Glycogen storage disease due to glycogen debranching enzyme deficiency
General Information (adopted from Orphanet):
Synonyms, Signs:
GSDIII
GSD III
AGL DEFICIENCY
GLYCOGEN DEBRANCHER DEFICIENCY
FORBES DISEASE
GSD3
GSD IIIc, INCLUDED
cori disease
Glycogenosis due to glycogen debranching enzyme deficiency
amylo-1,6-glucosidase deficiency
GSD due to glycogen debranching enzyme deficiency
GSD IIId, INCLUDED
GLYCOGEN STORAGE DISEASE IIIc, INCLUDED
GSD type 3
limit dextrinosis
GSD IIIa, INCLUDED
GDE DEFICIENCY GLYCOGEN STORAGE DISEASE IIIa, INCLUDED
GDE deficiency
Forbe disease
Glycogenosis type 3
GLYCOGEN STORAGE DISEASE IIId, INCLUDED
Glycogen storage disease type 3
Cori-Forbes disease
GLYCOGEN STORAGE DISEASE IIIb, INCLUDED
GSD IIIb, INCLUDED
GSD Type III (Cori Disease) comprises the following subgroups, that are distinguished by their residual enzyme activity: IIIa a liver and muscle form (0%), IIIb an isolated liver form (0% to 5%), IIIc an isolated muscle form (20% to 30%) and
IIId ( (isolated transferase deficiency, 30% to 50%) (PMID:17027861). Selective loss of only one of the two GDE activities, glucosidase or transferase, results in GSD IIIc or GSD IIId, respectively (PMID:20648714).
Glycogen storage disease III is an autosomal recessive metabolic disorder caused by deficiency of the glycogen debrancher enzyme and associated with an accumulation of abnormal glycogen with short outer chains. Most patients are enzyme-deficient in both liver and ... Glycogen storage disease III is an autosomal recessive metabolic disorder caused by deficiency of the glycogen debrancher enzyme and associated with an accumulation of abnormal glycogen with short outer chains. Most patients are enzyme-deficient in both liver and muscle (IIIa), but about 15% are enzyme-deficient in liver only (IIIb) (Shen et al., 1996). These subtypes have been explained by differences in tissue expression of the deficient enzyme (Endo et al., 2006). In rare cases, selective loss of only 1 of the 2 debranching activities, glucosidase or transferase, results in type IIIc or IIId, respectively. (Van Hoof and Hers, 1967; Ding et al., 1990). Clinically, patients with GSD III present in infancy or early childhood with hepatomegaly, hypoglycemia, and growth retardation. Muscle weakness in those with IIIa is minimal in childhood but can become more severe in adults; some patients develop cardiomyopathy (Shen et al., 1996). Lucchiari et al. (2007) provided a review of GSD III.
Shen et al. (1997) used 3 polymorphic markers within the AGL gene for linkage analysis of GSD III and showed the potential use of these markers for carrier detection and prenatal diagnosis.
Brunberg et al. (1971) reported an adult with GSD III who had diffuse muscle weakness and wasting. DiMauro et al. (1979) reported 5 adult patients with adult-onset, slowly progressive muscle weakness associated with debrancher enzyme deficiency. Two patients ... Brunberg et al. (1971) reported an adult with GSD III who had diffuse muscle weakness and wasting. DiMauro et al. (1979) reported 5 adult patients with adult-onset, slowly progressive muscle weakness associated with debrancher enzyme deficiency. Two patients had distal muscle wasting, 3 had hepatomegaly, and 2 had congestive heart failure. Electromyography showed a mixed pattern with abundant fibrillations, and serum creatine kinase was increased 5- to 45-fold. Skeletal muscle biopsy showed a vacuolar myopathy with increased glycogen content. DiMauro et al. (1979) suggested that debrancher deficiency myopathy may not be rare and should be considered in the differential diagnosis of adult-onset hereditary myopathies. Fellows et al. (1983) reported 2 unrelated adults with GSD III who presented with liver disease, one of whom developed fatal cirrhosis. Both had hepatomegaly since childhood. Histology showed unusual hepatic vacuolation. In Israel, Moses et al. (1989) performed cardiologic studies on 20 patients, aged 3 to 30 years, with enzymatically proven GSD IIIa. Seventeen patients showed subclinical evidence of cardiac involvement in the form of ventricular hypertrophy on ECG; 13 of 16 patients in whom an echocardiographic examination was performed had abnormal findings. Only 2 had cardiomegaly on x-ray. Moses et al. (1989) described in detail the findings in a 25-year-old female with clinically evident cardiomyopathy. Momoi et al. (1992) reviewed the case histories of 19 Japanese patients with GSD IIIa who developed muscular symptoms at various ages. They divided the patients into 4 groups: one with childhood onset of both muscle weakness and hepatic disorders; one with onset of muscular symptoms in adulthood while liver symptoms started in childhood; one with muscle weakness starting in adulthood long after liver symptoms in childhood had disappeared; and one with only muscle symptoms as adults without any sign or history of liver dysfunction