Glycogen storage diseases (glycogenoses)

name: Glycogen Storage Diseases
display_name: Glycogen storage diseases (glycogenoses)
creation_date: "2026-08-28T00:00:00Z"
description: >-
  The glycogen storage diseases (glycogenoses) are the inherited disorders in
  which a defect of glycogen synthesis, degradation, or its immediate
  regulatory and transport machinery produces abnormal glycogen quantity or
  structure in tissue. The classical Roman-numeral nosology numbers them by
  the deficient enzyme, and the clinical spectrum falls into two broad
  physiologies that many members straddle: hepatic forms presenting with
  fasting hypoglycemia and hepatomegaly (I, III, VI, IX, Fanconi-Bickel),
  and muscle forms presenting with exercise intolerance, cramps, and
  rhabdomyolysis (V, VII, XIII, XV), with two members standing outside the
  split: Pompe disease (II), a lysosomal disease of both muscle types, and
  PRKAG2 cardiac syndrome, whose storage is cardiac-restricted.
grouping_basis:
- SHARED_MECHANISM
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on the shared mechanism family (a lesion in the glycogen
  synthesis/degradation pathway or its immediate regulators, with abnormal
  tissue glycogen as the common intermediate phenotype) and on one of the
  oldest classification conventions in metabolic medicine, the Roman-numeral
  GSD nosology that still organizes textbooks, newborn metabolic workups,
  and management guidelines. The members are deliberately kept as separate
  Disease entries: the deficient enzymes act at different pathway steps and
  in different compartments (cytosol for the phosphorylase system, lysosome
  for Pompe disease), the storage material differs (normal glycogen versus
  the amylopectin-like polyglucosan of branching-enzyme disease), and the
  physiology diverges to the point of opposite hallmark presentations -
  fasting hypoglycemia in the hepatic forms versus exertional rhabdomyolysis
  with no hypoglycemia in the muscle forms.

  Boundary decisions, recorded because the MONDO class is broader than the
  clinical convention: Lafora disease is excluded (a progressive myoclonic
  epilepsy with neuronal polyglucosan inclusions from a
  glycogen-metabolism-adjacent lesion, outside the Roman-numeral GSD
  nosology); Danon disease is excluded (the historical "GSD IIb" label is a misnomer - LAMP2
  loss impairs autophagy, with no enzymatic defect of glycogen metabolism);
  PGM2L1 deficiency is excluded (a neurodevelopmental disorder of
  glucose-1,6-bisphosphate synthesis without tissue glycogen storage).
  Adult polyglucosan body disease is included: it is the allelic adult-onset
  GBE1 disease, i.e. the adult expression of the type IV lesion.
  PRKAG2 cardiac syndrome is included: the KB curates it as its own entry, a
  non-lysosomal glycogen storage disease of the heart and a genocopy - not a
  form - of sarcomeric hypertrophic cardiomyopathy.
  GSD 0 (glycogen synthase deficiency, GYS1/GYS2) and the rarer distal
  glycolytic forms have no entries yet - curation gaps, not exclusions
  (note the number XI has been used both for the Fanconi-Bickel GLUT2
  disease listed below and, after reassignment, for LDHA deficiency; the
  gap is the latter).
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0002412
      label: disorder of glycogen metabolism
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      broadMatch: the MONDO class is strictly broader than this grouping -
      defined by pathway (any disorder of glycogen metabolism), it includes
      Lafora disease, Danon disease, and PGM2L1 deficiency, which the
      clinical GSD convention curated here excludes, each for a reason
      recorded in the rationale. Members are descendants of the MONDO class;
      for PRKAG2 Cardiac Syndrome the closest anchor inside the class is
      lethal congenital glycogen storage disease of heart (MONDO:0009867),
      the classic fatal congenital PRKAG2 presentation, which the class
      carries as a descendant. The entry's own MONDO:0800484 term is a
      broader PRKAG2-cardiomyopathy concept whose subclass placement
      relative to this class was not verified here.
