CLINICAL AND BIOCHEMICAL PHENOTYPE IN 11 PATIENTS WITH MEVALONIC ACIDURIA

Objective. Mevalonic aciduria is a consequence of the deficiency of me valonate kinase, the first enzyme after 3-hydroxy-3-methylglutaryl-coe nzyme A reductase in the biosynthesis of cholesterol and nonsterol iso prenes. To establish the clinical and biochemical phenotype of mevalon ic aciduria, the authors assembled their experience with 11 patients i ncluding attempts at therapeutic interventions. Methods. Mevalonic aci d in body fluids was determined by stable isotope dilution gas chromat ography/mass spectroscopy with selected ion monitoring, ubiquinone-10 concentrations by reversed-phase high-pressure liquid chromatography. Results. Varying degrees of severity of clinical illness were observed despite uniform, virtual absence of residual activity of the enzyme. The most severely affected patients have had profound developmental de lay, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopat hy, and anemia, as well as diarrhea and malabsorption, and have died i n infancy. Less severely affected patients have had psychomotor retard ation, hypotonia, myopathy, and ataxia. All patients have had recurren t crises in which there was fever, lymphadenopathy, increase in size o f liver and spleen, arthralgia, edema, and a morbilliform rash. Neuroi maging studies revealed selective and progressive atrophy of the cereb ellum. Mevalonic acid concentrations were found to be grossly elevated in body fluids of all patients. Concentrations of plasma cholesterol were normal or only slightly reduced. Concentrations of ubiquinone-10 in plasma were found to be decreased in most patients. Abnormalities s uch as hypoglycemia, metabolic acidosis, or lactic acidemia, the usual concomitants of disorders of organic acid metabolism, were conspicuou sly absent. Conclusions. These observations establish the broad range of clinical symptoms and biochemical findings in mevalonic aciduria. I t is concluded that although patients with mevalonic aciduria have a r ecognizable phenotype of serious clinical manifestations, some patient s are likely to remain undiagnosed and may be found in a variety of su bspeciality clinics, including neurology, gastroenterology, cardiology , and genetics.