after childhood. Coleman et al. (1992) studied 13 patients with GSD III followed from infancy. Activities of serum aspartate and alanine transaminases, lactate dehydrogenase, and alkaline phosphatase were markedly elevated during infancy. The serum enzyme activities declined around puberty concomitantly with a decrease in liver size. Although periportal fibrosis and micronodular cirrhosis indicated the presence of hepatocellular damage during childhood, the decline in serum enzyme activities with age and the absence of overt hepatic dysfunction suggested to the authors that the fibrotic process may not always progress. Markowitz et al. (1993) described a white man in whom the diagnosis of GSD III was made on the basis of open liver biopsy at the age of 1 year. At the age of 31 years, he presented with variceal hemorrhage secondary to hepatic cirrhosis. No other cause of the cirrhosis was found, other than deficiency of debranching enzyme, which was documented both in liver and skeletal muscle. In a multicenter study in the United States and Canada, Talente et al. (1994) identified 9 patients with GSD III who were 18 years of age or older. Increased creatine kinase activity was observed in 6 patients; 4 had myopathy and cardiomyopathy. One of the patients reported in detail was a 55-year-old man who owned and managed a small business. At age 30, he had gradual onset of weakness in his hands and feet. The distal muscles atrophied, and weakness progressed to include the limb-girdle region. Hadjigeorgiou et al. (1999) reported 4 adult Italian patients with GSD IIIa confirmed by molecular analysis. All patients had a history of infantile hepatomegaly followed by myopathy in their twenties. AGL activity and protein were almost absent in muscle specimens. A remarkably severe clinical history was noted in 1 patient, who underwent liver transplantation at 23 years of age and developed a proximal myopathy and an obstructive hypertrophic cardiomyopathy by age 30 years. In 7 patients with GSD III, Cleary et al. (2002) identified consistent facial features including midface hypoplasia with a depressed nasal bridge and a broad upturned nasal tip, indistinct philtral pillars, and bow-shaped lips with a thin vermilion border. In addition, younger patients had deep-set eyes. Several children had clinical problems such as persistent otitis media or recurrent sinusitis. The similar features in these patients suggested a distinct facial phenotype for this disorder. Schoser et al. (2008) reported a family with variable presentation of GSD III. The 49-year-old female proband presented with hepatomegaly, cardiomyopathy, and moderate progressive proximal limb myopathy. She developed proximal muscle weakness at age 10 and signs and symptoms of cardiomyopathy at age 30. She also had progressive hearing impairment beginning at age 30. Skeletal muscle biopsy showed severe vacuolar myopathy with PAS-positive glycogen storage material that altered the contractile apparatus. Two brothers had died of severe infantile liver cirrhosis, and a sister died with cardiomyopathy, hepatomegaly, and myopathy at age 33. The proband was homozygous for a truncating mutation in the AGL gene. Heterozygous family members had exercise-inducted myalgia and weakness since their teens. Schoser et al. (2008) concluded that, with the exception of early infantile fatal cirrhosis, patients with GSD III may stay ambulatory until adulthood. Aoyama et al. (2009) reported a 14-year-old Turkish girl with GSD type IIIc, or isolated glucosidase deficiency, due to homozygosity for an AGL mutation (R1147G; 610860.0014). She had mild hepatomegaly, but no clinical muscle involvement or hypoglycemia. The authors stated that this was the first molecular diagnosis in a patient with GSD IIIc. - Clinical Variability Ebermann et al. (2008) reported an 11-year-old boy, born of Egyptian consanguineous parents, with a phenotype suggestive of Navajo neurohepatopathy (MTDPS6; 256810) including short stature, frequent painless fractures, bruises, and cuts, hepatomegaly with elevated liver enzymes, corneal ulcerations, and mild hypotonia. His 22-month-old sister had short stature, hepatomegaly, increased liver enzymes, and hypotonia. A cousin had died at age 8 years from liver failure. After genetic analysis excluded a mutation in the MPV17 gene (136960), Ebermann et al. (2008) postulated 2 recessive diseases. Genomewide linkage analysis and gene sequencing of the proband identified a homozygous mutation in the AGL gene, consistent with glycogen storage disease III, and a homozygous mutation in the SCN9A gene (603415), consistent with congenital insensitivity to pain (CIPA; 243000). His sister had the AGL mutation and GSD3 only. Ebermann et al. (2008) emphasized that consanguineous matings increase the risk of homozygous genotypes and recessive diseases, which may complicate genetic counseling.
