Lysosomal Storage Disorders (LSDs)

name: Lysosomal Storage Disorders
display_name: Lysosomal Storage Disorders (LSDs)
creation_date: "2026-06-12T00:00:00Z"
description: >-
  The lysosomal storage disorders (LSDs) are a large group of inherited
  metabolic diseases caused by deficiency of a lysosomal hydrolase, activator,
  membrane transporter, or trafficking protein. The common consequence is
  progressive accumulation of an undegraded macromolecular substrate within the
  lysosome, leading to storage-cell cytotoxicity, neuroinflammation, and a
  progressive multisystem and/or neurodegenerative phenotype. The group is
  classified biochemically by the stored substrate (sphingolipidoses,
  mucopolysaccharidoses, oligosaccharidoses, etc.).
grouping_basis:
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on the defining lysosomal storage mechanism: every member conforms to
  the lysosomal_substrate_accumulation module (hydrolase/cofactor deficiency ->
  undegraded substrate accumulation -> storage-cell cytotoxicity ->
  progressive disease). Members are kept as separate Disease entries because the
  deficient enzyme, stored substrate, and predominant tissue differ. This
  grouping also illustrates nesting: the mucopolysaccharidoses are themselves a
  Grouping and are included here as a single GROUPING member rather than by
  re-listing Hurler/Hunter/Sanfilippo/Morquio individually. Likewise, the
  Niemann-Pick diseases, the mucolipidoses, the neuronal ceroid
  lipofuscinoses, and the GM2 gangliosidoses are included as their own nested
  GROUPING members rather than mixing their individual subtypes at the LSD
  level; Niemann-Pick disease type C is therefore NOT listed as a direct
  member, because the nested Niemann-Pick Diseases grouping already carries
  it, and for the same reason Tay-Sachs, Sandhoff, and the AB variant are
  carried by the nested GM2 Gangliosidoses grouping rather than listed
  directly. Direct DISEASE members are the LSDs that no nested grouping
  covers, and they deliberately span every arm of the
  definition: primary hydrolase deficiency (Gaucher, Fabry, Pompe,
  Krabbe, MLD, GM1, LIPA, NAGA, ACP2), activator/cofactor deficiency
  (the PSAP saposin disorders), protective-protein deficiency
  (galactosialidosis/CTSA), oligosaccharidoses (sialidoses, alpha-mannosidosis,
  aspartylglucosaminuria), and trafficking/sorting failure with normal hydrolase
  activity (VPS33A, AP5Z1) — the arms the original sphingolipidosis- and
  MPS-weighted member list under-represented.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0002561
      label: lysosomal storage disease
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO lysosomal storage disease
      class, and the membership criterion mirrors its OWL logical definition
      (disease and RO:0004020 some GO:0005764 — "has basis in dysfunction of
      lysosome"). exactMatch records the intended conceptual alignment; MONDO
      descendants without DisMech entries are curation gaps rather than a reason
      to weaken the mapping predicate.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        The immediate DISEASE members are is-a descendants of MONDO:0002561;
        the remaining immediate members (Mucopolysaccharidoses,
        Niemann-Pick Diseases, Mucolipidoses, Neuronal Ceroid
        Lipofuscinoses, and GM2 Gangliosidoses) are nested GROUPING entries. Additional MONDO LSD
        descendants without DisMech entries should be surfaced as curation gaps
        from this exact mapping.
membership_criteria:
- description: >-
    A disorder is a lysosomal storage disorder if and only if it conforms to the
    lysosomal substrate accumulation module — i.e., a lysosomal degradation
    defect causing progressive accumulation of an undegraded substrate within
    the lysosome.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation
    description: >-
      Conforms to the lysosomal substrate accumulation module (lysosomal
      degradation defect with substrate storage).
members:
- member: Mucopolysaccharidoses
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      The mucopolysaccharidoses (a nested grouping) store glycosaminoglycans due
      to deficiency of GAG-degrading enzymes, with prominent skeletal disease
      (dysostosis multiplex) and coarse facies.
    module: lysosomal_substrate_accumulation
- member: Niemann-Pick Diseases
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      The Niemann-Pick diseases (a nested grouping) are lysosomal lipid-storage
      disorders spanning acid sphingomyelinase deficiency and NPC1/NPC2
      cholesterol-egress failure, with overlapping visceral and neurovisceral
      manifestations.
    module: lysosomal_substrate_accumulation
- member: Mucolipidoses
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      The mucolipidoses (a nested grouping) disrupt lysosomal hydrolase
      targeting, lysosomal trafficking, or endolysosomal ion-channel function,
      producing mixed mucopolysaccharide-like and lipid-storage features.
