Glycogen storage disease type II 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 2 (GSD type 2) results due to deficiency of lysosomal enzyme acid α-glucosidase (GAA). GSD type 2 is the most severe type of GSD leading to death in earlier stages of life. Deficiency of GAA leads to accumulation of glycogen in lysosomes of various tissues, most commonly in cardiac, skeletal, and smooth muscle cells. There is a progressive accumulation of glycogen and its substrates in tissues leading to debilitation, organ failure and finally death. GSD type 2 follows an autosomal recessive pattern. GAA gene mutation responsible for lysosomal enzyme acid α-glucosidase (GAA) deficiency in GSD type 2 and is located on chromosome locus 17q25. Glycogen storage disease type II may be classified according to the age of onset and presence of cardiomegaly into 2 subtypes including infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). According to the Recommended Uniform Screening Panel for newborn screening, screening for glycogen storage disease type 2 by Liquid Chromatography-Tandem Mass Spectrometry assay of leukocyte acid α-glucosidase is recommended for newborn. The symptoms of classic infantile glycogen storage disease type 2 (GSD type 2) usually develop in the first two months of life and start with symptoms of feeding difficulties and failure to thrive. If left untreated, patients with classic infantile GSD type 2 progress to cardiac failure resulting in death within first two years of life. Most common cause of mortality in late onset glycogen storage disease type 2 is respiratory failure followed by ruptured cerebral aneurysm. Patients with glycogen storage disease type 2 (GSD type 2) may have a positive history of GSD type 2 in family members, delay in developmental milestones, infant slips through when grasped under the arms, respiratory difficulties, frequent respiratory infections, and cardiac symptoms. Most common symptoms of infantile onset glycogen storage disease type 2 include hypotonia and muscle weakness. Most common symptoms of late onset glycogen storage disease type 2 include progressive muscle weakness, swallowing difficulties, ans respiratory problems.Physical examination of patients with glycogen storage disease type 2 (GSD type 2) is usually remarkable for muscular weakness, hypotonia, absent deep tendon reflex and paucity of movements. Patients with infantile GSD type 2 usually appear dyspneic, pale, and/or cyanotic. Acid α-glucosidase (GAA) activity in fibroblast of a dried blood sample is the gold standard test for the diagnosis of glycogen storage disease type 2. Decreased activity of GAA in fibroblasts a dried blood sample is confirmatory of glycogen storage disease type 2. Pharmacologic medical therapy is recommended among patients with infantile onset glycogen storage type 2 (GSD type 2). Pharmacologic medical therapies for GSD type 2 include enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase.
Historical Perspective
In 1932, J.C. Pompe, a Dutch pathologist described "idiopathic hypertrophy of the heart" as a post-mortem finding in a 7-month-old girl. This was later confirmed as glycogen storage disease type 2. In 2006, enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA, alglucosidase alpha) was approved by the US Food and Drug Administration (FDA) for patients with infantile-onset GSD type 2.
Classification
Glycogen storage disease type II may be classified according to the age of onset and presence of cardiomegaly into 2 subtypes including infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD).
Pathophysiology
Glycogen storage disease type 2 (GSD type 2) results due to deficiency of lysosomal enzyme acid α-glucosidase (GAA). GSD type 2 is the most severe type of GSD leading to death in earlier stages of life. Deficiency of GAA leads to accumulation of glycogen in lysosomes of various tissues, most commonly in cardiac, skeletal, and smooth muscle cells. There is a progressive accumulation of glycogen and its substrates in tissues leading to debilitation, organ failure and finally death. GSD type 2 follows an autosomal recessive pattern. GAA gene mutation responsible for lysosomal enzyme acid α-glucosidase (GAA) deficiency in GSD type 2 and is located on chromosome locus 17q25. On gross pathology, characteristic findings of glycogen storage disease type 2 include cardiomegaly and myopathy. On microscopic histopathological analysis, characteristic findings of glycogen storage disease type 2 include muscle has PAS-positive (diastase sensitive) vacuoles.
Causes
Glycogen storage disease type 2 is an autosomal recessive disorder. Glycogen storage disease type 2 is caused by the deficiency of the lysosomal acid alpha-1,4-glucosidase enzyme. GAA gene responsible for the lysosomal acid alpha-1,4-glucosidase enzyme deficiency is located on chromosome 17q25.
Differentiating Glycogen storage disease type II from Other Diseases
Infantile onset glycogen storage disease type 2 (GSD type 2) must be differentiated from other diseases on the basis of characteristics including hypotonia, myopathy, dyspnea, feeding diffculties, absent reflex, macroglossia, hepatomegaly, heart failure, elevated CK, and cardiomegaly. Infantile onset glycogen storage disease should be differentiated from glycogen storage disease type 3, glycogen storage disease type 4, acute Werdnig-Hoffman disease (spinal muscular atrophy), hypothyroidism, endocardial fibroelastosis, myocarditis, congenital muscular dystrophy, mitochondrial/respiratory chain disorder, peroxisomal disorders. Late onset glycogen storage disease type 2 (GSD type 2) must be differentiated from other diseases on the basis of characteristics including hypotonia, muscle weakness, respiratory imapirement, difficulty in walking, hepatomegaly, elevated CK, and cardiomyopathy. Late onset glycogen storage disease should be differentiated from glycogen storage disease type 3, glycogen storage disease type 4, limb girdle muscle atrophy (LGMD), Becker muscular dystrophy (BMD), scapuloperonral syndromes, mitochondrial myopathies, myasthenia gravis, spinal muscular atrophy, polymyositis.
