Glycogen storage disease type III overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]
Overview
Glycogen storage disease type 3 (GSD 3) results due to deficiency of glycogen debrancher enzyme. Glycogen debrancher enzyme is present in the liver and muscle. Glycogen debrancher enzyme catalyzes the conversion of phosphorylase limit dextrin into glucose-6-phosphate during glycogenolysis. This defect hinders this conversion. The inability of glucose to leave cells leads to fasting hypoglycemia. of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly. Hepatomegaly is more pronounced when the child is young and decreases as the age progresses. The hepatomegaly leads to protrusion of the abdomen. Myopathy is usually present and becomes more pronounced as age progress. AGL gene mutation is responsible for glycogen debrancher enzyme deficiency in GSD type 3 and is located on chromosome locus 1p21. GSD type 3 follows an autosomal recessive pattern. AGL gene mutation responsible for the glycogen debranching enzyme (GDE) deficiency is located on chromosome 1p21. The incidence of glycogen storage disease type 3 (GSD 3) is approximately 1 per 100,000 individuals in the United States of America. The most potent risk factor in the development of glycogen storage disease type 3 is a sibling with glycogen storage disease type 3. If left untreated, patients with glycogen storage disease type 3 grow slowly and puberty is delayed. The myopathy of glycogen storage disease type 3 typically develop in the third to fourth decades of life. It manifests as muscle weakness which is slow and progressive and usually involves large proximal muscle of the shoulder and hips. Common complications of glycogen storage disease type 3 include left ventricular hypertrophy, myopathy, cardiomyopathy, hepatic adenoma with transformation into hepatocellular carcinoma, cirrhosis and hyperlipidemia. Prognosis is generally good after treatment. The presence of liver disease is associated with a particularly poor prognosis among patients with glycogen storage disease type 3. The hallmark of glycogen storage disease type 3 is hepatomegaly. The most common symptoms of glycogen storage disease include abdominal protuberance and muscle weakness. Physical examination of patients with glycogen storage disease type 3 is usually remarkable for protruding abdomen due to marked hepatomegaly and proximal muscle weakness. Laboratory findings consistent with the diagnosis of glycogen storage disease type 3 include ketotic hypoglycemia, increased creatine kinase, hyperlipidemia, and elevated liver transaminases. Glycogen storage disease type 3 is diagnosed by identification of proband by molecular genetic testing. Molecular genetic testing shows biallelic pathogenic variants in AGL for patients with GSD type 3. The medical therapy of glycogen storage disease type 3 is directed towards management of hypoglycemia. However, hypoglycemic episodes are less marked in glycogen storage disease type 3 than glycogen storage disease type 1. A high protein diet is recommended, especially for children with growth failure and myopathy. A metabolic dietician should be consulted once a case of GSD type 3 is diagnosed. Preferred treatment is use of cornstarch. Liver transplantation is indicated for patients developing histologiocal evidence of cirrhosis. Effective measures for primary prevention of glycogen storage disease type 3 include genetic counseling, prenatal diagnosis, and screening.
Historical Perspective
In 1928, van Creveld first described a case of a 7-year-old boy presented with a marked hepatomegaly, obesity and small genitalia. In 1956, B Illingworth, GT Cori, and CF Cori confirmed that glycogen storage disease type 3 is due to deficiency of amylo-1, 6-glucosidase (glycogen debranching enzyme).
Classification
Glycogen storage disease type III may be classified according to the site and/or types of enzyme-deficient into 4 subtypes including glycogen storage disease type 3a, type 3b, type 3c, and type 3d.
Pathophysiology
Glycogen storage disease type 3 (GSD 3) results due to deficiency of glycogen debrancher enzyme. Glycogen debrancher enzyme is present in the liver and muscle. Glycogen debrancher enzyme catalyzes the conversion of phosphorylase limit dextrin into glucose-6-phosphate during glycogenolysis. This defect hinders this conversion. The inability of glucose to leave cells leads to fasting hypoglycemia. Impairment of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly. Hepatomegaly is more pronounced when the child is young and decreases as the age progresses. The hepatomegaly leads to protrusion of the abdomen. Myopathy is usually present and becomes more pronounced as age progress. AGL gene mutation is responsible for glycogen debrancher enzyme deficiency in GSD type 3 and is located on chromosome locus 1p21. GSD type 3 follows an autosomal recessive pattern.
Causes
Glycogen storage disease type 3 is an autosomal recessive disorder. Glycogen storage disease type 3 is caused by the deficiency of the glycogen debranching enzyme (GDE). AGL gene mutation responsible for the glycogen debranching enzyme (GDE) deficiency is located on chromosome 1p21.
Differentiating Glycogen Storage Disease Type III from Other Diseases
Epidemiology and Demographics
The incidence of glycogen storage disease type 3 (GSD 3) is approximately 1 per 100,000 individuals in the United States of America. 24% Cases of glycogen storage disease are of GSD type 3. In Israel, the prevalence of glycogen storage disease type 3 is approximately 18.5 per 100,000 individuals among North African Jews. Glycogen storage disease type 1 is usually first diagnosed in childhood. Glycogen storage disease type III affects men and women equally. In Faroese population of the Faroe Islands the prevalence of glycogen storage disease type 3a is approximately 32.25 per 100,000 individuals. This highest prevalence of glycogen storage disease type 3a worldwide is due to the founder effect.
