Muscle & peripheral nerve nontumor

Metabolic myopathies

Glycogen storage diseases



Last author update: 15 November 2022
Last staff update: 15 November 2022

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PubMed Search: Glycogen storage diseases

Truong Phan Xuan Nguyen, M.D.
Ichizo Nishino, M.D., Ph.D.
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Cite this page: Nguyen TPX, Nishino I. Glycogen storage diseases. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/muscleglycogen.html. Accessed December 2nd, 2022.
Definition / general
  • Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism
  • Occur due to a lack of specific enzymes that control the synthesis, regulation and degradation of glycogen
Essential features
  • After the discovery of deficient glucose 6 phosphatase in von Gierke disease (GSD I) by Carl F. Cori and Gerty T. Cori, a number of inborn errors of glycogen metabolism have been recognized (J Biol Chem 1929;81:389, J Med Biogr 2021;29:143)
  • Classified numerically in the order of recognition and identification of the enzyme defect causing the disorder
  • There are 15 types, most of them are autosomal recessive, except for X linked GSD IXd, phosphoglycerate kinase deficiency (J Endocrinol 2018;238:R131)
  • The most common presenting symptoms are hypoglycemia and exercise intolerance
  • Danon disease (lysosomal glycogen storage disease without acid maltase deficiency, pseudoglycogenosis II) caused by deficiency of lysosome associated membrane protein 2 (LAMP2), led to failure of cellular autophagy with accumulation of glycogen granules and intracytoplasmic vacuoles containing autophagic material; recently not recognized as GSD (Cell Death Dis 2017;8:e2565)
Terminology
  • GSD affecting the skeletal muscles are mainly involved
    • GSD 0 (glycogen synthase 1 deficiency)
    • GSD II (acid maltase deficiency, Pompe disease)
    • GSD III (debrancher enzyme deficiency, Cori-Forbes disease)
    • GSD IV (branching enzyme deficiency, Andersen disease)
    • GSD V (glycogen phosphorylase deficiency, McArdle disease)
    • GSD VII (phosphofructokinase deficiency, Tarui disease)
    • GSD IXd (phosphorylase kinase deficiency)
    • Phosphoglycerate kinase deficiency
    • GSD X (phosphoglycerate mutase deficiency)
    • GSD XI (lactate dehydrogenase deficiency)
    • GSD XII (aldolase A deficiency)
    • GSD XIII (β enolase deficiency)
    • GSD XIV (phosphoglucomutase deficiency)
    • GSD XV (glygogenin 1 deficiency)
ICD coding
  • ICD-10: E74.00 - glycogen storage disease, unspecified
  • ICD-11: 5C51.3 - glycogen storage disease
Epidemiology
Sites
Pathophysiology
  • Primary physiologic function of glycogen is to store and provide glucose
  • Liver glycogen stores are utilized to maintain glucose homeostasis in the serum; the muscle glycogen stores are utilized as a source of energy for muscular activity (Semin Hematol 2002;39:103)
  • Aerobically, glucose is metabolized into pyruvate and acetyl CoA, which enters the citric acid cycle to produce water, carbon dioxide and adenosine triphosphate (ATP) or is used for the synthesis of fatty acids
  • Failure to maintain glycolytic pathway (glycogenesis, glycogenolysis or glycolysis) leads to glycogen storage diseases
Etiology
  • Defects in the enzymes caused by inherited mutations that are required for glycolytic pathway, such as glycogen synthase (encoded by the GYS1 and GYS2 genes), acid maltase (GAA gene), branching enzyme (GBE1 gene), debrancher enzyme (AGL gene), myophosphorylase (PYGM gene), phosphorylase (PYGM), phosphofructokinase (PFKM), phosphorylase kinase (PHKA1), phosphoglycerate kinase (PGK1), phosphoglycerate mutase (PGAM2), lactate dehydrogenase (LDHA), aldolase A (ALDOA), β enolase (ENO3), phosphoglucomutase (PGM1), glygogenin 1 (GYG1) (World J Gastroenterol 2007;13:2541)
Diagrams / tables

Contributed by Truong Phan Xuan Nguyen, M.D.

