Mevalonic aciduria

The educational role fulfilled by active participation in EQA is demonstrable. Redistribution of the same sample following a gap of several years indicated a detection rate that improved by 20% for mevalonic aciduria, L-2-hydroxyglutaric aciduria, Canavan disease, 4-hydroxybutyric aciduria and long-chain hyroxy-acyl CoA dehydrogenase deficiency [6]. These results probably reflect the fact that many participants encounter rarer conditions for the first time as a member of an EQA scheme. Stored residual samples from such EQA schemes and unlabelled chromatograms can also be used as a valuable training aid or even a competency test for analysts. 

Fig. 5.1.1 Isoprenoid biosynthetic pathway. The enzyme mevalonate kinase (black solid bar) is deficient in patients affected with mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. -CoA -Coenzyme A, HMG-CoA 3-hydroxy-3-methyl-glutaryl-coenzyme A, -PP -pyrophosphate...

Table 5.1.1 Inherited disorders of isoprenoid/cholesterol biosynthesis. CDPX2 Conradi-Hunermann syndrome, CHILD congenital hemidysplasia with ichthyosiform nevus and limb defects, HEM hydrops-ectopic calcification-moth-eaten, MA/HIDS mevalonic aciduria/ hyperimmunoglobulinemia D and periodic fever syndrome, MIM Mendelian Inheritance in Man... 

Hoffmann GF, Sweetman L, et al. (1991) Facts and artefacts in mevalonic aciduria development of a stable isotope dilution GCMS assay for mevalonic acid and its application to physiological fluids, tissue samples, prenatal diagnosis and carrier detection. Clin Chim Acta 198 209-227... 

Hoffmann GF, Brendel SU, et al. (1992) Mevalonate kinase assay using DEAE-cellulose column chromatography for first-trimester prenatal diagnosis and complementation analysis in mevalonic aciduria. J Inherit Metab Dis 15 738-746... 

In animals all isoprenoid compounds are apparently synthesized from mevalonate, which is converted by the consecutive action of two kinases21 23 into mevalonate 5-diphosphate (Fig. 22-1, step b). Mevalonate kinase is found predominantly in peroxisomes, which are also active in other aspects of steroid synthesis in humans.2124 A deficiency of this enzyme is associated with mevalonic aciduria, a serious hereditary disease in which both blood and urine contain very high concentrations of mevalonate.23 Mevalonate diphosphate kinase, which is also a decarboxylase, catalyzes phosphorylation of the 3-OH group of mevalonate (step c, Fig. 22-1) and decarboxylative elimination of phosphate (step d)25 to form isopentenyl diphosphate. 

Patients with severe forms of inherited mevalonate kinase deficiencies exhibit mevalonic aciduria, failure to thrive, developmental delay, anemia, hepatosplenomegaly, gastroenteropathy, and dysmorphic features during neonatal development. These clinical manifestations underscore the importance of the formation of isoprenyl... 

The first recognized human metabolic defect in the biosynthesis of cholesterol and isoprenoids was mevalonic aciduria [10]. Mevalonic aciduria is an autosomal recessive disorder that is quite rare, with only 30 known patients (D. Haas, 2006). In normal individuals, a small amount of mevalonic acid diffuses from cells into the plasma at levels proportional to the rate of cellular cholesterol formation. Patients with the severe, classical form of mevalonic aciduria excrete 10,000-200,000 times the normal amount of mevalonic acid because they have severely reduced amounts of mevalonate kinase activity. Their clinical features include failure to thrive, anemia, gastroenteropathy, hepatosplenomegaly, psychomotor retardation, hypotonia, ataxia, cataracts, and dysmorphic features [10]. Surprisingly, patients with severe deficiencies in mevalonate kinase show normal plasma cholesterol levels and cultured mevalonic aciduria fibroblasts have a rate of cholesterol synthesis that is half that of normal cells. Close examination of cholesterogenic enzymes in mevalonic aciduria fibroblasts has revealed a 6-fold increase in HMG-CoA reductase activity, which is postulated to compensate for the low mevalonate kinase activity. Thus, mevalonate is overproduced. 

Methylglutaconic aciduria, other types Mevalonic aciduria... 

Cholesterol 4 3-Methylglutaconic acidurai, other types Mevalonic aciduria Abetalipoproteinemia Hypobetalipoproteinemia 3 -Hydroxy-A -C27-steroid dehydrogenase (3/ -HSDH) def 3reductase def (5 -reductase def) Smith-Lemli-Opilz syndrome Barth syndrome Glucosyltransferase I def CDG-Ic... 

Mevalonate kinase deficiency Mevalonic aciduria Hyper IgD syndrome All tissues I2q24.1 251170... 

Fig. 30.2. Diagnostic flow chart for mevalonic aciduria. FTTy failure-to-thrive MVK, mevalonate kinase...

Hoffmann GF, Gibson KM, Brandt IK, Bader PI, Wappner RS, Sweetman L. Mevalonic aciduria - an inborn error of cholesterol and non-sterol isoprene biosynthesis. New Eng J Med 1986 314 1610. 

Hoffmann GF, Charpentier C, Mayatepek E, Mancini J, Leichsenring M, Gibson KM, Divry P, Hrebicek M, Lehnert W, Sartor K, et al. Clinical and biochemical phenotype in 11 patients with mevalonic aciduria. Pediatrics 1993 91(5) 915. 

In disorders which affect cholesterol synthesis (e.g, mevalonic aciduria, 7-dehydrocholesterol reductase deficiency [Smith-Lemli-Opitz syndrome]) there may be markedly reduced bile acid synthesis - these disorders are beyond the scope of his chapter. As indicated in section 3, the synthesis of bile acids involves conversion of C27 bile acids (cholestanoic acids) to their C24 analogues (cholanic acids) and this occurs by a process of )5-oxidation in the peroxisomes. Thus defective bile acid synthesis occurs in disorders of peroxisomal yff-oxidation and in disorders of peroxisome biogenesis. These disorders affect pathways other than the bile acid synthesis pathway and are discussed in Chap. 23. 

---