold and fourfold elevation of specific DS-derived disaccharides in a morning urine sample, respectively"
    explanation: Quantifies the magnitude of the dermatan sulfate elevation on LC-MS/MS.
  - reference: PMID:40742107
    reference_title: "ARSK-Related Mucopolysaccharidosis Type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical analyses reveal variable dermatan sulfate (DS) excretion in urine, with some patients showing increased DS, while others had normal urinary glycosaminoglycans (GAGs), suggesting that a normal GAG profile does not exclude this condition."
    explanation: >-
      Supports both the dermatan sulfate signal and, critically, that its
      absence does not exclude the diagnosis.
  - reference: PMID:38292179
    reference_title: "A novel homozygous missense variant in ARSK causes MPS X, a new subtype of mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the urine GAG levels measured by a standard dimethyl methylene blue test in our patient at the initial evaluation were within normal ranges"
    explanation: >-
      A worked instance of the false-negative routine screen in a
      molecularly confirmed patient.
- name: Lysosomal enzyme activities for the established MPS subtypes
  presence: Normal
  context: >-
    Normal, by design of the diagnostic workup. Because the skeletal picture
    suggests MPS IVA or IVB, patients are routinely assayed for
    galactosamine-6-sulfatase and beta-galactosidase, and in the index family a
    full panel of GAG-degrading lysosomal hydrolases was measured in
    fibroblasts. All were normal. There is no clinically available ARSK enzyme
    assay; the published functional assays use a synthetic 2-sulfoglucuronate
    disaccharide substrate in a research setting.
  evidence:
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morquio disease, MPS type IVA, was suspected, but both children had normal serum levels of galactose‐6‐sulfatase and beta‐galactosidase."
    explanation: >-
      Documents the normal MPS IV enzyme assays that leave the diagnosis to
      sequencing.
genetic:
- name: ARSK pathogenic variants
  gene_term:
    preferred_term: ARSK
    term:
      id: hgnc:25239
      label: ARSK
  association: Causative
  inheritance:
  - name: Autosomal recessive
    description: >-
      Biallelic ARSK variants, homozygous in every family reported to date.
    evidence:
    - reference: PMID:34916232
      reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively."
      explanation: Homozygous variants in affected members of consanguineous families.
  features: >-
    ARSK (hgnc:25239, chromosome 5q15) encodes arylsulfatase K. The variants
    reported to date span both nonsense and missense classes and all converge on
    loss of catalytic activity: c.250C>T p.(Arg84Cys) and c.560T>A p.(Leu187Ter)
    in the two founding families, c.1251C>G p.(Tyr417Ter) in a Norwegian family,
    and c.1067C>A p.(Ser356Tyr) in a patient of Syrian ancestry. The alleles are
    rare or absent in gnomAD, and no homozygous loss-of-function individuals are
    represented there. Reference transcript NM_198150.
  evidence:
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both children were homozygous, and both parents heterozygous, for a predicted stop variant in ARSK"
    explanation: Documents the nonsense allele and its segregation.
  - reference: PMID:38292179
    reference_title: "A novel homozygous missense variant in ARSK causes MPS X, a new subtype of mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a novel homozygous missense germline variant, c.1067C>A (p.S356Y), in the ARSK gene"
    explanation: Documents the p.Ser356Tyr missense allele.
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In gnomAD, this variant is listed with a total allele frequency of 0.002129% (6/281810 alleles)."
    explanation: >-
      Documents the population rarity of the founding allele, supporting the
      rarity annotated in features.
diagnosis:
- name: Exome or genome sequencing in undiagnosed skeletal dysplasia
  description: >-
    The route by which every published MPS X patient was diagnosed. Children are
    referred with a skeletal-dysplasia phenotype, targeted skeletal gene panels
    and known-MPS-gene analysis are negative, and exome sequencing identifies
    biallelic ARSK variants. In the index family, homozygosity mapping in a
    consanguineous pedigree narrowed the search; in the Norwegian family the
    diagnosis was reached only after re-interpreting the exome data under a
    corrected assumption about which parent was affected.
