Neuronal Ceroid Lipofuscinoses (Batten Disease Spectrum)

name: Neuronal Ceroid Lipofuscinoses
display_name: Neuronal Ceroid Lipofuscinoses (Batten Disease Spectrum)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  A group of inherited lysosomal neurodegenerative disorders in which CLN-gene
  defects disrupt lysosomal enzymes, membrane proteins, endomembrane
  trafficking, or synaptic/endolysosomal protein handling, producing abnormal
  autofluorescent ceroid/lipopigment storage and progressive neuronal disease.
  The shared clinical space includes retinal degeneration or visual impairment,
  seizures, myoclonus, developmental or cognitive regression, dementia, motor
  decline, and cerebral or cerebellar neurodegeneration.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped as an auditable union of NCL entries rather than as a generic
  lysosomal-storage bucket. Members share lysosomal/endolysosomal dysfunction
  with autofluorescent ceroid or lipopigment accumulation and progressive
  neurodegeneration, but remain separate Disease entries because the causal
  branches differ: soluble lysosomal enzyme defects such as PPT1/TPP1/CTSD/CTSF,
  lysosomal membrane or endomembrane trafficking defects such as CLN3, CLN5,
  CLN6, CLN8, and MFSD8/CLN7, and adult-onset DNAJC5/CSPalpha synaptic-protein
  handling defects. The criteria are NECESSARY: NCL membership entails
  lysosomal-storage module conformance and a characteristic neurologic or
  retinal phenotype, but those criteria are not by themselves sufficient because
  many other lysosomal storage diseases also cause neurodegeneration, seizures,
  or retinal disease.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016295
      label: neuronal ceroid lipofuscinosis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      exactMatch: this grouping is intended to represent the same neuronal
      ceroid lipofuscinosis class as MONDO:0016295. Current DisMech member
      coverage is a curation-completeness signal, not a reason to weaken the
      conceptual mapping predicate.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        The listed subtype members are MONDO neuronal ceroid lipofuscinosis
        entities or immediate NCL specializations. Additional MONDO NCL
        descendants without DisMech entries should be surfaced as curation gaps
        from this exact mapping.
membership_criteria:
- description: >-
    A member conforms to the lysosomal substrate accumulation module and has a
    core NCL neurologic or retinal phenotype such as visual impairment, retinal
    degeneration, seizure, myoclonus, developmental regression, cognitive or
    mental deterioration, dementia, motor deterioration, progressive ataxia, or
    cerebral cortical atrophy.
  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 through
        lysosomal ceroid/lipopigment storage or an upstream lysosomal
        enzyme/membrane/trafficking defect.
    - operator: OR
      operands:
      - criterion_predicate: HAS_PHENOTYPE
        description: Visual impairment.
        phenotype_term:
          preferred_term: Visual impairment
          term:
            id: HP:0000505
            label: Visual impairment
      - criterion_predicate: HAS_PHENOTYPE
        description: Retinal degeneration.
        phenotype_term:
          preferred_term: Retinal degeneration
          term:
            id: HP:0000546
            label: Retinal degeneration
      - criterion_predicate: HAS_PHENOTYPE
        description: Cognitive impairment.
        phenotype_term:
          preferred_term: Cognitive impairment
          term:
            id: HP:0100543
            label: Cognitive impairment
      - criterion_predicate: HAS_PHENOTYPE
        description: Seizure.
        phenotype_term:
          preferred_term: Seizure
          term:
            id: HP:0001250
            label: Seizure
      - criterion_predicate: HAS_PHENOTYPE
        description: Developmental regression.
        phenotype_term:
          preferred_term: Developmental regression
          term:
            id: HP:0002376
            label: Developmental regression
      - criterion_predicate: HAS_PHENOTYPE
        description: Motor deterioration.
        phenotype_term:
          preferred_term: Motor deterioration
          term:
            id: HP:0002333
            label: Motor deterioration
      - criterion_predicate: HAS_PHENOTYPE
        description: Functional motor deficit.
        phenotype_term:
          preferred_term: Functional motor deficit
          term:
            id: HP:0004302
            label: Functional motor deficit
      - criterion_predicate: HAS_PHENOTYPE
        description: Myoclonus.
        phenotype_term:
          preferred_term: Myoclonus
          term:
            id: HP:0001336
            label: Myoclonus
      - criterion_predicate: HAS_PHENOTYPE
        description: Dementia.
        phenotype_term:
          preferred_term: Dementia
          term:
            id: HP:0000726
            label: Dementia
      - criterion_predicate: HAS_PHENOTYPE
        description: Mental deterioration.
        phenotype_term:
          preferred_term: Mental deterioration
          term:
            id: HP:0001268
            label: Mental deterioration
      - criterion_predicate: HAS_PHENOTYPE
        description: Progressive cerebellar ataxia.
        phenotype_term:
          preferred_term: Progressive cerebellar ataxia
          term:
            id: HP:0002073
            label: Progressive cerebellar ataxia
      - criterion_predicate: HAS_PHENOTYPE
        description: Cerebral cortical atrophy.
        phenotype_term:
          preferred_term: Cerebral cortical atrophy
          term:
            id: HP:0002120
            label: Cerebral cortical atrophy
members:
- member: Neuronal Ceroid Lipofuscinosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The umbrella NCL entry captures the childhood-predominant Batten disease
      spectrum with multiple definitive CLN genes, abnormal autofluorescent
      lysosomal storage material, visual loss, seizures, regression, and motor
      decline.
