A patient with common glycogen storage disease type Ib mutations without neutropenia or neutrophil dysfunction

Martens, Daniëlle H. J.; Kuijpers, Taco W.; Maianski, Nikolai A.; Rake, Jan Peter; Smit, Gerrit; Visser, Gepke

doi:10.1007/s10545-006-0146-x

Cited by 12 publications

(7 citation statements)

References 4 publications

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“…A few of the reported patients (about 10%) did not present with neutropenia and/or neutrophil dysfunction [38-40]. Interestingly, one of these patients [38] had a mutation that only partially affected the activity of the transporter [41].…”

Section: Clinical Description [126]mentioning

confidence: 99%

Glucose-6-phosphatase deficiency

Froissart

Piraud

Boudjemline

et al. 2011

Orphanet J Rare Dis

189

159

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Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatoc...

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Section: Clinical Description [126]mentioning

confidence: 99%

Glucose-6-phosphatase deficiency

Froissart

Piraud

Boudjemline

et al. 2011

Orphanet J Rare Dis

189

159

View full text Add to dashboard Cite

show abstract

“…Patients with GSD Ia and Ib manifest a nearly identical metabolic phenotype, including hypoglycemia, hepatomegaly, hyperuricemia, lactic acidemia and hyperlipidemia (Moses, 1990), but GSD Ib patients also present neutropenia and myeloid dysfunction, and these individuals are susceptible to recurrent bacterial infections, aphthous stomatitis, and inflammatory bowel disease (Visser et al , 2000). Nonetheless, neutropenia is not manifested by all GSD Ib patients (Kure et al , 2000; Martens et al , 2006). It is seen in only 20% of cases (Gitzelmann and Bosshard, 1993), and it has been proposed that it could be due to SLC37A4 mutations with residual transport activity (Kure et al , 2000).…”

mentioning

confidence: 93%

Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib

et al. 2013

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Glycogen storage disease (GSD) comprises a group of autosomal recessive disorders characterized by deficiency of the enzymes that regulate the synthesis or degradation of glycogen. Types Ia and Ib are the most prevalent; while the former is caused by deficiency of glucose-6-phosphatase (G6Pase), the latter is associated with impaired glucose-6-phosphate transporter, where the catalytic unit of G6Pase is located. Over 85 mutations have been reported since the cloning of G6PC and SLC37A4 genes. In this study, twelve unrelated patients with clinical symptoms suggestive of GSDIa and Ib were investigated by using genetic sequencing of G6PC and SLC37A4 genes, being three confirmed as having GSD Ia, and two with GSD Ib. In seven of these patients no mutations were detected in any of the genes. Five changes were detected in G6PC, including three known point mutations (p.G68R, p.R83C and p.Q347X) and two neutral mutations (c.432G > A and c.1176T > C). Four changes were found in SLC37A4: a known point mutation (p.G149E), a novel frameshift insertion (c.1338_1339insT), and two neutral mutations (c.1287G > A and c.1076-28C > T). The frequency of mutations in our population was similar to that observed in the literature, in which the mutation p.R83C is also the most frequent one. Analysis of both genes should be considered in the investigation of this condition. An alternative explanation to the negative results in this molecular study is the possibility of a misdiagnosis. Even with a careful evaluation based on laboratory and clinical findings, overlap with other types of GSD is possible, and further molecular studies should be indicated.

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“…Therefore, flowcharts have been presented for the diagnosis of GSD-Ia in which the presence or absence of myeloid dysfunction determines whether to perform mutation analysis of the G6PC gene [Rake et al, 2000a]. However, neutropenia is not manifest by all GSD-Ib patients [Galli et al, 1999; Kure et al, 2000; Melis et al, 2005; Angaroni et al, 2006; Martens et al, 2006] and some GSD-Ia patients suffer from mild neutropenia [Weston et al, 2000]. Therefore, a clear diagnosis may still warrant mutational analysis of both G6PC and G6PT genes.…”

Section: Introductionmentioning

confidence: 99%