In 3 unrelated patients with GSD IIIb, Shen et al. (1996) identified homozygous or compound heterozygous mutations in the AGL gene (see, e.g., 610860.0002-610860.0004). One of the mutations (17delAG; 610860.0004) was found in 8 of 10 additional GSD ... In 3 unrelated patients with GSD IIIb, Shen et al. (1996) identified homozygous or compound heterozygous mutations in the AGL gene (see, e.g., 610860.0002-610860.0004). One of the mutations (17delAG; 610860.0004) was found in 8 of 10 additional GSD IIIb patients. Mutations in exon 3 were present in 12 of 13 GSD IIIb patients, suggesting a specific association. In addition, the identification of exon 3 mutations may have clinical significance because it can distinguish GSD IIIb from IIIa. The 3 patients with GSD IIIb in whom mutations were studied in detail were aged 25 years, 18 years, and 41 years; they had no clinical or laboratory evidence of myopathy or cardiomyopathy. Shen et al. (1997) identified a homozygous mutation in the AGL gene (610860.0001) in a child with an unusually severe GSD IIIa phenotype. Okubo et al. (2000) identified 7 different mutations in the AGL gene, including 6 novel mutations, among 8 Japanese GSD IIIa patients from 7 families. Shaiu et al. (2000) reported 2 frequent mutations, each of which was found in homozygous state in multiple patients, and each of which was associated with a subset of clinical phenotype in those patients with that mutation. One mutation (IVS32-12A-G; 610860.0006) was identified in homozygosity in a confirmed GSD IIIa Caucasian patient who presented with mild clinical symptoms. This mutation had an allele frequency of approximately 5.5% in GSD III patients tested. The other common mutation (3964delT; 610860.0010) was identified in an African American patient who had a severe phenotype and early onset of clinical symptoms. The mutation was later identified in several other patients and was observed at a frequency of approximately 6.7%. Together, these 2 mutations can account for more than 12% of the molecular defects in GSD III patients. Shaiu et al. (2000) also identified 6 additional mutations and reviewed the nonmutation state. Lucchiari et al. (2002) identified 7 novel mutations of the AGL gene in patients with GSD IIIa in the Mediterranean area. Endo et al. (2006) identified 9 different mutations in the AGL gene, including 6 novel mutations, among 9 patients with GSD III. The patients were from Germany, Canada, Afghanistan, Iran, and Turkey. Aoyama et al. (2009) identified 10 different AGL mutations, including 8 novel mutations (see, e.g., 610860.0014 and 610860.0015), in 23 Turkish patients with GSD III. No genotype/phenotype correlations were observed.
In Israel, 73% of glycogen storage disease was of type III. All cases were non-Ashkenazim, being mainly of North African extraction, in which group the incidence was 1 in 5,420 (Levin et al., 1967).
The overall ... In Israel, 73% of glycogen storage disease was of type III. All cases were non-Ashkenazim, being mainly of North African extraction, in which group the incidence was 1 in 5,420 (Levin et al., 1967). The overall incidence of GSD III is about 1 in 100,000 live births in the U.S.; however, it is unusually frequent among North African Jewish individuals in Israel (1 in 5,400 with a carrier frequency of 1 in 35) (Parvari et al., 1997). Cohn et al. (1975) reported 2 families from the Faroe Islands with GSD III deficiency. The distribution supported the assumption of autosomal recessive inheritance. Santer et al. (2001) reported 5 families from the Faroe Islands affected with GSD IIIa. All carried the same mutation in the AGL gene (R408X; 610860.0013) and were homozygous for the same haplotype, supporting a founder effect. The results predicted a carrier frequency of 1 in 30 and a calculated prevalence of 1 per 3,600 in the Faroese population. The population of 45,000 of this small archipelago in the North Atlantic has its roots in the colonization by Norwegians in the 8th century and throughout the Viking Age. Santer et al. (2001) concluded that due to a founder effect, the Faroe Islands have the highest prevalence of GSD IIIa worldwide.
Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement....
