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Glycogen Storage Diseases

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Glycogen storage diseases are carbohydrate metabolism disorders and are caused by deficiencies of enzymes involved in glycogen synthesis or breakdown; the deficiencies may occur in the liver or muscles and cause hypoglycemia or deposition of abnormal amounts or types of glycogen (or its intermediate metabolites) in tissues.

Inheritance for glycogen storage diseases (GSDs) is autosomal recessive except for GSD type VIII/IX, which is X-linked. Incidence is estimated at about 1/25,000 births, which may be an underestimate because milder subclinical forms may be undiagnosed. For a more complete listing of glycogen storage diseases, see Table Glycogen Storage Diseases and Disorders of Gluconeogenesis.

Age of onset, clinical manifestations, and severity vary by type, but symptoms and signs are most commonly those of hypoglycemia and myopathy.

Diagnosis of glycogen storage diseases is suspected by history, examination, and detection of glycogen and intermediate metabolites in tissues by MRI or biopsy. Diagnosis is confirmed by significant decrease of enzyme activity in liver (types I, III, VI, and VIII/IX), muscle (types IIb, III, VII, and VIII/IX), skin fibroblasts (types IIa and IV), or RBCs (type VII) or by lack of an increase in venous lactate with forearm activity/ischemia (types V and VII). (Also see testing for suspected inherited disorders of metabolism.)

Prognosis and treatment of glycogen storage diseases vary by type, but treatment typically includes dietary supplementation with cornstarch to provide a sustained source of glucose for the hepatic forms of GSD and exercise avoidance for the muscle forms.

Defects in glycolysis (rare) may cause syndromes similar to GSDs. Deficiencies of phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase mimic the myopathies of GSD types V and VII; deficiencies of glucose transport protein 2 (Fanconi-Bickel syndrome) mimic the hepatopathy of other GSD types (eg, I, III, IV, VI).

Glycogen Storage Diseases and Disorders of Gluconeogenesis

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

GSD I (Von Gierke disease)

Most common type of GSD I: Ia (> 80%)

Onset: Before 1 yr

Clinical features: Before 1 yr, severe hypoglycemia, lactic acidosis, and hepatomegaly; later, hepatic adenomas, renomegaly with progressive renal insufficiency and hypertension, short stature, hypertriglyceridemia, hyperuricemia, platelet dysfunction with epistaxis, and anemia

In type Ib, less severe but including neutropenia, neutrophil dysfunction with recurrent infections, and inflammatory bowel disease

Treatment: Uncooked cornstarch 1.5–2.5 g/kg po q 4–6 h or lactose-free formula with maltodextrin to maintain normoglycemia; nocturnal feedings (important); fructose and galactose restriction; for lactic acidosis, bicarbonate 0.25 to 0.5 mmol/kg qid; allopurinol to keep uric acid to < 6.4 mg/dL; liver and kidney transplantation (may be successful)

For type Ib patients with neutropenia, G-CSF

Type Ia (232200)

Glucose-6-phosphatase

G6PC (17q21)*

Type Ib (232220)

Glucose-6-phosphate translocase

G6PT1 (11q23)*

Type Ic (232240)

Microsomal phosphate or pyrophosphate transporter

G6PT1 (11q23)*

Type Id

Microsomal glucose transporter

Probably same as Ic

GSD II (Pompe disease, 232300)

Onset: Infancy, childhood, or adulthood; residual enzyme activity in child and adult forms

Clinical features: In infantile form, cardiomyopathy with heart failure, severe hypotonia, macroglossia

In juvenile and adult forms, skeletal myopathy with delayed motor development, progressive peripheral and respiratory muscle weakness

In type IIb, intellectual disability

Treatment: None known

For cardiomyopathy, heart transplantation

Type IIa

Lysosomal acid α-glucosidase

GAA (17q25)*

Type IIb (Danon)

Lysosomal membrane protein-2

LAMP2 (Xq24)*

GSD III (Forbes disease, Cori disease, limit dextrinosis; 232400)

Frequency: IIIa, 85%; IIIb, 15%; IIIc and IIId, rare

Onset: Infancy or childhood

Clinical features: In type IIIa, liver and muscle involvement with features of type Ia and II

