Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 11179002, 124267007; ICD10CM: E74.09; ORPHA: 308621, 308638, 308655, 308670, 308684, 308698, 308712, 367; DO: 2750;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p12.2 | Glycogen storage disease IV | 232500 | Autosomal recessive | 3 | GBE1 | 607839 |
A number sign (#) is used with this entry because glycogen storage disease IV (GSD4) is caused by homozygous or compound heterozygous mutation in the GBE1 gene (607839), which encodes the glycogen branching enzyme, on chromosome 3p12.
Mutation in the GBE1 gene also causes an allelic disorder, adult polyglucosan body neuropathy (APBN; 263570).
Glycogen storage disease IV (GSD4) is a clinically heterogeneous disorder. The typical 'classic' hepatic presentation is liver disease of childhood, progressing to lethal cirrhosis. The neuromuscular presentation of GSD IV is distinguished by age at onset into 4 groups: perinatal, presenting as fetal akinesia deformation sequence (FADS) and perinatal death; congenital, with hypotonia, neuronal involvement, and death in early infancy; childhood, with myopathy or cardiomyopathy; and adult, with isolated myopathy or adult polyglucosan body disease (Bruno et al., 2004). The enzyme deficiency results in tissue accumulation of abnormal glycogen with fewer branching points and longer outer branches, resembling an amylopectin-like structure, also known as polyglucosan (Tay et al., 2004).
Bruno et al. (2007) provided a review of the neuromuscular forms of glycogen branching enzyme deficiency.
Classic Hepatic Form
Andersen (1956) originally reported GSD IV as 'familial cirrhosis of the liver with storage of abnormal glycogen.' Brown and Brown (1966) determined that the defect in GSD IV was a deficiency of the alpha-1,4-glucan branching enzyme.
Bao et al. (1996) noted that the most common form of GSD IV presents in the first 18 months of life with failure to thrive, hepatosplenomegaly, and liver cirrhosis. There is progression to portal hypertension, ascites, and liver failure, leading to death by age 5 years. A simple iodine test shows formation of a blue colored complex of glycogen and iodine. The liver shows the main involvement, resulting from a defect of amylo(1,4 to 1,6) transglucosidase (brancher enzyme).
Nonprogressive Hepatic Form
Less frequently, patients may have liver dysfunction without liver failure, referred to as 'nonprogressive hepatic GSD IV.' Greene et al. (1988) reported a 5-year-old boy who was first noted to have elevated serum transaminase levels and hepatomegaly at age 2 years following an acute febrile illness. Successive liver biopsies showed hepatocellular periodic-acid Schiff-positive diastase-resistant inclusions and hepatic fibrosis that was nonprogressive over 3 years. Enzymatic assays showed deficient branching enzyme in liver, skeletal muscle, and skin fibroblasts. The child showed normal growth and development.
McConkie-Rosell et al. (1996) found that 6 patients with nonprogressive hepatic GSD IV did not develop progressive liver cirrhosis, cardiac, or neurologic involvement, despite residual branching enzyme activity in skin fibroblasts that was indistinguishable from patients with more severe forms of GSD IV. The authors concluded that residual enzyme activity could not be used to predict the clinical course in GSD IV, that not all patients require liver transplant, and that caution should be used in genetic counseling.
Fatal Perinatal Neuromuscular Form
Alegria et al. (1999) reported hydrops fetalis as a presenting manifestation of glycogen storage disease type IV. The infant, delivered by cesarean section at 34 weeks, had generalized edema, severe hypotonia, and arthrogryposis of the lower limbs at birth. There were no signs of cirrhosis or liver failure. She died on the fourth day of life.
Cox et al. (1999) reported 3 sib fetuses who were shown to have type IV glycogen storage disease by pathologic and biochemical studies, with onset of hydrops, limb contractures, and akinesia in the early second trimester.
Congenital Neuromuscular Form
Zellweger et al. (1972) reported infantile onset of GSD IV with hypotonia.
McMaster et al. (1979) reported a 30-month old girl with GSD IV in whom extensive involvement of the nervous system was found at autopsy. In a review of the literature, the authors noted that approximately 50% of GSD IV patients have neuromuscular signs and symptoms.