DiagnosisClinical Diagnosis Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement.Four subtypes of GSD type III, based on differences in tissue expression of the deficient enzyme [Endo et al 2006], are recognized: GSD IIIa (~85% of all GSD III). Liver and muscle involvement, presumably resulting from enzyme deficiency in both liver and muscle GSD IIIb (~15% of all GSD III). Only liver involvement, presumably resulting from enzyme deficiency in liver onlyGSDIIIc (extremely rare). Presumably the result of deficiency of only glucosidase debranching activity GSDIIId (extremely rare). Presumably the result of deficiency of only transferase debranching activity The cardinal features of GSD IIIa and GSD IIIb:In infancy and early childhood, cardinal features are related to liver involvement: ketotic hypoglycemia, hepatomegaly, hyperlipidemia, and elevated hepatic transaminases. Hepatomegaly becomes evident early in infancy and may be the presenting feature. The liver is firm and may be markedly enlarged on clinical examination. In GSD IIIa cardiomyopathy usually appears during childhood, rarely as early as the first year of life; skeletal myopathy is absent or minimal.In adolescence and adulthood, the liver manifestations become less prominent, possibly due to progressing hepatic fibrosis and decreased glucose demands. However, hepatic cirrhosis and adenomas are seen in a small percentage of affected individuals. Hypertrophic cardiomyopathy develops in the majority of people with GSD IIIa. Its clinical significance varies as most affected individuals are asymptomatic [Lee et al 1997]; however, severe cardiac dysfunction, congestive heart failure, and (rarely) sudden death have been reported. The myopathy, presenting as weakness, progresses slowly, becoming prominent in the third to fourth decade of life [Lucchiari et al 2007].TestingHepatomegaly and ketotic hypoglycemia in the setting of elevated serum concentrations of transaminases and CK are the hallmarks of GSD III.Ketotic hypoglycemia with fasting is a prominent feature of GSD III. However, non-ketotic hypoglycemia has been reported [Seigel et al 2008]. Ketone concentrations of 0.5-1.5 mmol/L after an overnight fast can be seen in the untreated state; they resolve when hypoglycemia is prevented. Serum concentrations of:Creatine kinase (CK) is elevated once toddlers become active; however, a normal CK in the first few years of life does not exclude muscle involvement. Likewise isolated CK elevation without clinical evidence of myopathy or muscle weakness is common in the first two decades of life. [Chen 2000]. Triglycerides, cholesterol, and liver transaminases are elevated in the untreated state: Serum concentrations of triglycerides of 200-500 mg/dL and occasionally up to 4000 mg/dL have been noted. With treatment, the triglycerides normalize, but they may also be elevated in the treated state when metabolic control is suboptimal.Liver transaminases in GSD III are highest among all the glycogen storage diseases; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually higher than500 U/L and often higher than 1000 U/L. Uric acid and lactic acid are usually normal [Chen 2000, Wolfsdorf & Weinstein 2003].The debranching enzyme is a single polypeptide with two catalytic sites, amylo-1,6-glucosidase (EC 3.2.1.33) and 4-alpha-glucanotransferase (EC 2.4.1.25). Normal enzyme activity in the liver is 0.31 ± 0.10 units. Debranching enzyme activity can be measured in muscle and liver biopsy specimens and compared to controls. In Europe many centers measure debranching enzyme in white blood cells as an initial screen for GSD type III. Such testing is not performed clinically in the United States. Liver biopsy shows prominent distension of hepatocytes by glycogen; fibrous septa and periportal fibrosis are frequently present. The extent of fibrosis in GSD III is typically greater than in the other forms of GSD, and will increase during the course of the disease. Fibrosis is not a feature of GSD I, and steatosis is less than that seen in GSD I. Fibrosis can also be seen in GSD IV and less prominent fibrosis occurs in GSD IX. Molecular Genetic Testing Gene. AGL is the only gene in which mutations are known to cause glycogen storage disease type III.Table 1. Summary of Molecular Genetic Testing Used in Glycogen Storage Disease Type IIIView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAGLSequence analysisSequence variants 2~95% 3, 4 ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletionsUnknown 61. The ability of the test method used to detect a mutation that is present in the indicated gene 2. 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.3. Most AGL mutations are private and only four alleles (p.Arg864*, p.Arg1228*, c.3964delT, and c.4349-12A>G) have been found in more than 5% of unselected persons with GSD III [Shaiu et al 2000]. Three mutations (p.Arg864*, p.Arg1228*, and p.Trp680*) account for approximately 28% of the known mutations in individuals of European origin [Demo et al 2007]. See Table 2. 4. Some mutations result from founder effects (see Molecular Genetics).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. Exon deletion(s) or complex rearrangements [Endo et al 2009]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 probandA triad of hepatomegaly, ketotic hypoglycemia, and elevated serum concentration of transaminases and CK is pathognomonic of GSD III. Molecular genetic testing is the next step in confirming the diagnosis.Note: (1) Although debranching enzyme activity can be measured in liver biopsy specimens, this is now not necessary for diagnosis. Genetic testing is the recommended test if GSD III is suspected. If genetic testing cannot establish a diagnosis, testing of debranching enzyme activity in leukocytes is the preferred second line test, if available. (2) Since normal serum CK concentrations do not preclude the muscle phenotype, a muscle biopsy was required in the past to assess debranching enzyme activity and glycogen content in order to distinguish the GSD IIIa phenotype from the GSD IIIb phenotype. Evolving understanding of genotype-phenotype correlations may obviate this need. See Genotype-Phenotype Correlations.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: 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.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in AGL.
