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ABBREVIATIONS. SSADH, succinic semialdehyde dehydrogenase; GABA, y-aminobutyric acid; MRI, magnetic resonance imaging; EEG, electroencephalogram; CT, computed tomography; EMG, electromyography. Succinic semialdehyde dehydrogenase (SSADH, EC 1.2.1.24) deficiency (4-hydroxybutyric aciduria, McKusick 271980) [...]

The symptoms, behavior and treatment of 11 children with mevalonic aciduria are discussed. Mevalonic aciduria is a metabolic disorder caused by reduced levels of the enzyme mevalonate kinase. All of the children had varying degrees of mental retardation as well as failure to grow. They suffered from repeated bouts of fever, vomiting and diarrhea. Four died during the first few years of life. All of the children had reduced mevalonate kinase activity and elevated levels of mevalonic acid in their blood. However, their blood levels of cholesterol and other fats were normal or slightly reduced. Magnetic resonance imaging (MRI) revealed atrophy of the brain in 10 of the children. Treatment with cholesterol appeared to have little effect. Treatment with the drug lovastatin, which blocks the formation of mevalonic acid, caused a severe reaction in two children. This crisis resolved when they were treated with corticosteroids, which also seemed to reduce the symptoms of mevalonic aciduria., 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, gastroenterology, cardiology, and genetics. Pediatrics 1993; 91:915-921; mevalonic aciduria, enzyme deficiency, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, rhabdomyolysis, cerebellar atrophy, ubiquinone-10, leukotriene [E.sub.4].

Abstract Background Despite its first description over 40 years ago, knowledge of the clinical course of isovaleric acidemia (IVA), a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation. Methods Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality. Results 57% of study patients (12/21) were diagnosed within the first weeks of life and 43% (9/21) in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44% of investigated study patients (7/16) showed mild motor dysfunction and only 19% (3/16) had cognitive deficits. No other organ complications were found. The patients' intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days. Conclusions Within the group of "classical" organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening.

Studies the identification of four mutations in the short-chain acyl-CoA dehydrogenase gene in two patients. Elevation of urinary excretion of ethylmalonic acid; Lack of enzyme activity after expression in COS-7 cells.