Glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form
General Information (adopted from Orphanet):
Synonyms, Signs:
AMYLOPECTINOSIS
GSD IV, NEUROMUSCULAR FORM, CHILDHOOD, INCLUDED
GLYCOGENOSIS IV
CIRRHOSIS, FAMILIAL, WITH DEPOSITION OF ABNORMAL GLYCOGEN GSD IV, CLASSIC HEPATIC, INCLUDED
GSD IV
GSD IV, NEUROMUSCULAR FORM, FATAL PERINATAL, INCLUDED
GSD IV, NEUROMUSCULAR FORM, CONGENITAL, INCLUDED
GSD IV, NEUROMUSCULAR FORM, ADULT, WITH ISOLATED MYOPATHY, INCLUDED
GBE1 DEFICIENCY
BRANCHER DEFICIENCY
ANDERSEN DISEASE
GLYCOGEN BRANCHING ENZYME DEFICIENCY
GSD IV, NONPROGRESSIVE HEPATIC, INCLUDED
GSD4
GSDIV, adult neuromuscular form
Glycogenosis due to glycogen branching enzyme deficiency, adult neuromuscular form
GSD due to glycogen branching enzyme deficiency, adult neuromuscular form
Glycogen storage disease type 4, adult neuromuscular form
Glycogenosis type 4, adult neuromuscular form
GBE deficiency, adult neuromuscular form
GSD type 4, adult neuromuscular form
Glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form is a sub-type of Glycogen storage disease due to glycogen branching enzyme deficiency. For symptom annotation please refer to Glycogen storage disease due to glycogen branching enzyme deficiency.
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 ... 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.
Glycogen storage disease type IV 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 ... Glycogen storage disease type IV 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.
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 ... 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.
The diagnosis of glycogen storage disease type IV (GSD IV) is suspected based on the clinical presentation and the finding of abnormally branched glycogen accumulation in muscle or liver tissue. The diagnosis is confirmed by the demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts [Brown & Brown 1983], and/or the identification of biallelic mutations in GBE1....
DiagnosisThe diagnosis of glycogen storage disease type IV (GSD IV) is suspected based on the clinical presentation and the finding of abnormally branched glycogen accumulation in muscle or liver tissue. The diagnosis is confirmed by the demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts [Brown & Brown 1983], and/or the identification of biallelic mutations in GBE1.Clinical Diagnosis GSD IV can manifest as several different subtypes, with variable ages of onset, severity, and clinical features, including the following: Fatal perinatal neuromuscular subtype. Decreased fetal movements, polyhydramnios, and fetal hydrops that may be detected prenatally; arthrogryposis, severe hypotonia, muscle atrophy at birth, early neonatal deathCongenital neuromuscular subtype. Profound neonatal hypotonia at birth, respiratory failure, dilated cardiomyopathy, early infantile deathClassic (progressive) hepatic subtype. Failure to thrive, hepatomegaly, liver dysfunction, progressive liver cirrhosis with portal hypertension, ascites, and esophageal varices, hypotonia, and cardiomyopathy; death typically by age five years from liver failureNon-progressive hepatic subtype. Liver dysfunction, myopathy, and hypotonia in childhoodChildhood neuromuscular subtype. Chronic, progressive myopathy, with dilated cardiomyopathy in someAlthough subtypes have been recognized, the GSD IV phenotype is a continuum that ranges from mild to severe [Burrow et al 2006]. Thus, categorizing an individual or family into one specific subtype may be difficult.TestingLiver function tests. Liver enzymes are typically elevated in the hepatic subtypes. Hypoalbuminemia and prolonged partial thromboplastin time (PTT) and prothrombin time (PT) are also observed with progressive deterioration of liver function due to the accumulation of abnormally branched glycogen. Note: These abnormalities are not specific for or diagnostic of GSD IV. Abdominal ultrasound examination. The liver is typically enlarged with signs of fibrosis or cirrhosis. Note: Hepatomegaly is not specific or diagnostic for GSD IV nor does its absence rule out the diagnosis of GSD IV.Glycogen branching enzyme (GBE) activity is most commonly assayed in cultured skin fibroblasts, but may also be assayed in muscle or liver tissue. All individuals with GSD IV have reduced GBE activity. Histopathology of affected tissues, such as the liver, heart, or muscle, is very helpful in making an accurate diagnosis of GSD IV.In general, hepatocytes are markedly enlarged and contain periodic acid-Schiff (PAS)-positive and diastase-resistant inclusions, features characteristic of the abnormally branched glycogen found in GSD IV. Widespread infiltrates of foamy histiocytes with intra-cytoplasmic deposits within the reticuloendothelial system (RES) have been reported [Magoulas et al 2012]. Interstitial fibrosis with wide fibrous septa and distorted hepatic architecture are observed [Moses & Parvari 2002].Electron microscopy may demonstrate fine fibrillary aggregates of electron-dense amylopectin-like material within the cytoplasm of hepatocytes. Molecular Genetic Testing Gene. GBE1 is the only gene in which mutations are known to cause glycogen storage disease type IV.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Glycogen Storage Disease Type IV View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1, 2Test AvailabilityGBE1Sequence analysisSequence variants 334/37 4ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletions7/37 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Bao et al [1996], Bruno et al [1999], Nambu et al [2003], Bruno et al [2004], Janecke et al [2004], Tay et al [2004], L'Herminé-Coulomb et al [2005], Akman et al [2006], Burrow et al [2006], Shin [2006], Assereto et al [2007], Nolte et al [2008], Raju et al [2008], Lamperti et al [2009], Li et al [2010], Li et al [2012], Magoulas et al [2012]3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Of 37 affected individuals, 28 had biallelic mutations and six had one identifiable mutation, implying that the second causative mutation was not identified. 