Novel AGL mutation in a Turkish patient with glycogen storage disease type IIIa

Abstract

Key words AGL, deletion, glycogen debranching enzyme, glycogen storage disease type IIIa, Turkey.Glycogen storage diseases (GSD) are heterogeneous groups of inborn errors of glycogen metabolism and are divided into several types based on deficient enzymes. 1,2 Glycogen is metabolized by glycogen phosphorylase and glycogen debranching enzyme (GDE). GDE is a single protein with two independent catalytic activities: oligo-1, 4-1, 4 glucantransferase (EC 2.4.1.25) and amylo-1, 6-glucosidase (AGL) (EC 3.2.1.33). The gene encoding GDE is designated as the AGL gene. Deficiency of GDE is GSD type III (GSD III; OMIM 232400), an autosomal recessive inherited disorder. The disease is characterized by fasting hypoglycemia, growth retardation, and hepatomegaly. Most GSD III patients are GDE deficient in both liver and muscle (type IIIa) and present muscle weakness in adulthood, whereas 15% of patients have GDE absent in liver but present in muscle tissue (type IIIb) and do not show any muscular symptoms. These clinical manifestations are almost indistinguishable from those in GSD type Ia (OMIM 232200), glucose-6-phosphatase deficiency. Long-term complications, however, are different between the two GSD types. GSD IIIa involves cardiomyopathy, 3 liver cirrhosis, and hepatocellular carcinoma, 4 while gout, hepatic adenomas, osteoporosis, and renal disease are present in patients with GSD Ia. Clear differential diagnosis of the two hepatic GSD requires both an enzymatic and a molecular assessment.Here, we present a patient with GSD IIIa who was referred to Istanbul University Hospital as having GSD Ia, and describe a novel AGL mutation in this patient of Turkish ancestry. Case reportThe present patient was an 11-year-old Turkish boy. He was born at full term and hepatomegaly was noticed at the age of 7 months. A liver biopsy, performed in a hospital in Turkey at the age of 1 year, showed elevated glycogen content, enlarged hepatocytes with glycogen, and mild portal fibrosis. He was then diagnosed as having 'GSD Ia' and had been on dietary therapy with corn starch to prevent hypoglycemia.The patient was referred to Istanbul University when he was 3 1 /2 years old. At the first evaluation he had short stature (height 86 cm, <3rd percentile), a doll-like face, hepatomegaly, and splenomegaly. Laboratory data showed elevated liver enzymes (aspartate aminotransferase, 718 IU/L; alanine aminotransferase, 333 IU/L), hypercholesterolemia (total cholesterol, 278 mg/dL), and hypertriglyceridemia (triglyceride, 665 mg/dL). The patient had chronic hypochromic normocytic anemia (hemoglobin, 8.8 g/dL), which gradually resolved. His plasma lactate level fluctuated between 63.1 and 7.2 mg/dL (normal range, <19.8 mg/ dL). In contrast, fasting plasma glucose, uric acid, and creatine phosphokinase (CPK) levels were within normal range (106 mg/ dL, 3.6 mg/dL, and 49 IU/L, respectively). An echocardiogram was normal at that time.Diagnosis of 'GSD Ia' in the patient did not fit the clinical data: he had higher liver enzymes and glucose levels and lowe...

Molecular features of 23 patients with glycogen storage disease type III in Turkey: a novel mutation p.R1147G associated with isolated glucosidase deficiency, along with 9 AGL mutations

“…For example, specific mutations are prevalent in North African Jewish population and in an 16 along with one deletion (c.2474delC). 17 To investigate further molecular characteristic in Turkey, we examined 23 new cases with Turkish GSD III.…”

Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III

“…11,29 Turkish and Egyptian patients' haplotype are different, suggesting that W1327X can be a recurrent mutation in various ethnic groups. 30 The IVS32-12A4G mutation found in one patient (number 13), has been previously reported in Japanese population. 31 This mutation causes retention of the 11 bp intronic sequence in the debrancher mRNA.…”

Glikojen depo hastalığı tip III tanılı 10 Türk olgunun mutasyon analizleri: dört yeni mutasyonun tanımlanması

“…Among 29 Turkish GSD III patients, one of two mutations (p.Q1376X and p.W1327X) in exon 31was found in 10 patients (12,13,21). As a result of these findings exon 31 is included in approximately 1/3 of the mutations found in the Turkish patients until the present time.…”

“…In a recent study, nine different mutations including p.R1147G, p.W373X, p.R595X, p.Q1205X, p.Q667X, p.Q1376X, c.293+2T>C, p.W1327X and c.1019delA have been determined (12). c.2474delC which is a novel mutation was reported in a Turkish GSD III patient (21). At least four mutations in the AGL gene have come to the forefront as the most common mutations in studies performed until the present time.…”