In type IIIb, only liver involvement plus features of type Ia

In types IIIc and IIId, various features depending on tissue affected

Treatment: Uncooked cornstarch and continuous feeding to maintain normoglycemia, high-protein diet to stimulate gluconeogenesis

Types IIIa and IIIb

Debrancher enzyme (amyloglucosidase and oligoglucanotransferase)

AGL (1p21)*

Type IIIc

Amyloglucosidase only

Type IIId

Oligoglucanotransferase only

GSD IV (Andersen disease; 232500)

Branching enzyme

GBE1 (3p12)*

Onset: Early infancy; rarely, the neonatal period, late childhood, or adulthood (manifesting as a variant nonprogressive or a neuromuscular form)

Clinical features:Hepatomegaly with progressive cirrhosis and hypoglycemia, esophageal varices, and ascites; splenomegaly; failure to thrive

In neuromuscular forms, hypotonia and muscle atrophy

Treatment: None known

For cirrhosis, liver transplantation, which treats the primary disease as well

GSD V (McArdle disease; 232600)

Muscle phosphorylase

PYGM (11q13)*

Onset: Adolescence or early adulthood

Clinical features: Exercise intolerance due to muscle cramps, rhabdomyolysis

Treatment: Carbohydrate administration before exercise, high-protein diet

GSD VI (Hers disease; 232700)

Liver phosphorylase

PYGL (14q21-q22)*

Frequency: Rare

Onset: Early childhood

Clinical features: Benign course with symptoms lessening with aging; growth retardation, hepatomegaly, hypoglycemia, hyperlipidemia, ketosis

Treatment: None necessary

GSD VII (Tarui disease; 232800)

Phosphofructokinase

PFKM (12q13.3)*

Onset: Middle childhood

Clinical features: Exercise intolerance due to muscle cramps, rhabdomyolysis, hemolysis

Treatment: Nonspecific, avoidance of exercise

GSD VIII/IX (306000, 172490, 604549, 311870)

Onset: Heterogeneous

Clinical features:Heterogeneous; hepatomegaly, growth retardation, muscle hypotonia, hypercholesterolemia

Treatment: Nonspecific

Type VIII/IXa:

X-linked phosphorylase kinase

PHKA2 (Xp22)*

Type IXb

Liver and muscle phosphorylase kinase

PHKB (16q12-q13)*

Type IXc

Liver phosphorylase kinase

PHKG2 (16p12.1-p11.2)*

Type IXd

Muscle phosphorylase kinase

PHKA1 (Xq13)*

GSD O (240600)

Glycogen synthase

GYS2 (12p12)*

Onset: Variable but often after cessation of nighttime feedings or intercurrent illness

Clinical features: Fasting hypoglycemia and ketosis, postprandial lactic acidosis

Treatment: Frequent protein-rich meals, uncooked cornstarch at bedtime

Fanconi-Bickel syndrome (227810)

Glucose transporter-2

GLUT2 (3q26)*

Onset: Infancy

Clinical features: Failure to thrive, abdominal distention, hepatomegaly, renomegaly, mild fasting hypoglycemia and hyperlipidemia, glucose intolerance, renal Fanconi syndrome

Treatment: Diet similar to that for diabetes, replacement of renally lost electrolytes, vitamin D

Fructose 1,6-biphosphatase

FBP1 (9q22)*

Onset: Infancy or early childhood

Clinical features: Episodic hyperventilation, apnea, hypoglycemia, ketosis, or lactic acidosis; episodes provoked by fasting, febrile infection, or ingestion of fructose, sorbitol, or glycerol

Treatment: Avoidance of fasting and fructose, sorbitol, and glycerol; uncooked cornstarch

Phosphoenolpyruvate carboxykinase deficiency (261680)

Phosphoenolpyruvate carboxykinase

PCK1 (20q13.31)*

Onset: Childhood

Clinical features: Failure to thrive, hypotonia, hepatomegaly, lactic acidosis, hypoglycemia

Treatment: Avoidance of fasting, uncooked cornstarch

*Gene has been identified, and molecular basis has been elucidated.

G-CSF = granulocyte colony-stimulating factor; GSD = glycogen storage disease; OMIM = online mendelian inheritance in man (see the OMIM database ).

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