5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Of 37 affected individuals, three were homozygous for exonic or multi-exonic deletions and four were compound heterozygous for one exonic or multi-exonic deletion and one sequence variant detectable by sequence analysis [Li et al 2012, Magoulas et al 2012].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandIf a liver biopsy, obtained as a part of the workup for hepatomegaly and abnormal liver function studies, shows PAS-positive and partially diastase-resistant deposits (i.e., abnormally branched glycogen) within the hepatocyte cytoplasm, additional recommended studies are typically glycogen branching enzyme (GBE) assay and/or GBE1 molecular genetic testing. If GSD IV is suspected based on clinical findings and liver biopsy cannot be performed, additional recommended studies are typically GBE assay on fibroblast or muscle tissue, and/or GBE1 molecular genetic testing.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family, the preferred method of carrier detection. Note: (1) Analysis of GBE activity alone is not sufficient to determine carrier status since enzyme activity in carriers may be within the normal range. (2) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. If the disease-causing mutations have not been identified, GBE activity can be measured in cultured amniocytes.Genetically Related (Allelic) Disorders Adult onset polyglucosan body disease (APBD) is the only other phenotype known to be associated with mutations in GBE1 (see Adult Polyglucosan Body Disease). APBD is characterized by adult-onset progressive neurogenic bladder, gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement, sensory loss predominantly in the distal lower extremities, and mild cognitive difficulties (often executive dysfunction). In APBD GBE activity is reduced or normal. Affected individuals are either homozygous or compound heterozygous for a missense mutation in GBE1 including p.Tyr329Ser, p.Arg515His, and p.Arg524Gln [Lossos et al 1998, Ziemssen et al 2000, Klein et al 2004]. Inheritance is autosomal recessive.
The clinical manifestations of glycogen storage disease type IV (GSD IV) span a continuum from mild to severe [Burrow et al 2006]. Within this continuum several different subtypes with variable age of onset, severity, and clinical features have been recognized. Although prognosis tends to depend on the subtype of GSD IV, clinical findings vary extensively both within and between families. ...
Natural History The clinical manifestations of glycogen storage disease type IV (GSD IV) span a continuum from mild to severe [Burrow et al 2006]. Within this continuum several different subtypes with variable age of onset, severity, and clinical features have been recognized. Although prognosis tends to depend on the subtype of GSD IV, clinical findings vary extensively both within and between families. The fatal perinatal neuromuscular subtype, the most severe subtype, presents in utero with fetal akinesia deformation sequence (FADS) with decreased fetal movements, polyhydramnios, and fetal hydrops. Newborns may have arthrogryposis, severe hypotonia, and muscular atrophy, often resembling infants with the severe forms of spinal muscular atrophy [Janecke et al 2004, Tay et al 2004]. Death usually occurs in the neonatal period frequently due to cardiopulmonary compromise. The congenital neuromuscular subtype presents in the newborn period with profound hypotonia, respiratory distress, dilated cardiomyopathy, and death in early infancy typically due to cardiopulmonary compromise [Moses & Parvari 2002]. Li et al [2012] recently reported two unrelated infants with this subtype of GSD IV who were also small for gestational age. Both died between ages two and three months. The hepatic subtype, the most common presentation of GSD IV, can be classified as progressive (classic) or non-progressive. In the progressive hepatic subtype children may appear normal at birth, but then rapidly deteriorate in the first few months of life with failure to thrive, hepatomegaly, and elevated liver enzymes. This stage is typically followed by progressive liver dysfunction and cirrhosis with hypoalbuminemia, prolonged partial thromboplastin time (PTT) and prothrombin time (PT), portal hypertension, ascites, and esophageal varices. Muscle tone, often normal at the time of diagnosis, progresses to generalized hypotonia within the first one to two years of life [Magoulas et al 2012]. Without liver transplantation, death from liver failure usually occurs by age five years [Chen 2001, Moses & Parvari 2002]. Dilated cardiomyopathy and progressive cardiac failure, reported to occur following orthotopic liver transplantation, have resulted in death [Sokal et al 1992, Rosenthal et al 1995]. In the less common non-progressive hepatic subtype, presentation can be in childhood with hepatomegaly, liver dysfunction, myopathy, and hypotonia. These individuals tend to survive without evidence of progression of the liver disease [Moses & Parvari 2002]. They also may not show cardiac, skeletal muscle, or neurologic involvement. Liver enzymes are usually abnormal in childhood at the time of presentation, but subsequently may return to (and remain) normal [McConkie-Rosell et al 1996].The childhood neuromuscular subtype of GSD IV is rare [Reusche et al 1992, Schröder et al 1993]. Individuals typically present in the second decade and may have mild to severe myopathy and dilated cardiomyopathy. The natural history is variable: some individuals have a mild disease course throughout life while others have a more severe, progressive course resulting in death in the third decade.
