![Mevalonic-acid-2D-skeletal](https://upload.wikimedia.org/wikipedia/commons/6/68/Mevalonic-acid-2D-skeletal.png)
Mevalonate kinase deficiency (MKD) is an
autosomal
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...
recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
metabolic disorder
A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...
that disrupts the
biosynthesis
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
of
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
and
isoprenoid
The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes", ...
s.
It is a
very rare genetic disease.
It is characterized by an elevated level of immunoglobulin D in the blood.
Mevalonate kinase
Mevalonate kinase is an enzyme (specifically a kinase) 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:
.
Funct ...
(MVK) is an enzyme involved in biosynthesis of cholesterols and isoprenoids and is necessary for the conversion of mevalonate to mevalonate-5-phosphate in the presence of Mg
2+. MKD is due to a mutation in the gene that encodes mevalonate kinase which results in a reduced or deficient activity of this enzyme. Because of this deficiency,
mevalonic acid
Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonate ...
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); a more severe, but rarer form.
Genetics
Mevalonate kinase deficiency is inherited in an
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
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
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
. The gene which codes for mevalonate kinase consists of 10
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s at locus 12q14.
About 63 pathological sequence variations in the gene have been characterized. The most common of these are V377I, I268T, H20P/N and P167L, present in 70% of affected individuals.
Immunoglobulin D
Immunoglobulin D
Immunoglobulin D (IgD) is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually co-expressed with another cell surface antibody called IgM. IgD is also produced in a secreted ...
(IgD) is a protein produced by a certain type of white blood cells. There are five classes of
Immunoglobulin
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
: 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.
Biochemistry
![Mevalonate Pathway Wiki Page](https://upload.wikimedia.org/wikipedia/commons/d/d0/Mevalonate_Pathway_Wiki_Page.png)
There is an increased secretion of the fever promoting
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
interleukin 1 beta
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
(IL-1β) in MKD, most likely mediated by defective protein
prenylation
Prenylation (also known as isoprenylation or lipidation) 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 ...
. Prenylation refers to addition of hydrophobic isoprenoids to proteins, such as
farnesyl pyrophosphate (FPP) or
geranylgeranyl pyrophosphate
Geranylgeranyl pyrophosphate is an intermediate in the biosynthesis of diterpenes and diterpenoids. It is also the precursor to carotenoids, gibberellins, tocopherols, and chlorophylls.
It is also a precursor to geranylgeranylated proteins, whi ...
(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
Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the ''RHOA'' gene. While the effects of RhoA activity are not all well known, it is ...
. This causes an increased level of
Rac1 and
PKB which in turn affects
GTPase
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
s 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
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
(elongated and instable) in the cell. Normally, defective mitochondria are cleared in the cell by the mechanism of
autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
. But, in MKD the clearance of defective mitochondria from the cytosol is disrupted. As a result,
mitochondrial DNA
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...
starts accumulating in the cytosol, binding and activating
NLRP3
NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1.
NLRP3 is ...
, 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
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(ROS).
It is known that
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...
s and
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s in affected individuals also produce higher levels of tumor necrosis factor alpha (
TNF-α
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
), interleukin 6 (
IL-6) other than
IL-Iβ During febrile (fever) attacks, C-reactive protein (
CRP) also increases.
CRP is released by liver which causes inflammation.
Hyper-IgD syndrome
Hyperimmunoglobulinemia D with recurrent fever is a
periodic fever syndrome
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 ...
originally described in 1984 by the
internist Jos van der Meer
Jos W.M. van der Meer (born April 15, 1947) 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 Aca ...
,
then at
Leiden University
Leiden University (abbreviated as ''LEI''; nl, Universiteit Leiden) is a Public university, public research university in Leiden, Netherlands. The university was founded as a Protestant university in 1575 by William the Silent, William, Prince o ...
Medical Centre. No more than 300 cases have been described worldwide. It is now recognised as an allelic variant of MKD.
Signs and symptoms
HIDS is one of a number of
periodic fever syndrome
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 ...
s. It is characterised by attacks of
fever
Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...
,
arthralgia
Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication.
According to MeSH, ...
,
skin lesions
A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this sy ...
including
cyclical mouth ulcers
Aphthous stomatitis, or recurrent aphthous stomatitis (RAS), is a common condition characterized by the repeated formation of benign and non-contagious mouth ulcers (aphthae) in otherwise healthy individuals. The informal term ''canker sore'' i ...
, and
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
. Laboratory features include an
acute phase response
Acute-phase proteins (APPs) are a class of proteins whose concentrations in blood plasma either increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the ''acute-p ...
(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
)
, anthem = ( en, "William of Nassau")
, image_map =
, map_caption =
, subdivision_type = Sovereign state
, subdivision_name = Kingdom of the Netherlands
, established_title = Before independence
, established_date = Spanish Netherl ...
and
France
France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...
, although the international registry includes a number of cases from other countries.
[
The ]differential diagnosis
In healthcare, a differential diagnosis (abbreviated DDx) is a method of analysis of a patient's history and physical examination to arrive at the correct diagnosis. It involves distinguishing a particular disease or condition from others that p ...
includes fever of unknown origin, familial Mediterranean fever
Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are su ...
(FMF) and familial Hibernian fever (or TNFα reception associated periodic syndrome/TRAPS).[
]
Cause
Virtually all people with the syndrome have mutations in the gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
for mevalonate kinase
Mevalonate kinase is an enzyme (specifically a kinase) 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:
.
Funct ...