    module: lysosomal_substrate_accumulation
- member: Neuronal Ceroid Lipofuscinoses
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      The neuronal ceroid lipofuscinoses (a nested grouping) store
      autofluorescent ceroid/lipopigment through CLN-gene defects spanning
      soluble lysosomal enzymes (PPT1, TPP1, CTSD/CTSF), lysosomal membrane and
      endomembrane trafficking proteins (CLN3, CLN5, CLN6, CLN8, MFSD8), and
      synaptic protein handling (DNAJC5), producing progressive neurodegeneration
      with retinal degeneration, seizures, and dementia.
    module: lysosomal_substrate_accumulation
- member: Gaucher Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Glucocerebrosidase (GBA) deficiency stores glucosylceramide in
      macrophages (Gaucher cells), causing hepatosplenomegaly, cytopenias, and
      bone disease; the prototypical sphingolipidosis.
    gene:
      preferred_term: GBA
      term:
        id: hgnc:4177
        label: GBA
- member: Fabry disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      X-linked alpha-galactosidase A (GLA) deficiency stores globotriaosylceramide
      (Gb3) in vascular endothelium, causing acroparesthesias, angiokeratomas,
      renal and cardiac disease.
    gene:
      preferred_term: GLA
      term:
        id: hgnc:4296
        label: GLA
- member: Pompe Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Acid alpha-glucosidase (GAA) deficiency stores lysosomal glycogen,
      predominantly in cardiac and skeletal muscle, causing cardiomyopathy and
      myopathy; the glycogen-storage LSD.
    gene:
      preferred_term: GAA
      term:
        id: hgnc:4065
        label: GAA
- member: GM2 Gangliosidoses
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      The GM2 gangliosidoses (a nested grouping) store GM2 ganglioside in
      neurons through failure of the hexosaminidase A / GM2 activator system,
      spanning the hydrolase-deficiency arm (Tay-Sachs via HEXA, Sandhoff via
      HEXB) and the activator-deficiency arm (the AB variant via GM2A) of the
      LSD definition.
    module: lysosomal_substrate_accumulation
- member: Krabbe Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Galactocerebrosidase (GALC) deficiency stores psychosine, causing globoid-
      cell leukodystrophy with severe demyelination of central and peripheral
      nervous systems.
    gene:
      preferred_term: GALC
      term:
        id: hgnc:4115
        label: GALC
- member: Metachromatic Leukodystrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Arylsulfatase A (ARSA) deficiency stores sulfatides, causing
      demyelinating leukodystrophy with metachromatic deposits.
    gene:
      preferred_term: ARSA
      term:
        id: hgnc:713
        label: ARSA
- member: Sialidosis type 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Partial neuraminidase-1 (NEU1) deficiency stores sialyloligosaccharides in
      the milder, normosomatic (non-dysmorphic) form — cherry-red spot myoclonus
      syndrome — with later (juvenile/adult) onset of progressive myoclonus and
      visual loss and a macular cherry-red spot, but without the coarse facies or
      dysostosis multiplex of the type 2 forms; represents the oligosaccharidosis
      (glycoproteinosis) arm of the LSDs largely absent from the sphingolipidosis-
      and MPS-weighted member list.
    gene:
      preferred_term: NEU1
      term:
        id: hgnc:7758
        label: NEU1
- member: Congenital Sialidosis Type 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Profound NEU1 deficiency stores sialyloligosaccharides from before birth in
      the most severe, congenital-onset type 2 form, causing nonimmune hydrops
      fetalis/neonatal ascites, coarse facies, hepatosplenomegaly, and dysostosis
      multiplex.
    gene:
      preferred_term: NEU1
      term:
        id: hgnc:7758
        label: NEU1
- member: Juvenile Sialidosis Type 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NEU1 deficiency in the childhood-onset (juvenile) type 2 form stores
      sialyloligosaccharides, producing dysmorphic (coarse) facies, dysostosis
      multiplex, hepatosplenomegaly, a macular cherry-red spot, and progressive
      neurological impairment intermediate in severity between the congenital
      type 2 and type 1 forms.
    gene:
      preferred_term: NEU1
      term:
        id: hgnc:7758
        label: NEU1
- member: GM1 Gangliosidosis Type 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Beta-galactosidase (GLB1) deficiency stores GM1 ganglioside and keratan
      sulfate; the infantile form combines rapid neurodegeneration with
      MPS-like somatic disease (coarse facies, dysostosis multiplex,
      hepatosplenomegaly) — the sphingolipidosis that most resembles an MPS.
