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Arthritis↗
Biomedical subjects
Shimon W Moses
Publications and source records attributed to Shimon W Moses.
Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases.
Muscle-specific deficiency of phosphorylase kinase (Phk) causes glycogen storage disease, clinically manifesting in exercise intolerance with early fatiguability, pain, cramps and occasionally myoglobinuria. In two patients and in a mouse mutant with muscle Phk deficiency, mutations were previously found in the muscle isoform of the Phk alpha subunit, encoded by the X-chromosomal PHKA1 gene (MIM # 311870). No mutations have been identified in the muscle isoform of the Phk gamma subunit (PHKG1). In the present study, we determined Q1the structure of the PHKG1 gene and characterized its relationship to several pseudogenes. In six patients with adult- or juvenile-onset muscle glycogenosis and low Phk activity, we then searched for mutations in eight candidate genes. The coding sequences of all six genes that contribute to Phk in muscle were analysed: PHKA1, PHKB, PHKG1, CALM1, CALM2 and CALM3. We also analysed the genes of the muscle isoform of glycogen phosphorylase (PYGM), of a muscle-specific regulatory subunit of the AMP-dependent protein kinase (PRKAG3), and the promoter regions of PHKA1, PHKB and PHKG1. Only in one male patient did we find a PHKA1 missense mutation (D299V) that explains the enzyme deficiency. Two patients were heterozygous for single amino-acid replacements in PHKB that are of unclear significance (Q657K and Y770C). No sequence abnormalities were found in the other three patients. If these results can be generalized, only a fraction of cases with muscle glycogenosis and a biochemical diagnosis of low Phk activity are caused by coding, splice-site or promoter mutations in PHKA1, PHKG1 or other Phk subunit genes. Most patients with this diagnosis probably are affected either by elusive mutations of Phk subunit genes or by defects in other, unidentified genes.
Adult↗
Historical highlights and unsolved problems in glycogen storage disease type 1.
UNLABELLED: Thirty-three years after Von Gierke described the first patient with glycogen storage disease type 1 (GSD1) in 1929, the Coris detected glucose-6-phosphatase (G6Pase) deficiency. The first mutation of this enzyme was identified 41 years later and subsequently the gene was mapped to chromosome 17q21, its enzyme topology defined, a nine transmembrane helical model suggested, an enzyme deficient knockout mouse created and by infusing an adenoviral vector associated murine G6Pase gene, correction of the clinical and laboratory abnormalities was observed. A similar successful gene transfer has been performed in enzyme deficient canine puppies. To explain the function of the G6Pase complex, a multicomponent translocase catalytic model has been proposed in which different transporters shuttle glucose-6-phosphate (G6P), inorganic phosphate (Pi) and glucose across the microsomal membrane. It was suggested that GSD1b patients suffered from a G6P transporter (G6PT) defect and the first mutation in the G6PT gene subsequently recognised. The gene mapped to chromosome 11q23 and its structural organisation was defined which showed a close functional linkage between G6PT and hydrolysis. Nordlie identified the first patient with Pi transport deficiency (GSD1c). However putative GSD1c and 1d patients based on kinetic studies were found to harbour mutations in the G6PT gene so that GSD1 patients are presently divided into 1a and non-1a. G6PT deficient patients suffer from numerical and functional leucocyte defects. A mRNA leucocyte G6PT deficiency has been suggested to account for the glucose phosphorylation and subsequent calcium sequestration defects observed in theses cells. Inflammatory bowel disease which occurs frequently in GSD non-1a patients has been related to their leucocyte abnormalities. Dietary management of GSD1 patients, designed to maintain a normal blood glucose level can be achieved during the night by nocturnal gastric infusions of glucose-containing solution or by the administration of uncooked cornstarch around the clock or by a combination of both. Both therapeutic modalities, if conducted in a meticulous manner, have a major impact on the quality of life, prevention of complications and subsequent prognosis. Open questions relate to the source of endogenous glucose production in GSD1 patients which increases as a function of age from 50% to 100% of normal, concomitant with an improvement in the patients fasting tolerance. Several complications, the nature of which is incompletely understood, tend to occur after the first decade: Liver adenomata with a small risk of transforming into hepatoma, progressive renal disease, which may be related to the hyperlipidaemia observed in this disease, often leading to end stage renal failure, osteopenia apparently based on high bone turnover, growth retardation and delayed puberty. CONCLUSION: this review highlights the present knowledge of glycogen storage disease type 1 and subtypes, discussing unsolved questions, which reflect the limitation of our knowledge in the understanding of this intriguing group of diseases.
Animals↗
The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies.
Glycogen storage disease type IV (GSD-IV), also known as Andersen disease or amylopectinosis (MIM 23250), is a rare autosomal recessive disorder caused by a deficiency of glycogen branching enzyme (GBE) leading to the accumulation of amylopectin-like structures in affected tissues. The disease is extremely heterogeneous in terms of tissue involvement, age of onset and clinical manifestations. The human GBE cDNA is approximately 3-kb in length and encodes a 702-amino acid protein. The GBE amino acid sequence shows a high degree of conservation throughout species. The human GBE gene is located on chromosome 3p14 and consists of 16 exons spanning at least 118 kb of chromosomal DNA. Clinically the classic Andersen disease is a rapidly progressive disorder leading to terminal liver failure unless liver transplantation is performed. Several mutations have been reported in the GBE gene in patients with classic phenotype. Mutations in the GBE gene have also been identified in patients with the milder non-progressive hepatic form of the disease. Several other variants of GSD-IV have been reported: a variant with multi-system involvement including skeletal and cardiac muscle, nerve and liver; a juvenile polysaccharidosis with multi-system involvement but normal GBE activity; and the fatal neonatal neuromuscular form associated with a splice site mutation in the GBE gene. Other presentations include cardiomyopathy, arthrogryposis and even hydrops fetalis. Polyglucosan body disease, characterized by widespread upper and lower motor neuron lesions, can present with or without GBE deficiency indicating that different biochemical defects could result in an identical phenotype. It is evident that this disease exists in multiple forms with enzymatic and molecular heterogeneity unparalleled in the other types of glycogen storage diseases.
1,4-alpha-Glucan Branching Enzyme↗