Niemann-Pick Diseases

name: Niemann-Pick Diseases
display_name: Niemann-Pick Diseases
creation_date: "2026-06-14T00:00:00Z"
description: >-
  A curated grouping of explicit Niemann-Pick disease entries spanning the
  acid sphingomyelinase deficiency branch (SMPD1-related types A, A/B, and B)
  and the cholesterol-trafficking branch (NPC1/NPC2-related type C). Members
  share lysosomal lipid storage with overlapping hepatosplenomegaly, pulmonary,
  ocular, neurologic, and visceral manifestations, but differ sharply in primary
  gene, stored lipid, neuronopathic burden, and treatment implications.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped as an explicit curated union of Disease entries named as
  Niemann-Pick disease types or direct modern subtype equivalents, not as all
  sphingolipidoses or all lysosomal storage disorders. Types A, A/B, and B are
  SMPD1-related acid sphingomyelinase deficiency disorders with sphingomyelin
  storage and variable neuronopathic involvement, whereas type C is an NPC1/NPC2
  cholesterol egress disorder with secondary sphingolipid storage and
  progressive neurovisceral disease. The shared boundary is historical and
  clinical as well as mechanistic: each member has lysosomal lipid storage and
  overlapping hepatosplenomegaly or neurovisceral features, but the grouping
  excludes unrelated Pick disease frontotemporal degeneration and other
  lysosomal storage diseases unless a standalone entry is explicitly curated as
  a Niemann-Pick disease.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0001982
      label: Niemann-Pick disease
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      closeMatch: the grouping corresponds to the MONDO Niemann-Pick disease
      class, but is implemented as an explicit curated subset of current
      dismech Disease entries.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Listed members are MONDO Niemann-Pick disease type A, chronic
        neurovisceral ASMD/type A-B, type B, type C, and the historical type E
        entries. Niemann-Pick disease type D is not separately curated: it has
        been resolved as an NPC1 founder haplotype (Nova Scotia) and is covered
        by the type C member.
membership_criteria:
- description: >-
    A member is an explicit Niemann-Pick disease entry with lysosomal lipid
    storage and at least one characteristic shared clinical feature such as
    hepatosplenomegaly, hepatomegaly, splenomegaly, neurodegeneration, or
    vertical supranuclear gaze palsy.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: Hepatosplenomegaly.
      phenotype_term:
        preferred_term: Hepatosplenomegaly
        term:
          id: HP:0001433
          label: Hepatosplenomegaly
    - criterion_predicate: HAS_PHENOTYPE
      description: Hepatomegaly.
      phenotype_term:
        preferred_term: Hepatomegaly
        term:
          id: HP:0002240
          label: Hepatomegaly
    - criterion_predicate: HAS_PHENOTYPE
      description: Splenomegaly.
      phenotype_term:
        preferred_term: Splenomegaly
        term:
          id: HP:0001744
          label: Splenomegaly
    - criterion_predicate: HAS_PHENOTYPE
      description: Neurodegeneration.
      phenotype_term:
        preferred_term: Neurodegeneration
        term:
          id: HP:0002180
          label: Neurodegeneration
    - criterion_predicate: HAS_PHENOTYPE
      description: Vertical supranuclear gaze palsy.
      phenotype_term:
        preferred_term: Vertical supranuclear gaze palsy
        term:
          id: HP:0000511
          label: Vertical supranuclear gaze palsy
members:
- member: Niemann-Pick Disease Type A
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Severe infantile neuronopathic acid sphingomyelinase deficiency caused by
      biallelic SMPD1 variants with profound enzyme deficiency, lysosomal
      sphingomyelin storage, early hepatosplenomegaly, cherry-red macular spots,
      and rapidly fatal neurodegeneration.
    gene:
      preferred_term: SMPD1
      term:
        id: hgnc:11120
        label: SMPD1
- member: Niemann-Pick Disease Type B
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Chronic non-neuronopathic visceral acid sphingomyelinase deficiency caused
      by biallelic SMPD1 variants with residual enzyme activity, producing
      hepatosplenomegaly, interstitial lung disease, cytopenias, dyslipidemia,
      growth delay, and survival often into adulthood.
    gene:
      preferred_term: SMPD1
      term:
        id: hgnc:11120
        label: SMPD1
- member: Chronic Neurovisceral Acid Sphingomyelinase Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Intermediate chronic neurovisceral acid sphingomyelinase deficiency,
      historically Niemann-Pick disease type A/B, caused by biallelic SMPD1
      variants with residual acid sphingomyelinase activity and combined
      chronic visceral disease plus mild to severe neurologic involvement.
    gene:
      preferred_term: SMPD1
      term:
        id: hgnc:11120
        label: SMPD1
- member: Niemann-Pick Disease Type C
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NPC1/NPC2-related lysosomal cholesterol egress failure, distinct from
      acid sphingomyelinase deficiency, with unesterified cholesterol and
      secondary glycosphingolipid storage causing neonatal visceral disease or
      progressive neurologic disease with vertical supranuclear gaze palsy,
      ataxia, dysphagia, dystonia, seizures, and psychiatric features.
    gene:
      preferred_term: NPC1
      term:
        id: hgnc:7897
        label: NPC1
  - description: >-
      NPC2-related type C disease accounts for a smaller subset of NPD-C and
      disrupts the soluble lysosomal cholesterol-transfer partner of NPC1,
      producing the same cholesterol-egress failure and secondary lipid storage
      phenotype.
    gene:
      preferred_term: NPC2
      term:
        id: hgnc:14537
        label: NPC2
- member: Niemann-Pick Disease Type E
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A historical, molecularly unresolved Niemann-Pick label applied to rare
      (mostly adult) patients with hepatomegaly, foamy-macrophage tissue
      infiltration, sphingomyelin storage, and only partial acid
      sphingomyelinase deficiency who fitted neither type A/B nor type C. It is
      differentiated from the other members not by a distinct gene but by the
      absence of one: in the molecular era these cases are re-assignable to
      SMPD1-related ASMD or to NPC1/NPC2 disease, so the entry is retained as a
      nosologic-history member rather than as a separate disease mechanism.
notes: >-
  Exclude Pick disease/frontotemporal lobar degeneration, Gaucher disease,
  Tay-Sachs disease, Sandhoff disease, Salla disease, and broad lysosomal
  storage or sphingolipidosis entries unless the disease entry is explicitly a
  Niemann-Pick disease. Niemann-Pick disease type E is listed as a
  nosologic-history member: it names a historical residual category rather than
  a distinct molecular disease, and satisfies the grouping criteria through
  hepatomegaly and neurodegeneration.