The citrullinemias (citrullinemia type I and citrin deficiency)

name: Citrullinemias
display_name: The citrullinemias (citrullinemia type I and citrin deficiency)
creation_date: "2026-08-28T00:00:00Z"
description: >-
  The citrullinemias are the two inherited diseases defined by elevated plasma
  citrulline: citrullinemia type I, caused by deficiency of argininosuccinate
  synthetase itself (ASS1), and citrin deficiency (historically "citrullinemia
  type II"), caused by loss of the mitochondrial aspartate-glutamate carrier
  citrin (SLC25A13), which starves the same argininosuccinate synthetase
  reaction of its cytosolic aspartate substrate. The shared biochemical
  hallmark reflects the same blocked reaction reached by two entirely
  different lesions - one in the enzyme, one in the supply of its substrate.
grouping_basis:
- SHARED_PHENOTYPE
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on the shared defining biochemical phenotype (hypercitrullinemia
  from a blocked argininosuccinate synthetase step) and on the entrenched
  clinical convention of numbering the two diseases as citrullinemia types I
  and II - the frame in which clinicians first meet both, and the reason a
  plasma amino acid profile alone cannot separate them. The members are
  deliberately kept as separate Disease entries because everything past the
  citrulline elevation diverges: citrullinemia type I is a proximal urea
  cycle enzyme deficiency presenting with classic neonatal hyperammonemic
  encephalopathy and managed with protein restriction and ammonia-scavenging
  therapy, while citrin deficiency is a mitochondrial transport defect with
  age-dependent phenotypes (neonatal intrahepatic cholestasis, then a
  distinctive protein- and fat-seeking, carbohydrate-averse diet, then
  adult-onset type II citrullinemia with recurrent hyperammonemia) in which
  the standard high-carbohydrate hyperammonemia management of type I is
  actively harmful. That treatment inversion is the practical reason the
  distinction inside this grouping matters.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015991
      label: citrullinemia
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO citrullinemia class. Its
      descendants are the two members and their onset-based subtypes (acute
      neonatal and adult-onset type I; neonatal intrahepatic cholestasis and
      adult-onset type II under citrin deficiency), so the class is the union
      curated here rather than a broader concept.
membership_criteria:
- description: >-
    Every member is caused by failure of the argininosuccinate synthetase
    step of the urea cycle - whether from deficiency of the enzyme itself
    (ASS1) or of the citrin-dependent aspartate supply to it (SLC25A13).
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_GENE
      description: Deficiency of argininosuccinate synthetase (ASS1).
      gene:
        preferred_term: ASS1
        term:
          id: hgnc:758
          label: ASS1
    - criterion_predicate: HAS_GENE
      description: Deficiency of the aspartate-glutamate carrier citrin (SLC25A13).
      gene:
        preferred_term: SLC25A13
        term:
          id: hgnc:10983
          label: SLC25A13
- description: >-
    Elevated plasma citrulline is a defining biochemical feature of every
    member, recorded either as an HP phenotype annotation or as a citrulline
    marker in the entry's biochemical section.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: Elevated plasma citrulline annotated as a phenotype.
      phenotype_term:
        preferred_term: Elevated plasma citrulline
        term:
          id: HP:0011966
          label: Elevated plasma citrulline
    - criterion_predicate: OTHER
      description: >-
        Elevated plasma citrulline documented as a biochemical marker entry
        (a citrulline row in biochemical:), which the evaluator cannot check
        against an HP term.
members:
- member: Citrullinemia Type I
  member_type: DISEASE
  display_name: Citrullinemia type I (ASS1 deficiency)
  differentiating_mechanisms:
  - description: >-
      The enzyme itself is deficient: loss of argininosuccinate synthetase
      blocks the urea cycle directly, producing severe neonatal
      hyperammonemic encephalopathy in the classic form. Management follows
      the standard proximal urea cycle disorder playbook - protein
      restriction, ammonia scavengers, arginine supplementation, and liver
      transplantation for severe disease.
    gene:
      preferred_term: ASS1
      term:
        id: hgnc:758
        label: ASS1
- member: Citrin Deficiency
  member_type: DISEASE
  display_name: Citrin deficiency (SLC25A13; citrullinemia type II)
  differentiating_mechanisms:
  - description: >-
      The enzyme is intact but starved of substrate: loss of the
      mitochondrial aspartate-glutamate carrier deprives cytosolic
      argininosuccinate synthetase of aspartate and simultaneously disrupts
      the malate-aspartate NADH shuttle. The phenotype is age-dependent
      (neonatal intrahepatic cholestasis, failure to thrive with a
      characteristic carbohydrate-averse diet, adult-onset type II
      citrullinemia), and the metabolic logic inverts type I management:
      carbohydrate loading - including the glucose infusions and
      low-protein/high-carbohydrate regimens standard for other urea cycle
      disorders - aggravates the NADH imbalance and can precipitate
      encephalopathy, while medium-chain triglycerides and a
      protein/fat-replete diet are beneficial.
    gene:
      preferred_term: SLC25A13
      term:
        id: hgnc:10983
        label: SLC25A13
notes: >-
  Created from the stub-queue lump/split review: the seeded stub for
  MONDO:0015991 (citrullinemia) resolved as entry_type GROUPING because both
  constituent diseases are already curated as separate entries and the shared
  label names their union, not one disease - the two mechanisms (enzyme
  deficiency vs substrate transport failure) and their opposed dietary
  management are exactly the distinctions a merged entry would blur. The
  citrulline-hallmark criterion pairs its HP leaf with an OTHER leaf because
  Citrullinemia Type I currently records citrulline elevation as a
  biochemical: marker row rather than an HP:0011966 phenotype annotation, so
  the evaluator reports that member as UNKNOWN on this criterion - the
  correct three-valued answer, not a membership violation. Annotating
  HP:0011966 on that entry would let the criterion resolve to SATISFIED.

  The gene criterion is deliberately NECESSARY rather than
  NECESSARY_AND_SUFFICIENT: the umbrella Urea Cycle Disorder entry also
  lists ASS1 among its genes, so a sufficiency direction would propose that
  umbrella entry as a member. The boundary the clinical category draws is
  around the two diseases defined by the citrulline hallmark, and that
  boundary is recorded in the rationale rather than as machine-checkable
  sufficiency.