    gene:
      preferred_term: GLB1
      term:
        id: hgnc:4298
        label: GLB1
- member: GM1 Gangliosidosis Type 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The same GLB1 deficiency with greater residual beta-galactosidase activity
      gives a late-infantile/juvenile form: neurodegeneration dominates, somatic
      storage is mild, and survival extends into childhood or adolescence.
    gene:
      preferred_term: GLB1
      term:
        id: hgnc:4298
        label: GLB1
- member: GM1 Gangliosidosis Type 3
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The adult/chronic GLB1 form, in which the highest residual enzyme activity
      restricts GM1 storage largely to the basal ganglia, producing generalized
      dystonia and parkinsonism rather than a systemic storage phenotype.
    gene:
      preferred_term: GLB1
      term:
        id: hgnc:4298
        label: GLB1
- member: Combined Saposin Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A PSAP prosaposin-precursor defect abolishing all four saposins (A-D) at once,
      producing a severe neonatal storage disease that combines the substrates of
      several sphingolipidoses — the most complete demonstration that activator
      (cofactor) loss, not enzyme loss, is sufficient to cause lysosomal storage.
    gene:
      preferred_term: PSAP
      term:
        id: hgnc:9498
        label: PSAP
- member: Gaucher Disease Due To Saposin C Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Selective loss of saposin C leaves glucocerebrosidase protein and in-vitro
      activity intact yet produces a Gaucher phenotype, distinguishing an
      activator-deficient Gaucher variant from GBA-deficient Gaucher disease and
      explaining enzymatically 'normal' Gaucher-like presentations.
    gene:
      preferred_term: PSAP
      term:
        id: hgnc:9498
        label: PSAP
- member: Krabbe Disease Due To Saposin A Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Selective loss of saposin A impairs galactosylceramide degradation with normal
      GALC enzyme, producing an atypical late-onset Krabbe/globoid-cell phenotype —
      the saposin A counterpart of the saposin C Gaucher variant.
    gene:
      preferred_term: PSAP
      term:
        id: hgnc:9498
        label: PSAP
- member: Alpha-mannosidosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Lysosomal alpha-mannosidase (MAN2B1) deficiency stores mannose-rich
      oligosaccharides, giving intellectual disability, hearing loss, immunodeficiency
      with recurrent infection, and skeletal disease — an oligosaccharidosis with a
      prominent, distinguishing immune phenotype.
    gene:
      preferred_term: MAN2B1
      term:
        id: hgnc:6826
        label: MAN2B1
- member: Aspartylglucosaminuria
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Aspartylglucosaminidase (AGA) deficiency blocks the final step of N-linked
      glycoprotein degradation, storing aspartylglucosamine. A Finnish-enriched
      oligosaccharidosis with slowly progressive intellectual decline and
      comparatively long survival.
    gene:
      preferred_term: AGA
      term:
        id: hgnc:318
        label: AGA
- member: Glycoprotein Storage Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A grouping-level entry for the glycoproteinoses/oligosaccharidoses — the
      N-linked glycan catabolic block shared by fucosidosis (FUCA1) and
      aspartylglucosaminuria (AGA) — distinguished from the GAG-storing MPS and the
      lipid-storing sphingolipidoses by the stored glycopeptide/oligosaccharide.
    gene:
      preferred_term: FUCA1
      term:
        id: hgnc:4006
        label: FUCA1
- member: Galactosialidosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Cathepsin A (CTSA) deficiency destabilises the beta-galactosidase/neuraminidase-1
      multienzyme complex, so a protective-protein defect causes combined secondary
      deficiency of two hydrolases and dual substrate storage — mechanistically distinct
      from a primary hydrolase or activator defect.
    gene:
      preferred_term: CTSA
      term:
        id: hgnc:9251
        label: CTSA
- member: Schindler Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Alpha-N-acetylgalactosaminidase (NAGA) deficiency in its severe infantile form
      stores sialylated/asialo glycopeptides and causes early neuroaxonal dystrophy
      with rapid neurodegeneration.
    gene:
      preferred_term: NAGA
      term:
        id: hgnc:7631
        label: NAGA
- member: Kanzaki Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The adult-onset NAGA phenotype: the same enzyme deficiency presents with diffuse
      angiokeratoma corporis diffusum and mild cognitive impairment rather than
      infantile neuroaxonal dystrophy — the clearest allelic-severity contrast within
      the NAGA series.
    gene:
      preferred_term: NAGA
      term:
        id: hgnc:7631
        label: NAGA
- member: NAGA Deficiency Type 3
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The intermediate NAGA phenotype, with mild intellectual disability and autistic
      features and without the angiokeratomas of Kanzaki disease or the neuroaxonal
      dystrophy of Schindler disease.
