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S W Moses

Publications and source records attributed to S W Moses.

At least 19 recordsLinked to original sources
PubMed2004

Carnitine-acylcarnitine translocase deficiency: identification of a novel molecular defect in a Bedouin patient.

Carnitine-acylcarnitine translocase CACT deficiency is a very rare autosomal recessive disease. The neonatal phenotype of CACT deficiency is characterized by hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy and skeletal muscle weakness culminating in early death. The disease is caused by mutations in the CACT gene, which encodes a protein transporting long-chain fatty acid carnitine esters into the mitochondrial matrix. In this report, we describe the first case of CACT deficiency in the Bedouin population in Israel. The patient, the first son of consanguineous parents, was born at term after uneventful delivery. During the second day of life, he developed clinical signs of an acute metabolic crisis with severe hypoglycaemia and hyperammonaemia. Biochemical investigation suggested the diagnosis of CACT deficiency. Genetic molecular analysis confirmed this diagnosis by demonstrating that the affected child was homozygous for a novel missense mutation 793A>G, substituting glutamine by arginine (Q238R) in exon 7 of the CACT gene. Despite medical treatment and adequate nutrition, the patient died at 6 months of age.

Arabs↗
PubMed2001

Neurophysiologic studies in congenital insensitivity to pain with anhidrosis.

Thirteen patients with congenital insensitivity to pain and anhidrosis, carrying a mutation at the TRK-A gene, were studied. Neurologic examination revealed vestigial pain sensitivity, suggesting an incomplete involvement of the affected nerves. All 13 patients manifested normal electrophysiologic studies but striking absence of sympathetic skin responses. We suggest the use of the sympathetic skin response test in the clinical evaluation of patients suspected of having congenital insensitivity to pain and anhidrosis.

Child↗
PubMed1999

Inactivation of the glucose 6-phosphate transporter causes glycogen storage disease type 1b.

Glycogen storage disease type 1b (GSD-1b) is proposed to be caused by a deficiency in microsomal glucose 6-phosphate (G6P) transport, causing a loss of glucose-6-phosphatase activity and glucose homeostasis. However, for decades, this disorder has defied molecular characterization. In this study, we characterize the structural organization of the G6P transporter gene and identify mutations in the gene that segregate with the GSD-1b disorder. We report the functional characterization of the recombinant G6P transporter and demonstrate that mutations uncovered in GSD-1b patients disrupt G6P transport. Our results, for the first time, define a molecular basis for functional deficiency in GSD-1b and raise the possibility that the defective G6P transporter contributes to neutropenia and neutrophil/monocyte dysfunctions characteristic of GSD-1b patients.

Animals↗
PubMed1999

Glycogen storage disease type 1a in three siblings with the G270V mutation.

Glycogen storage disease type 1a (von Gierke disease, GSD1a) is caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) activity. The cloning of G6Pase cDNA and characterization of the human G6Pase gene enabled the identification of the mutations causing GSD1a. Here we report on the clinical and biochemical features of three GSD1a siblings of a Muslin Arab family with a G270V mutation. Two older patients presented with an unusually mild clinical and biochemical course.

Child↗
PubMed1998

Two new mutations in the 3' coding region of the glycogen debranching enzyme in a glycogen storage disease type IIIa Ashkenazi Jewish patient.

Glycogen storage disease type III (GSD III) is an autosomal recessive disease caused by the deficiency of glycogen debranching enzyme (AGL). We report the finding of two new mutations in a GSD IIIa Ashkenazi Jewish patient. Both mutations are insertion of an adenine into a stretch of 8 adenines towards the 3' end of the coding region, one at position 3904 (3904insA) in exon 30, the second at position 4214 (4214insA) in exon 32. The mutations cause frameshifts and premature terminations of the glycogen debranching enzyme, the first causing a frameshift at amino acid 1304, the second causing a frameshift at amino acid 1408 of the total of 1532. These mutations demonstrate the importance of the 125 amino acids at the carboxy-terminus of the debrancher enzyme for its activity and support the suggestion that the putative glycogen binding domain is located in the carboxy-terminus of the AGL. The mutations cause distinctive single-strand conformation polymorphism (SSCP) patterns enabling easy detection.

Child, Preschool↗
PubMed1998

The gene for glycogen-storage disease type 1b maps to chromosome 11q23.

