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Glycogen debranching enzyme (GDE) deficiency, also called glycogen storage disease type III (GSDIII), has an estimated prevalence of approximately 1/100,000 births (USA) with higher incidence in some populations including the North African Jewish population (1/5,400). There are two major clinical types: GSDIIIa is the most common (~85% of all GSDIII) and is characterized by liver and muscle involvement, while GSDIIIb (~15% of all GSD III) is characterized by liver involvement only.

Patients with GSD III present in infancy or early childhood with hepatomegaly, hypoglycemia, and growth retardation. Muscle weakness in patients with IIIa is minimal in childhood and may progress slowly, becoming more severe in adults. Hepatomegaly may decrease (owing to fibrosis) with adulthood. Some patients develop cardiomyopathy in childhood. Most affected individuals are asymptomatic; however, severe cardiac dysfunction, congestive heart failure, and sudden death have occasionally been reported. Osteoporosis and osteopenia are common findings. Polycystic ovary disease may be seen in women with GSD III. After puberty, metabolic manifestations often improve, whereas hepatic fibrosis may develop in up to 30% of patients. More rarely, cirrhosis may also develop. Muscular symptoms become prominent in adults. Biological findings include fasting hypoglycemia without acidosis, hypertriglyceridemia, and hypertransaminasemia during childhood.

GSDIII is an autosomal recessive disorder caused by biallelic pathogenic variants in the AGL gene (1p21) leading to a deficiency in GDE activity and consequently the accumulation of abnormal glycogen with short outer chains called "limit dextrin". Together with glycogen phosphorylase, GDE degrades glycogen to release glucose and glucose-1-phosphate for use as a source of energy.

The diagnosis is classically based on the evidence of glycogen debranching enzyme (amylo-1,6-glucosidase) deficiency measured in leukocytes (or exceptionally in cultured fibroblasts). Glycogen increase can be evidenced in red blood cells. The diagnosis of GSD III can also be established by a molecular genetic testing approach by sequencing the AGL gene in case of a strong suspicion of GSDIII (or to confirm an abnormal biochemical work-up), or using a multigene panel (including genes involved in GSD or myopathies or hepatic pathologies...) useful for differential diagnosis. There is considerable allelic heterogeneity, and pathogenic variants in most of the 35 exons of AGL have been reported.

Differential diagnoses include the other forms of glycogen storage diseases.

Prenatal diagnosis is possible by DNA analysis when the pathogenic variants have been identified in the index case. However, since GSD III is a disease of both variable severity, and intra-familial phenotypic expression, prenatal diagnosis should be discussed on a case-by-case basis and its indication should be validated in the context of multidisciplinary prenatal diagnosis meetings.

Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy, and to at-risk relatives.

Treatment is based on a specific diet, with enteral nasogastric drip feeding at night in case of hypoglycemia, frequent meals, and uncooked starch supplements in childhood. By the age of eight to ten, the switch is progressively made to a high protein diet, with simultaneous decrease of carbohydrates.

Patients may develop complications such as cirrhosis or hepatocellular carcinoma. Their muscle symptoms may also evolve to severe myopathy.

Last update: October 2025 - Expert reviewer(s): Dr Roseline FROISSART | EURO-NMD* - Pr Philippe LABRUNE | MetabERN*

* European Reference Network