Mevalonic aciduria is a rare autosomal recessive metabolic disorder, characterized by psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. The disorder is caused by a deficient activity of mevalonate kinase due to mutations in the encoding gene. Thus far, only two disease-causing mutations have been identified. We now report four different missense mutations including three novel ones, which were identified by sequence analysis of mevalonate kinase cDNA from three mevalonic aciduria patients. All mutations affect conserved amino acids. Heterologous expression of the corresponding mutant mevalonate kinases as fusion proteins with glutathione S -transferase in Escherichia coli showed a profound effect of each of the mutations on enzyme activity. In addition, immunoblot analysis of fibroblast lysates from patients using specific antibodies against mevalonate kinase identified virtually no protein. These results demonstrate that the mutations affect not only the activity but also the stability of the mutant proteins.
Objective -To assess whether physical growth is affected in early treated Dutch patients with phenylketonuria (PKU). Methods -The birth weights of all 137 early detected patients with PKU born in the period from 1974 to 1988 in the Netherlands were compared with reference values. Height, head circumference, and weight were measured at the age at which treatment started (commonly about 2-3 weeks), at 6 months of age, and yearly from the child's first birthday up to the age of 10 years. These measurements were compared with reference values. Results -The adjusted birth weight in patients with PKU was 141 g (95% confidence interval (CI) 66 to 216 g) less than Dutch reference values by Kloosterman and 103 g (95% CI 9 to 196 g) less compared with the birth weight ofanother reference group. At the age at which treatment started, z scores of patients for height by age were -0-23 (95% CI -0 44 to -0.02) and z scores for head circumference by age were -0 25 (95% CI -0 44 to -0.06). From the age at which treatment started up to the age of 3 years z scores for height by age further decreased to -0 74 (95% confidence interval -0 93 to -0.56), after which no additional decrease occurred. In contrast, z scores for head circumference increased from -0 25 at the first visit to 0-08 (95% CI -0-14 to 0.30) at the age of 1 year, after which they remained close to zero. Weight by height was close to the expected centiles for all ages. Conclusion -Patients with PKU are growth retarded at birth and have smaller head circumferences than the normal population. In Dutch patients further growth retardation occurs in the first three years of life.
The G985A mutation represents about 90% of all medium-chain acyl-CoA dehydrogenase (MCAD) allele mutations that cause the clinical symptoms of MCAD deficiency. The prevalence of carriers varies between different European populations, with high frequencies in the northwestern part of Europe. To determine the prevalence of MCAD carriers with the G985A mutation in The Netherlands, we collected 6195 Guthrie cards of newborns. Mutation detection was performed with the polymerase chain reaction (PCR), in which a NcoI restriction site was created in the presence of a G985A mutation in the PCR product, followed by NcoI digestion, and gel electrophoresis. We detected a G985A carrier frequency of 1 in 59 (95% CI 1/50-1/73) in The Netherlands. The total prevalence of carriers was estimated to be 1 in 55 (95% CI 1/46- 1/68), based on a relative G985A frequency of 94% in The Netherlands.
Five patients with a combined deficiency of xanthine dehydrogenase, sulphite oxidase and, possibly, also of aldehyde oxidase are described. This remarkable coincidence of three inborn errors of metabolism in a single individual was demonstrated to result from a deficiency of the 'molybdenum cofactor', an essential constituent of all three enzymes. The main biochemical findings in these patients included: hypouricaemia, xanthinuria, an increased excretion of sulphite, thiosulphate and S-SUL-sulphocysteine and a decreased excretion of inorganic sulphate. Plasma molybdenum was normal. The ultimate diagnosis was made by the measurement of 'molybdenum cofactor' in a liver biopsy specimen in three out of five patients. The clinical hallmarks in these patients were: feeding difficulties, mental retardation, neurological symptoms, lens dislocation, an abnormal muscle tone, myoclonia and an abnormal physiognomy. The majority of these were already present in the neonatal period. So far, attempts at treatment have been unsuccessful.
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