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

  • Neutrophiles and GSD type Ib
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Abstract

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 (5μM 2-DOG) transport was found to be similar to controls. In contrast 2-DOG uptake at high concentrations (2mM) was reduced by 70% in GSD 1b patients compared with control cells. Transport of 3-OMG was no different in patient PMN compared with controls. These results are compatible with the following hypothesis: as a result of a decreased glucose phosphorylation, metabolic functions which are dpendent on glucose, are deficient in PMNs of GSD 1b patients, while no differences were observed in glucose independent calcium mobilization when measured directly or indirectly in form of degranulation.

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Abbreviations

fMLP:

N-formyl-methionyl-leucyl-phenylalanine

Glc-6-P:

glucose-6-phosphate

Glc-6-P'ase:

glucose-6-phosphatase

GSD:

glycogen storage disease

HMP:

hexose monophosphate

OB:

oxydative burst

PMA:

phorbol myristate acetate

2-DOG:

2-Deoxyglucose

3-OMG:

3-O-methylglucose

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Authors and Affiliations

  1. Paediatric Research Laboratory, Clinical Biochemistry Unit, Soroka Medical Centre of Kupat Holim, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    N. Bashan, R. Potashnik, A. Peist, N. Peleg, A. Moran & S. W. Moses

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  1. N. Bashan
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  2. R. Potashnik
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  3. A. Peist
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  4. N. Peleg
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  5. A. Moran
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  6. S. W. Moses
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Bashan, N., Potashnik, R., Peist, A. et al. Deficient glucose phosphorylation as a possible common denominator and its relation to abnormal leucocyte function, in glycogen storage disease 1b patients. Eur J Pediatr 152 (Suppl 1), 44–48 (1993). https://doi.org/10.1007/BF02072087

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