membership_criteria:
- description: >-
    A disease belongs to the glycogen storage diseases if an inherited defect
    of glycogen synthesis, degradation, or its immediate regulatory/transport
    machinery - or a distal glycolytic block that dams glucose flux back into
    glycogen - produces abnormal glycogen quantity or structure in tissue.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: >-
        Annotates a glycogen metabolic process lesion (evaluated over GO
        closure, so glycogen catabolic and biosynthetic process qualify).
      biological_processes:
      - preferred_term: Glycogen metabolic process
        term:
          id: GO:0005977
          label: glycogen metabolic process
    - criterion_predicate: OTHER
      description: >-
        A distal glycolytic enzyme deficiency (e.g. muscle
        phosphofructokinase in type VII, beta-enolase in type XIII) whose
        secondary consequence is muscle glycogen accumulation - the entries
        annotate the glycolytic lesion rather than a glycogen-process term,
        so this arm is not machine-checkable.
members:
- member: Glycogen Storage Disease Type I
  member_type: DISEASE
  display_name: GSD I (von Gierke; G6PC1/SLC37A4)
  differentiating_mechanisms:
  - description: >-
      The final-step block: glucose-6-phosphatase (Ia) or its transporter
      (Ib) fails, so neither glycogenolysis nor gluconeogenesis can release
      free glucose - the most severe fasting hypoglycemia in the group, with
      lactic acidosis, hyperuricemia, hypertriglyceridemia, and, in Ib,
      neutropenia from the transporter's immune role.
- member: Pompe Disease
  member_type: DISEASE
  display_name: GSD II (Pompe; GAA)
  differentiating_mechanisms:
  - description: >-
      The only lysosomal member: acid alpha-glucosidase deficiency traps
      glycogen inside lysosomes, so the pathology is autophagic buildup and
      myofiber destruction (cardiomyopathy and skeletal myopathy), not
      hypoglycemia - cytosolic glycogenolysis is intact. The infantile- and
      late-onset presentations also exist as separate sibling entries
      (Infantile-Onset and Late-Onset Pompe Disease), deliberately not
      double-listed here since this member carries them as subtypes, and
      Pompe disease is the group's enzyme-replacement-therapy precedent.
- member: Cori Forbes Disease
  member_type: DISEASE
  display_name: GSD III (Cori/Forbes; AGL)
  differentiating_mechanisms:
  - description: >-
      Debranching enzyme deficiency: glycogenolysis stalls at the branch
      points, storing abnormal short-branched limit dextrin in liver and
      (in IIIa) muscle - hepatic disease that, unlike type I, spares
      gluconeogenesis, plus a progressive myopathy and cardiomyopathy.
- member: Glycogen Storage Disease Type IV
  member_type: DISEASE
  display_name: GSD IV (Andersen; GBE1)
  differentiating_mechanisms:
  - description: >-
      Branching enzyme deficiency stores a structurally abnormal,
      amylopectin-like polyglucosan rather than excess normal glycogen; the
      classic hepatic form progresses to cirrhosis and liver failure - the
      member whose harm comes from the storage material's structure, not
      its amount.
- member: Adult Polyglucosan Body Disease
  member_type: DISEASE
  display_name: APBD (adult-onset GBE1 disease)
  differentiating_mechanisms:
  - description: >-
      The allelic adult expression of the type IV lesion: partial GBE1
      deficiency accumulates polyglucosan bodies in the nervous system,
      presenting as adult-onset neurogenic bladder, spastic gait, and
      neuropathy rather than childhood liver disease - included as the
      adult face of branching-enzyme disease.
- member: Glycogen Storage Disease Type V
  member_type: DISEASE
  display_name: GSD V (McArdle; PYGM)
  differentiating_mechanisms:
  - description: >-
      Muscle phosphorylase deficiency: the prototypical muscle
      glycogenolysis block, with exercise intolerance, the pathognomonic
      second-wind phenomenon, and exertional rhabdomyolysis - and no
      hypoglycemia, since the hepatic isozyme is intact.