Both GSD IIIa and GSD IIIb typically present in childhood with hepatomegaly and ketotic hypoglycemia with markedly elevated liver transaminases and hypertriglyceridemia. The spectrum of presentation may include severe hypoglycemia as seen in GSD I or asymptomatic hepatomegaly. ...
Natural History Both GSD IIIa and GSD IIIb typically present in childhood with hepatomegaly and ketotic hypoglycemia with markedly elevated liver transaminases and hypertriglyceridemia. The spectrum of presentation may include severe hypoglycemia as seen in GSD I or asymptomatic hepatomegaly. It was previously believed that hepatomegaly and elevated transaminases improve or normalize by adolescence with or without treatment; however, it has been noted more recently that progressive liver disease occurs throughout life with the development of liver fibrosis and, in some cases, cirrhosis and hepatocellular carcinoma [Siciliano et al 2000, Cosme et al 2005, Demo et al 2007, Lucchiari et al 2007]. Elevated prothrombin time and low serum concentration of albumin are noted in those with GSD III who develop cirrhosis [Demo et al 2007]. Unlike GSD I in which hepatocellular carcinoma develops in existing adenomas, hepatic cirrhosis contributes mainly to hepatocellular carcinoma formation in GSD III [Demo et al 2007]. Although hepatic adenomas have been observed in as many as 25% of individuals with GSD III in small cohorts, the true prevalence is thought to be less. The relationship between metabolic control and formation of lesions has not been elucidated. Cardiomyopathy with an echocardiographic appearance of hypertrophic cardiomyopathy occurs in the majority of individuals with GSD IIIa. Cardiomyopathy usually appears during childhood, but rarely has been documented in the first year of life. Its clinical significance is uncertain as most affected individuals are asymptomatic; however, severe cardiac dysfunction, congestive heart failure, and sudden death have occasionally been reported. Recently, three separate groups reported affected individuals in whom a diet high in protein and limited in carbohydrates reduced or even normalized severe cardiac hypertrophy on ultrasound and ECG [Dagli et al 2009, Valayannopoulos et al 2011, Sentner et al 2012].Myopathy is absent or minimal in childhood and progresses slowly, becoming prominent in the third to fourth decade of life. Proximal muscles are primarily affected but involvement of distal muscles involving the calves, peroneal muscles [Lucchiari et al 2007], and hands is also seen.Recent studies suggest that altered perfusion [Wary et al 2010] and nerve dysfunction may contribute to exercise intolerance and muscle weakness [Hobson-Webb et al 2010], respectively. Growth may be compromised by poor metabolic control. Catch-up growth may be observed with the establishment of good metabolic control.Osteoporosis and osteopenia have been noted in GSD III as in other glycogen storage diseases. Mundy et al [2008] suggested that the cause of the osteoporosis is probably multifactorial with muscle weakness, abnormal metabolic environment, and suboptimal nutrition playing roles in pathogenesis.Polycystic ovary disease may be seen in GSD III; fertility does not appear to be affected [Chen 2000].
There is a clear genotype-phenotype correlation with at least two mutations in exon 3 (c.17_18delAG and c.16C>T) associated with GSD IIIb. It is unclear, however, what mechanism enables individuals with mutations in exon 3 to retain debranching enzyme activity in muscle tissue. A possible explanation was proposed by Goldstein et al [2010] in which the exon 3 mutation is bypassed using a downstream start codon, thus creating a fully functioning isoform without the exon 3 mutations. ...