Metabolic glycolytic pathway



GSD
Gene name
Enzyme defect
Inheritance
Alternative names
GSD 0 GYS1 (skeletal muscle) or GYS2 (liver) Glycogen synthase 1 Autosomal recessive Glycogen synthase 1 deficiency
GSD II GAA Acid maltase Autosomal recessive Acid maltase deficiency; Pompe disease
GSD III AGL Debrancher enzyme Autosomal recessive Debrancher enzyme deficiency; Cori-Forbes disease
GSD IV GBE1 Branching enzyme Autosomal recessive Branching enzyme deficiency; Andersen disease
GSD V PYGM Glycogen phosphorylase Autosomal recessive Glycogen phosphorylase deficiency; McArdle disease
GSD VII PFKM Phosphofructokinase Autosomal recessive Phosphofructokinase deficiency; Tarui disease
GSD IXd PHKA1 Phosphorylase kinase X linked inheritance Phosphorylase kinase deficiency
Phosphoglycerate kinase deficiency PGK1 Phosphoglycerate kinase X linked inheritance N/A
GSD X PGAM2 Phosphoglycerate mutase Autosomal recessive Phosphoglycerate mutase deficiency
GSD XI LDHA Lactate dehydrogenase Autosomal recessive Lactate dehydrogenase deficiency
GSD XII ALDOA Aldolase A Autosomal recessive Aldolase A deficiency
GSD XIII ENO3 β enolase Autosomal recessive β enolase deficiency
GSD XIV PGM1 Phosphoglucomutase Autosomal recessive Phosphoglucomutase deficiency
GSD XV GYG1 Glygogenin 1 Autosomal recessive Glygogenin 1 deficiency
Clinical features
Diagnosis
Laboratory
Radiology description
  • Chest Xray: massive cardiomegaly in GSD II infant onset (Genet Med 2006;8:267)
  • MRI in GSD II:
    • In late onset, T1 weighted shows fatty replacement commonly in the tongue, subscapularis, latissimus dorsi, paraspinal and abdominal muscles, psoas, glutei, adductor magnus, posterior muscles of the thigh (especially the semimembranosus) and vastus intermedius
      • Vastus lateralis and medialis can be affected in the progression of the disease
      • Noticeable loss of muscle volume in the psoas and adductor magnus muscles
    • In infant onset, T1 weighted shows normal or identifies only mild fatty replacement, although patients may have significant muscle weakness; muscles commonly affected include the tongue, glutei and adductor magnus muscles (Muscle Nerve 2021;63:640)
Prognostic factors
Case reports
Treatment
Microscopic (histologic) description
  • GSD 0, muscle:
    • Glycogen depletion in all fibers
    • Mitochondrial proliferation
    • Type I fiber predominance
    • Phosphorylase is deficient in all muscle fibers
  • GSD II:
    • Histopathological features vary with the phenotypic forms: infant form, childhood form and adult form
    • Marked sarcoplasmic membrane bound vacuoles containing basophilic amorphous material (glycogen) in most fibers
    • Type 1 muscle fibers are more involved than type 2
    • Little muscle fiber degeneration or increased connective tissue
    • Abundant acid phosphatase activity (increased lysosomes)
  • GSD III:
    • Subsarcolemmal nonmembrane bound vacuoles with glycogen accumulation
    • At a later stage, the muscle may appear dystrophic with atrophy and connective tissue infiltration and no apparent glycogen storage
  • GSD IV:
    • Adult form shows PAS positivity and sarcoplasmic rounded opalescent inclusions
    • Perinatal forms show polyglucosan bodies which have variable size, shape and reaction to PAS
  • GSD V, VII, IXd:
    • Muscle pathology is variable from minor nonspecific changes to subsarcolemmal nonrimmed vacuoles and occasional fibers with accumulation
    • Excess glycogen on PAS staining may be visible but may only be apparent at the periphery of the fiber
  • GSD X, XIV, XV, phosphoglycerate kinase deficiency:
    • May reveal variation in myofiber size with normal to mild glycogen distribution
  • Reference: Goebel: Muscle Disease, 2nd Edition, 2013
Microscopic (histologic) images

Contributed by Ichizo Nishino, M.D., Ph.D.

GSD 0: no specific changes

GSD 0: glycogen depletion

GSD II childhood: marked sarcoplasmic vacuoles

GSD II childhood: PAS

GSD II childhood: epon PAS


GSD II childhood: NADH TR

GSD II childhood:
predominant
involved
type 1 fibers

GSD II childhood:
high acid
phosphatase
activity

GSD II childhood: modified Gomori trichrome

GSD II childhood:
MHC I

GSD II adult: small vacuoles


GSD II adult: modified Gomori trichrome

GSD II adult: epon PAS

GSD II adult: increased acid phosphatase activity

GSD III: nonmembrane bound vacuoles

GSD III: PAS positive


GSD III: MHC I

GSD IV: fibrosis
fibers and rounded
opalescent
inclusions

GSD IV: PAS

GSD IV: modified Gomori trichrome

GSD V: small sarcolemmal vacuoles


GSD V: PAS

GSD V: negative PHS

GSD VII: small sarcolemmal vacuoles

GSD VII: PAS

GSD VII:
phosphofructokinase
is negative

Virtual slides

Images hosted on other servers:

McArdle disease

Positive stains
  • PAS stain is intense positive in cytoplasm and vacuoles (except GSD 0)
  • PAS stain is normal or mild positive in GSD X, XIV, XV, phosphoglycerate kinase deficiency
  • ACP stain: acid phosphatase activity increases (increased lysosomes in GSD II)
  • In GSD II, vacuoles are surrounded by MHC I (Goebel: Muscle Disease, 2nd Edition, 2013)
Negative stains
Electron microscopy description
Electron microscopy images

Contributed by Ichizo Nishino, M.D., Ph.D.

