Mevalonic Aciduria

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A number sign (#) is used with this entry because mevalonic aciduria (MEVA) is caused by homozygous or compound heterozygous mutation in the mevalonate kinase gene (MVK; 251170) on chromosome 12q24.

Description

Mevalonic aciduria, the first recognized defect in the biosynthesis of cholesterol and isoprenoids, is a consequence of a deficiency of mevalonate kinase (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36). Mevalonic acid accumulates because of failure of conversion to 5-phosphomevalonic acid, which is catalyzed by mevalonate kinase. Mevalonic acid is synthesized from 3-hydroxy-3-methylglutaryl-CoA, a reaction catalyzed by HMG-CoA reductase (142910).

Mevalonic aciduria is characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and to periodic fever syndrome (HIDS; 260920), which is also caused by mutation in the MVK gene (summary by Prietsch et al., 2003).

Clinical Features

Hoffmann et al. (1986) delineated this inborn error of metabolism in a boy who came to their attention at age 2 years and in an unborn female sib. The boy presented with severe failure to thrive, developmental delay, anemia, hepatosplenomegaly, central cataracts, and dysmorphic facies. In the urine, they found massive quantities of mevalonic acid, a precursor of cholesterol and nonsterol isoprenes: 46,000 and 56,200 mmol per mole of creatinine, as compared with 0.2-0.3 mmol per mole in normal children. In plasma, the concentration of mevalonic acid was about 9,000 times normal. The activity of mevalonate kinase, the enzyme that catalyzes the first step in mevalonate metabolism, was severely deficient in the patient's fibroblasts, lymphocytes, and lymphoblasts, and was about half-normal in each parent. The proband died at 24.5 months. In the mother's next pregnancy, the concentration of mevalonic acid was found to be very high in the amniotic fluid. A therapeutic abortion was performed at 19 weeks. The fetus was female and seemingly normal. Defects in synthetic pathways such as this are fewer than defects in catabolic pathways. As in the porphyrias and in glutathione synthetase deficiency (266130), feedback inhibition is lacking because the final product is underproduced. This leads to overproduction and massive urinary excretion of intermediates such as delta-aminolevulinic acid and porphyrins in porphyrias and 5-oxoproline in glutathione synthetase deficiency. The failure to thrive may have been due to loss of almost 9 grams daily of mevalonic acid in the urine.

Berger et al. (1985) described a milder case of mevalonic aciduria, with cerebellar ataxia. In the family first reported by Hoffmann et al. (1986), Gibson et al. (1987) found enzyme levels indicating heterozygosity in 1 sib of the proband, both parents, and 3 other relatives of each of the parents. Gibson et al. (1988) documented mevalonate kinase deficiency in an 8-year-old child who presented with cerebellar ataxia, hypotonia, and mevalonic aciduria. Heterozygotes showed intermediate levels of the enzyme in cultured skin fibroblasts and transformed lymphoblasts. Mancini et al. (1993) described the disorder in 2 girls and 1 boy, the offspring of parents related as first cousins once removed. All 3 showed failure to thrive, susceptibility to infections, hepatosplenomegaly, cataract, and psychomotor retardation. Dysmorphic features included microcephaly, triangular face, and hypoplastic alae nasi. Urinary organic acid analysis by gas chromatography/mass spectrometry invariably demonstrated a high urinary excretion of mevalonic acid. Mevalonate kinase activity assayed in fibroblasts was very low.

To establish the clinical and biochemical phenotype of mevalonic aciduria, a consortium of authors (Hoffmann et al., 1993) assembled their experience with 11 patients, including attempts at therapeutic intervention. Varying degrees of severity of clinical illness were observed despite uniform, virtual absence of residual activity of mevalonate kinase. The most severely affected patients had profound developmental delay, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, and anemia, as well as diarrhea and malabsorption, and died in infancy. Less severely affected patients had psychomotor retardation, hypotonia, myopathy, and ataxia. All patients 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 grossly elevated in body fluids in 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.