Glycogen-storage disease type 1 (GSD-1), also known as "von Gierke disease," is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase) activity. There are four distinct subgroups of this autosomal recessive disorder: 1a, 1b, 1c, and 1d. All share the same clinical manifestations, which are caused by abnormalities in the metabolism of glucose-6-phosphate (G6P). However, only GSD-1b patients suffer infectious complications, which are due to both the heritable neutropenia and the functional deficiencies of neutrophils and monocytes. Whereas G6Pase deficiency in GSD-1a patients arises from mutations in the G6Pase gene, this gene is normal in GSD-1b patients, indicating a separate locus for the disorder in the 1b subgroup. We now report the linkage of the GSD-1b locus to genetic markers spanning a 3-cM region on chromosome 11q23. Eventual molecular characterization of this disease will provide new insights into the genetic bases of G6P metabolism and neutrophil-monocyte dysfunction.

Chromosome Deletion↗
PubMed1998

Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI.

Deficiency of glycogen phosphorylase in the liver gives rise to glycogen-storage disease type VI (Hers disease; MIM 232700). We report the identification of the first mutations in PYGL, the gene encoding the liver isoform of glycogen phosphorylase, in three patients with Hers disease. These are two splice-site mutations and two missense mutations. A mutation of the 5' splice-site consensus of intron 14 causes the retention of intron 14 and the utilization of two illegitimate 5' splice sites, whereas a mutation of the 3' splice-site consensus of intron 4 causes the skipping of exon 5. Two missense mutations, N338S and N376K, both cause nonconservative replacements of amino acids that are absolutely conserved even in yeast and bacterial phosphorylases. We also report corrections of the PYGL coding sequence, sequence polymorphisms, and a partial PYGL gene structure with introns in the same positions as in PYGM, the gene of the muscle isoform of phosphorylase. Our findings demonstrate that PYGL mutations cause Hers disease, and they may improve laboratory diagnosis of deficiencies of the liver phosphorylase system.

Amino Acid Sequence↗
PubMed1997

Glycogen storage disease type 1a in Israel: biochemical, clinical, and mutational studies.

Glycogen storage disease type 1a (von Gierke disease, GSD 1a) is caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) activity which catalyzes the final common step of glycogenolysis and gluconeogenesis. The recent cloning of the G6Pase cDNA and characterization of the human G6Pase gene enabled the characterization of the mutations causing GSD 1a. This, in turn, allows the introduction of a noninvasive DNA-based diagnosis that provides reliable carrier testing and prenatal diagnosis. In this study, we report the biochemical and clinical characteristics as well as mutational analyses of 12 Israeli GSD 1a patients of different families, who represent most GSD 1a patients in Israel. The mutations, G6Pase activity, and glycogen content of 7 of these patients were reported previously. The biochemical data and clinical findings of all patients were similar and compatible with those described in other reports. All 9 Jewish patients, as well as one Muslim Arab patient, presented the R83C mutation. Two Muslim Arab patients had the V166G mutation which was not found in other patients' populations. The V166G mutation, which was introduced into the G6Pase cDNA by site-directed mutagenesis following transient expression in COS-1 cells, was shown to cause complete inactivation of the G6Pase. The characterization of all GSD 1a mutations in the Israeli population lends itself to carrier testing in these families as well as to prenatal diagnosis, which was carried out in 2 families. Since all Ashkenzai Jewish patients harbor the same mutation, our study suggests that DNA-based diagnosis may be used as an initial diagnostic step in Ashkenazi Jews suspected of having GSD 1a, thereby avoiding liver biopsy.

Arabs↗
PubMed1997

Phosphorylase-kinase-deficient liver glycogenosis with an unusual biochemical phenotype in blood cells associated with a missense mutation in the beta subunit gene (PHKB).