Tang et al. (1994) reported a neonate with GSD IV who presented with severe hypotonia and dilated cardiomyopathy. The classic clinical manifestation of liver cirrhosis was not present, although amylopectin-like inclusions were found in hepatocytes. He died of cardiorespiratory failure at 4 weeks of age. In the child reported by Tang et al. (1994), Bao et al. (1996) identified a mutation in the GBE1 gene (607839.0001).
Tay et al. (2004) reported 2 unrelated patients with the congenital variant of GSD IV confirmed by mutation in the GBE1 gene (607839.0008). Both pregnancies were complicated by polyhydramnios, and both neonates showed hypotonia and poor respiratory effort at birth. Only 1 had contractures. Both died within the first weeks of life. Branching enzyme activities were 0.9% and 0.8% of normal controls. Postmortem examination of 1 infant showed pale, atrophic skeletal muscles, and PAS-positive, diastase-resistant globules in liver, heart, skeletal muscle, and neurons of the brain and spinal cord.
Bruno et al. (2004) reported 2 sibs with congenital GSD IV confirmed by mutation in the GBE1 gene (607839.0011; 607839.0012). In both cases, pregnancy was complicated by polyhydramnios, reduced fetal movements, and fetal hydrops. At birth, both infants had severe hypotonia, hyporeflexia, and no spontaneous respiration. Death occurred at ages 4 months and 4 weeks, respectively, due to cardiorespiratory failure. Autopsy showed hypertrophy of the left cardiac ventricle. Residual GBE1 activity in fibroblasts was less than 5%.
Assereto et al. (2007) reported 2 unrelated newborns who showed severe hypotonia at birth and died of cardiorespiratory failure at ages 4 and 12 weeks, respectively. Both pregnancies were complicated by polyhydramnios and reduced fetal movements. One infant had equinovarus feet with flexion contractures. GBE1 activity in cultured fibroblasts was less than 5% in both cases. Molecular analysis identified a homozygous null mutation in the GBE1 gene in each patient (607839.0017 and 607839.0018, respectively).
Childhood Neuromuscular Form
Guerra et al. (1986) reported an 8-year-old child with Andersen syndrome. Servidei et al. (1987) reported a 7.5-year-old girl with exercise intolerance and exertional dyspnea. She developed congestive heart failure and died 1 year later. Endomyocardial biopsy showed abundant PAS-positive, diastase-resistant cytoplasmic deposits that were also seen in muscle, skin, and liver specimens. Glycogen branching enzyme was absent in all postmortem tissues.
In 3 Turkish male sibs suffering from chronic progressive myopathy, Reusche et al. (1992) identified a mild juvenile form of type IV glycogenosis which was confirmed by the finding of profound deficiency of the brancher enzyme. They pointed out that when polyglucosan inclusions are observed in myofibers, it is mandatory to examine muscle tissue for brancher enzyme activity since this enzyme activity was normal in circulating erythrocytes and leukocytes in all 3 affected sibs and their parents; the disorder in this family was limited to muscle tissues.
Schroder et al. (1993) reported a case of juvenile type IV glycogenosis with total branching enzyme deficiency in skeletal muscle and liver tissue in a male who presented with severe myopathy, dilated cardiomyopathy, heart failure, dysmorphic features, and subclinical neuropathy. He died from sudden cardiac death at age 19. His 15-year-old brother had similar clinical and histologic findings.
Bruno et al. (2004) reported a 4-year-old boy with childhood neuromuscular GSD IV confirmed by mutation in the GBE1 gene (607839.0006; 607839.0013). He developed generalized hypotonia at age 11 months; at age 3 years, he had myopathic face, muscular hypotrophy and hypotonia, and waddling gait with hyperlordosis. Serum creatine kinase was normal, and there were no signs of liver involvement. Residual GBE1 activity in fibroblasts was 15 to 25%.
Adult Neuromuscular Form with Isolated Myopathy
Ferguson et al. (1983) presented the case of a 59-year-old man with a 30-year history of a limb-girdle muscular dystrophy due to a presumably allelic form of this disease. Symptoms began at age 29 years with progressive difficulty walking up stairs. He showed hyperlordotic posture, waddling gait, and proximal limb weakness which was greater in the arms than the legs.