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted variant analysis of known MPS-associated genes in the exome data set of S1 did not reveal pathogenic or likely pathogenic variants in GALNS, GLB1, GNS, GUSB, HYAL1, IDUA, ARSB, HGSNAT, NAGLU, SGSH and IDS."
    explanation: >-
      Shows that the established MPS gene set is negative, which is why MPS X
      requires unbiased sequencing to reach.
- name: LC-MS/MS urinary glycosaminoglycan disaccharide quantification
  description: >-
    The confirmatory biochemical test, and the only one that reliably detects
    the MPS X signal. Enzymatic digestion followed by LC-MS/MS quantification of
    heparan, dermatan, and keratan sulfate disaccharides shows the dermatan
    sulfate elevation that dimethylmethylene blue screening misses. It should be
    used specifically when MPS is suspected on skeletal grounds and routine
    screening is normal.
  evidence:
  - reference: PMID:40742107
    reference_title: "ARSK-Related Mucopolysaccharidosis Type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical analyses reveal variable dermatan sulfate (DS) excretion in urine, with some patients showing increased DS, while others had normal urinary glycosaminoglycans (GAGs), suggesting that a normal GAG profile does not exclude this condition."
    explanation: >-
      Establishes both the value of sensitive disaccharide quantification and
      the limits of routine total-GAG screening.
treatments:
- name: Supportive orthopaedic and analgesic care
  description: >-
    No disease-modifying therapy exists for MPS X. There is no approved or
    investigational enzyme replacement therapy, no substrate reduction therapy,
    and no reported use of hematopoietic stem cell transplantation. Management
    is orthopaedic care for progressive hip dysplasia and femoral head
    osteonecrosis, analgesia for joint pain, and physiotherapy. Because the
    disease is chondro-osseous and the reported burden is pain and disability
    rather than organ failure, the authors of the fourth-patient report
    explicitly identify enzyme replacement therapy development as the unmet need.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:38292179
    reference_title: "A novel homozygous missense variant in ARSK causes MPS X, a new subtype of mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It will be very important to develop enzyme replacement therapy and potentially other treatments, given the pain and disability associated with this disorder."
    explanation: >-
      States that no disease-modifying therapy is available and identifies
      enzyme replacement therapy as the unmet need.
- name: Cardiac, ophthalmological and audiological surveillance
  description: >-
    Once ARSK-related MPS is molecularly confirmed, targeted surveillance is
    warranted even in an asymptomatic child, because the cardiac and ocular
    involvement documented in the index family was found only on deliberate
    reverse phenotyping and was clinically silent. Surveillance also
    substantiates genetic counselling for the family.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of MPS type X allows for tailored cardiac, ophthalmologic and audiological surveillance, and can inform genetic counseling."
    explanation: >-
      States the clinical utility of the diagnosis, which is surveillance and
      counselling rather than treatment.
differential_diagnoses:
- name: Morquio syndrome
  description: >-
    MPS IVA and IVB are the differential that has been actively pursued in
    essentially every reported MPS X patient, because the short-trunk skeletal
    phenotype, platyspondyly, joint hypermobility, and enamel defects all
    overlap. Normal galactosamine-6-sulfatase and beta-galactosidase activity
    excludes MPS IV and leaves MPS X reachable only by sequencing.
  distinguishing_features:
  - Normal GALNS and GLB1 enzyme activity excludes Morquio syndrome.
  - Metaphyseal striation of the long bones favors MPS X.
  - Progressive femoral head osteonecrosis with a Legg-Calve-Perthes appearance favors MPS X.
  - Corneal clouding and marked keratan sulfate excretion favor Morquio syndrome.
  disease_term:
    preferred_term: Morquio syndrome
    term:
      id: MONDO:0018938
      label: mucopolysaccharidosis type 4
  evidence:
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morquio disease, MPS type IVA, was suspected, but both children had normal serum levels of galactose‐6‐sulfatase and beta‐galactosidase."
    explanation: >-
      A worked instance of MPS IV being suspected and excluded enzymatically
      before MPS X was found.
