Different clinical aspects of debrancher deficiency myopathy.
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OBJECTIVE: To characterise the main clinical phenotypes of debrancher deficiency myopathy and to increase awareness for this probably underdiagnosed disorder. METHODS: The diagnosis of debrancher deficiency was established by laboratory tests, EMG, and muscle and liver biopsy. RESULTS: Four patients with debrancher deficiency myopathy were identified in the Tyrol, a federal state of Austria with half a million inhabitants. Clinical appearance was highly variable. The following phenotypes were differentiated: (1) adult onset distal myopathy; (2) subacute myopathy of the respiratory muscles; (3) severe generalised myopathy; and (4) minimal variant myopathy. Exercise intolerance was uncommon. The clinical course was complicated by advanced liver dysfunction in two patients and by severe cardiomyopathy in one. All had raised creatine kinase concentrations (263 to 810 U/l), myogenic and neurogenic features on EMG, and markedly decreased debrancher enzyme activities in muscle or liver biopsy specimens. The findings were substantiated by a review of 79 previously published cases with neuromuscular debrancher deficiency. CONCLUSIONS: This study illustrates the heterogeneity of neuromuscular manifestations in debrancher deficiency. Based on the clinical appearance, age at onset, and course of disease four phenotypes may be defined which differ in prognosis, frequency of complications, and response to therapy. (+info)
Liver transplantation for glycogen storage disease types I, III, and IV.
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Glycogen storage disease (GSD) types I, III, and IV can be associated with severe liver disease. The possible development of hepatocellular carcinoma and/or hepatic failure make these GSDs potential candidates for liver transplantation. Early diagnosis and initiation of effective dietary therapy have dramatically improved the outcome of GSD type I by reducing the incidence of liver adenoma and renal insufficiency. Nine type I and 3 type III patients have received liver transplants because of poor metabolic control, multiple liver adenomas, or progressive liver failure. Metabolic abnormalities were corrected in all GSD type I and type III patients, while catch-up growth was reported only in two patients. Whether liver transplantation results in reversal and/or prevention of renal disease remains unclear. Neutropenia persisted in both GSDIb patients post liver transplantation necessitating continuous granulocyte colony stimulating factor treatment. Thirteen GSD type IV patients were liver transplanted because of progressive liver cirrhosis and failure. All but one patient have not had neuromuscular or cardiac complications during follow-up periods for as long as 13 years. Four have died within a week and 5 years after transplantation. Caution should be taken in selecting GSD type IV candidates for liver transplantation because of the variable phenotype, which may include life-limiting extrahepatic manifestations. It remains to be evaluated, whether a genotype-phenotype correlation exists for GSD type IV, which may aid in the decision making. CONCLUSION: Liver transplantation should be considered for patients with glycogen storage disease who have developed liver malignancy or hepatic failure, and for type IV patients with the classical and progressive hepatic form. (+info)
Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands.
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Glycogen storage disease type IIIA (GSD IIIA) is caused by mutations of the amyloglucosidase gene (AGL). For most populations, none of the AGL mutations described to date is particularly frequent. In this paper, we report that six children with GSD IIIA from the Faroe Islands were found to be homozygous for the novel nonsense mutation c.1222C>T (R408X) of the AGL gene. This mutation is easily detected by restriction enzyme digest with NsiI after mismatch PCR. Investigating five intragenic polymorphisms, we could show that this mutation was always associated with the same haplotype. The c.1222C>T mutation could be detected on two chromosomes of another 50 unselected GSD IIIA patients of other European or North American origin which means that this mutation plays a minor role worldwide. From the fact that we are currently aware of a total of 14 GSD IIIA cases in the Faroese population of 45 000, the observed prevalence is 1 : 3100. While the novel AGL mutation c.1222C>T was not detectable among 198 German newborns, nine out of 272 children from the Faroese neonatal screening program were found to be heterozygous for this mutation. Thus, the calculated prevalence is 1 : 3600 (95% CI 1:700-1:6400). We conclude that due to a founder effect, the Faroe Islands have the highest prevalence of GSD IIIA world-wide. The detection of the molecular defect has facilitated the diagnosis and has offered the opportunity for prenatal diagnosis in this patient group. (+info)
Liver transplantation-associated hypercalcemia followed by acute renal dysfunction.
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A 34-year-old woman with liver insufficiency due to glycogen storage disease III underwent a living spousal liver transplantation. Soon after the successful operation, moderate hypercalcemia along with hyperbilirubinemia emerged without clarified reasons. The hypercalcemia persisted for over a month despite calcitonin treatment and the serum calcium level surged to 13.2 mg/dl with albumin correction. Renal dysfunction was indicated by an acute increase in serum creatinine (approximately 0.8 to approximately 2.8 mg/ml), which was assumed to be hypercalcemia-induced and was effectively treated with bisphosphonate, pamidronate (30 mg, i.v.). Recent topics related to transplantation-associated hypercalcemia are discussed. (+info)
Glycogen storage disease type III in Inuit children.
