NORD gratefully acknowledges Grant S. Schulert, MD, PhD, Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, for assistance in the preparation of this report.
Mevalonate kinase deficiency (MKD) is a rare genetic autoinflammatory disorder. Autoinflammatory syndromes are a group of disorders characterized by seemingly random or unprovoked episodes of inflammation generally due to an abnormality of the innate immune system. They are not the same as autoimmune disorders, in which the adaptive immune system malfunctions and mistakenly attacks healthy tissue.
Mevalonate kinase deficiency is a spectrum of disease, ranging from more mild to severe complications. Hyper IgD syndrome (HIDS) is part of this spectrum and is characterized by episodes or “attacks” of fever associated with other symptoms including joint pain (arthralgia), muscle pain (myalgia), skin rash and abdominal pain. Most episodes last several days and can repeat throughout life. The frequency of episodes and their severity vary greatly from one person to another. Mevalonate aciduria is a more severe form. In addition to symptoms associated with HIDS, mevalonate aciduria can cause growth deficiency before and after birth, neurological abnormalities and ocular problems. Sometimes, mevalonate aciduria can cause life-threatening complications in childhood. Mevalonate kinase deficiency is caused by changes (mutations) in the MVK gene.
Mevalonate kinase deficiency is a spectrum of disease that can range from milder symptoms to severe, even life-threatening complications. Affected individuals can fall anywhere along this spectrum and it is important to remember every person is unique and the disorder may affect them differently from how it affects another person.
The milder end of the spectrum, also known as hyper IgD syndrome, is more common and is characterized by recurrent episodes of unexplained fever. There is often an abrupt onset of fever with no associated infection. These episodes are accompanied by fatigue, chills, abdominal pain, swelling of affected lymph nodes (lymphadenopathy), a rash, joint inflammation (arthritis) and pain (arthralgia). Additional symptoms include nausea, diarrhea, vomiting, headaches, small ulcers in the mouth and abnormal enlargement of the liver and spleen (hepatosplenomegaly). The rash consists of reddish (erythematous) spots (macules) or bumps (papules). Some individuals have a cough and inflammation of the back of the throat (pharyngitis).
The specific symptoms present during an episode and their severity vary from person to person. For an affected individual, the severity of individual episodes also varies. Episodes usually last for three to seven days, but can be shorter or longer. The frequency of episodes varies greatly. Some individuals have an episode every month, some more frequently and others less frequently. The frequency of episodes may also increase or decrease during a person’s life. Between episodes, individuals with mevalonate kinase deficiency may not display symptoms, while others may experience fatigue, headaches or ulcers in the mouth. Joint and skin problems may persist for a short time after an episode ends.
Mevalonate kinase deficiency is often more severe in children. Affected children often have a high spiking fever that, in rare instances, can cause seizures. Children are also more likely to have an abnormally enlarged spleen (splenomegaly). Episodes occur more frequently in children than adults. Episodes of fever may be set off by minor “triggers” such as emotional or physical stress. In children, episodes can follow vaccination. Adults may have mood and psychiatric features including depression.
Less common symptoms include inflammation of conjunctiva, which is the mucous membrane that covers the front of the eye and lines the inside of the eyelids (conjunctivitis), inflammation of the middle layer of the eye (uveitis), and inflammation of the main nerve of the eye that sends impulses from the brain to the retina (optic neuritis). In rare instances, kidney (renal) problems may develop including benign (non-cancerous) tumors of the kidney called angiomyolipomas. Some people may be prone to developing infection, particularly pneumococcal infection. Additional findings that have been associated with this disorder include retinitis pigmentosum, an eye disorder in which abnormal pigmented materials builds up in the retina causing a decline in vision; inflammation of the lining of the colon (colitis), which can cause abdominal bloating and pain, a constant urge to have a bowel movement, dehydration, diarrhea, bloody stools, and fever; and disseminated superficial actinic porokeratosis (DSAP), which is a skin disorder causing dry patches of skin and small growths (papules), mainly on the arms and legs.
In rare instances, people with mevalonate kinase deficiency develop long-term complications including AA amyloidosis, joint contractures, and abdominal adhesions. AA amyloidosis can occur in many chronic inflammatory disorders and is characterized by the accumulation of amyloid proteins in the kidneys. This can lead to progressive damage and dysfunction of the kidneys. Joint contractures occur when a joint becomes fixed in a bent or extended position, completely or partially restricting the movement of the joint. Abdominal adhesions are abnormal bands of fibrous tissues that form in the abdomen and cause abdominal organs and tissue to stick together. They may not cause symptoms or can cause chronic abdominal pain.
