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 0b (muscle/heart glycogen synthase deficiency, GYS1) is now curated
  and listed below; it is the group's synthesis-side member and the one
  whose biopsy shows an absence of glycogen rather than its accumulation.
  GSD 0a (hepatic glycogen synthase deficiency, 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 0a
  member_type: DISEASE
  display_name: GSD 0a (hepatic glycogen synthase deficiency; GYS2)
  differentiating_mechanisms:
  - description: >-
      The hepatic synthesis-side member, and the one whose name is most
      plainly a misnomer: loss of the liver glycogen synthase isoform means
      the liver never builds the reserve, so there is neither hepatomegaly
      nor stored glycogen. It is distinguished from every degradation-side
      member by a fasting profile of ketotic hypoglycemia with low rather
      than raised lactate, and from its own GYS1 counterpart GSD 0b by
      postprandial hyperglycemia with lactic acidemia, since ingested
      glucose is shunted to glycolysis rather than to glycogen.
- member: Glycogen Storage Disease Type 0b
  member_type: DISEASE
  display_name: GSD 0b (muscle glycogen synthase deficiency; GYS1)
  differentiating_mechanisms:
  - description: >-
      The synthesis-side member, and the only one whose muscle biopsy shows
      too little glycogen rather than too much: loss of the muscle glycogen
      synthase isoform means the reserve is never built, so the harm is a
      missing fuel store rather than a stored material. Because the hepatic
      isoform GYS2 is intact, glucose tolerance is normal - the physiology
      that separates it both from the hepatic glycogenoses and from its own
      GYS2 counterpart, GSD 0a.
- 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.