Abstract
Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS.
Highlights
Mevalonic aciduria (MVA) is an autosomal recessively inherited disorder caused by deficiency of mevalonate kinase (MVK; E.C. 2.7.1.36; ATP:(R)-mevalonate 5-phosphotransferase) and identified as the first defect in cholesterol biosynthesis (Figure 1) by Hoffmann et al in 1986 [1]
Mutations in the MVK gene and reduced activity of MVK have been identified as underlying cause of both MVA and hyperimmunoglobulinemia D syndrome (HIDS) syndrome
MVA is caused by homozygosity or compound heterozygosity for disease-causing mutations in the MVK gene, which has been localized to chromosome 12q24 [2]
Summary
MVA is an autosomal recessively inherited disorder caused by deficiency of mevalonate kinase (MVK; E.C. 2.7.1.36; ATP:(R)-mevalonate 5-phosphotransferase) and identified as the first defect in cholesterol biosynthesis (Figure 1) by Hoffmann et al in 1986 [1]. Mutations in the MVK gene and reduced activity of MVK have been identified as underlying cause of both MVA and HIDS syndrome. Orphanet Journal of Rare Diseases 2006, 1:13 http://www.OJRD.com/content/1/1/13 patients might suggest chromosomal aberrations or congenital infections. When hematological abnormalities such as anemia, leukocytosis, thrombocytopenia and abnormal blood cell forms predominate, myelodysplastic syndromes may be suspected. The diagnosis of MVA should be suspected in patients with mild dysmorphic features, progressive cerebellar ataxia, psychomotor retardation, failure to thrive, hepatosplenomegaly and recurrent febrile episodes. The diagnosis is confirmed by demonstration of deficient MVK enzyme activity or by identification of two disease-causing mutations in the MVK gene
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