Shin et al. (1988) demonstrated that the diagnosis of both homozygotes and heterozygotes can be made on the basis of the study of branching enzyme activity in erythrocytes. Brown and Brown (1989) described successful prenatal testing for GSD IV based on levels of branching enzyme activity in cultured amniotic fluid cells and cultured chorionic villi.
In a review and consensus paper focused on GSD IV and APBD, Koch et al. (2023) discussed diagnostic approaches. GBE1 sequencing detected about 74% of the pathogenic and likely pathogenic variants, and, when combined with deletion duplication analysis, this detection rate increased to about 85%. If genetic testing was inconclusive, enzyme analysis was recommended in skin fibroblasts, white blood cells, heart, muscle, liver, or peripheral nerves. However, liver was not the preferred tissue because of interference with other isoenzymes. Other findings that could aid in diagnosis included histopathology of affected tissues with positive staining for PAS that is resistant to diastase digestion and elevated glycogen content in affected tissues.
Selby et al. (1991) reported liver transplantation in 7 boys, including 2 sets of brothers. Two of the 7 died 7 and 36 days after liver transplantation, from bowel perforation and thrombosis of the hepatic artery, respectively. The 5 other recipients were healthy and had normal liver function 16 to 73 months after transplantation. The longest survival was 73 months in a patient who received a transplant at the age of 31 months. As pointed out by Howell (1991), some would have predicted that although the liver failure would be reversed by successful transplantation, progressive and probably fatal myopathy, cardiomyopathy, or encephalopathy would develop. However, the experience of Selby et al. (1991) showed that that was not the case; indeed, the patients remained healthy and the accumulations of glycogen in the heart and muscle at the time of liver transplantation seemed to diminish. Starzl et al. (1993) likewise reported 2 patients with GSD IV in whom cardiac deposits of amylopectin were dramatically reduced after liver transplantation. They also reported a striking reduction in lymph node deposits of glucocerebrosidase in patients with Gaucher disease (230800) after transplantation. They concluded that systemic microchimerism occurs after liver allotransplantation and can ameliorate pancellular enzyme deficiencies.
Koch et al. (2023) discussed a multidisciplinary approach to the varied manifestations of GSD IV, which was dependent on age of disease presentation and individual organ involvement. This included evaluation and monitoring for liver dysfunction and presence of/progression of portal hypertension, generally in the setting of pediatric-onset GSD IV. All patients with GSD IV were recommended to have a comprehensive cardiac evaluation at the time of diagnosis, followed by long-term care with a cardiologist. Other specialty care recommendations included care management with neurology, nutrition, and rehabilitation.
Bao et al. (1996) found 2 missense mutations (607839.0004, 607839.0005) and 1 nonsense mutation (607839.0006) in the GBE gene in 2 patients with the classic hepatic form of GSD IV. Transient expression experiments showed that these mutations inactivated glycogen branching enzyme activity. In a patient with the nonprogressive hepatic form of GSD IV, they identified compound heterozygosity for 2 GBE1 mutations; one of these resulted in complete loss of GBE activity (607839.0003), whereas the other resulted in loss of approximately 50% of GBE activity (607839.0002). In a patient with the fatal congenital neuromuscular form, they identified a 210-bp deletion in the GBE cDNA (607839.0001). The findings indicated that all 3 forms of GSD IV are caused by mutations in the same gene and that significant retention of GBE activity may be the reason for mild disease.
In the patient with fatal perinatal GSD IV reported by Alegria et al. (1999), Bruno et al. (2004) identified a homozygous 274-bp insertion in the GBE1 gene (607839.0009).
Burrow et al. (2006) reported a 30-month-old girl with GSD IV who had stable congenital hypotonia with gross motor delay and severe fibrofatty replacement of the musculature, but no hepatic or cardiac involvement. Molecular analysis identified compound heterozygosity for 2 missense mutations in the GBE1 gene (607839.0015-607839.0016). Burrow et al. (2006) suggested that the unusually mild phenotype in this patient might be due to residual enzyme activity.
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