- member: Glycogen Storage Disease Type VI
  member_type: DISEASE
  display_name: GSD VI (Hers; PYGL)
  differentiating_mechanisms:
  - description: >-
      Liver phosphorylase deficiency: the mirror image of McArdle disease -
      a comparatively mild hepatic glycogenolysis defect with ketotic
      hypoglycemia and hepatomegaly that often attenuates with age.
- member: Glycogen Storage Disease Type VII
  member_type: DISEASE
  display_name: GSD VII (Tarui; PFKM)
  differentiating_mechanisms:
  - description: >-
      Muscle phosphofructokinase deficiency: the block is glycolytic, distal
      to glycogenolysis, so glycogen accumulates secondarily; distinguished
      from McArdle disease by absent second wind, exercise intolerance
      worsened by glucose (which lowers free fatty acid fuel), and
      compensated hemolysis from the erythrocyte isozyme.
- member: Glycogen Storage Disease Type IX
  member_type: DISEASE
  display_name: GSD IX (phosphorylase kinase deficiency)
  differentiating_mechanisms:
  - description: >-
      The regulatory member: deficiency of phosphorylase kinase subunits
      (PHKA2, PHKB, PHKG2, PHKA1) fails to activate phosphorylase rather
      than deleting it, giving the group's mildest and most heterogeneous
      hepatic phenotype and its most common X-linked form (PHKA2).
- member: Glycogen Storage Disease Due to Muscle Beta-Enolase Deficiency
  member_type: DISEASE
  display_name: GSD XIII (ENO3)
  differentiating_mechanisms:
  - description: >-
      Distal glycolytic block (beta-enolase) with secondary muscle glycogen
      accumulation - an ultra-rare adult myopathy at the far end of the
      muscle-glycolytic wing that types VII, X, XI, XII, and XIV occupy.
- member: Glycogen Storage Disease XV
  member_type: DISEASE
  display_name: GSD XV (glycogenin-1 deficiency; GYG1)
  differentiating_mechanisms:
  - description: >-
      Loss of the glycogen primer protein glycogenin-1: the synthesis-side
      member, with glycogen-depleted fibers alongside polyglucosan
      inclusions in muscle and heart - storage disease by structure and
      distribution rather than bulk excess.
- member: Fanconi-Bickel Syndrome
  member_type: DISEASE
  display_name: Fanconi-Bickel syndrome (formerly GSD XI; SLC2A2)
  differentiating_mechanisms:
  - description: >-
      The transport member: GLUT2 loss traps glucose intracellularly in
      hepatocytes and proximal tubule, combining hepatorenal glycogen
      accumulation with a renal Fanconi tubulopathy and both fasting
      hypoglycemia and postprandial hyperglycemia - a physiology no
      enzymatic member reproduces.
- member: PRKAG2 Cardiac Syndrome
  member_type: DISEASE
  display_name: PRKAG2 cardiac syndrome (AMPK gamma-2 glycogenosis)
  differentiating_mechanisms:
  - description: >-
      The regulatory-kinase member: CBS-domain variants in the AMPK gamma-2
      subunit corrupt the kinase's nucleotide sensing, driving non-lysosomal
      cardiomyocyte glycogen storage. The lesion is in a metabolic sensor
      rather than a glycogen enzyme, transporter, or primer, the storage is
      cardiac-restricted, and the phenotype - ventricular hypertrophy with
      ventricular pre-excitation and progressive conduction disease - is a
      triad no other member produces.
notes: >-
  Created from the stub-queue lump/split review: the seeded stub for
  MONDO:0002412 (disorder of glycogen metabolism) resolved as entry_type
  GROUPING - the concept is the classical glycogenosis category over
  thirteen already-curated entries, not a disease with one pathograph. The
  membership criterion's OTHER arm exists because the type VII and XIII
  entries annotate their glycolytic lesion rather than a GO glycogen
  process, so the evaluator reports those two members UNKNOWN and the rest
  SATISFIED - expected three-valued behavior. Members should gain the more
  specific GO annotation (or the criterion a HAS_GENE enumeration) only if
  curation of those entries supports it; the grouping does not force it.