Mucopolysaccharidoses (MPS)

name: Mucopolysaccharidoses
display_name: Mucopolysaccharidoses (MPS)
creation_date: "2026-06-12T00:00:00Z"
description: >-
  The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders
  caused by deficiency of the enzymes that catabolize glycosaminoglycans (GAGs,
  formerly mucopolysaccharides). Each MPS type results from a distinct enzyme
  deficiency, leading to progressive lysosomal accumulation of one or more GAG
  species (dermatan, heparan, keratan, chondroitin sulfate, or — in MPS IX —
  the non-sulfated GAG hyaluronan) and a multisystem disease with overlapping
  skeletal, visceral, and—type dependent—neurological involvement. Roughly a
  dozen enzyme defects are now assigned to the numbered MPS types, the most
  recent being MPS X (ARSK, glucuronate 2-sulfatase), described in humans in
  2022. The group is numbered rather than named systematically, and the
  numbering carries historical accidents: there is no MPS V (Scheie syndrome
  was renumbered into the MPS I spectrum) and no MPS VIII (a proposed entity
  that was retracted).
grouping_basis:
- SHARED_MECHANISM
- SHARED_GENE_FAMILY
grouping_rationale: >-
  Grouped on a shared final-common-pathway mechanism: every member is caused by
  deficiency of a lysosomal GAG-degrading enzyme, producing lysosomal GAG
  storage (conforming to the lysosomal_substrate_accumulation trunk and to its
  GAG-specific refinement, the mps_gag_storage module, which every member
  reaches at its GAG-accumulation hub or through whichever of its heparan,
  dermatan, or keratan sulfate arms the member's stored GAG switches on). The
  members are deliberately kept as separate Disease entries rather than merged,
  because they differ in the specific deficient enzyme and gene, the GAG
  species that accumulates, the mode of inheritance (MPS II / Hunter syndrome is
  X-linked, the others autosomal recessive), and the presence and severity of
  CNS involvement. This is therefore a grouping over distinct entities, not a
  lumping of them into one disease.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019249
      label: mucopolysaccharidosis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO mucopolysaccharidosis class.
      exactMatch records the intended conceptual alignment; MONDO MPS subtypes
      without DisMech entries are curation gaps rather than evidence that the
      grouping concept is only a close match.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Every listed member resolves to an is-a descendant of MONDO:0019249,
        either through its own disease_term (MPS II, III, IV, VI, VII, IX, X)
        or through its curated subtypes (attenuated MPS I, via Hurler-Scheie
        MONDO:0011759 and Scheie MONDO:0011760). Additional MONDO MPS
        descendants without DisMech entries should be surfaced as curation gaps
        from this exact mapping. Two descendants carry no exact or narrow match,
        for different reasons. MONDO:0001586 "mucopolysaccharidosis type 1" is
        the parent of Hurler, Hurler-Scheie and Scheie and is spanned jointly by
        the two MPS I entries, neither of which claims it: Hurler syndrome is
        exact to MONDO:0011758 and Attenuated MPS I records MONDO:0001586 as a
        broadMatch, so a coverage report that counts only exact and narrow
        matches will list it as uncovered although no MPS I concept is
        uncurated. MONDO:0009647 "Morquio syndrome C" has no entry at all; it
        is a disputed historical entity discussed in the notes below.
membership_criteria:
- description: >-
    A disorder belongs to the mucopolysaccharidoses if it is a lysosomal
    storage disease of glycosaminoglycan catabolism: it conforms to the
    lysosomal substrate accumulation module AND is caused by deficiency of a
    GAG-degrading lysosomal enzyme AND presents with a characteristic
    connective-tissue GAG-storage manifestation (coarse facial features,
    dysostosis multiplex, or joint/periarticular storage disease — either
    structural, such as periarticular soft-tissue masses, or restrictive, such
    as joint stiffness and contracture).
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: CONFORMS_TO_MODULE
      module: lysosomal_substrate_accumulation
      description: >-
        Has a pathophysiology node conforming to the lysosomal substrate
        accumulation module. Anchored to the module stem rather than to its
        "Lysosomal Substrate Accumulation" node because the members conform at
        two different nodes of that trunk by design: MPS I, II, III and IV bind
        their GAG-accumulation node to it, while MPS VI, VII, IX and X bind
        their enzyme-deficiency node to "Lysosomal Hydrolase or Cofactor
        Deficiency" and bind the accumulation node to the MPS-specific hub
        below instead. A node-anchored leaf would report half the members as
        conforming elsewhere in the module (dismech#9403).
    - criterion_predicate: CONFORMS_TO_MODULE
      module: mps_gag_storage
      description: >-
        Has a pathophysiology node conforming to the MPS glycosaminoglycan
        storage module, the GAG-specific refinement of the trunk above. Stem
        only, deliberately: the module is a hub with three arms, and each
