Mucolipidoses

name: Mucolipidoses
display_name: Mucolipidoses
creation_date: "2026-06-18T00:00:00Z"
description: >-
  The mucolipidoses are lysosomal storage disorders that combine
  mucopolysaccharide-like and lipid-storage features, but arise from lysosomal
  hydrolase trafficking, targeting, or endolysosomal membrane-transport defects
  rather than a single GAG-degrading enzyme deficiency. The current DisMech
  grouping spans GNPTAB/GNPTG GlcNAc-1-phosphotransferase defects and
  MCOLN1/TRPML1 channel dysfunction.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped as a mechanistic lysosomal-storage subgroup: members conform to the
  lysosomal_substrate_accumulation module but are distinguished from the
  mucopolysaccharidoses by failure of lysosomal hydrolase targeting/trafficking
  or endolysosomal ion-channel function rather than deficiency of one
  GAG-catabolic enzyme. They are kept as separate Disease entries because
  GNPTAB loss causes severe I-cell disease, GNPTG loss causes the attenuated
  mucolipidosis III gamma phenotype, and MCOLN1 loss causes mucolipidosis IV
  with prominent neurodevelopmental and ocular disease.
membership_criteria:
- description: >-
    A member is a lysosomal storage disorder that conforms to the lysosomal
    substrate accumulation module and perturbs lysosomal hydrolase targeting,
    lysosomal transport, or autophagic-endolysosomal membrane function.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: CONFORMS_TO_MODULE
      module: lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation
      description: >-
        Conforms to the lysosomal substrate accumulation module.
    - operator: OR
      description: >-
        Perturbs hydrolase targeting, lysosomal transport, or autophagic
        endolysosomal membrane function.
      operands:
      - criterion_predicate: HAS_BIOLOGICAL_PROCESS
        description: Defective protein targeting to lysosome.
        biological_processes:
        - preferred_term: protein targeting to lysosome
          term:
            id: GO:0006622
            label: protein targeting to lysosome
          modifier: DECREASED
      - criterion_predicate: HAS_BIOLOGICAL_PROCESS
        description: Abnormal lysosomal transport.
        biological_processes:
        - preferred_term: lysosomal transport
          term:
            id: GO:0007041
            label: lysosomal transport
          modifier: ABNORMAL
      - criterion_predicate: HAS_BIOLOGICAL_PROCESS
        description: Abnormal autophagy.
        biological_processes:
        - preferred_term: autophagy
          term:
            id: GO:0006914
            label: autophagy
          modifier: ABNORMAL
members:
- member: Mucolipidosis Type II
  member_type: DISEASE
  display_name: Mucolipidosis type II (I-cell disease)
  differentiating_mechanisms:
  - description: >-
      Severe GNPTAB-associated loss of GlcNAc-1-phosphotransferase abolishes
      mannose-6-phosphate tagging of soluble lysosomal hydrolases, causing
      missorting, hypersecretion, and multisubstrate lysosomal storage.
    gene:
      preferred_term: GNPTAB
      term:
        id: hgnc:29670
        label: GNPTAB
- member: GNPTG-Mucolipidosis
  member_type: DISEASE
  display_name: Mucolipidosis III gamma
  differentiating_mechanisms:
  - description: >-
      GNPTG gamma-subunit deficiency attenuates GlcNAc-1-phosphotransferase
      function, producing a later-onset mucolipidosis III gamma phenotype with
      skeletal dysplasia, joint limitation, pain, and cardiac valve disease.
    gene:
      preferred_term: GNPTG
      term:
        id: hgnc:23026
        label: GNPTG
- member: Mucolipidosis Type IV
  member_type: DISEASE
  display_name: Mucolipidosis type IV
  differentiating_mechanisms:
  - description: >-
      MCOLN1/TRPML1 loss disrupts endolysosomal calcium signaling, autophagy,
      and membrane trafficking, producing a neurodevelopmental and ocular
      mucolipidosis rather than a hydrolase-targeting defect.
    gene:
      preferred_term: MCOLN1
      term:
        id: hgnc:13356
        label: MCOLN1
- member: Mucolipidosis Type III Alpha/Beta
  member_type: DISEASE
  display_name: Mucolipidosis III alpha/beta (pseudo-Hurler polydystrophy)
  differentiating_mechanisms:
  - description: >-
      Attenuated GNPTAB variants retain residual GlcNAc-1-phosphotransferase
      activity, so the same alpha/beta-subunit gene that causes mucolipidosis II
      instead produces a slowly progressive, later-onset disorder of skeletal
      dysplasia, joint stiffness and pain, cardiac valve disease, and only mild
      CNS involvement — the allelic-severity counterpart of ML II and the
      alpha/beta-subunit counterpart of GNPTG-mucolipidosis (ML III gamma).
    gene:
      preferred_term: GNPTAB
      term:
        id: hgnc:29670
        label: GNPTAB
notes: >-
  Nested LSD subgroup. It should be represented as a GROUPING member of
  Lysosomal Storage Disorders rather than mixing its individual members at the
  parent LSD level.