dolichols and Metabolism--Inborn-Errors

Patients with mevalonate kinase deficiency suffer from psychomotor retardation, ataxia with progredient cerebellar atrophy, and myopathy. The pathophysiology of the disease remains unclear. The mevalonate kinase product, cholesterol, is within the normal range in patient plasma and fibroblasts. In search of the pathophysiology of this disorder, another mevalonate kinase product, ubiquinone-10, was studied. The concentrations of ubiquinone-10 in patient plasma (n = 6) and ubiquinol-10 in patient LDL (n = 2) and the synthesis of ubiquinone-10 in patient fibroblasts (n = 4) were determined. After oxidative modification of LDL by copper in vitro, the concentrations of alpha-tocopherol and polyunsaturated fatty acids in LDL and the relative electrophoretic mobility of LDL were measured to determine the antioxidant capacity of LDL samples of two affected siblings. The ubiquinone-10 concentrations in plasma samples (median = 508 micrograms/L, range = 488-642 micrograms/L) versus controls (median = 613 micrograms/L, range = 564-809 micrograms/L; p < 0.005) were decreased. In LDL samples of two affected siblings, the concentration of ubiquinol-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 conclude that mevalonate kinase deficiency leads to a decreased synthesis of ubiquinone-10 and that ubiquinone-10 deficiency is responsible for the clinical progression of this disease characterized by increased lipid peroxidation, cerebellar atrophy, cataract development, and myopathy with increased creatine kinase activity.

Topics: Cells, Cultured; Child; Child, Preschool; Creatine Kinase; Dolichols; Female; Fibroblasts; Humans; Infant; Lipoproteins, LDL; Male; Metabolism, Inborn Errors; Mevalonic Acid; Oxidation-Reduction; Phosphotransferases (Alcohol Group Acceptor); Ubiquinone; Vitamin E

Slightly elevated serum dolichol levels have so far been demonstrated only in alcoholics. We now report two diseases with exceptionally high serum dolichol levels. They are autosomal, recessively inherited lysosomal storage diseases, aspartylglucosaminuria (AGU) and mannosidosis. In 16 patients with AGU the mean serum level of total dolichols (457 +/- 43 ng/ml) was more than two-fold when compared to healthy controls (170 +/- 4 ng/ml). In two patients with mannosidosis the levels were almost two-fold. The percentage distribution of the dolichol homologues with 18, 19 or 20 isoprene units did not differ between the patients and controls. The inclusion of an additional control group excluded the possible influence of mental retardation and imparied moving ability on the results. Elevated serum dolichols in patients with lysosomal storage diseases may reflect a disturbance in lysosomal function and serve as a diagnostic marker. The biochemical mechanisms leading to this phenomenon remain to be established.

Topics: Acetylglucosamine; Adult; alpha-Mannosidosis; Dolichols; Female; Glucosamine; Humans; Male; Metabolism, Inborn Errors; Middle Aged

The Hermansky-Pudlak syndrome, a triad of albinism, platelets lacking dense bodies, and storage of ceroid-like material in tissues, occurs approximately once in 2,000 northwestern Puerto Ricans. The manifestations of storage disease are variable and include granulomatous colitis, restrictive lung disease, kidney failure, and cardiomyopathy. The autofluorescent material stored in the Hermansky-Pudlak syndrome is histochemically similar to that stored in neuronal ceroid/lipofuscinosis. The material in neuronal ceroid/lipofuscinosis contains dolichols, which are components of lysosomes, and patients show increased urinary excretion of dolichols. This study of 49 patients with the Hermansky-Pudlak syndrome found that urinary dolichol levels are increased in those patients with evidence of ceroid storage in the kidneys but are not elevated when storage occurs in tissues other than the kidneys. The excretion of ceroid was not influenced by the saturation state of dietary fat. A defect in processing of membranes of lysosomes, melanosomes, and dense bodies may be involved in the syndrome.

Topics: Albinism; Bone Marrow Diseases; Ceroid; Diterpenes; Dolichols; Hemorrhagic Disorders; Humans; Lipofuscin; Lysosomes; Macrophages; Metabolism, Inborn Errors; Syndrome; von Willebrand Diseases