Genotype-Phenotype Correlations There is a clear genotype-phenotype correlation with at least two mutations in exon 3 (c.17_18delAG and c.16C>T) associated with GSD IIIb. It is unclear, however, what mechanism enables individuals with mutations in exon 3 to retain debranching enzyme activity in muscle tissue. A possible explanation was proposed by Goldstein et al [2010] in which the exon 3 mutation is bypassed using a downstream start codon, thus creating a fully functioning isoform without the exon 3 mutations. No genotype-phenotype correlations between other AGL mutations and disease severity have been reported. Heterogeneity even within a given family has been noted [Lucchiari et al 2007].
Findings in GSD III that may help distinguish it from other forms of GSD include the following:...
Differential DiagnosisFindings in GSD III that may help distinguish it from other forms of GSD include the following:A history of hypoglycemia and hepatomegaly in childhood.Elevated serum CK concentrations in the setting of a hepatic glycogen storage disease in a young child.Remarkably elevated serum transaminases often in the 1000 range prior to commencement of treatment. No other GSD is associated with such marked elevation of AST and ALT [Chen 2000, Wolfsdorf & Weinstein 2003]. Glycogen storage disease type I. GSD III may be indistinguishable from GSD I in infancy. However, some important differences may help distinguish the two. GSD III does not usually have the elevations in uric acid and lactic acid seen in GSD I. In contrast to GSD I, ketotic hypoglycemia is seen in GSD III, and ketones are grossly elevated in morning urine samples of untreated individuals. Hypoglycemia and hypertriglyceridemia are more severe in GSD I than in GSD III. Glycogen storage disease type VI andtype IX are caused by a deficiency of hepatic glycogen phosphorylase and phosphorylase kinase, respectively. Phosphorylase kinase is responsible for activation of hepatic glycogen phosphorylase that cleaves the terminal glucose moieties from the glycogen chain. The phenotypes of GSD VI and GSD IX are clinically indistinguishable. Affected individuals present with ketotic hypoglycemia and hepatomegaly. They do not have elevated serum concentrations of CK, and AST and ALT are usually not as high as in GSD III. Other muscle forms of GSDs including GSD V and VII present with muscle weakness and rhabdomyolysis in adulthood. 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).
To establish the extent of disease and needs of an individual diagnosed with glycogen storage disease type III (GSD III), the following are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with glycogen storage disease type III (GSD III), the following are recommended:Liver ultrasound examination to determine the size of the liver and to identify adenomas if presentBaseline electrocardiogram and echocardiogramMedical genetics consultationTreatment of ManifestationsThe mainstay of management of GSD III is a high-protein diet with cornstarch supplementation to maintain euglycemia. In infancy, feeds every three to four hours are recommended. Unlike the diet used to treat infants with GSD I, the diet used to treat infants with GSD III can include fructose and galactose, as individuals with GSD III can utilize these sugars; special formulas are not required.Toward the end of the first year of life, cornstarch is tolerated and can be used to avoid hypoglycemia. Initially one to three doses per day may be required with typical starting dose of 1 g/kg every six hours. The doses can be titrated based on the results of glucose and ketone monitoring. A protein intake of 3 g/kg is recommended as gluconeogenesis is intact and protein can be used as a source of glucose. A high-protein diet prevents breakdown of endogenous muscle protein in times of glucose need and preserves skeletal and cardiac muscles.Metabolic control can be monitored using home blood glucose and blood ketone monitoring. Elevated ketones reflect poor metabolic control as ketones are produced when glucose is unavailable and instead fatty acid oxidation is used as a source of energy. Additionally, morning urine ketone measurements can be monitored with regular urine dipsticks to give an overview of overnight metabolic control.Monitoring blood ketones upon awakening at least several times per month using a portable blood ketone meter is recommended. The goal is to maintain blood beta-OH-butyrate concentrations in the normal range (<0.3 mmol/L). Hypoglycemia upon awakening is uncommon in older children and adults since counter-regulation can raise blood glucose concentrations; however, monitoring blood glucose concentrations at 2 to 4 AM can reveal periods of suboptimal control. Existing skeletal and cardiac myopathies can be improved with high-protein diet and avoidance of excessive carbohydrate intake [Slonim et al 1982, Slonim et al 1984, Dagli et al 2009, Valayannopoulos et al 2011, Sentner et al 2012]. Titration of protein and cornstarch in the diet is the primary treatment for elevated cholesterol and triglyceride concentrations, which usually result from suboptimal metabolic control.Emergency protocol. An emergency protocol to avoid dangerous