- name: Legg-Calve-Perthes disease
  description: >-
    Bilateral Legg-Calve-Perthes disease is the single most common
    misclassification of MPS X. Idiopathic Legg-Calve-Perthes disease is
    usually unilateral; bilateral disease, particularly with metaphyseal
    striation, vertebral changes, or delayed carpal ossification, should prompt
    consideration of a mucopolysaccharidosis including MPS X.
  distinguishing_features:
  - Bilaterality favors a storage or dysplasia diagnosis over idiopathic Legg-Calve-Perthes disease.
  - Metaphyseal striation, platyspondyly, and delayed carpal ossification are extrinsic to Legg-Calve-Perthes disease.
  evidence:
  - reference: PMID:35959767
    reference_title: "Phenotypic expansion of ARSK-related mucopolysaccharidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral LCPD should result in considering the possibility of MPS type X as well as other MPS subtypes"
    explanation: Directly states the discriminating rule annotated here.
- name: Spondyloepiphyseal dysplasia
  description: >-
    The radiographic label most often applied to MPS X before molecular
    diagnosis, on the basis of platyspondyly with small epiphyses. Multiple
    epiphyseal dysplasia and Meyer dysplasia have also been proposed in reported
    patients. None of these is excluded radiographically; the discriminator is
    the finding of biallelic ARSK variants.
  distinguishing_features:
  - Metaphyseal striation of the long bones is atypical for spondyloepiphyseal dysplasia and favors MPS X.
  - Elevated urinary dermatan sulfate on LC-MS/MS favors MPS X.
  - Biallelic ARSK variants are definitive.
  evidence:
  - reference: PMID:34916232
    reference_title: "Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both families, parents were consanguineous and had two affected children with skeletal dysplasia, resembling spondyloepiphysial dysplasia."
    explanation: >-
      Documents that the presenting radiographic impression in both founding
      families was spondyloepiphyseal dysplasia.
animal_models:
- name: Arsk knockout mouse
  species: Mouse
  genotype: Constitutive Arsk knockout
  publication: PMID:32856704
  description: >-
    The constitutive Arsk-knockout mouse established the biochemical consequence
    of ARSK loss two years before any human patient was described, and it is the
    reason ARSK was already a candidate MPS gene when the first families were
    sequenced. It reproduces the biochemistry faithfully and the disease poorly.
  modeled_mechanisms:
  - target: Lysosomal accumulation of 2-O-sulfoglucuronate-capped GAG fragments
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Complete loss of glucuronate desulfation with organ-specific accumulation
      of heparan and chondroitin sulfate metabolites bearing 2-O-sulfated
      glucuronate at their non-reducing ends, which is precisely the predicted
      biochemical lesion.
    readouts:
    - name: Non-reducing-end 2-O-sulfated glucuronate GAG metabolites in tissue
      target: Lysosomal accumulation of 2-O-sulfoglucuronate-capped GAG fragments
      direction: INCREASED
      interpretation: >-
        Direct biochemical readout of the blocked degradation step in the
        storage node.
      evidence:
      - reference: PMID:32856704
        reference_title: "Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Arsk-deficient mice show, in an organ-specific manner, a moderate accumulation of HS and CS metabolites characterized by 2-O-sulfated glucuronate moieties at their non-reducing ends."
        explanation: Reports the measured accumulation of the expected metabolites.
    evidence:
    - reference: PMID:32856704
      reference_title: "Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Recently, we identified and characterized the lysosomal enzyme arylsulfatase K (Arsk) exhibiting glucuronate-2-sulfatase activity as needed for the degradation of heparan sulfate (HS), chondroitin sulfate (CS) and dermatan sulfate (DS)."
      explanation: >-
        Establishes that the mouse model targets the same enzymatic step that is
        lost in human MPS X, making it informative for the storage node.
  - target: Chondro-osseous storage and epiphyseal-metaphyseal dysplasia
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The mouse does not develop the skeletal disease that defines human MPS X.