    gene:
      preferred_term: CLN3
      term:
        id: hgnc:2074
        label: CLN3
    module: "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation"
  - description: >-
      Soluble lysosomal enzyme branches, especially PPT1/CLN1 and TPP1/CLN2,
      distinguish enzyme-deficiency NCL subtypes and motivate future subtype
      split-out disease entries.
    gene:
      preferred_term: TPP1
      term:
        id: hgnc:2073
        label: TPP1
- member: Neuronal Ceroid Lipofuscinosis 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      PPT1/CLN1 is a soluble lysosomal thioesterase branch in which impaired
      depalmitoylation of S-palmitoylated proteins produces autofluorescent
      lysosomal storage material, synaptic trafficking defects,
      neuroinflammation, mTORC1/autophagy dysregulation, seizures, visual loss,
      and infantile neurodegeneration.
    gene:
      preferred_term: PPT1
      term:
        id: hgnc:9325
        label: PPT1
    module: "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation"
- member: Neuronal Ceroid Lipofuscinosis 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      TPP1/CLN2 is a soluble lysosomal peptidase deficiency branch in which loss
      of tripeptidyl peptidase 1 causes autofluorescent lysosomal storage,
      early language delay or regression, epilepsy, motor-language decline,
      retinal dystrophy, and a disease-targeted enzyme-replacement therapy
      branch with intracerebroventricular cerliponase alfa.
    gene:
      preferred_term: TPP1
      term:
        id: hgnc:2073
        label: TPP1
    module: "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation"
- member: Neuronal Ceroid Lipofuscinosis 3
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CLN3 is the classic juvenile Batten disease branch, linking an
      endolysosomal membrane protein defect to lysosomal fingerprint inclusions,
      cholesterol storage, rapid childhood visual loss, retinal degeneration,
      cognitive or behavioral decline, seizures, and motor deterioration.
    gene:
      preferred_term: CLN3
      term:
        id: hgnc:2074
        label: CLN3
    module: "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation"
- member: Juvenile Neuronal Ceroid Lipofuscinosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      This member is the MONDO juvenile-onset grouping rather than a synonym
      for CLN3 alone. Classic CLN3 supplies the most familiar vision-first
      branch, while the entry keeps genotype-specific proximal lesions
      separate and converges them only at lysosomal ceroid-lipofuscin storage.
    gene:
      preferred_term: CLN3
      term:
        id: hgnc:2074
        label: CLN3
    module: "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation"
  - description: >-
      Juvenile PPT1/CLN1, TPP1/CLN2, and CTSD/CLN10 presentations represent
      soluble lysosomal-enzyme branches within the onset-defined grouping;
      cerliponase alfa joins specifically to the TPP1 lesion rather than to the
      grouping as a whole.
    gene:
      preferred_term: TPP1
      term:
        id: hgnc:2073
        label: TPP1
  - description: >-
      Protracted juvenile MFSD8/CLN7 and juvenile CLN8 EPMR demonstrate that
      onset and presenting sequence cannot be inferred from the classic CLN3
      branch alone.
    gene:
      preferred_term: MFSD8
      term:
        id: hgnc:28486
        label: MFSD8
- member: Neuronal Ceroid Lipofuscinosis 7
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      MFSD8/CLN7 is a lysosomal membrane major facilitator superfamily protein;
      biallelic loss causes variant late-infantile NCL with lysosomal
      autofluorescent storage material, seizures, regression, retinal
      degeneration, and model-supported autophagy/mitochondrial stress branches.
    gene:
      preferred_term: MFSD8
      term:
        id: hgnc:28486
        label: MFSD8
    module: "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation"
- member: Adult Neuronal Ceroid Lipofuscinosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CLN6-related Kufs disease links adult NCL to ER-to-Golgi lysosomal enzyme
      trafficking defects and ceroid storage without the childhood retinal-loss
      pattern.
    gene:
      preferred_term: CLN6
      term:
        id: hgnc:2077
        label: CLN6
    module: "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation"
  - description: >-
      DNAJC5/CSPalpha variants define the autosomal dominant CLN4 adult branch,
      connecting synaptic protein handling to lysosomal ceroid deposition and
      progressive myoclonus epilepsy/dementia.
    gene:
      preferred_term: DNAJC5
      term:
        id: hgnc:16235
        label: DNAJC5
  - description: >-
      CTSF/cathepsin F variants define a recessive Kufs type B branch through
      impaired lysosomal proteolysis and ceroid lipopigment accumulation.
    gene:
      preferred_term: CTSF
      term:
        id: hgnc:2531
        label: CTSF
notes: >-
  Batten disease is treated as a synonym for the neuronal ceroid lipofuscinosis
  spectrum rather than a separate member. This grouping currently enumerates the
  NCL Disease entries present in the knowledge base, including the new
  CLN1/PPT1, CLN2/TPP1, and CLN3 subtype entries. High-value future subtype
  split-outs include CLN5, CLN6, CLN8, CTSD/CLN10, GRN/CLN11, CTSF/CLN13, and
  KCTD7/CLN14 where separate curated Disease entries would improve
  subtype-specific mechanism, treatment, and progression modeling.