We have identified mutations in the phosphorylase kinase (Phk) beta subunit gene in a male patient with liver glycogenosis caused by Phk deficiency. The patient's DNA has been analyzed for mutations in the genes encoding the alpha L, beta, and gamma TL subunits of Phk, all of which can be responsible for liver glycogenosis, by a strategy primarily based on reverse transcription/polymerase chain reaction of blood RNA and complemented by analysis of genomic DNA. His alpha L and gamma TL coding sequences are normal, whereas he is compound-heterozygous for two mutations in the beta subunit gene, PHKB. The first is a splice-site mutation (IVS4 [-2A-->G]) causing the reading-frame-disrupting deletion of exon 5 in the mRNA from this allele. The second is an Ala117Pro missense mutation, also in exon 5. This is the first missense mutation identified in PHKB, as opposed to nine translation-terminating mutations described to date. It offers an explanation for the unique biochemical phenotype of this patient. In his leukocytes, low Phk activity is measured when tested with the endogenous liver isoform of phosphorylase as the protein substrate, but normal activity is observed when tested with muscle phosphorylase added in vitro. In contrast, Phk activity in his erythrocytes is low with both substrates. The missense mutation may selectively impair the interaction of Phk with one isoform of its substrate protein and may destabilize the enzyme in a cell-type-specific way. This phenotype shares some aspects with X-linked liver glycogenosis subtype 2 (XLG2), a variant of liver Phk deficiency arising from missense mutations in the alpha L subunit gene (PHKA2), but differs from XLG2 in other respects. The present case demonstrates that mutations in Phk genes other than PHKA2 can also be associated with untypically high activity in certain blood cell types. Moreover, it emphasizes that missense mutations in Phk may cause unusual patterns of tissue involvement that would not be predicted a priori from the tissue specificity of expression of the mutated gene sequences.

Blood Cells↗
PubMed1994

Postnatal regression of glucose transport in a patient with glycogen storage disease type 1b.

Decreased 2-deoxyglucose (2-DOG) uptake is well described in the neutrophils of patients with glycogen storage disease type 1b (GSD 1b). We report a patient with GSD 1b who presented with a normal antenatal and perinatal 2-deoxyglucose uptake that showed a slow regression during the first months of life. These indicate limitations of 2-deoxyglucose uptake in the diagnosis of GSD 1b. While it appears that low uptake rate below 0.25 nmol/min in 10(6) cells is of significance, normal uptake does not rule out the presence of the disease. It seems that antenatal diagnosis of GSD 1b cannot be made by measurement of 2-deoxyglucose uptake in the fetal neutrophils.

Aging↗
PubMed1993

Deficient glucose phosphorylation as a possible common denominator and its relation to abnormal leucocyte function, in glycogen storage disease 1b patients.

Patients with glycogen storage disease (GSD) 1b suffer from recurrent bacterial infections related to neutropenia and impairment of neutrophil functions. One of these functions is the oxidative burst activity which is initiated by NADPH oxidase and depends on the availability of glucose. This activity was markedly reduced in the patient's intact neutrophils when either N-formyl-methionyl-leucyl-phenylalanine (fMLP), or phorbol myristate acetate were used as stimulants. In disrupted GSD 1b polymorphonuclear leucocytes (PMNs), in the presence of exogenous NADPH, this activity was within the normal range. Degranulation, which is calcium dependent but glucose independent, was not significantly different in neutrophils from the patients as compared to controls. Resting cytosolic calcium concentration was indistinguishable from controls. Activation with 10(-7) M fMLP, in the presence or absence of glucose, triggered a prompt and rapid elevation of cytosolic calcium both in the control and the patients' cells. We have previously shown that hexose monophosphate (HMP) shunt activity and glycolytic rate were found to be lower by 70% in intact PMN cells of the patients compared with controls. These activities were normal in disrupted neutrophils. The uptake of the non-metabolized glucose analogues 2-deoxyglucose (2-DOG) and 3-O-Methylglucose (3-OMG) into PMN of GSD 1b patients was studied. 2-DOG is phosphorylated within the cells, thus its uptake rate reflects hexose transport at low concentrations, as long as phosphorylation is not rate limiting. Under those conditions (5 microM 2-DOG) transport was found to be similar to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

3-O-Methylglucose↗
PubMed1991

Fructose-1,6-diphosphatase deficiency in Israel.

The clinical and biochemical data on nine patients belonging to six families with fructose-1,6-diphosphatase deficiency are reported. Two of the six families were Jewish, three were Moslem Arabs and one was of Druze origin. All patients had had neonatal hypoglycemia, lactic acidosis and an abnormal fructose or glycerol loading test. At a later age, instances of hypoglycemia occurred in patients both with and without preceding illness. Hypoglycemic attacks were associated with severe hyperuricemia and metabolic acidosis. Therapeutic measures included a restriction in fructose intake and avoidance of prolonged fasting, particularly during febrile episodes.