Hinson et al. (1998) reported 2 additional patients with MVK deficiency. Both patients presented in infancy, one with severe normocytic anemia, petechiae, cutaneous extramedullary hematopoiesis, hepatosplenomegaly, leukocytosis, and recurrent febrile episodes, and the other with minor anomalies, hepatosplenomegaly, anemia, thrombocytopenia, recurrent febrile crises, and facial rashes. Neither patient had significant neurologic abnormalities. The authors noted that MVK deficiency can mimic congenital infections, myelodysplastic syndromes, or chronic leukemia, and emphasized the importance of considering this diagnosis in patients with hematologic abnormalities.

Prietsch et al. (2003) reported a 15-year-old girl and her 14-year-old brother with mevalonic aciduria, previously described by Hoffmann et al. (1993), in whom the phenotype shifted with age, with ataxia becoming the predominant clinical manifestation and febrile attacks occurring less frequently as they grew older. Both sibs showed marked elevations of immunoglobulin D (IgD) and also exhibited short stature, kyphoscoliosis, obesity, and delayed psychomotor development. Additional findings included the development of nuclear cataract and retinal dystrophy in both patients; electroretinography in the brother showed undetectable scotopic and photopic responses. Prietsch et al. (2003) also described a 6-year-old boy whose mevalonic aciduria was discovered on metabolic screening at 5.5 years of age due to mild psychomotor retardation and general 'clumsiness.' He never underwent febrile crises and his IgD levels were repeatedly normal. MRI showed severe cerebellar atrophy, consistent with his predominant symptom of moderate cerebellar ataxia. Ophthalmologic examination showed retinal dystrophy with field constriction and lack of dark adaptation, primarily in the retinal periphery, as well as thinned retinal vessels, uneven retinal surface reflections, and moderate optic atrophy, but no bone-spicule pigmentation. Prietsch et al. (2003) stated that this was the first report of adolescent MEVA patients, and that in patients who survive infancy, the predominant findings include short stature, ataxia caused by cerebellar atrophy, and ocular involvement with retinal dystrophy. They noted that recurrent febrile crises seem to diminish with increasing age and might not be an obligatory finding, and they suggested that IgD elevation might be a secondary phenomenon linked to recurrent febrile crises.

Mandey et al. (2006) reviewed aspects of mevalonate kinase deficiency (MKD), of which classic mevalonic aciduria and the autoinflammatory hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; 260920) represent the severe and mild clinical ends of the spectrum. Patients with the HIDS phenotype typically present only with recurrent episodes of fever and associated inflammatory symptoms, whereas patients with mevalonic aciduria show, in addition to these episodes, developmental delay, dysmorphic features, ataxia, cerebellar atrophy, and psychomotor retardation and may die in early childhood (Hoffmann et al., 1993). Cells from patients with the HIDS phenotype still contain residual mevalonate kinase enzyme activities from 1 to 8% of the activities of control cells, while in cells from patients with the mevalonic aciduria phenotype the enzyme activity is below the level of detection. This difference in residual enzyme activity is also reflected in the occurrence of high levels of mevalonic acid in plasma, urine, and tissues of patients with the mevalonic aciduria phenotype and low to moderately increased levels of mevalonic acid in patients with the HIDS presentation.

Molecular Genetics

For a complete discussion of the molecular genetics of mevalonic aciduria and other manifestations of mevalonate kinase deficiency, see the entry for the mevalonate kinase gene (MVK; 251170).

In 2 adolescent sibs with mevalonic aciduria, in whom symptomatology had gradually shifted from febrile crises to ataxia, and who also exhibited nuclear cataract and retinal dystrophy, Prietsch et al. (2003) identified homozygosity for a missense mutation in the MVK gene (A334T; 251170.0006). In a 6-year-old boy with mevalonic aciduria, who had cerebellar ataxia but no febrile crises or elevated IgD, and who also showed retinal dystrophy, Prietsch et al. (2003) identified compound heterozygosity for the A334T mutation and a 1-bp insertion (251170.0016).