Nonlysosomal muscle glycogenoses

Hasan O Akman PhD (Dr. Akman of Columbia University Medical Center has no relevant financial relationships to disclose.)
Salvatore DiMauro MD (Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.)
Originally released February 25, 2013; last updated January 3, 2017; expires January 3, 2020

This article includes discussion of nonlysosomal muscle glycogenoses, glycogen storage diseases, glycogenoses, aldolase deficiency, beta-enolase deficiency, Debrancher deficiency, glycogen branching enzyme deficiency, glycogenin deficiency, glycogenosis type 0, glycogenosis type III, glycogenosis IV, glycogenosis type V, glycogenosis type VII, glycogenosis type IX, glycogenosis type X, glycogenosis type XI, glycogenosis type XII, glycogenosis type XIII, glycogenosis type XIV, glycogenosis type XV, GSD VIII, lactate dehydrogenase deficiency, McArdle disease, muscle glycogen synthetase deficiency, myophosphorylase deficiency, phosphorylase kinase deficiency, phosphoglucomutase deficiency, phosphofructokinase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, Tarui disease, and GSD. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


In this review of the muscle glycogenoses (excepting acid maltase deficiency, the only lysosomal glycogen storage disease), the authors provide brief descriptions of the still increasing list of specific enzyme defects as well as a more general rational diagnostic framework. After discussing the importance of glycogen as a metabolic fuel, they divide the glycogenoses into 2 clinical groups: (i) those that cause exercise intolerance, cramps, and recurrent episodes of muscle breakdown (rhabdomyolysis) with myoglobinuria and (ii) those clinically characterized by fixed progressive weakness. Finally, they present therapeutic strategies, including palliative and research-based approaches.

Key points


• Disorders of glycogen metabolism can be due to defects in glycogen synthesis or glycogen breakdown.


• These defects may result in deposits of normal glycogen, abnormal glycogen (phosphorylase-limit-dextrin, PLD), or polyglucosan. They may also result in the absence of glycogen (glycogenoses type 0).


• Excepting debrancher deficiency (glycogen storage type III, GSD III), defects of glycogen breakdown cause exercise intolerance with premature fatigue, cramps, and myalgia, often culminating in acute muscle breakdown with discoloration of urine (myoglobinuria).


• GSD III and GSD IV (branching enzyme deficiency) cause congenital or later-onset weakness, sometimes accompanied by liver disease or cardiomyopathy. A late-onset form of GSD IV causes adult polyglucosan body disease (APBD), a motor neuron disease that can mimic amyotrophic lateral sclerosis. Lafora disease, better known as a progressive myoclonus epilepsy, is also a polyglucosan storage disease.


• The differential diagnosis of glycogenoses with exercise intolerance, cramps, and myoglobinuria includes other metabolic myopathies, especially defects of fatty acid oxidation and defects of the mitochondrial respiratory chain, and, more generally, all genetic causes of recurrent myoglobinuria.


• The differential diagnosis of glycogenoses with weakness includes the muscular dystrophies, congenital myopathies, and other metabolic myopathies.


• Depending on the tissue specificity of the isozyme or enzyme subunit involved, glycogenoses can be confined to muscle or involve other tissues, such as erythrocytes, cardiac muscle, or the central nervous system.


• All muscle glycogenoses are inherited as autosomal recessive traits, excepting 2 variants of phosphorylase b kinase (PHK) deficiency and phosphoglycerate kinase (PGK) deficiency, which are X-linked disorders.

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