Risk Factors
The most potent risk factor in the development of glycogen storage disease type 3 is a sibling with glycogen storage disease type 3.
Screening
Glycogen storage disease type 3 is an autosomal recessive disease so carrier screening of at-risk relatives may be done. Screening requires prior identification of AGL pathogenic variants in the family.
Natural History, Complications, and Prognosis
If left untreated, patients with glycogen storage disease type 3 grow slowly and puberty is delayed. The myopathy of glycogen storage disease type 3 typically develop in the third to fourth decades of life. It manifests as muscle weakness which is slow and progressive and usually involves large proximal muscle of the shoulder and hips. Common complications of glycogen storage disease type 3 include left ventricular hypertrophy, myopathy, cardiomyopathy, hepatic adenoma with transformation into hepatocellular carcinoma, cirrhosis and hyperlipidemia. Prognosis is generally good after treatment. The presence of liver disease is associated with a particularly poor prognosis among patients with glycogen storage disease type 3.
Diagnosis
Diagnostic Study of Choice
Glycogen storage disease type 3 is diagnosed by identification of proband by molecular genetic testing. Molecular genetic testing shows biallelic pathogenic variants in AGL for patients with GSD type 3.
History and Symptoms
The hallmark of glycogen storage disease type 3 is hepatomegaly. The most common symptoms of glycogen storage disease include abdominal protuberance and muscle weakness.
Physical Examination
Physical examination of patients with glycogen storage disease type 3 is usually remarkable for protruding abdomen due to marked hepatomegaly and proximal muscle weakness.
Laboratory Findings
Laboratory findings consistent with the diagnosis of glycogen storage disease type 3 include ketotic hypoglycemia, increased creatine kinase, hyperlipidemia, and elevated liver transaminases.
Electrocardiogram
An ECG may be helpful in the diagnosis of cardiac abnormalities associated with glycogen storage disease type 3. Findings on an ECG suggestive of cardiac abnormalities associated with glycogen storage disease type 3 include left ventricular hypertrophy.
X-ray
There are no x-ray findings associated with glycogen storage disease type 3.
Ultrasound
Echocardiography may be helpful in the detection of cardiomyopathy due to glycogen storage disease type 3. Findings on an echocardiography suggestive of cardiomyopathy due to echocardiography include elevated left ventricular mass and thickness. Ultrasound may be helpful in the diagnosis of glycogen storage disease type 3. Findings on an ultrasound suggestive of glycogen storage disease type 3 include hepatomegaly and increased hepatic echogenicity. Abdominal ultrasound should be performed at baseline and every 12-24 months to detect evidence of cirrhosis, hepatic adenoma, and hepatocellular carcinoma.
CT scan
Abdominal computed tomography or magnetic resonance imaging with contrast is performed to screen for evidence of liver cirrhosis, hepatic adenoma, and hepatocellular carcinoma.
MRI
Abdominal magnetic resonance imaging or computed tomography with contrast is performed to screen for evidence of liver cirrhosis, hepatic adenoma, and hepatocellular carcinoma.
Other Imaging Findings
Dual energy X-ray absorptiometry (DXA) may be helpful in the diagnosis of low bone mineral density (BMD) in patients with glycogen storage disease type 3.
Other Diagnostic Studies
Other studies used for diagnosis of glycogen storage disease type 3 include identification of proband by either molecular genetic testing or enzyme activity assay. Molecular genetic testing shows biallelic pathogenic variants in AGL gene for patients with GSD type 3. Enzyme activity assay is performed for glycogen debranching enzyme activity. Molecular genetic testing is the diagnostic study of choice for glycogen storage disease type 3.
Treatment
Medical Therapy
The medical therapy of glycogen storage disease type 3 is directed towards management of hypoglycemia. However, hypoglycemic episodes are less marked in glycogen storage disease type 3 than glycogen storage disease type 1. A high protein diet is recommended, especially for children with growth failure and myopathy. A metabolic dietician should be consulted once a case of GSD type 3 is diagnosed. Preferred treatment is use of cornstarch. Careful monitoring of blood glucose is needed during illness, if diet or schedule is changed, start of exercise routine, and randomly to detect asymptomatic hypoglycemia.
Surgery
Liver transplantation is indicated for patients developing histologiocal evidence of cirrhosis. There is resolution of metabolic derangements after liver transplantation in patients with glycogen storage disease type 3 (GSD 3). As hepatic abnormalities in GSD 3 are due to single-gene and cell-autonomous defect, the recurrence of primary liver disease in the transplanted allograft in not possible. However, skeletal manifestations or cardiac manifestations doesnot correct even after liver transplantation.
Primary Prevention
Effective measures for primary prevention of glycogen storage disease type 3 include genetic counseling, prenatal diagnosis, and screening.
Secondary Prevention
Effective measures for the secondary prevention of glycogen storage disease type 3 include blood glucose monitoring, prevent overtreatment, general medical care recommendations, gastrointestinal/nutritional recommendations, cardiology recommendations, physical therapy, surgery/anesthesia recommendations, and gynecological/obstetrical recommendations.