Consanguinity↗
PubMed1990

The long-term outcome of patients with glycogen storage diseases.

In this retrospective study from five centres, 139 patients over 10 years of age with glycogen storage disease types I, III, VI and IX are described. Almost half of the patients with glycogen storage disease type Ia had retarded growth and most had hyperlipidaemia. One-third of the patients had adenomas, although none of these showed malignant transformations. With increasing age the growth, liver size and hyperlipidaemia of patients with glycogen storage disease type III improve. However, there was a high incidence of myopathy and cardiomyopathy. Patients with glycogen storage disease types VI and IX had a normal growth pattern after childhood. Hepatomegaly and hypercholesterolaemia, however, were still present in half of the patients.

Child↗
PubMed1990

Muscle glycogenosis.

This review describes clinical, biochemical and genetic features of the four inborn errors affecting muscle glycogen breakdown, namely deficiencies of phosphorylase, phosphorylase kinase, amylo-1,6-glucosidase and acid alpha-glucosidase. They are characterized by a wide spectrum of clinical manifestation, affecting age of onset, clinical features, progress of disease and tissue involvement. Biochemically, variability of all four enzyme deficiencies is evident in terms of differences in residual enzyme present in tissues, and in the presence or absence of enzyme protein. Genetic heterogeneity, which has been documented in each of the enzyme deficiencies, manifests itself in terms of the presence, absence, quantity or size of mRNA. In phosphorylase deficiency heterogeneity has also been documented at the DNA level. In acid maltase deficiency nine mutant phenotypes have been described affecting various stages of lysosomal enzyme processing.

DNA↗
PubMed1990

Hexose uptake and transport in polymorphonuclear leukocytes from patients with glycogen storage disease Ib.

Neutrophil functions and glucose metabolism are known to be impaired in glycogen storage disease (GSD) Ib patients. The uptake of nonmetabolizing glucose analogues into polymorphonuclear leukocytes (PMN) of GSD Ib patients was studied. 2-Deoxyglucose (2-DOG) and 3-O-methylglucose are transported across the cell membrane by facilitated diffusion mediated by the glucose transporter. Because 2-DOG is phosphorylated within the cell, its uptake rate reflects hexose transport as long as phosphorylation is not rate-limiting. These conditions prevail only at low 2-DOG concentrations. Transport of 5 microM DOG into GSD Ib patient PMN was found to be similar to controls (4.3 +/- 0.5 and 4.65 +/- 1.77 pmol/min X 10(6), respectively). In contrast, 2-DOG uptake at high concentrations (2 mM) decreased by 70% in patient PMN compared with control cells (0.17 +/- 0.06 and 0.51 +/- 0.11 nmol/min X 10(6), for patients and controls, respectively). Transport of 3-O-methylglucose (a glucose analogue that does not undergo intracellular phosphorylation) was not different in patient PMN compared with controls (1.86 +/- 0.53 and 2.19 +/- 0.30 nmol/min X 10(6), respectively). Hexose monophosphate shunt activity in PMN of GSD Ib patients at a glucose concentration of 2 mM was 43% of control values, whereas at 10 microM it was similar to controls. Taken together, these results suggest that the defect in glucose uptake and metabolism found in GSD Ib patient PMN is due to an impairment in hexose phosphorylation rather than in a reduction in the transmembrane glucose transport activity.

3-O-Methylglucose↗
PubMed1989

Cardiac involvement in glycogen storage disease type III.

Twenty patients with enzymatically proven glycogen storage disease type III (GSD III) aged 3-30 years underwent cardiological evaluation. Seventeen showed subclinical evidence of cardiac involvement in form of ventricular hypertrophy on ECG. Of 16 patients in whom an ECG examination was performed, 13 had abnormal echocardiographic features. Only 2 patients had cardiomegaly on X-ray. The cardiac findings in 1 of the patients, a 25-year-old female with clinically evident cardiomyopathy are described in detail. In view of our findings, patients with established GSD III, should not only be investigated regarding their muscular involvement, but should also undergo a detailed evaluation of their cardiac status.

Adolescent↗