    gene:
      preferred_term: NAGA
      term:
        id: hgnc:7631
        label: NAGA
- member: Wolman Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Complete lysosomal acid lipase (LIPA) deficiency stores cholesteryl esters and
      triglycerides, causing infantile hepatosplenomegaly, malabsorption, and the
      characteristic adrenal calcification, and is fatal within the first year
      untreated.
    gene:
      preferred_term: LIPA
      term:
        id: hgnc:6617
        label: LIPA
- member: Cholesteryl Ester Storage Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Residual LIPA activity produces the attenuated end of lysosomal acid lipase
      deficiency: dyslipidaemia with microvesicular steatosis and progressive hepatic
      fibrosis presenting in childhood or adulthood rather than infancy.
    gene:
      preferred_term: LIPA
      term:
        id: hgnc:6617
        label: LIPA
- member: Infantile-Onset Pompe Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The severe end of acid alpha-glucosidase (GAA) deficiency, with essentially
      absent enzyme activity, hypertrophic cardiomyopathy, and profound hypotonia in
      the first months of life; CRIM-negative status drives immune tolerance induction
      alongside enzyme replacement.
    gene:
      preferred_term: GAA
      term:
        id: hgnc:4065
        label: GAA
- member: Late-Onset Pompe Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Residual GAA activity spares the heart and produces a progressive limb-girdle
      and diaphragmatic myopathy presenting from childhood to late adulthood — the
      attenuated arm of the same glycogen-storage LSD.
    gene:
      preferred_term: GAA
      term:
        id: hgnc:4065
        label: GAA
- member: Spinal Muscular Atrophy-Progressive Myoclonic Epilepsy Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Acid ceramidase (ASAH1) deficiency with residual activity stores ceramide but
      presents as SMA with progressive myoclonic epilepsy rather than as Farber
      lipogranulomatosis — an allelic LSD whose clinical label conceals its lysosomal
      mechanism.
    gene:
      preferred_term: ASAH1
      term:
        id: hgnc:735
        label: ASAH1
- member: Lysosomal Acid Phosphatase Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ACP2 deficiency of lysosomal acid phosphatase 2, an ultra-rare storage disorder
      with vomiting, hypotonia, opisthotonus, and early death; included as the acid
      phosphatase arm of the hydrolase-deficiency spectrum.
    gene:
      preferred_term: ACP2
      term:
        id: hgnc:123
        label: ACP2
- member: Mucopolysaccharidosis-Plus Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      VPS33A-related failure of HOPS/CORVET-mediated endosome-lysosome tethering
      causes GAG accumulation with entirely normal lysosomal hydrolase activity, plus
      renal and haematopoietic 'plus' features. Listed directly rather than under the
      Mucopolysaccharidoses because it fails that grouping's necessary
      GAG-degrading-enzyme-deficiency criterion: the storage is a trafficking failure,
      not a catabolic one.
    gene:
      preferred_term: VPS33A
      term:
        id: hgnc:18179
        label: VPS33A
- member: Hereditary Spastic Paraplegia 48
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      AP5Z1 loss disrupts the AP-5/SPG11/SPG15 endolysosomal sorting complex, causing
      lysosomal storage that presents as a complicated hereditary spastic paraplegia —
      the corticospinal-predominant edge of the LSD spectrum, and a reminder that
      lysosomal storage is not always diagnosed as a storage disease.
    gene:
      preferred_term: AP5Z1
      term:
        id: hgnc:22197
        label: AP5Z1
notes: >-
  Worked example demonstrating a NECESSARY_AND_SUFFICIENT defining criterion
  (single CONFORMS_TO_MODULE leaf) and nested GROUPING members (the
  Mucopolysaccharidoses, Niemann-Pick Diseases, and Mucolipidoses groupings).
  Because the criterion is defining,
  `just check-groupings` will both audit listed members and scan kb/disorders/
  for any other module-conforming disorder as a candidate member. A defining
  criterion means an unlisted candidate is a contradiction rather than a
  backlog item, so the member list is maintained to keep that candidate scan
  empty. Known LSD entries that the scan cannot see are a separate, real gap:
  Fucosidosis, Beta Mannosidosis, Farber Disease, Cystinosis, Danon disease,
  Salla Disease, Free Sialic Acid Storage Disease, and Multiple Sulfatase
  Deficiency are lysosomal storage disorders whose entries declare no
  `conforms_to` on the lysosomal_substrate_accumulation module, so they are
  invisible to this criterion and are not listed here. Wiring those entries to
  the module is the prerequisite for adding them, not a reason to list them
  unconformed.