        member engages the subset of arms its stored GAG switches on, so no
        single node is common to all members.
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: Deficient catabolism of glycosaminoglycans.
      biological_processes:
      - preferred_term: Glycosaminoglycan catabolic process
        term:
          id: GO:0006027
          label: glycosaminoglycan catabolic process
        modifier: DECREASED
    - operator: OR
      description: >-
        At least one hallmark connective-tissue GAG-storage manifestation is
        present. The joint operands are not decoration; two members fail the
        two classic hallmarks and are admitted only by the joint arms. MPS IX
        (Natowicz syndrome) stores hyaluronan rather than a sulfated GAG and has
        neither coarse facies nor dysostosis multiplex, presenting instead with
        periarticular soft-tissue masses. MPS X is admitted the same way from
        the other direction: its primary reports state explicitly that typical
        dysostosis multiplex was not observed and that coarse facies is
        age-dependent and absent in younger patients, while progressive hip
        dysplasia and interphalangeal joint hypermobility are near-universal. A
        criterion admitting only coarse facies and dysostosis multiplex would
        contradict both curated memberships.
      operands:
      - criterion_predicate: HAS_PHENOTYPE
        description: Coarse facial features in many or most cases.
        phenotype_term:
          preferred_term: Coarse facial features
          term:
            id: HP:0000280
            label: Coarse facial features
        min_frequency: FREQUENT
      - criterion_predicate: HAS_PHENOTYPE
        description: Dysostosis multiplex.
        phenotype_term:
          preferred_term: Dysostosis multiplex
          term:
            id: HP:0000943
            label: Dysostosis multiplex
      - criterion_predicate: HAS_PHENOTYPE
        description: >-
          Structural joint or periarticular storage manifestation (joint
          swelling or periarticular soft-tissue mass). Kept separate from the
          mobility operand below because HP splits joint structure from joint
          function, and the two MPS joint phenotypes fall on opposite sides of
          that split.
        phenotype_term:
          preferred_term: Abnormal joint morphology
          term:
            id: HP:0001367
            label: Abnormal joint morphology
      - criterion_predicate: HAS_PHENOTYPE
        description: >-
          Joint mobility restriction from periarticular GAG storage (joint
          stiffness or contracture) — the near-universal MPS joint phenotype.
        phenotype_term:
          preferred_term: Abnormality of joint mobility
          term:
            id: HP:0011729
            label: Abnormality of joint mobility
members:
- member: Hurler syndrome
  member_type: DISEASE
  display_name: Hurler syndrome (severe MPS I)
  differentiating_mechanisms:
  - description: >-
      Autosomal recessive deficiency of alpha-L-iduronidase (IDUA), causing
      lysosomal accumulation of dermatan sulfate and heparan sulfate; the severe
      end of the MPS I spectrum, with prominent neurodegeneration. Distinguished
      from its attenuated sibling below by the absence of residual enzyme
      activity, which is what permits cerebral heparan sulfate storage to reach
      the neurodegenerative threshold.
    gene:
      preferred_term: IDUA
      term:
        id: hgnc:5391
        label: IDUA
- member: Attenuated Mucopolysaccharidosis Type I
  member_type: DISEASE
  display_name: Attenuated MPS I (Hurler-Scheie and Scheie syndromes)
  differentiating_mechanisms:
  - description: >-
      The same IDUA deficiency as Hurler syndrome, but with residual
      alpha-L-iduronidase activity. That residual activity keeps cerebral
      heparan sulfate storage below the neurodegenerative threshold while
      leaving the dermatan-sulfate connective-tissue arm fully engaged, so the
      disease is a progressive somatic disorder of joints, cornea, valves,
      airway, and spinal cord with preserved cognition. The two MPS I entries
      are kept separate in this grouping rather than merged because they differ
      in age at presentation, in which organ systems carry the morbidity, and in
      which disease-modifying therapy is indicated - enzyme replacement here,
      transplantation for the severe arm.
    gene:
      preferred_term: IDUA
      term:
        id: hgnc:5391
        label: IDUA
- member: Hunter syndrome
  member_type: DISEASE
  display_name: Hunter syndrome (MPS II)
  differentiating_mechanisms:
  - description: >-
      X-linked deficiency of iduronate-2-sulfatase (IDS)—the only X-linked
      MPS—causing accumulation of dermatan and heparan sulfate. Absence of
      corneal clouding helps distinguish it clinically from MPS I.
    gene:
      preferred_term: IDS
      term:
        id: hgnc:5389
        label: IDS
- member: Sanfilippo syndrome
  member_type: DISEASE
  display_name: Sanfilippo syndrome (MPS III)
  differentiating_mechanisms:
  - description: >-
      Deficiency of one of four enzymes of heparan sulfate degradation, causing
      selective heparan sulfate accumulation. Distinguished by severe, early