      This is a substantive negative result rather than a gap: it means the
      mouse cannot serve as a preclinical efficacy model for the outcome that
      matters clinically, and any enzyme replacement therapy programme would need
      a different readout or a different species.
    limitations: >-
      No bone abnormalities or prominent lysosomal storage pathology develop,
      despite complete loss of glucuronate desulfation and measurable metabolite
      accumulation. The mouse phenotype is limited to behavioural changes, which
      is close to the inverse of the human picture, where skeletal disease is
      universal and cognition is normal. The species divergence most likely
      reflects differences in glucuronate-2-O-sulfation abundance or in the
      growth-plate load carried by the affected chains; it has not been resolved
      experimentally.
    evidence:
    - reference: PMID:32856704
      reference_title: "Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Pathophysiological studies reflect a rather mild phenotype including behavioral changes. Interestingly, no prominent lysosomal storage pathology like bone abnormalities were detected."
      explanation: >-
        States explicitly that bone abnormalities are absent in the knockout,
        which is the failure to recapitulate annotated here.
discussions:
- discussion_id: mpsx_mouse_skeletal_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Chondro-osseous storage and epiphyseal-metaphyseal dysplasia
  prompt: >-
    Why does the Arsk-knockout mouse accumulate the predicted GAG metabolites
    yet develop no skeletal disease, when skeletal disease is essentially the
    entire human phenotype?
  rationale: >-
    The mismatch is not a failure of the model to reproduce a subtle feature; it
    is close to an inversion. The mouse has the biochemistry without the
    skeletal pathology and a behavioural phenotype instead, while humans have
    the skeletal pathology with normal cognition. Because the storage burden in
    MPS X is small in both species, the human skeletal phenotype is unlikely to
    be a simple dose effect of accumulated substrate. A more plausible reading
    is that glucuronate-2-O-sulfation is differentially abundant on the specific
    chondroitin and dermatan sulfate chains that carry load in the human growth
    plate and epiphysis, so the same enzymatic block has a tissue-specific
    consequence in humans that it does not have in mice. Resolving this matters
    practically: the mouse is the only available model, and it lacks the outcome
    an enzyme replacement therapy would need to move.
  proposed_experiments:
  - experiment_id: exp_mpsx_species_sulfation_comparison
    name: Compare glucuronate-2-O-sulfation abundance in human and murine growth-plate GAGs
    description: >-
      Quantify the fraction of chondroitin, dermatan, and heparan sulfate chains
      bearing 2-O-sulfated glucuronate in human versus murine epiphyseal and
      growth-plate cartilage by LC-MS/MS disaccharide analysis, to test whether
      differential substrate abundance in the relevant tissue explains the
      species divergence.
    would_support:
    - pathophysiology#Chondro-osseous storage and epiphyseal-metaphyseal dysplasia
    supporting_outcome:
    - >-
      Human growth-plate and epiphyseal cartilage carries a substantially higher
      fraction of 2-O-sulfated glucuronate than the murine equivalent, matching
      the tissue distribution of human disease.
    refuting_outcome:
    - >-
      The modification is present at comparable abundance in both species'
      cartilage, indicating that the species difference lies downstream of
      substrate abundance, in how chondrocytes tolerate the stalled fragments
      rather than in how many are produced.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ten patients from six families had been reported as of the 2025 review, with
    a median age at presentation of 9.5 years. The true frequency is unknown and
    probably understated: the phenotype is mild, routine urinary GAG screening
    is often normal, and the skeletal picture is readily absorbed into a
    spondyloepiphyseal-dysplasia or Legg-Calve-Perthes label. gnomAD carries
    roughly 386 unique ARSK missense, in-frame, and truncating variants, over
    95 percent of them below an allele frequency of 1 in 10,000, which is
    consistent with a low but non-zero incidence.
  evidence:
  - reference: PMID:40742107
    reference_title: "ARSK-Related Mucopolysaccharidosis Type 10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 10 ARSK-related MPS10 patients from six families have been reported, with a median age at presentation of 9.5 years."
    explanation: Supports the reported case count and typical age at presentation.