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Glycogen storage disease type III (GSD III) was diagnosed in 4 Inuit children (3 confirmed, 1 suspected case) at our institution over the last decade. This rare autosomal recessive disease, which results from a deficiency of the debranching enzyme required for complete degradation of the glycogen molecule, has not been previously described in this population. The possible clinical presentations are heterogeneous, as is the spectrum of severity of this disease. The long-term sequelae can be severe, including recurrent hypoglycemia, hepatic cirrhosis and progressive muscle weakness. These 4 cases would suggest an increased prevalence of GSD III in the Inuit population. Therefore, it is important for health care providers caring for this population to consider and recognize this rare but serious disease. (+info)
Glycogen storage disease type III-hepatocellular carcinoma a long-term complication?
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BACKGROUND/AIMS: Glycogen storage disease III (GSD III) is caused by a deficiency of glycogen-debranching enzyme which causes an incomplete glycogenolysis resulting in glycogen accumulation with abnormal structure (short outer chains resembling limit dextrin) in liver and muscle. Hepatic involvement is considered mild, self-limiting and improves with age. With increased survival, a few cases of liver cirrhosis and hepatocellular carcinoma (HCC) have been reported. METHODS: A systematic review of 45 cases of GSD III at our center (20 months to 67 years of age) was reviewed for HCC, 2 patients were identified. A literature review of HCC in GSD III was performed and findings compared to our patients. CONCLUSIONS: GSD III patients are at risk for developing HCC. Cirrhosis was present in all cases and appears to be responsible for HCC transformation There are no reliable biomarkers to monitor for HCC in GSD III. Systematic evaluation of liver disease needs be continued in all patients, despite lack of symptoms. Development of guidelines to allow for systematic review and microarray studies are needed to better delineate the etiology of the hepatocellular carcinoma in patients with GSD III. (+info)
Long-term results of living donor liver transplantation for glycogen storage disorders in children.
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Liver transplantation (LT) may be indicated in glycogen storage disorders (GSD) when medical treatment fails to control the metabolic problems or when hepatic adenomas develop. We present our institutional experience with living donor LT (LDLT) for children with GSD. A total of 244 patients underwent primary LDLT at our institution from June 1994 to December 2005. A total of 12 (5%) children (8 female and 4 male) were afflicted with GSD and were not responsive to medical treatment. Nine patients had GSD type I and 3 had GSD type III. The median age at the time of transplantation was 7.27 yr (range, 2.4-15.7). All patients presented with metabolic abnormalities, including hypoglycemia, and lactic acidosis. In addition, 4 patients presented with growth retardation. A total of 11 patients received left lobe grafts and 1 received a right lobe graft. The mean graft-to-recipient weight ratio was 1.25 (range, 0.89-1.61). Two patients had hepatic vein stenoses that were treated by balloon dilatation; 1 patient had bile leak, which settled spontaneously. The overall surgical morbidity rate was 25%. Three patients had hepatic adenomas in the explanted liver. There was a single mortality at 2 months posttransplantation due to acute pancreatitis and sepsis. The mean follow up was 47.45 months. The metabolic abnormalities were corrected and renal function remained normal. In patients with growth retardation, catch-up growth was achieved posttransplantation. In conclusion, LDLT is a viable option to restore normal metabolic balance in patients with GSD when medical treatment fails. Long-term follow-up after LT for GSD shows excellent graft and patient survival. (+info)
A Japanese patient with cardiomyopathy caused by a novel mutation R285X in the AGL gene.
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Left ventricular hypertrophy (LVH) is primarily or secondarily caused by a cardiovascular or systemic disease. The pattern of LVH is distinctive in hypertrophic or metabolic cardiomyopathy and differs from that seen in LVH caused by hypertension or aortic stenosis. A 42-year-old Japanese man had LVH similar to that with hypertrophic cardiomyopathy. The patient was diagnosed with glycogen storage disease type IIIa (GSD-IIIa). Echocardiography showed that he had severe LVH, and concomitant hepatomegaly and hypoglycemia, which led to measurement of glycogen debranching enzyme (GDE) activity; it was undetectable. Sequence analysis of the AGL gene encoding GDE showed a novel nonsense mutation: a C-to-T transition at codon 285 in exon 8, resulting in substitution of the arginine codon by the stop codon (R285X). The patient was homozygous for the mutation. Cardiomyopathy in this patient was caused by a nonsense mutation in the AGL gene. Five other Japanese GSD-IIIa patients over 30 years of age have all presented with cardiomyopathy, as well as hepatomegaly and hypoglycemia. Patients with LVH associated with hepatomegaly and hypoglycemia should undergo biochemical and genetic analyses for GSD-IIIa. (+info)