GSD II childhood: membrane bound vacuoles

GSD II adult: membrane bound vacuoles

GSD III: nonmembrane bound glycogen

GSD IXd: sarcoplasmic glycogen deposits

Molecular / cytogenetics description
  • GSDs are inherited by an autosomal recessive trait, except for X linked GSD IXd and phosphoglycerate kinase deficiency (Ann Transl Med 2018;6:474)
    • GSD 0: gene GYS1 (skeletal muscle) or GYS2 (liver) mutation
    • GSD II: gene GAA mutation
    • GSD III: gene AGL mutation
    • GSD IV: gene GBE1 mutation
    • GSD V: gene PYGM mutation
    • GSD VII: gene PFKM mutation
    • GSD IXd: gene PHKA1 (X linked) mutation
    • Phosphoglycerate kinase deficiency, gene PGK1 (X linked) mutation
    • GSD X: gene PGAM2 mutation
    • GSD XI: gene LDHA mutation
    • GSD XII: gene ALDOA mutation
    • GSD XIII: gene ENO3 mutation
    • GSD XIV: gene PGM1 mutation
    • GSD XV: gene GYG1 mutation
Sample pathology report
  • Left vastus lateralis, muscle biopsy, serial frozen sections were stained with H&E, modified Gomori trichrome (mGT) and a battery of histochemical methods:
    • Compatible with glycogen storage disease (see comment)
    • Comment:
      • On H&E, there is mild to moderate variation in fiber size ranging from 20 to 105 microns in diameter. There are some fibers with multiple cytoplasmic vacuoles mainly in the subsarcolemmal region. No necrotic and regenerating fibers are seen. Scattered fibers with internal nuclei are seen. Mononuclear cell infiltration is not seen in endomysium. Perifascicular atrophy is not seen. Endomysial fibrosis is not seen.
      • On mGT, no ragged red fibers, fibers with rimmed vacuoles or nemaline rods are seen.
      • On NADH TR, intermyofibrillar networks are mildly disorganized in many fibers.
      • On SDH, strongly SDH reactive blood vessels (SSVs) are not highlighted.
      • On ALP, enzymatic activity is not seen in perimysium.
      • On acid phosphatase, enzymatic activity is increased.
      • On ATPase, moderate type 2 fiber atrophy is seen. Some type 2C fibers are seen.
      • On PAS, strongly positive in vacuoles.
      • On PHS, enzymatic activity is decreased.
      • Other stains, including COX, AChE, NSE, AMP and MAG, show no additional abnormalities.
      • The above findings are compatible with glycogen storage disease. Genetic analysis should be tested.
Differential diagnosis
  • Limb girdle muscular dystrophy:
    • Can resemble GDS II in late onset
    • Has a similar pattern of muscle involvement and disease course
    • Muscle MRI: usually shows (in contrast to GSD II) fatty replacement of leg muscles
    • Immunohistochemistry and genetic analysis help to differentiate
  • Duchenne-Becker muscular dystrophy:
    • Can resemble GDS II in late onset
    • Progressive proximal muscle weakness, respiratory insufficiency and difficulty ambulating are seen
    • Primarily affects males; inheritance is X linked
    • Immunohistochemistry and genetic analysis help to differentiate
Board review style question #1
GSD II (Pompe disease) is characterized by the deficiency of which of the following enzymes?

  1. Acid maltase
  2. Debrancher enzyme
  3. Glucose 6 phosphatase
  4. Phosphoglucomutase
  5. Phosphorylase
Board review style answer #1
A. Acid maltase. In Pompe disease or GSD II, the accumulation of glycogen is due to a deficiency of lysosomal acid maltase (GAA gene mutation), which hydrolyzes maltose, linear oligosaccharides and the outer chains of glycogen to glucose.

Comment Here

Reference: Glycogen storage diseases
Board review style question #2

GSD V (McArdle disease) causes muscle cramps and muscle fatigue with increased muscle glycogen. Which of the following enzymes is deficient?

  1. Hepatic hexokinase
  2. Muscle debrancher enzyme
  3. Muscle hexokinase
  4. Muscle phosphofructokinase
  5. Muscle phosphorylase
Board review style answer #2
E. Muscle phosphorylase. McArdle disease or GSD V is caused by mutations in the PYGM gene that encodes the muscle associated enzyme glycogen phosphorylase.

Comment Here

Reference: Glycogen storage diseases
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