Molecular, Biochemical, and Clinical Characterization of Thirteen Patients with Glycogen Storage Disease 1a in Malaysia.

Background: Glycogen storage disease type 1a (GSD1a) is a rare autosomal recessive metabolic disorder characterized by hypoglycaemia, growth retardation, lactic acidosis, hepatomegaly, hyperlipidemia, and nephromegaly. GSD1a is caused by a mutation in the G6PC gene encoding glucose-6-phosphatase (G6Pase); an enzyme that catalyses the hydrolysis of glucose-6-phosphate (G6P) to phosphate and glucose. Objective: To elaborate on the clinical findings, biochemical data, molecular genetic analysis, and short-term prognosis of 13 GSD1a patients in Malaysia. Methods: The information about 13 clinically classified GSD1a patients was retrospectively studied. The G6PC mutation analysis was performed by PCR-DNA sequencing. Results: Patients were presented with hepatomegaly (92%), hypoglycaemia (38%), poor weight gain (23%), and short stature (15%). Mutation analysis revealed nine heterozygous mutations; eight previously reported mutations (c.155 A > T, c.209 G > A, c.226 A > T, c.248 G > A, c.648 G > T, c.706 T > A, c.1022 T > A, c.262delG) and a novel mutation (c.325 T > C). The most common mutation found in Malaysian patients was c.648 G > T in ten patients (77%) of mostly Malay ethnicity, followed by c.248 G > A in 4 patients of Chinese ethnicity (30%). A novel missense mutation (c.325 T > C) was predicted to be disease-causing by various in silico software. Conclusions: The establishment of G6PC molecular genetic testing will enable the detection of presymptomatic patients, assisting in genetic counselling while avoiding the invasive methods of liver biopsy.

Clinical and Mutational Analysis of the GCDH Gene in Malaysian Patients with Glutaric Aciduria Type 1.

Glutaric aciduria type 1 (GA1) is an autosomal recessive metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase enzyme encoded by the GCDH gene. In this study, we presented the clinical and molecular findings of seven GA1 patients in Malaysia. All the patients were symptomatic from infancy and diagnosed clinically from large excretion of glutaric and 3-hydroxyglutaric acids. Bidirectional sequencing of the GCDH gene revealed ten mutations, three of which were novel (Gln76Pro, Glu131Val, and Gly390Trp). The spectrum of mutations included eight missense mutations, a nonsense mutation, and a splice site mutation. Two mutations (Gln76Pro and Arg386Gln) were homozygous in two patients with parental consanguinity. All mutations were predicted to be disease causing by MutationTaster2. In conclusion, this is the first report of both clinical and molecular aspects of GA1 in Malaysian patients. Despite the lack of genotype and phenotype correlation, early diagnosis and timely treatment remained the most important determinant of patient outcome.

Late-Onset Glycogen Storage Disease Type II (Pompe's Disease) with a Novel Mutation: A Malaysian Experience.

Pompe's disease (acid maltase deficiency, glycogen storage disease type II) is an autosomal recessive disorder caused by a deficiency of lysosomal acid α-1,4-glucosidase, resulting in excessive accumulation of glycogen in the lysosomes and cytoplasm of all tissues, most notably in skeletal muscles. We present a case of adult-onset Pompe's disease with progressive proximal muscles weakness over 5 years and respiratory failure on admission, requiring prolonged mechanical ventilation. Electromyography showed evidence of myopathic process with small amplitudes, polyphasic motor unit action potentials, and presence of pseudomyotonic discharges. Muscle biopsy showed glycogen-containing vacuoles in the muscle fibers consistent with glycogen storage disease. Genetic analysis revealed two compound heterozygous mutations at c.444C>G (p.Tyr148∗) in exon 2 and c.2238G>C (p.Trp746Cys) in exon 16, with the former being a novel mutation. This mutation has not been reported before, to our knowledge. The patient was treated with high protein diet during the admission and subsequently showed good clinical response to enzyme replacement therapy with survival now to the eighth year. Conclusion. In patients with late-onset adult Pompe's disease, careful evaluation and early identification of the disease and its treatment with high protein diet and enzyme replacement therapy improve muscle function and have beneficial impact on long term survival.