, which is part of the HMG-CoA reductase pathway, an important cellular metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
. Indeed, similar fever attacks (but normal IgD) have been described in patients with mevalonic aciduria – an inborn error of metabolism
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrat ...
now seen as a severe form of HIDS.[
]
Pathophysiology
It is not known how mevalonate kinase mutations cause the febrile episodes, although it is presumed that other products of the cholesterol biosynthesis pathway, the prenylation
Prenylation (also known as isoprenylation or lipidation) 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 ...
chains (geranylgeraniol
Geranylgeraniol is a diterpenoid alcohol. It is a colorless waxy solid.
Geranylgeraniol is an important intermediate in the biosynthesis of other diterpenes, of vitamins E, and of K. It also used in the post-translational modification known ...
and farnesol
Farnesol is a natural 15-carbon organic compound which is an acyclic sesquiterpene alcohol. Under standard conditions, it is a colorless liquid. It is hydrophobic, and thus insoluble in water, but miscible with oils.
Farnesol is produced from 5- ...
) might play a role.[
]
Diagnosis
Mevalonate kinase deficiency causes an accumulation of mevalonic acid
Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonate ...
in the urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
, resulting from insufficient activity of the enzyme mevalonate kinase
Mevalonate kinase is an enzyme (specifically a kinase) 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:
.
Funct ...
(ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36).
The disorder was first described in 1985.
Classified as an inborn error of metabolism
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrat ...
, mevalonate kinase deficiency usually results in developmental delay
Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech, c ...
, hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...
, anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
, hepatosplenomegaly
Hepatosplenomegaly (commonly abbreviated HSM) is the simultaneous enlargement of both the liver (hepatomegaly) and the spleen (splenomegaly). Hepatosplenomegaly can occur as the result of acute viral hepatitis, infectious mononucleosis, and hist ...
, various dysmorphic
A dysmorphic feature is an abnormal difference in body structure. It can be an isolated finding in an otherwise normal individual, or it can be related to a congenital disorder, Genetics, genetic syndrome or birth defect. Dysmorphology is the stud ...
features, mental retardation
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signific ...
, an overall failure to thrive
Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...
and several other features.
Treatment
There is no treatment for MKD. But, the inflammation and the other effects can be reduced to a certain extent.
* IL-1 targeting drugs can be used to reduce the effects of the disorder. Anakinra is antagonist to IL-1 receptors. Anakinra binds the IL-1 receptor, preventing the actions of both IL-1α and IL-1β, and it has been proved to reduce the clinical and biochemical inflammation in MKD. It can effectively decreases the frequency as well as the severity of inflammatory attacks when used on a daily basis. Disadvantages with the usage of this drug are occurrence of painful injection site reaction and as the drug is discontinued in the near future the febrile attacks start. (Examined in a 12-year-old patient).
* Canakinumab is a long acting monoclonal antibody which is directed against IL-1β has shown to be effective in reducing both frequency and severity in patients with mild and severe MKD in case reports and observational case series. It reduces the physiological effects but the biochemical parameter still remain elevated (Galeotti et al. demonstrated that it is more effective than anakinra –considered 6 patients with MKD).
* Anti-TNF therapy might be effective in MKD, but the effect is mostly partial and therapy failure and clinical deterioration have been described frequently in patients on infliximab
Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spon ...
or etanercept
Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It h ...
. A beneficial effect of human monoclonal anti-TNFα antibody adalimumab was seen in a small number of MKD patients.
* Most MKD patients are benefited by anti-IL-1 therapy. However, anti-IL-1-resistant disease may also occur. Example. tocilizumab (a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor). This drug is used when the patients are unresponsive towards Anakinra. (Shendi et al. treated a young woman in whom anakinra
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 recombinant and slightly modifi ...
was ineffective with tocilizumab
Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID19. It is a hu ...
). It was found that it was effective in reducing the biochemical and clinical inflammation 0Stoffels et al. observed reduction of frequency and severity of the inflammatory attacks, although after several months of treatment one of these two patients persistently showed mild inflammatory symptoms in the absence of biochemical inflammatory markers.
* A beneficial effect of hematopoietic stem cell transplantation
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produc ...
can be used in severe mevalonate kinase deficiency conditions (Improvement of cerebral myelinisation
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to Insulator (electricity), insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The ...
on MRI after allogenic stem cell transplantation
Hematopoietic stem-cell transplantation (HSCT) is the Organ transplantation, transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a ...
was observed in one girl). But, liver transplantation did not influence febrile attacks in this patient.
Treatment for HIDS
Canakinumab
Canakinumab (International Nonproprietary Name, INN), sold under the brand name Ilaris, is a medication for the treatment of systemic juvenile idiopathic arthritis (SJIA) and active Still's disease, including adult-onset Still's disease (AOSD). ...
has been approved for treatment of HIDS and has shown to be effective. The immunosuppressant drugs etanercept
Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It h ...
and anakinra
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 recombinant and slightly modifi ...
have also shown to be effective. Statin
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.
Low- ...
drugs might decrease the level of mevalonate and are presently being investigated. A recent single case report highlighted bisphosphonates as a potential therapeutic option.
Epidemiology
Globally, less than 1 in 100,000 people have HIDS, and of these, ~200 individuals have MKD. This categorises the condition as a rare genetic disease
A rare disease is any disease that affects a small percentage of the population. In some parts of the world, an orphan disease is a rare disease whose rarity means there is a lack of a market large enough to gain support and resources for discove ...
.
Additional images
Image:Mevalonic-acid-2D-skeletal.png, Mevalonic acid
Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonate ...
References
External links
*
{{Defects of cholesterol and steroid metabolism
Cholesterol and steroid metabolism disorders
Neurological disorders
Autosomal recessive disorders