Mevalonate Kinase Deficiency (MKD)
Mevalonic aciduria (MVA)
Hyperimmunoglobulinemia D syndrome (HIDS)
Mevalonate Kinase Deficiency (MKD) is an autosomal recessive inherited disorder caused by deficiency of the enzyme mevalonate kinase (ATP: mevalonate 5-phosphotransferase) causing a defect in cholesterol biosynthesis. This deficiency can lead to one of two ends of a clinical spectrum: mevalonic aciduria (MVA) and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS).
Mutations in the MVK gene which lead to reduced activity of MVK are the underlying cause of both MVA and HIDS.
MVA is caused by homozygous or compound heterozygous disease-causing mutations in the MVK gene, localized to chromosome 12q24. MVA is characterized biochemically by accumulation of mevalonic acid and its metabolites such as mevalonolactone. Most patients with HIDS are compound heterozygotes for missense mutations in the MVK gene. In HIDS patients, MVK may have a residual activity of 5-15%. In contrast, no residual activity is present in MVA patients.
Patients severely affected with MVA present from birth with congenital malformations (microcephaly, dolicocephaly and wide irregular fontanels, low set posteriorly rotated ears, downslanting palpebral fissures, blue sclerae, and central cataracts). Cholestatic liver disease may be present.
Cardinal manifestations from late infancy include mild to severe intellectual disability, recurrent crises of fever, vomiting and diarrhea, failure to thrive, hypotonia and myopathy. Some hematological abnormalities may include anemia, leukocytosis, and thrombocytopenia.
In childhood, short stature and ataxia due to progressive cerebellar atrophy and ocular involvement with uveitis, cataracts and tapetoretinal degeneration become predominant findings.
Frequent crisis characterized by fever, vomiting and diarrhea are often accompanied by arthralgia, subcutaneous edema and a morbilliform rash. The severity and frequency of attacks may decline over the years.
At the other end of the clinical spectrum, HIDS is characterized by recurrent febrile attacks that usually begin before the end of the first year of life. The fever may be provoked by vaccination, minor trauma, surgery or stress and is often associated with abdominal pain, vomiting, diarrhea and cervical lymphadenopathy. Other common symptoms include hepatosplenomegaly, headache, arthralgia and rashes. Most patients display no malformations or neurological abnormalities. However, a subgroup of HIDS patients may also develop neurologic abnormalities including intellectual disability, ataxia, ocular symptoms and epilepsy, suggesting that mevalonate kinase deficiency represents a spectrum of disorders rather than two completely distinct clinical syndromes.
The diagnosis of MVA is established by the detection of elevated excretion of mevalonic acid in urine typically detected by urine organic acid analysis in the setting of clinical features of the condition. The diagnosis of MVA can be confirmed by demonstration of deficient MVK enzyme activity and/or by mutation analysis of the MVK gene. Mevalonic acid and metabolite levels in HIDS are often normal especially between episodes, and individuals may have increased immunoglobulins IgD and IgA. The diagnosis of HIDS can be confirmed mutation analysis of the MVK gene as demonstration of deficient MVK enzyme activity is not widely available and may be challenging in HIDS.
Approximately 30 patients have been reported with MVA and approximately 180 with HIDS.
There is no established therapeutic regime for patients with MVA and treatment has been largely supportive. Recently, successful disease modifying liver and hematopoietic stem cell transplantation has been reported in one child with MVA. With regards to HIDS, pharmacologic mediators of inflammation such as Etanercept, Anakinra, and Adalimumab have been increasingly used, apparently with some success, in attempts to treat HIDS.