Genotype-phenotype correlations between phenotypes associated with biallelic GBE1 mutations (various subtypes of GSD IV and APBD; see Genetically Related Disorders) remain unclear, but are emerging [Bao et al 1996, Ziemssen et al 2000, Nambu et al 2003, Bruno et al 2004, Janecke et al 2004, Assereto et al 2007, Magoulas et al 2012]. ...
Genotype-Phenotype Correlations Genotype-phenotype correlations between phenotypes associated with biallelic GBE1 mutations (various subtypes of GSD IV and APBD; see Genetically Related Disorders) remain unclear, but are emerging [Bao et al 1996, Ziemssen et al 2000, Nambu et al 2003, Bruno et al 2004, Janecke et al 2004, Assereto et al 2007, Magoulas et al 2012]. APBD is typically the result of homozygous or compound heterozygous missense mutations (Table 2). In GSD IV, generally: Individuals with the perinatal and congenital subtypes tend to have two null mutations, including nonsense, frameshift, and splice site mutations leading to premature truncation of the protein likely resulting in complete absence of glycogen branching enzyme (GBE) activity; Individuals with the classic hepatic subtype tend to be compound heterozygotes for a null and a missense mutation. Despite these generalizations, considerable overlap exists both between and within the subtypes of GSD IV [Li et al 2010].
Differential diagnoses for the perinatal and congenital neuromuscular subtypes of GSD IV include spinal muscular atrophy, Pompe disease, Zellweger syndrome, and congenital disorders of glycosylation. ...
Differential DiagnosisDifferential diagnoses for the perinatal and congenital neuromuscular subtypes of GSD IV include spinal muscular atrophy, Pompe disease, Zellweger syndrome, and congenital disorders of glycosylation. Differential diagnoses for the classic hepatic subtype of GSD IV include other glycogen storage disorders (e.g., GSD III) and mitochondrial DNA depletion syndromes (e.g., MPV17-related hepatocerebral mitochondrial DNA depletion syndrome, DGUOK-related mitochondrial DNA depletion syndrome, hepatocerebral form).Differential diagnoses for the childhood neuromuscular subtype of GSD IV include muscular dystrophies (e.g., Duchenne muscular dystrophy, limb-girdle muscular dystrophy) and mitochondrial myopathies. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Childhood neuromuscular GSD IVCongenital neuromuscular GSD IVFatal perinatal neuromuscular GSD IVHepatic GSD IV
To establish the extent of disease and needs of an individual diagnosed with glycogen storage disease type IV (GSD IV), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with glycogen storage disease type IV (GSD IV), the following evaluations are recommended:Liver function studies including albumin, transaminases, and coagulation profile Abdominal ultrasound examination to assess liver size and textureReferral to a cardiologist for baseline echocardiogram and electrocardiogram (ECG) to assess for cardiomyopathy Neurodevelopmental evaluationNeurologic consultation and comprehensive neurologic examination with a baseline assessment of skeletal muscle involvement that can be used to monitor disease progression Medical or biochemical genetics consultationTreatment of ManifestationsManagement should involve a multidisciplinary team including specialists in hepatology, neurology, nutrition, medical or biochemical genetics, and child development. Hepatic manifestations. Liver transplantation is the only treatment option for individuals with the progressive hepatic subtype of GSD IV who develop liver failure. Of the 18 individuals with GSD IV who have received a liver transplant to date, two required a second liver transplant and six died: four from sepsis, one from hepatic artery thrombosis, and one from cardiomyopathy. The prognosis in persons with GSD IV who undergo liver transplantation is poor because of the significant risk for morbidity and mortality, which is in part attributed to the extrahepatic manifestations of GSD type IV, especially cardiomyopathy [Davis & Weinstein 2008, Magoulas et al 2012].Selecting appropriate candidates for liver transplantation can be complex. Histologic, molecular, or clinical predictors of disease progression are likely to be useful in stratifying patients prior to liver transplantation [Davis & Weinstein 2008]. Factors such as glycogen branching enzyme (GBE) activity may not be the best predictor of outcome since the level of GBE activity in different tissues can vary by disease subtype and severity.Neurologic manifestations. Children with skeletal myopathy and/or hypotonia who experience motor developmental delay warrant developmental evaluation and physical therapy as needed. Cardiac manifestations. For those