Null mutations and lethal congenital form of glycogen storage disease type IV.

Muscular and Neurodegenerative Disease Unit, Department of Pediatrics, Istituto Giannina Gaslini, University of Genova, Largo G. Gaslini 5, I-16147 Genova, Italy.
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 09/2007; 361(2):445-50. DOI: 10.1016/j.bbrc.2007.07.074
Source: PubMed

ABSTRACT Glycogen branching enzyme deficiency (glycogen storage disease type IV, GSD-IV) is a rare autosomal recessive disorder of the glycogen synthesis with high mortality. Two female newborns showed severe hypotonia at birth and both died of cardiorespiratory failure, at 4 and 12 weeks, respectively. In both patients, muscle biopsies showed deposits of PAS-positive diastase-resistant material and biochemical analysis in cultured fibroblasts showed markedly reduced glycogen branching enzyme activity. Direct sequencing of GBE1 gene revealed that patient 1 was homozygous for a novel c.691+5 g>c in intron 5 (IVS5+5 g>c). RT-PCR analysis of GBE1 transcripts from fibroblasts cDNA showed that this mutation produce aberrant splicing. Patient 2 was homozygous for a novel c.1643G>A mutation leading to a stop at codon 548 in exon 13 (p.W548X). These data underscore that in GSD-IV a severe phenotype correlates with null mutations, and indicate that RNA analysis is necessary to characterize functional consequences of intronic mutations.

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    ABSTRACT: The clinical manifestations of glycogen storage disease type IV (GSD IV) discussed in this entry span a continuum of different subtypes with variable ages of onset, severity, and clinical features. Clinical findings vary extensively both within and between families. The diagnosis 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, and/or the identification of biallelic mutations in GBE1, the only gene in which mutations are known to cause GSD IV. Treatment of manifestations: Management should involve a multidisciplinary team including specialists in hepatology, neurology, nutrition, medical or biochemical genetics, and child development. Liver transplantation is the only treatment option for individuals with the progressive hepatic subtype of GSD IV who develop liver failure; however, the risk for morbidity and mortality is high, in part because of the extrahepatic manifestations of GSD type IV, especially cardiomyopathy. Children with skeletal myopathy and/or hypotonia warrant developmental evaluation and physical therapy as needed. Those with cardiomyopathy warrant care by a cardiologist. Heart transplant may be an option in patients with severe cardiac involvement. Prevention of secondary complications: Prevent nutritional deficiencies (e.g., of fat-soluble vitamins) by ensuring adequate dietary intake; prevent perioperative bleeding by assessment of a coagulation profile and use of fresh frozen plasma as needed. Surveillance: No clinical guidelines for surveillance are available. The following evaluations are suggested (with frequency varying according to disease severity): liver function tests including liver transaminases, albumin, and coagulation profile (PT and PTT); abdominal ultrasound examination; echocardiogram; neurologic assessment; nutritional assessment. If cardiomyopathy was not observed on baseline screening echocardiogram at the time of initial diagnosis, repeat echocardiograms every three months during infancy, every six months during early childhood, and annually thereafter. Evaluation of relatives at risk: If the GBE1 disease-causing mutations have been identified in an affected family member, test at-risk relatives to allow early diagnosis and management of disease manifestations. GSD IV is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Although affected sibs are expected to manifest the same subtype of GSD IV, the age of onset and presentation may differ. Carrier testing for at-risk family members and prenatal and prenatal diagnosis for pregnancies at increased risk are possible based on molecular testing if the disease-causing mutations in the family have been identified. If the disease-causing mutations have not been identified, glycogen branching enzyme (GBE) testing on cultured amniocytes can be performed for prenatal diagnosis.
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Jun 1, 2014