Mevalonate kinase deficiency

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Mevalonate kinase deficiency
Other namesMevalonic aciduria [1] and Hyper immunoglobulin D syndrome (HIDS)
Mevalonic.jpg
A patient with mevalonate kinase deficiency at the age of 21 months, displaying characteristic craniofacial features
Specialty Hematology, neurology, immunology, medical genetics, endocrinology   OOjs UI icon edit-ltr-progressive.svg
Mevalonic acid Mevalonic-acid-2D-skeletal.png
Mevalonic acid

Mevalonate kinase deficiency (MKD) is an autosomal recessive [2] metabolic disorder that disrupts the biosynthesis of cholesterol and isoprenoids. [3] It is a rare genetic disorder, but a high frequency is observed in Northern European regions.

Contents

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.

Presentation

MKD is a periodic fever syndrome originally described in 1984 by the internist Jos van der Meer, [4] 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. [1] 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. [5]

It has mainly been described in the Netherlands and France, although the international registry also includes a number of cases from other countries. [5]

The differential diagnosis includes fever of unknown origin, familial Mediterranean fever (FMF) and familial Hibernian fever (or TNF receptor associated periodic syndrome/TRAPS). [5]

Genetics

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. [2] It is an example of a loss-of-function mutation. The gene which codes for mevalonate kinase consists of 10 exons at locus 12q14. [6] 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. [6]

People with the syndrome have variants in the gene for mevalonate kinase, which is part of the mevalonate pathway, an important cellular metabolic pathway. [7] [8] 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. [5]

Biochemistry

The biosynthesis of isoprenoids Mevalonate Pathway Wiki Page.png
The biosynthesis of isoprenoids

There is an increased secretion of the fever promoting cytokine interleukin 1 beta (IL-1β) in MKD, most likely mediated by defective protein prenylation. Prenylation refers to addition of hydrophobic isoprenoids to proteins, such as farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP). When isoprenoids such as these are coupled to a target protein, this affects the protein's cellular location and function. In a human monocytic MKD model it was found that the deficiency of GGPP leads to overproduction of IL-1β and defective prenylation of RhoA. This causes an increased level of Rac1 and PKB which in turn affects GTPases and B7-glycoproteins. It was earlier found that Rac1/PI3K/PKB pathway had been linked to the pathogenesis of MKD. The inactivation of RhoA acts an inducer of IL-1β mRNA transcription independent of NLRP3- or caspase-1 activity. Due to defective RhoA there is a formation of defective mitochondria (elongated and instable) in the cell. Normally, defective mitochondria are cleared in the cell by the mechanism of autophagy. But, in MKD the clearance of defective mitochondria from the cytosol is disrupted. As a result, mitochondrial DNA starts accumulating in the cytosol, binding and activating NLRP3, which is responsible for the production of IL-1β. The activation can be direct or indirect. It can also be activated by reactive oxygen species (ROS). [9] It is known that monocytes and macrophages in affected individuals also produce higher levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) other than IL-Iβ [9] During febrile (fever) attacks, C-reactive protein (CRP) also increases. [6] CRP is released by liver which causes inflammation.[ citation needed ]

Pathophysiology

The pathophysiology of MKD is complex and currently under activate investigation. [10] Defects in protein prenylation appear to drive the inflammatory phenotype by leading to activation of the pyrin and NLRP3 inflammasome through loss of RhoA and Rac1 membrane localization. Activation of the inflammasome leads to increase processing and release of interleukin-1 family cytokines.[ citation needed ]

Diagnosis

Mevalonate kinase deficiency causes an accumulation of mevalonic acid in the urine, resulting from insufficient activity of the enzyme mevalonate kinase [11] (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36).

Mevalonate pathway Mevalonate pathway.png
Mevalonate pathway

The disorder was first described in 1985. [12]

Classified as an inborn error of metabolism, mevalonate kinase deficiency usually results in developmental delay, hypotonia, anemia, hepatosplenomegaly, various dysmorphic features, an overall failure to thrive and several other features.[ citation needed ]

Mevalonate kinase deficiency has an autosomal recessive pattern of inheritance. Autorecessive.svg
Mevalonate kinase deficiency has an autosomal recessive pattern of inheritance.

Treatment

There is no treatment for MKD. But, the inflammation and the other effects can be reduced to a certain extent.[ citation needed ]

Treatment for HIDS

Canakinumab has been approved for treatment of HIDS and has shown to be effective. [13] [14] The immunosuppressant drugs etanercept [15] and anakinra [16] have also shown to be effective. Statin drugs might decrease the level of mevalonate and are presently being investigated. A recent single case report highlighted bisphosphonates as a potential therapeutic option. [17]

Epidemiology

Globally, less than 1 in 100,000 people have HIDS, and of these, ~200 individuals have MKD. [6] This categorises the condition as a rare genetic disease.

