Glycogen Storage Disease 0, Muscle

A number sign (#) is used with this entry because of evidence that muscle glycogen storage disease-0 (GSD0B) is caused by homozygous mutation in the GYS1 gene (138570), which encodes muscle glycogen synthase, on chromosome 19q13.

Clinical Features

Among the offspring of consanguineous parents of Syrian origin, Kollberg et al. (2007) described cardiomyopathy and exercise intolerance associated with complete absence of muscle glycogen. The oldest brother developed normally until the age of 4 years, when he had an episode of tonic-clonic seizures. At the age of 10.5 years, while playing outside his school, he suddenly collapsed as the result of cardiac arrest. At autopsy, the heart weighed 200 g (normal range, 139 to 178). The left ventricular wall was thickened. The cause of death was listed as hypertrophic cardiomyopathy. Two years later, an 11-year-old brother was investigated. After the age of 6 years, he had been unable to keep up with the physical activity of his peers and had muscle symptoms similar to those of patient 1. He likewise had signs of hypertrophic cardiomyopathy and an abnormal heart rate and blood pressure while exercising. Low normal IQ was reported. A 2-year-old sister had no clinical symptoms and had normal psychomotor development, however, cardiac exam indicated cardiac involvement ('subtly impaired systolic function at rest'). In muscle biopsy specimens obtained from the 2 younger sibs there was lack of glycogen, predominance of oxidative fibers, and mitochondrial proliferation. Glucose tolerance was normal.

Cameron et al. (2009) reported an 8-year-old boy, born to consanguineous parents of South Indian ancestry, who died suddenly while exercising with classmates at school. He had been healthy and had no history of exercise intolerance. At autopsy, the heart appeared structurally normal, with appropriate size, weight, and ventricular wall thickness; however, skeletal muscle showed evidence suggestive of an underlying mitochondrial abnormality, with proliferation of mitochondria, pre-ragged-red fibers, and type 1 fiber predominance. Cytochrome oxidase activity was preserved, but mitochondrial ultrastructure appeared to be abnormal, and glycogen stores were depleted. Some cardiac mitochondria appeared to have an abnormal ultrastructure similar to that seen in skeletal muscle. Family history revealed a sister who had died at 6 days of life of undetermined cause.

Molecular Genetics

In 3 sibs with muscle and heart glycogen deficiency, Kollberg et al. (2007) found a premature termination mutation in the muscle glycogen synthase gene (R462X; 138570.0001). Several findings in the patients reported by Kollberg et al. (2007) were in accord with the findings in muscle glycogen synthase knockout mice: increased cardiac mass, absence of muscle glycogen, predominance of oxidative muscle fibers, and normal-to-improved glucose clearance (Pederson et al. (2004, 2005, 2005)) The first patient had epilepsy; whether this was coincidental to the glycogen storage disease was not clear. Glycogen is stored in the normal brain, and one hypothesis is that the primary function of the cerebral glycogen pool is to help provide energy to support rapid glutamate neurotransmitter clearance by astrocytes (Shulman et al., 2001).

In an 8-year-old boy who died suddenly after exercise and had abnormal mitochondrial ultrastructure and pre-ragged-red fibers seen on autopsy, Cameron et al. (2009) performed extensive metabolic mitochondrial testing but found no mitochondrial DNA mutations. Due to similarities to the family previously studied by Kollberg et al. (2007), including type 1 fiber predominance, lack of glycogen staining, and increased numbers of mitochondria, Cameron et al. (2009) sequenced the GYS1 gene using DNA from patient fibroblasts and identified homozygosity for a 2-bp deletion (138570.0002). The unaffected parents and an unaffected sib were heterozygous for the mutation.

Nomenclature

Kollberg et al. (2007) suggested that the entity they described be termed muscle glycogen storage disease 0 in analogy with the disease caused by liver glycogen synthase deficiency (240600).