      progressive CNS degeneration with comparatively mild somatic/skeletal
      disease. The four subtypes are biochemically distinct and clinically
      near-identical: MPS IIIA is heparan N-sulfatase (SGSH) deficiency.
    gene:
      preferred_term: SGSH
      term:
        id: hgnc:10818
        label: SGSH
  - description: >-
      MPS IIIB is alpha-N-acetylglucosaminidase (NAGLU) deficiency, the
      exoglycosidase that removes the terminal N-acetylglucosamine residue
      once HGSNAT has acetylated it.
    gene:
      preferred_term: NAGLU
      term:
        id: hgnc:7632
        label: NAGLU
  - description: >-
      MPS IIIC is heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT)
      deficiency, the only MPS enzyme that is a lysosomal membrane transferase
      rather than a hydrolase: it acetylates the terminal glucosamine so that
      NAGLU can remove it.
    gene:
      preferred_term: HGSNAT
      term:
        id: hgnc:26527
        label: HGSNAT
  - description: >-
      MPS IIID is N-acetylglucosamine-6-sulfatase (GNS) deficiency, removing the
      6-O-sulfate from N-acetylglucosamine residues of heparan sulfate.
    gene:
      preferred_term: GNS
      term:
        id: hgnc:4422
        label: GNS
- member: Morquio syndrome
  member_type: DISEASE
  display_name: Morquio syndrome (MPS IV)
  differentiating_mechanisms:
  - description: >-
      Deficiency of N-acetylgalactosamine-6-sulfatase (GALNS, MPS IVA) causing
      keratan and chondroitin-6-sulfate accumulation. Distinguished by a
      predominantly skeletal phenotype (spondyloepiphyseal dysplasia,
      odontoid hypoplasia) with preserved intelligence.
    gene:
      preferred_term: GALNS
      term:
        id: hgnc:4122
        label: GALNS
  - description: >-
      MPS IVB is beta-galactosidase (GLB1) deficiency, the same enzyme whose
      deficiency causes GM1 gangliosidosis; keratan sulfate storage with a
      Morquio skeletal phenotype and without the neurodegeneration of GM1
      gangliosidosis is what makes it MPS IVB, and the two are allelic.
    gene:
      preferred_term: GLB1
      term:
        id: hgnc:4298
        label: GLB1
- member: Maroteaux-Lamy syndrome
  member_type: DISEASE
  display_name: Maroteaux-Lamy syndrome (MPS VI)
  differentiating_mechanisms:
  - description: >-
      Autosomal recessive deficiency of N-acetylgalactosamine-4-sulfatase
      (arylsulfatase B, ARSB) causing selective dermatan sulfate accumulation.
      Distinguished by severe somatic and skeletal disease — dysostosis
      multiplex, valvular heart disease, corneal clouding — with intelligence
      characteristically preserved, because heparan sulfate (the CNS-toxic GAG
      of MPS I/II/III) is not a substrate of ARSB.
    gene:
      preferred_term: ARSB
      term:
        id: hgnc:714
        label: ARSB
- member: Sly syndrome
  member_type: DISEASE
  display_name: Sly syndrome (MPS VII)
  differentiating_mechanisms:
  - description: >-
      Deficiency of beta-glucuronidase (GUSB), the exoglycosidase acting on
      dermatan, heparan, and chondroitin sulfate, so all three GAG species
      accumulate. Distinguished by the highest frequency of presentation as
      non-immune hydrops fetalis among the MPS disorders, alongside a variable
      postnatal spectrum with CNS involvement.
    gene:
      preferred_term: GUSB
      term:
        id: hgnc:4696
        label: GUSB
- member: Mucopolysaccharidosis type IX
  member_type: DISEASE
  display_name: Mucopolysaccharidosis type IX (Natowicz syndrome)
  differentiating_mechanisms:
  - description: >-
      Deficiency of lysosomal hyaluronidase 1 (HYAL1) causing hyaluronan — not
      a sulfated GAG — to accumulate. The mechanistic outlier of the group: an
      ultra-rare, essentially non-neuronopathic disorder of periarticular soft
      tissue masses and short stature, without the coarse facies or classic
      dysostosis multiplex that the other MPS types share.
    gene:
      preferred_term: HYAL1
      term:
        id: hgnc:5320
        label: HYAL1
- member: Mucopolysaccharidosis type X
  member_type: DISEASE
  display_name: Mucopolysaccharidosis type X (ARSK deficiency)
  differentiating_mechanisms:
  - description: >-
      Deficiency of arylsulfatase K (ARSK, glucuronate 2-sulfatase), which
      removes the 2-O-sulfate from 2-sulfoglucuronate. The most recently defined
      MPS, and the mechanistic outlier at the opposite end from MPS IX: its
      substrate modification is a rare decoration of heparan, dermatan, and
      chondroitin sulfate rather than a backbone-defining feature, so only a
      minority of chains stall and the storage burden is small. The result is
      the mildest and most narrowly skeletal MPS - progressive hip dysplasia
      with metaphyseal striation and no organomegaly, neurodegeneration, or
      classic dysostosis multiplex - and a urinary GAG screen that is often
      normal.
    gene:
      preferred_term: ARSK
      term:
        id: hgnc:25239
        label: ARSK
notes: >-
  Worked example of the Grouping schema. Members reference existing Disease
  entries by name; differentiating mechanisms cite the disorder-specific
  deficient enzyme/gene. CNS involvement and GAG species differ across types.