Related Research Articles

<span class="mw-page-title-main">Familial Mediterranean fever</span> Genetic autoinflammatory disease

Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in the Mediterranean fever (MEFV) gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are susceptible to FMF, it usually occurs in people of Mediterranean origin—including Sephardic Jews, Mizrahi Jews, Ashkenazi Jews, Assyrians, Armenians, Azerbaijanis, Druze, Levantines, Kurds, Greeks, Turks and Italians.

<span class="mw-page-title-main">Mevalonate pathway</span> Series of interconnected biochemical reactions

The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 biomolecules such as cholesterol, vitamin K, coenzyme Q10, and all steroid hormones.

<span class="mw-page-title-main">HMG-CoA reductase</span> Mammalian protein found in Homo sapiens

HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia.

<span class="mw-page-title-main">Prenylation</span> Addition of hydrophobic moieties to proteins or other biomolecules

Prenylation is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to lipid anchors like the GPI anchor, though direct evidence of this has not been observed. Prenyl groups have been shown to be important for protein–protein binding through specialized prenyl-binding domains.

<span class="mw-page-title-main">Anakinra</span> Pharmaceutical drug

Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a slightly modified recombinant version of the human interleukin 1 receptor antagonist protein. It is marketed by Swedish Orphan Biovitrum. Anakinra is administered by subcutaneous injection.

<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Muckle–Wells syndrome</span> Medical condition

Muckle–Wells syndrome (MWS) is a rare autosomal dominant disease which causes sensorineural deafness and recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and joint pain. As a result, MWS is considered a type of periodic fever syndrome. MWS is caused by a defect in the CIAS1 gene which creates the protein cryopyrin. MWS is closely related to two other syndromes, familial cold urticaria and neonatal onset multisystem inflammatory disease—in fact, all three are related to mutations in the same gene and subsumed under the term cryopyrin-associated periodic syndromes (CAPS).

Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of the adaptive immune system, people with autoinflammatory diseases do not produce autoantibodies or antigen-specific T or B cells. Instead, the autoinflammatory diseases are characterized by errors in the innate immune system.

Neonatal-onset multisystem inflammatory disease is a rare genetic periodic fever syndrome which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period. Symptoms include skin rashes, severe arthritis, and chronic meningitis leading to neurologic damage. It is one of the cryopyrin-associated periodic syndromes.

<span class="mw-page-title-main">Mevalonate kinase</span> Mammalian protein found in Homo sapiens

Mevalonate kinase is an enzyme that in humans is encoded by the MVK gene. Mevalonate kinases are found in a wide variety of organisms from bacteria to mammals. This enzyme catalyzes the following reaction:

<span class="mw-page-title-main">CDC42</span> Protein-coding gene in humans

Cell division control protein 42 homolog is a protein that in humans is encoded by the CDC42 gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.

<span class="mw-page-title-main">Canakinumab</span> Pharmaceutical drug

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Diphosphomevalonate decarboxylase (EC 4.1.1.33), most commonly referred to in scientific literature as mevalonate diphosphate decarboxylase, is an enzyme that catalyzes the chemical reaction

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An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

<span class="mw-page-title-main">Cryopyrin-associated periodic syndrome</span> Medical condition

Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome, the Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway, and keratoendotheliitis fugax hereditaria in which the autoinflammatory symptoms affect only the anterior segment of the eye.

<span class="mw-page-title-main">Jos van der Meer</span> Dutch scientist

Jos W.M. van der Meer is emeritus professor and former chairman at the department of internal medicine of the Radboud University Nijmegen Medical Centre in Nijmegen, Netherlands. He is a member of the Royal Netherlands Academy of Arts and Sciences, of which he was vice president and chairman of the division of natural sciences (2006-2012). He is a member of Academia Europaea. Between 2014 and 2016 he was president of European Academies Science Advisory Council (EASAC). He performs research on cytokines and host defence, chronic fatigue syndrome and hyper-immunoglobulinemia D syndrome (HIDS). He is also active in graphic art and makes cartoons, for example for the Dutch science journal Mediator.