hypoglycemia should be established. An intravenous (IV) infusion of 10% dextrose with 0.5 normal saline administered at 1.5 times the maintenance rate should be given immediately on admission to the emergency room. Serum concentrations of electrolytes, glucose, and ketones should be monitored. Efforts should be made to correct ketosis as it can induce vomiting and worsen the catabolic state.Liver transplantation. In GSD III hepatic complications are not the main cause of morbidity. Also, modern treatment strategies and good metabolic control can prevent major complications. Liver transplantation should therefore be viewed as a treatment of last resort for individuals with GSD III. A liver transplantation will prevent hypoglycemia in both subtypes; the muscular defect, however, will remain present in individuals with GSD IIIa. Liver transplantation does not cure the heart and muscle problems, and transplantation has been associated with worsening myopathy and cardiomyopathy.Therefore, liver transplantation is only indicated in affected individuals with severe hepatic cirrhosis, liver dysfunction, and/or hepatocellular carcinoma [Davis & Weinstein 2008].Prevention of Primary ManifestationsMost of the primary manifestations of GSD III can be diminished or avoided with good metabolic (dietary) control. When euglycemia is maintained and ketosis is avoided, hepatomegaly regresses and other abnormal laboratory values (e.g., elevated AST and ALT, increased serum concentration of triglycerides) normalize or come close to baseline [Bernier et al 2008].Myopathy and cardiomyopathy may be partially avoided by good dietary control. Prevention of Secondary ComplicationsSurgery. Persons with GSD III undergoing surgery should be admitted the night before the procedure and an IV infusion containing 10% dextrose started within two hours of the last cornstarch dose or the last meal. Glucose and ketone monitoring should continue overnight and during the procedure. IV dextrose infusion should not be stopped abruptly as dangerous hypoglycemia can occur from a hyper-insulinemic state. IV fluids need to be tapered slowly once optimal oral intake has been established and tolerated.Osteoporosis may occur in adults with GSD III. Good metabolic control leads to improved muscle strength and decreased ketosis. Bone mineralization is adversely affected in acidic environments. In contrast, improved muscle condition and strength increase bone mineralization. Supplementation with vitamin D and calcium is also recommended to augment bone mineralization.SurveillanceMonitoring of blood glucose concentration and blood ketones to assess control is recommended routinely and around periods of increased activity and illness: Monitoring of blood ketones upon awakening at least several times per month using a portable blood ketone meter is recommended. The goal is to maintain blood beta-OH-butyrate concentrations less than 0.3 mmol/L. Alternatively, morning urine ketone measurements may be assessed with regular urine dipsticks to give an overview of overnight metabolic control.Hypoglycemia is uncommon in older children and adults upon awakening since counter-regulation can raise blood glucose concentrations; however, monitoring blood glucose concentrations at 2 to 4 AM can reveal periods of suboptimal control. The following are appropriate annually:Measurement of height and weight to monitor growth Liver ultrasound examination to screen for adenomas and evidence of liver scarring. MRI scans are limited to those individuals with abnormalities on the primary ultrasound screen. Laboratory studies: LFTs, CK, lipid profileEchocardiogram to monitor for cardiomyopathy; ECGBone density measurements are recommended after growth is complete.Agents/Circumstances to AvoidAvoid the following:High sugar intake as excess sugar is stored as glycogen, which cannot be broken downSteroid-based drugs as they interfere with glucose metabolism and utilization. Long-term steroid usage itself can cause muscle weakness.Growth hormone replacement as it interferes with glucose metabolism, worsens ketosis, and may theoretically cause liver adenomas to growUse the following with caution:Hormonal contraceptives in women as they can cause hepatic adenoma formation Statins for control of hyperlipidemia. Use of statins requires CK monitoring because of the potential of exacerbating the muscle disease of GSD IIIa.Beta blockers as they can induce hypoglycemiaEvaluation of Relatives at RiskDiagnosis of at-risk sibs at birth allows for early dietary intervention to prevent development of hypoglycemia associated with GSD III. If the disease-causing mutations in the family are known, molecular genetic testing is the best way to determine the genetic status of an at-risk sib. If the disease-causing mutations in the family are not known, diagnosis can be established by presence of fasting ketotic hypoglycemia. