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Disease summary:
Glycogen storage diseases (GSDs) are a group of inherited disorders of glycogen degradation or synthesis. Because glycogen is stored mainly in the liver, skeletal muscle, and heart muscle, the clinical spectrum of the GSDs is defined by involvement of these organs.
Currently, there are 10 well-defined types initially enumerated in order by which the enzymatic defect was identified. As the genetics of the glycogen pathway became clearer, different types of GSD have been grouped together, as is the case with type VIII and X which are now considered part of type VI.
Types 0, I, III, VI, IX, and XI mainly involve the liver, causing hypoglycemia and hepatomegaly. Type IV disease also involves the liver, but typically causes cirrhosis and liver failure in the absence of significant hypoglycemia. Types II, V, and VII mostly affect the muscle. Patients with type II classically have cardiomyopathy and skeletal muscle weakness, whereas muscle pain, fatigue, and exercise intolerance characterize the latter two types.
Hereditary basis:
Most GSDs follow an autosomal recessive inheritance. Some patients with GSD V who were thought to be manifesting heterozygotes (only one mutation found in the PYGM gene) recently were found to carry a putative mutant allele when studies were performed on the cDNA in skeletal muscle.
GSD type IX is subdivided depending on the affected subunit of the phosphorylase kinase. When the α subunit is affected, this disorder follows an X-linked inheritance, whereas β and γ subunit deficiency follow an autosomal recessive inheritance pattern.
Differential diagnosis:
The initial approach to diagnosing a GSD is based on the primary presenting feature. For example, patients with hypoglycemia and hepatomegaly should be evaluated for the hepatic GSDs (I, III, VI, IX) whereas patients with myopathy and muscular weakness in the absence of hypoglycemia should be evaluated for the muscular GSDs (II, V, VII).
The differential diagnosis of hypoglycemia is extensive and includes excessive insulin production or poorly controlled diabetes, disorders of cortisol production, and liver disease. The differential diagnosis of hypoglycemia with hepatomegaly is more limited, and includes mitochondrial hepatopathies, congenital disorders of glycosylation, fructose 1,6 bisphosphatase deficiency, Beckwith-Wiedemann syndrome, and fatty acid oxidation defects.
The differential diagnosis of myopathy and hypotonia includes spinal muscular atrophy, mitochondrial or respiratory chain disorders, limb-girdle muscular dystrophy, Duchenne-Becker muscular dystrophy, hypothyroidism, and fatty acid oxidation defects, such as very long chain acyl coenzyme A dehydrogenase (VLCAD).
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Diagnostic Criteria and Clinical Characteristics
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There are no universal diagnostic criteria for the various glycogen storage diseases but the following clinical information should direct the diagnosis:
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Clinical Characteristics
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GSD type Ia usually presents within the first few months of life with hypoglycemia, hepatomegaly, lactic acidosis (>2.5 mmol/L), hyperuricemia (>5 mg/dL), hyperlipidemia (TGL >250 mg/dL, cholesterol >200 mg/dL) and typical doll-like faces with fat cheeks, protuberant abdomen, and short stature. GSD type Ib has ...