Glycogen storage diseases (GSDs) are a group of inherited inborn errors of metabolism characterized by the deficiency of any one of the enzymes involved in glycogen metabolism, and subsequent build-up of excessive levels of glycogen in the body tissues. GSD I is caused by deficiency of the glucose 6 phosphatase or glucose 6 phosphate translocase enzyme. The cardinal features of this disorder are post absorptive hypoglycemia, lactic acidosis, hypertriglyceridemia, and hyperuricemia. These effects are a consequence of impaired gluconeogenesis and/or glycogenolysis, along with low insulin levels and increased use of the pentose phosphate pathway. Other clinical features of this condition are severe hepatomegaly, growth retardation, and kidney enlargement. About 25% of all GSD cases are due to GSD I. Worldwide, the incidence of this disorder is estimated at about 1 affected patient in every 100,000 to 200,000 live births.
As in all GSDs, diagnosis of the condition relies on blood serum level of metabolites, as well as imaging studies of organs. DNA testing for mutations in the G6PC gene is also available. Managing GSD I is now much easier than it was some years ago. The most important strategy is to severely cut back on the dietary intake of fructose and galactose. Instead, cornstarch is considered a good carbohydrate source, since it is digested slowly. It is important to provide small, frequent meals during the day, and if needed, tube feeding by night. Diet may be needed to be supplemented with vitamin and mineral tablets. With effective management, prognosis is good for patients.
Glucose 6 phosphatase is a multi-pass membrane protein, localized to the endoplasmic reticulum membrane that catalyzes the hydrolysis of glucose 6 phosphate to glucose and orthophosphate. This is a major step in the breakdown of glycogen into simple sugar, thereby releasing energy for the body during fasting. The glucose 6 phosphatase enzyme includes both a catalytic as well as translocase subunit.
The enzyme is coded for by the G6PC gene, located on chromosome 17q21. The gene spans a length of approximately 12 kb, while the enzyme weighs approximately 40 kDa and consists of 357 amino acids. Mutations in this gene result in defective enzyme production, which in turn, causes impaired breakdown of glycogen into glucose. This results in the characteristic build-up of glycogen in the liver, muscles, and kidneys, as well as severe hypoglycemia.
Al-Arrayed (2006) indicated that glycogen storage disease occurs in Bahrain frequently. However, further studies are needed to determine its prevalence.
The Centre for Arab Genomic Studies Work Group (2006) conducted a retrospective study for metabolic disorders described at AlWasl Hospital in Dubai between 1997 and 2006. Only one cases of glycogen storage disease was observed in 2-year-old Jordanian boy who was resident of the UAE.
Joshi et al. (2002) carried out a retrospective analysis of all patients born with inborn errors of metabolism in Oman between June 1998 and December 2000. Among the 82 patients, three were diagnosed with GSD type I [CTGA Database Editor's note: Computed annual incidence rate is 2.4/100,000].
Parvari et al. (1997) reported the biochemical and clinical characteristics as well as mutational analyses of 12 GSD Ia patients of Jewish and Muslim Arab families. All patients were found to have the R83C mutation. Two Muslim Arab patients had the missense val166-to-gly (V166G) mutation, which had not been found in other populations.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. GSD was found in 17/248 patients. The diagnosis was confirmed in all cases of GSD by measuring enzymatic activity in leukocytes, cultured fibroblasts or liver biopsy. Among GSD cases in this cohort, 4 cases from 2 families were found to have GSD IA. The estimated incidence of GSD IA in this cohort was 2 in 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
Monies et al. (2017) portrayed the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, an 8-year-old female from a consanguineous family, presented with GSD type 1, bleeding tendency and hypoglycemia. Using a multigene panel for inborn errors of metabolism, she was found to have dual molecular diagnosis: a homozygous c.247C>T (p.R83C) variant in exon 2 of the G6PC gene and a homozygous c.266G>A (p.R89H) variant in exon 2 of the GAA (Glucosidase Alpha, Acid) gene. Dual molecular diagnoses were rarely detected and occurred in only 1.5% of the cohort.
[See: Jordan > CAGS Work Group, 2006].
Al-Shamsi et al., 2016 performed Whole Exome Sequencing in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism and other genetic disorders. Among the cohort in whom variants of uncertain significance were likely pathogenic, 1 patient harboring a deleterious variant of G6PC was diagnosed with glycogen storage disease Ia. The patient had presented with hypoglycemia, hepatosplenomegaly, elevated serum lactate levels, and hypertrophy of the left ventricle. The patient has a family history of cardiomyopathy.
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