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WAS is a severe, X-linked disorder, characterized by eczema, immunodeficiency and an increased bleeding tendency caused by thrombocytopenia and platelet malfunction. There is a diminished epinephrine-induced aggregation response and an abnormal mitochondrial CO2 production during platelet activation. From this, Shapiro et al (The Lancet 1978) concluded that WAS-platelets have a defect in mitochondrial ATP regeneration, which could be employed for detection of WAS- carriers, who are clinically normal and have only minor platelet defects. The test consists of an epinephrine-induced aggregation in the presence of an inhibitor of glycolytic ATP production (deoxyglucose, 2 DG), and showed impaired second wave aggregation in obligate carriers but not in normal controls. We tested 4 unrelated obligate WAS-carriers and found impaired aggregations in all. Five out of 7 female relatives also showed aggregation abnormalities, suggestive for WAS-carriership. However, in 8 out of 15 normal controls (males and females) the test was also positive. The nature of a possible defect in mitochondrial ATP supply was further studied in gel-filtered platelets by analyzing the metabolic ATP level before and during epinephrine-induced aggregation in the presence of inhibitors of glycolysis and glycogenoly- sis and during incubation in substrate-depleted medium. These studies showed that mitochondrial energy generation depended on sugar supply either from glycolysis or glycoge- nolysis and was unable to maintain a normal metabolic ATP level when these pathways were inhibited. Incubation with 2DG led to a fall in metabolic ATP and - consequently - to an impaired epinephrine-induced aggregation. The fall of metabolic ATP (2DG present) was much steeper in platelets from 2 unrelated WAS-patients than in cells from normal controls; most (but not all) obligate carriers showed intermediate values. It is concluded that the impaired epinephrine-induced aggregation in the presence of 2DG in WAS reflects disturbances in ATP homeostasis, which are consistent with a mitochondrial defect.

The Wiskott-Aldrich Syndrome (WAS): Studies On A Possible Defect In Mitochondrial ATP Regeneration In Platelets