PEDIATRICS Vol. 91 No. 5 May 1993, pp. 915-921
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Clinical and Biochemical Phenotype in 11 Patients With Mevalonic Aciduria

Georg F. Hoffmann MD1, Christiane Charpentier PhD2, Ertan Mayatepek MD1, Josette Mancini MD3, Michael Leichsenring MD1, K. Michael Gibson PhD4, Priscille Divry PhD5, Martin Hrebicek MD6, Willy Lehnert PhD7, Klaus Sartor MD8, Friedrich K. Trefz MD1, Dietz Rating MD1, Hans J. Bremer MD1, and William L. Nyhan MD, PhD9

1 From the Departments of Pediatrics, University of Heidelberg, FRG
2 From the Departments of Pediatrics, Department of Biochemistry B, Hopital Necker-Enfants Malades, Paris, France
3 From the Departments of Pediatrics, Hopital de la Timone, Marseille, France
4 From the Departments of Pediatrics, Kimberly H. Courtwright and Joseph W. Summers Metabolic Disease Center and Baylor Research Institute, Baylor University Medical Center, Dallas, TX
5 From the Departments of Pediatrics, Department of Biochemistry, Hopital Debrousse, Lyon, France
6 From the Departments of Pediatrics, Charles University, Prague, Czechoslovakia
7 From the Departments of Pediatrics, University of Freiburg, FRG
8 From the Departments of Pediatrics, Department of Neuroradiology, University of Heidelberg
9 From the Departments of Pediatrics, University of California, San Diego

Objective. Mevalonic aciduria is a consequence of the deficiency of mevalonate kinase, the first enzyme after 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the biosynthesis of cholesterol and nonsterol isoprenes. To establish the clinical and biochemical phenotype of mevalonic aciduria, the authors assembled their experience with 11 patients including attempts at therapeutic interventions.

Methods. Mevalonic acid in body fluids was determined by stable isotope dilution gas chromatography/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 delay, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, and anemia, as well as diarrhea and malabsorption, and have died in infancy. Less severely affected patients have had psychomotor retardation, hypotonia, myopathy, and ataxia. All patients have had recurrent crises in which there was fever, lymphadenopathy, increase in size of liver and spleen, arthralgia, edema, and a morbilliform rash. Neuroimaging studies revealed selective and progressive atrophy of the cerebellum. 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 such as hypoglycemia, metabolic acidosis, or lactic acidemia, the usual concomitants of disorders of organic acid metabolism, were conspicuously absent.

Conclusions. These observations establish the broad range of clinical symptoms and biochemical findings in mevalonic aciduria. It is concluded that although patients with mevalonic aciduria have a recognizable phenotype of serious clinical manifestations, some patients are likely to remain undiagnosed and may be found in a variety of subspeciality clinics, including neurology, troenterology, cardiology, and genetics.

Key Words: mevalonic aciduria • enzyme deficiency • 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors • rhabdomyolysis • cerebellar atrophy • ubiquinone-l0 • leukotriene E4

Submitted on August 7, 1992
Accepted on December 2, 1992




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