Mevalonate kinase deficiency (MKD) - MVK gene

Mevalonate kinase deficiency (MKD), also called hyper-IgD syndrome or hyperimmunoglobulin D with periodic fever, is an alteration characterized by recurrent febrile episodes which usually begin in childhood. Each febrile episode lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. These episodes appear to be more frequent in childhood, with the individuals manifesting around 25 episodes a year. However, as the person ages the episodes occur less frequently. This syndrome is characterized by additional signs and symptoms, and the severity varies depending on the type of the disease. Two types of MKD have been described: a less severe type syndrome called hyperimmunoglobulinemia D (HIDS) and a more severe type called mevalonic aciduria (MVA).

During febrile episodes, people with HIDS manifest lymphadenopathy, abdominal pain, joint pain, diarrhea, skin rashes and headaches. Occasionally, aphthous ulcers may develop around the mouth, and in women these ulcers may also appear around the vagina. In addition, a low percentage of people with HIDS manifest intellectual disability, ataxia, eye problems and epilepsy. Rarely, affected individuals develop renal amyloidosis, which can lead to kidney failure. Febrile episodes in individuals with HIDS can be caused by vaccines, surgery, injuries or stress. Most people with HIDS have abnormally high concentrations of immunoglobulin D (IgD) and immunoglobulin A (IgA) in the blood. High concentrations of these immunoglobulins do not appear to cause any signs or symptoms. Usually, individuals with HIDS have a normal life expectancy.

On the other hand, people with MVA manifest signs and symptoms of the disease at all times, not only during febrile episodes. Affected children have developmental delay, progressive ataxia, progressive vision problems and growth retardation. Additional signs and symptoms of MVA may include a small and elongated head, uveitis, blue sclera, and retinitis pigmentosa that cause vision loss and cataracts. In addition, affected adults may have short stature and myopathy. During febrile episodes, people with MVA may have hepatosplenomegaly, lymphadenopathy, abdominal pain, diarrhea and skin rashes. Children with MVA who are very affected, with multiple problems, usually live only during early childhood, while slightly affected individuals may have a normal life expectancy.

This process is due to mutations in the MVK (mevalonate kinase) gene, located on the long arm of chromosome 12 (12q24.11). This gene encodes the enzyme mevalonate kinase, involved in the production of cholesterol, which is later transformed into steroid hormones and bile acids. Steroid hormones are necessary for normal organism development and reproduction, and bile acids are used to digest fats. Mevalonate kinase also helps produce other substances that are necessary for certain cellular functions, such as cell growth and differentiation, cytoskeleton formation, gene expression, and coding and modification of proteins.

At least 80 mutations in the MVK gene have been identified in individuals with MKD. Most MVK gene mutations change amino acids in the enzyme mevalonate kinase, which results in an unstable enzyme folded in an incorrect 3-dimensional form, with reduced function. A mutation that replaces the amino acid valine with the amino acid isoleucine at position 337 in the enzyme (Val337Ile or V337I) is found in approximately 80% of people with HIDS. The V337I mutation has never been found in people with MVA. In general, despite the enzyme deficiency, people with MKD have normal production of cholesterol, steroid hormones and bile acids. Although it is not clear how the deficiency of mevalonate kinase activity results in the signs and symptoms of this syndrome, it is likely that the characteristics of the disease are due to an accumulation of mevalonic acid, the substance on which mevalonate kinase normally acts. It is also believed that the deficiency of substances produced from mevalonic acid, such as the substances necessary for certain cellular functions, results in episodes of fever and other characteristics of this disease. The severity of the enzyme deficiency determines the severity of the disease. In general, people who have about 1% to 20% of normal mevalonate kinase activity develop HIDS, while people who have less than 1% of normal enzyme activity generally develop MVA.

Mevalonate kinase deficiency (MKD) is inherited with an autosomal recessive pattern, that is, both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with mevalonate kinase deficiency (MKD), by means of the complete PCR amplification of the exons of the MVK gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).