  The KB also carries a Disease entry named Mucopolysaccharidosis whose
  disease_term is the same MONDO:0019249 this grouping maps to. That entry is
  an umbrella over the numbered types with per-gene genetic rows and a shared
  pathograph; it is not a member here, because it is not a distinct disease,
  and it is not this grouping's source of membership. The union of MPS
  diseases is recorded here, by explicit members; the umbrella entry's own
  lump/split review is tracked in dismech#3614.

  Boundary cases, and why they are not members. The NECESSARY criterion above
  requires deficiency of a GAG-degrading lysosomal enzyme, which is what
  excludes several disorders that would otherwise look like members. Recording
  them here keeps the exclusions auditable rather than merely absent.

  Mucopolysaccharidosis-plus syndrome (VPS33A) is the sharpest case. It
  phenocopies an MPS - coarse facies, dysostosis multiplex, hepatosplenomegaly,
  and markedly raised urinary and plasma GAG - yet every known GAG-degrading
  hydrolase is normal, because the lesion is in HOPS/CORVET membrane tethering
  rather than in catabolism. It is storage disease without an enzyme
  deficiency, so it fails the enzyme operand while satisfying every phenotype
  operand. dismech curates it under Lysosomal Storage Disorders instead.

  Multiple sulfatase deficiency (SUMF1) fails the criterion from the other
  direction: it produces genuine MPS storage, but by removing the
  formylglycine-generating enzyme that activates all sulfatases at once, so the
  primary defect is a post-translational modification failure rather than a
  single GAG-degrading enzyme deficiency, and the disease is simultaneously a
  sulfatidosis. Grouping it here would misdescribe both its mechanism and its
  scope.

  The mucolipidoses are the classic near-miss and have their own grouping. ML II
  and ML III (GNPTAB/GNPTG) mislocalize a whole cohort of lysosomal hydrolases
  by failing to attach the mannose-6-phosphate tag, so GAG-degrading enzymes are
  deficient in the lysosome as a consequence, but the primary lesion is in
  trafficking. ML III alpha/beta is even named pseudo-Hurler polydystrophy for
  the resemblance.

  ARSG deficiency is a nomenclature trap worth flagging explicitly, because it
  is one gene away from MPS X. Arsg-deficient mice accumulate heparan sulfate
  and were designated MPS IIIE, an MPS III subtype letter that persists in the
  literature. In humans, however, the same enzyme deficiency presents as Usher
  syndrome type 4 - late-onset retinitis pigmentosa with hearing loss - and not
  as a mucopolysaccharidosis phenotype, so the human disease fails the
  connective-tissue operand of the criterion above. dismech curates it as Usher
  Syndrome Type 4, and that entry states its glycosaminoglycan mechanism. If
  human ARSG deficiency is later shown to carry MPS-typical connective-tissue
  storage, its membership here should be revisited.

  Morquio syndrome C (MONDO:0009647) is the one MONDO descendant of
  mucopolysaccharidosis with no dismech entry. It is a historical designation
  for a proposed Morquio variant whose enzyme defect was never securely
  established, and it is not carried by contemporary MPS classifications. It is
  left uncurated deliberately rather than by oversight; a curator revisiting it
  should expect to record it as an obsolete or unsubstantiated concept rather
  than as a disease entry.