Epidemiology and Demographics
The incidence of glycogen storage disease type 2 (GSD type 2) is approximately 2.5 per 100,000 individuals. Patients of all age groups may develop glycogen storage disease type 2. However, glycogen storage disease type 2 most commonly affects individuals younger than 1 year of age. Glycogen storage disease type 2 usually affects individuals of the Caucasian race.
Risk Factors
The most potent risk factor in the development of glycogen storage disease type 2 is a sibling with glycogen storage disease type 2.
Screening
According to the Recommended Uniform Screening Panel for newborn screening, screening for glycogen storage disease type 2 by Liquid Chromatography-Tandem Mass Spectrometry assay of leukocyte acid α-glucosidase is recommended for newborn.
Natural History, Complications, and Prognosis
The symptoms of classic infantile glycogen storage disease type 2 (GSD type 2) usually develop in the first two months of life and start with symptoms of feeding difficulties and failure to thrive. If left untreated, patients with classic infantile GSD type 2 progress to cardiac failure resulting in death within first two years of life. Most common cause of mortality in late onset glycogen storage disease type 2 is respiratory failure followed by ruptured cerebral aneurysm. Common complications of glycogen storage disease type 2 include cardiomegaly, cardiomyopathy, respiratory failure, respiratory infections, and cerebral aneurysm. Depending on the age of onset of glycogen storage disease type 2, the prognosis may vary. The prognosis is comparatively better as the age of onset increases. The presence of classic infantile GSD type 2 is associated with an extremely poor prognosis and the majority of the patients are on ventilator support by a median age of 5.9 months with a median age of death at 8.7 months. Childhood/juvenile GSD type 2 have a relatively good prognosis. Patients may survive up to the third decade of life.
Diagnosis
Diagnostic Study of Choice
Acid α-glucosidase (GAA) activity in fibroblast of a dried blood sample is the gold standard test for the diagnosis of glycogen storage disease type 2. Decreased activity of GAA in fibroblasts a dried blood sample is confirmatory of glycogen storage disease type 2.
History and Symptoms
Patients with glycogen storage disease type 2 (GSD type 2) may have a positive history of GSD type 2 in family members, delay in developmental milestones, infant slips through when grasped under the arms, respiratory difficulties, frequent respiratory infections, and cardiac symptoms. Most common symptoms of infantile onset glycogen storage disease type 2 include hypotonia and muscle weakness. Most common symptoms of late onset glycogen storage disease type 2 include progressive muscle weakness, swallowing difficulties, ans respiratory problems.
Physical Examination
Physical examination of patients with glycogen storage disease type 2 (GSD type 2) is usually remarkable for muscular weakness, hypotonia, absent deep tendon reflex and paucity of movements. Patients with infantile GSD type 2 usually appear dyspneic, pale, and/or cyanotic.
Laboratory Findings
Laboratory findings consistent with the diagnosis of glycogen storage disease type 2 (GSD type 2) include elevated CK, elevated CK-MB, elevated LDH, elevated liver aminotransferases, elevated urinary glc 4, and deficiency of α-glucosidase in fibroblasts, leukocytes, and/or in muscle tissue.
Electrocardiogram
An ECG may be helpful in the diagnosis of glycogen storage disease type 2 (GSD type 2). Findings on an ECG suggestive of GSD type 2 include short PR interval, tall QRS, and left ventricular hypertrophy.
X-ray
There are no X-ray findings associated with glycogen storage disease type 2 (GSD type 2). However, an X-ray may be helpful in the diagnosis of the cardiac complication of GSD type 2, which include cardiomegaly.
CT Scan
There are no CT scan findings associated with glycogen storage disease type 2 (GSD type 2). However, a CT scan may be helpful in the diagnosis of neurological complications of GSD type 2, which include possible widening of the anterior horn of the lateral ventricle and/or peripheral liquor spaces.
MRI
There are no MRI findings associated with glycogen storage disease type 2 (GSD type 2). However, an MRI may be helpful in the diagnosis of neurologic complications of GSD type 2, which include central and cortical atrophy.
Electrocardiography
An echocardiography may be helpful in the diagnosis of cardiac complications of glycogen storage disease type 2 (GSD type 2). Findings for infantile GSD type 2 include cardiomegaly and findings for late onset GSD type 2 include dilated cardiomyopathy.
Other Imaging Findings
Dual energy X-ray absorptiometry (DXA) may be helpful in the diagnosis of osteoporosis, osteopenia, and/or fracture in patients with glycogen storage disease type 2. Findings on an dual energy X-ray absorptiometry suggestive of osteoporosis and/or osteopenia in patients with glycogen storage disease type 2 include low bone mineral density (BMD).
Other Diagnostic Studies
Other diagnostic studies for glycogen storage disease type 2 (GSD type 2) include electromyography and molecular genetic testing. Electromyography findings suggestive of GSD type 2 include myopathy.
Treatment
Medical Therapy
Pharmacologic medical therapy is recommended among patients with infantile onset glycogen storage type 2 (GSD type 2). Pharmacologic medical therapies for GSD type 2 include enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase.
Surgery
Surgical intervention is not recommended for the management of glycogen storage disease type 2.
Primary Prevention
Effective measures for primary prevention of glycogen storage disease type 2 (GSD type 2) include genetic counselling, prenatal diagnosis, and screening.
Secondary Prevention
Effective measures for the secondary prevention of glycogen storage disease type 2 (GSD type 2) include general medical recommendations, cardiology recommendations, pulmonary recommendations, gastrointestinal/nutritional recommendations, musculoskeletal/functional/rehabilitation recommendations, neurological recommendations., and surgery/anesthesia recommendations.