DECREASED PLASMA UBIQUINONE-10 CONCENTRATION IN PATIENTS WITH MEVALONATE KINASE-DEFICIENCY

Patients with mevalonate kinase deficiency suffer from psychomotor ret ardation, ataxia with progredient cerebellar atrophy, and myopathy. Th e pathophysiology of the disease remains unclear. The mevalonate kinas e product, cholesterol, is within the normal range in patient plasma a nd fibroblasts. In search of the pathophysiology of this disorder, ano ther mevalonate kinase product, ubiquinone-10, was studied. The concen trations of ubiquinone-10 in patient plasma (n = 6) and ubiquinol-10 i n patient LDL (n = 2) and the synthesis of ubiquinone-10 in patient fi broblasts (n = 4) were determined. After oxidative modification of LDL by copper in vitro, the concentrations of alpha-tocopherol and polyun saturated fatty acids in LDL and the relative electrophoretic mobility of LDL were measured to determine the antioxidant capacity of LDL sam ples of two affected siblings. The ubiquinone-10 concentrations in pla sma samples (median = 508 mug/L, range = 488-642 mug/L) versus control s (median = 613 mug/L, range = 564-809 mug/L; p < 0.005) were decrease d. In LDL samples of two affected siblings, the concentration of ubiqu inol-10 and the resistance to oxidation in vitro were found decreased during intercurrent patient crisis condition. In patient fibroblasts ( median = 533 dpm/mg protein, range = 399-1 047 dpm/mg protein) versus controls (median = 40 731 dpm/mg protein, range = 12 774-54 739 dpm/mg protein), the synthesis of ubiquinone was found to be decreased. We c onclude that mevalonate kinase deficiency leads to a decreased synthes is of ubiquinone-10 and that ubiquinone-10 deficiency is responsible f or the clinical progression of this disease characterized by increased lipid peroxidation, cerebellar atrophy, cataract development, and myo pathy with increased creatine kinase activity.