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementAffected mother. Increased monitoring and support are required in pregnancy of women with GSD III as glucose needs will increase. The metabolic requirements will gradually increase throughout the second and third trimesters, and close monitoring of both glucose and ketones is critical to ensure optimal metabolic control. In the third trimester and close to term, it is imperative to maintain ketones within normal levels as ketosis can precipitate uterine contractions and preterm labor. During labor and in the postnatal period, intravenous glucose supplementation must be available at all times to prevent hypoglycemic episodes.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 III: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDAGL1p21.2Glycogen debranching enzymeAGL homepage - Mendelian genesAGLData 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 III (View All in OMIM) View in own window 232400GLYCOGEN STORAGE DISEASE III 610860AMYLO-1,6-GLUCOSIDASE, 4-ALPHA-GLUCANOTRANSFERASE; AGLNormal allelic variants. AGL is 85 kb in size with 34 exons (NM_000642.2). Bao et al [1997] recognized the presence of six different isoforms that differ in the 5’ end by using several cryptic splice sites upstream of the translation initiation site. This allows the inclusion or removal of exons. Isoform 1 is the generalized form present in liver, muscle, kidney, and lymphoblastoid cells. Isoforms 2, 3, and 4 are present in the muscle and heart. These isoforms are formed as a result of alternative splicing or of a difference in transcription start points. Isoform 1 contains exons 1 and 3; isoforms 2, 3, and 4 start with exon 2. Isoforms 1 through 4 all contain exon 3 which includes the normal initiation codon for protein translation. Exons 4-35 are present in isoforms [Bao et al 1996, Bao et al 1997]. The glycogen binding site is encoded by exons 31 and 32 and the active site is encoded by exons 6, 13, 14, and 15 [Elpeleg 1999].Pathologic allelic variants. Certain populations have common mutations as a result of a founder effect. For example: c.1222C>T in persons with GSD III from the Faroe Islands [Santer et al 2001] c.4455delT in North African Jewish individuals [Parvari et al 1997] Table 2. Selected AGL Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1) Protein Amino Acid Change (Alias 1)Reference Sequencesc.16C>T 2p.Gln6*NM_000642.2 NP_000633.2 c.17_18delAG 2p.Gln6Hisfs*20 3(25*)c.1222C>Tp.Arg408*c.2039G>Ap.Trp680*c.2590C>Tp.Arg864*c.3682C>Tp.Arg1228*c.3965delTp.Val1322Alafs*27 4c.4349-12A>G 5(IVS32-12 A>G)--c.4455delT 3p.Ser1486Profs*18See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Associated with the GSD IIIb phenotype [Shen et al 1996]3. Parvari et al [1997]4. Mutation causes a premature stop codon, translating a truncated AGL protein of 1321 wild-type amino acids plus 26 novel residues. The protein product lacks 211 amino acid residues, from exon 31, which is one of glycogen binding areas [Shaiu et al 2000].5. Mutation creates a novel splice site, such that the 11 intronic nucleotides from the immediate 3’ end of intron 32 are adjoined to the 3’ end of exon 32 creating a frameshift [Shaiu et al 2000].Normal gene product. Glucose molecules forming UDP glucose are added via alpha 1,4 linkages to the matrix for glycogen, called glycogenin. This process is catalyzed by glycogen synthase. When the chain reaches a certain length, “branching enzyme” cleaves off the terminal portion of the chain and attaches it via an alpha 1,6 linkage to the parent chain. This process is repeated over and over again on all the different branches of the chain and the complex glycogen molecules are created.When digestion of a meal is complete, insulin levels fall and glucagon is secreted. In a process mediated by the enzyme glycogen phosphorylase, these hormones stimulate cleavage of glucose molecules from the terminal strands of glycogen as glucose-1-phosphate. This process continues until four glucose molecules remain before the alpha 1,6 bond. At this point, the human debranching enzyme with its two distinct catalytic activities comes into play. The 1,4-α-D-glucan 4-α-D-glycosyl transferase component transfers the terminal three glucose molecules to the parent chain and the amylo-1,6-glucosidase component cleaves the alpha 1,6 bond to release free glucose.Abnormal gene product. With debranching enzyme deficiency, glycogen cannot be degraded and an abnormal glycogen with branched outer points called “limit dextrin” accumulates.Except for the founder mutations described previously and some common mutations, most mutations are unique. Missense and splice site mutations, small deletions and insertions, and large intragenic deletions and insertions have been described, many of which produce truncated proteins. The c.4455delT mutation in the North African Jewish community generates a truncated protein that is about 97% of its length. This proves that the carboxy terminus, downstream of the glycogen binding site, is essential for normal enzyme function [Parvari et al 1997].Individuals with GSD IIIb have mutations in exon 3 of one of their AGL alleles. The nonsense mutation p.Gln6* and the frameshift deletion c.17_18delAG both generate truncated proteins with few amino acids. It is thought that alternative exon or translation initiation in muscle isoforms does not require exon 3, thus leading to normal enzyme activity in the muscles of persons with GSD IIIb who have an exon 3 deletion [Shen et al 1996, Elpeleg 1999].