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Mevalonate kinase deficiency
Mevalonate kinase deficiency (MKD) is an autosomal recessive metabolic disorder that disrupts the biosynthesis of cholesterol and isoprenoids. It is a rare genetic disorder, but a high frequency is observed in Northern European regions.
Mevalonate kinase (MVK) is an enzyme involved in biosynthesis isoprenoids and is necessary for the conversion of mevalonate to mevalonate-5-phosphate in the presence of Mg2+
. Downstream of this enzyme, mevalonate-5-phosphate is converted into non-sterol (geranylgeranyl, farnesyl) or sterol isoprenoids (cholesterol). MKD is due to a pathogenic variants in the gene that encodes mevalonate kinase which results in a reduced or deficient activity of this enzyme. Because of this deficiency, mevalonic acid can build up in the body, with high levels found in the urine.
The severity of MKD depends on the level of this deficiency, with hyperimmunoglobulinemia D syndrome (first described as HIDS in 1984) being less severe but more common, and mevalonic aciduria (MVA) being a more severe but rarer form.
MKD is a periodic fever syndrome originally described in 1984 by the internist Jos van der Meer, then at Leiden University Medical Centre. No more than 300 cases have been described worldwide. MKD was originally described as hyperimmunoglobulin D syndrome (HIDS), but HIDS is now recognized as a mild manifestation of MKD. Immunoglobulin D (IgD) is a protein produced by a certain type of white blood cells. There are five classes of immunoglobulin: IgG, IgA, IgM, IgE and IgD. They each play an important role in the immune system. The function of IgD is still unclear, although one of its many effects is to activate the immune system.[citation needed]
MKD is characterized by attacks of fever, arthralgia, skin lesions including cyclical mouth ulcers, and diarrhea. Laboratory features include an acute phase response (elevated CRP and ESR) and markedly elevated IgD (and often IgA), although cases with normal IgD have been described.
It has mainly been described in the Netherlands and France, although the international registry also includes a number of cases from other countries.
The differential diagnosis includes fever of unknown origin, familial Mediterranean fever (FMF) and familial Hibernian fever (or TNF receptor associated periodic syndrome/TRAPS).
Mevalonate kinase deficiency is inherited in an autosomal recessive manner, meaning that a child must inherit a defective copy of the gene from both parents to be affected. It is an example of a loss-of-function mutation. The gene which codes for mevalonate kinase consists of 10 exons at locus 12q14. About 63 pathological sequence variations in the gene have been characterized.[citation needed] The most common of these are V377I, I268T, H20P/N and P167L, present in 70% of affected individuals.
People with the syndrome have variants in the gene for mevalonate kinase, which is part of the mevalonate pathway, an important cellular metabolic pathway. Indeed, similar fever attacks have been described in patients with mevalonic aciduria—an inborn error of metabolism now seen as a severe form of MKD.
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Mevalonate kinase deficiency
Mevalonate kinase deficiency (MKD) is an autosomal recessive metabolic disorder that disrupts the biosynthesis of cholesterol and isoprenoids. It is a rare genetic disorder, but a high frequency is observed in Northern European regions.
Mevalonate kinase (MVK) is an enzyme involved in biosynthesis isoprenoids and is necessary for the conversion of mevalonate to mevalonate-5-phosphate in the presence of Mg2+
. Downstream of this enzyme, mevalonate-5-phosphate is converted into non-sterol (geranylgeranyl, farnesyl) or sterol isoprenoids (cholesterol). MKD is due to a pathogenic variants in the gene that encodes mevalonate kinase which results in a reduced or deficient activity of this enzyme. Because of this deficiency, mevalonic acid can build up in the body, with high levels found in the urine.
The severity of MKD depends on the level of this deficiency, with hyperimmunoglobulinemia D syndrome (first described as HIDS in 1984) being less severe but more common, and mevalonic aciduria (MVA) being a more severe but rarer form.
MKD is a periodic fever syndrome originally described in 1984 by the internist Jos van der Meer, then at Leiden University Medical Centre. No more than 300 cases have been described worldwide. MKD was originally described as hyperimmunoglobulin D syndrome (HIDS), but HIDS is now recognized as a mild manifestation of MKD. Immunoglobulin D (IgD) is a protein produced by a certain type of white blood cells. There are five classes of immunoglobulin: IgG, IgA, IgM, IgE and IgD. They each play an important role in the immune system. The function of IgD is still unclear, although one of its many effects is to activate the immune system.[citation needed]
MKD is characterized by attacks of fever, arthralgia, skin lesions including cyclical mouth ulcers, and diarrhea. Laboratory features include an acute phase response (elevated CRP and ESR) and markedly elevated IgD (and often IgA), although cases with normal IgD have been described.
It has mainly been described in the Netherlands and France, although the international registry also includes a number of cases from other countries.
The differential diagnosis includes fever of unknown origin, familial Mediterranean fever (FMF) and familial Hibernian fever (or TNF receptor associated periodic syndrome/TRAPS).
Mevalonate kinase deficiency is inherited in an autosomal recessive manner, meaning that a child must inherit a defective copy of the gene from both parents to be affected. It is an example of a loss-of-function mutation. The gene which codes for mevalonate kinase consists of 10 exons at locus 12q14. About 63 pathological sequence variations in the gene have been characterized.[citation needed] The most common of these are V377I, I268T, H20P/N and P167L, present in 70% of affected individuals.
People with the syndrome have variants in the gene for mevalonate kinase, which is part of the mevalonate pathway, an important cellular metabolic pathway. Indeed, similar fever attacks have been described in patients with mevalonic aciduria—an inborn error of metabolism now seen as a severe form of MKD.