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References

  1. 1 2 Online Mendelian Inheritance in Man (OMIM): MEVALONATE KINASE; MVK - 251170
  2. 1 2 "Mevalonate kinase deficiency".
  3. ↑ Mancini J, Philip N, Chabrol B, Divry P, Rolland MO, Pinsard N (May–June 1993). "Mevalonic aciduria in 3 siblings: a new recognizable metabolic encephalopathy". Pediatr. Neurol. 9 (3): 243–6. doi:10.1016/0887-8994(93)90095-T. PMID   8352861.
  4. ↑ van der Meer JW, Vossen JM, Radl J, et al. (May 1984). "Hyperimmunoglobulinaemia D and periodic fever: a new syndrome". Lancet. 1 (8386): 1087–90. doi:10.1016/S0140-6736(84)92505-4. PMID   6144826. S2CID   43579408.
  5. 1 2 3 4 Drenth JP, van der Meer JW (December 2001). "Hereditary periodic fever". N. Engl. J. Med. 345 (24): 1748–57. doi:10.1056/NEJMra010200. PMID   11742050.
  6. 1 2 3 4 "Mevalonate Kinase Deficiency".
  7. ↑ Drenth JP, Cuisset L, Grateau G, et al. (June 1999). "Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group". Nat. Genet. 22 (2): 178–81. doi:10.1038/9696. PMID   10369262. S2CID   22522985.
  8. ↑ Houten SM, Kuis W, Duran M, et al. (June 1999). "Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome". Nat. Genet. 22 (2): 175–7. doi:10.1038/969. PMID   10369261. S2CID   19807247.
  9. 1 2 3 4 Mulders-Manders, CM; Simon, A (2015). "Hyper-IgD syndrome/mevalonate kinase deficiency: what is new?". Semin Immunopathol. 37 (4): 371–6. doi:10.1007/s00281-015-0492-6. PMC   4491100 . PMID   25990874.
  10. ↑ Park YH, Wood G, Kastner DL, Chae JJ (August 2016). "Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS". Nat Immunol. 17 (8): 914–21. doi:10.1038/ni.3457. PMC   4955684 . PMID   27270401.
  11. ↑ Bretón Martínez JR, Cánovas Martínez A, Casaña Pérez S, Escribá Alepuz J, Giménez Vázquez F (Oct 2007). "Mevalonic aciduria: report of two cases". J. Inherit. Metab. Dis. 30 (5): 829. doi:10.1007/s10545-007-0618-7. PMID   17578678. S2CID   38318961.
  12. ↑ Berger R, Smit GP, Schierbeek H, Bijsterveld K, le Coultre R (Oct 1985). "Mevalonic aciduria: an inborn error of cholesterol biosynthesis?". Clin. Chim. Acta. 152 (1–2): 219–222. doi:10.1016/0009-8981(85)90195-0. PMID   4053401.
  13. ↑ Aróstegui, JI; Anton, J.; Calvo, I.; Robles, A.; Speziale, A.; Joubert, Y.; Junge, G.; Yagüe, J. (2015-01-01). "Long-term efficacy and safety of Canakinumab in active Hyper-IgD syndrome (HIDS): results from an open-label study". Pediatric Rheumatology. 13 (1): O58. doi: 10.1186/1546-0096-13-S1-O58 . ISSN   1546-0096. PMC   4596954 .
  14. ↑ Kozlova, A.; Mamzerova, E.; Maschan, A.; Shcherbina, A. (2014-06-01). "AB0918 Efficacy and Safety of Treatment of Children with Traps and Hids with IL1 Blocker (CANAKINUMAB)". Annals of the Rheumatic Diseases. 73 (Suppl 2): 1103–4. doi:10.1136/annrheumdis-2014-eular.3697. ISSN   0003-4967. S2CID   75513414.
  15. ↑ Takada, Kazuki; Aksentijevich, Ivona; Mahadevan, Vijayabhanu; Dean, Jane A.; Kelley, Richard I.; Kastner, Daniel L. (2003-09-01). "Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome". Arthritis and Rheumatism. 48 (9): 2645–51. doi:10.1002/art.11218. ISSN   0004-3591. PMID   13130485.
  16. ↑ Rigante D, Ansuini V, Bertoni B, et al. (November 2006). "Treatment with anakinra in the hyperimmunoglobulinemia D/periodic fever syndrome". Rheumatol. Int. 27 (1): 97–100. doi:10.1007/s00296-006-0164-x. PMID   16871408. S2CID   20846202.
  17. ↑ Cantarini, L; Vitale, A; Magnotti, F; Lucherini, O. M.; Caso, F; Frediani, B; Galeazzi, M; Rigante, D (2013). "Weekly oral alendronate in mevalonate kinase deficiency". Orphanet Journal of Rare Diseases. 8 (1): 196. doi: 10.1186/1750-1172-8-196 . PMC   3880037 . PMID   24360083.
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