with cardiomyopathy, care by a cardiologist is warranted. Individuals with severe cardiomyopathy secondary to glycogenosis may be candidates for cardiac transplantation [Ewert et al 1999]; however, consideration of potential contraindications to cardiac transplantation, including myopathy, liver failure, and cachexia, is essential before pursuing this treatment option.Prevention of Secondary ComplicationsNutritional deficiencies (e.g., of fat-soluble vitamins) can be prevented by ensuring adequate dietary intake based on frequent assessments by and recommendations of a dietitian experienced in managing children with liver disease.Bleeding due to coagulopathy can occur especially with surgical procedures; therefore, it is recommended that a coagulation profile be assessed before surgical procedures and fresh frozen plasma be given preoperatively as needed. SurveillanceNo clinical guidelines for surveillance are available. The following evaluations are suggested with frequency varying according to the severity of the condition: Liver function tests including liver transaminases, albumin, and coagulation profile (PT and PTT)Abdominal ultrasound examinationEchocardiogramNeurologic assessmentNutritional assessmentNote: If cardiomyopathy was not observed on the baseline screening echocardiogram at the time of initial diagnosis, repeat echocardiograms are recommended every three months during infancy, every six months during early childhood, and annually thereafter.Evaluation of Relatives at RiskIf the GBE1 disease-causing mutations have been identified in an affected family member, at-risk relatives can be tested so that those with the disease-causing mutations can be evaluated for involvement of the liver, skeletal muscle, and heart to allow early diagnosis and management of disease manifestations.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Glycogen Storage Disease Type IV: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGBE13p12.21,4-alpha-glucan-branching enzymeGBE1 homepage - Mendelian genesGBE1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Glycogen Storage Disease Type IV (View All in OMIM) View in own window 232500GLYCOGEN STORAGE DISEASE IV 607839GLYCOGEN BRANCHING ENZYME; GBE1Normal allelic variants. GBE1 comprises 16 exons.Pathologic allelic variants. To date, 40 GBE1 mutations have been identified in individuals with GSD IV or adult-onset polyglucosan body disease (APBD). See Genetically Related Disorders, Table 2, and Table 3 (pdf).Of the 40 GBE1 mutations, 16 are missense mutations, six nonsense mutations, five splice-site mutations, seven frameshift mutations, and six exonic or multiexonic deletions [Li et al 2012, Magoulas et al 2012]. Seven of the 40 mutations are located in exon 12, previously reported as a potential mutation hotspot [Moses & Parvari 2002]. Of the 40 mutations identified, 29 are within the catalytic domain of the enzyme. Twelve of the 16 missense mutations have occurred in the enzyme catalytic domain, indicating that such mutations disturb the enzymatic activity of the protein [Magoulas et al 2012]. Table 2.Selected GBE1 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeClinical PhenotypeReference Sequencesc.986A>Cp.Tyr329SerNon-progressive hepatic, APBDNM_000158.3 NP_000149.3c.1544G>Ap.Arg515HisAPBDc.1571G>Ap.Arg524GlnClassic hepatic; Non-progressive hepatic, APBDSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). See Table 3 (pdf) for a complete list of GBE1 mutations identified to date.Normal gene product. Glycogen branching enzyme (GBE), a 702-amino acid protein, catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, reduce the osmotic pressure within cells [Thon et al 1993]. The GBE protein contains two highly conserved domains at the N- and C-terminals with sequences similar to isoamylase (glycoside hydrolase) and alpha-amylase, respectively. These two domains flank the alpha-amylase catalytic domain that encompasses the central portion of the enzyme [Moses & Parvari 2002].Abnormal gene product. The underlying molecular defects in GBE1 lead to the production of little or no functional GBE, resulting in abnormally formed glycogen (with fewer branch points and longer unbranched outer chains) with an amylopectin-like structure that accumulates in various tissues, most commonly the liver, heart, muscle, brain, spinal cord, peripheral nerve, and skin [Thon et al 1993, Chen 2001, Moses & Parvari 2002]. It has been postulated that alteration in the glycogen branching structure that makes it less soluble may result in a foreign body reaction that leads to the tissue injury and dysfunction observed in GSD IV [Howell 1991]; however, the specific pathologic mechanisms remain unknown.