The severe end of the spectrum, known as mevalonate aciduria, is characterized by episodes or fever and accompanying symptoms as described for the milder end of the spectrum. These episodes are usually more frequent and more severe. Affected infants and children may also have growth deficiency before and after birth, failure to grow and gain weight (failure to thrive), and distinctive facial features including widely spaced eyes (hypertelorism), a large forehead (frontal bossing), long eyelashes, and a triangularly-shaped face. Some infants may have microcephaly, a condition where the circumference of the head is smaller than would be expected. They may also experience delays in reaching developmental milestones (developmental delays), delays in reaching milestones that require the coordination of muscular and mental activity (psychomotor delays), intellectual disability, problems with voluntary muscle control leading to poor coordination (ataxia), and seizures. Some infants have diminished muscle tone (hypotonia). Cataracts have also been reported. Children may be prone to developing infections. The severe end of the spectrum of mevalonate kinase deficiency can be severe enough to cause life-threatening complications in some instances.
Mevalonate kinase deficiency is caused by changes (mutations) in the MKV gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the specific protein, this can affect many organ systems of the body.
The MKV gene contains instructions (encodes) for creating the mevalonate kinase enzyme. This enzyme is important in the mevalonate pathway. A pathway is a series of chemical reactions in the body that produce a substance or substances essential for the proper function and health of the body. The mevalonate pathway produces cholesterol and unsaturated lipid (fat) chains called nonsterol isoprenoids. Because of changes in the MKV gene, people with mevalonate kinase deficiency have reduced levels and/or activity of the mevalonate kinase enzyme. People with HIDS have between 1.8% and 28% of residual enzyme activity. People with mevalonate aciduria have less than .5% of residual enzyme activity. This causes a lack of cholesterol and isoprenoids in the body. It also causes mevalonate acid to build up in the body and high levels of this acid will be found in the urine. The immune system makes higher levels of interleukin 1b, which contributes to episodes of hyperinflammation. An interleukin is a type of cytokine. Cytokines are specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. The complete effects in the body of reduced levels of mevalonate kinase enzyme and the exact underlying reasons that symptoms develop in mevalonate kinase deficiency are not fully understood. Less residual enzyme is generally associated with more severe symptoms.
Researchers believe that additional factors influence the severity of mevalonate kinase deficiency including modifier genes. Modifier genes, unlike the gene that causes the disorder, affect the clinical severity of the disorder. More research is necessary to discover the various modifier genes associated with mevalonate kinase deficiency and their exact role in the development of the disorder. Sometimes, episodes are caused or “triggered” by an event including trauma, surgery, stress or vaccination. However, many times an episode occurs without an identified trigger.
In most instances, mevalonate kinase deficiency is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Sometimes, individuals develop mevalonate kinase deficiency but only one altered MKV gene can be found.
Some individuals with mevalonate kinase deficiency can have abnormally high levels of immunoglobulin IgD in the fluid portion (serum) of the blood (thus, the term hyper IgD). Immunoglobulins or antibodies are proteins produced by certain white blood cells. There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Immunoglobulins play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells. While the specific function of other immunoglobulins is well-known, the specific function of IgD within the immune system is unknown. Some people can also have elevated levels of IgD without having HIDS or mevalonate kinase deficiency.
Mevalonate kinase deficiency affects males and females in equal numbers. More than 300 individuals worldwide are known to have the disorder, but the true number is likely greater. Most people with the disorder are individuals of western European heritage with approximately 60% occurring in Dutch or French individuals. The exact incidence and prevalence is unknown and it is likely that the disorder goes misdiagnosed or undiagnosed. This makes it difficult to determine the exact incidence or prevalence of mevalonate kinase deficiency in the general population.
A diagnosis of a mevalonate kinase deficiency is made based upon a thorough clinical evaluation, identification of characteristic symptoms (e.g., lifelong recurrent fevers not due to infection), and a variety of tests including blood tests to determine the levels of immunoglobulin D (IgD) in the blood, urine tests to detect the presence of mevalonate kinase, and DNA analysis to detect the genetic mutation associated with the disorder.
A high level of immunoglobulin D (IgD) is indicative of mevalonate kinase deficiency, but does not confirm a diagnosis. Some individuals do not show this finding and their IgD levels may be normal. Also, other periodic fever syndromes may have high levels of IgD in the blood. Further testing is required to determine whether a person has mevalonate kinase deficiency.
A urine test can reveal high levels of mevalonate acid. This is indicative of mevalonate kinase deficiency. However, many people with this disorder have normal levels of mevalonate acid in the urine, making this test unreliable on its own to diagnose mevalonate kinase deficiency.
A diagnosis of mevalonate kinase deficiency can be confirmed through molecular genetic testing. This type of testing identifies changes in the MKV gene that causes the disorder. This type of testing is available only as a diagnostic service at specialized laboratories.
There are new classification criteria that have been proposed for mevalonate kinase deficiency and other hereditary periodic fever syndromes. A person would be classified as having mevalonate kinase deficiency if they have genetic testing showing mutations in the MVK gene and either GI symptoms, enlarged lymph nodes in the neck, or mouth sores.
Treatment is directed toward the specific symptoms that are apparent in each individual.
Various drugs including paracetamol (acetaminophen) have been used to treat affected individuals. Corticosteroids, such as prednisone, have been used to treat some individuals. Nonsteroidal anti-inflammatories and pain medications (analgesics) have also been tried. These drugs have led to complete or partial remissions during a fever episode but success is inconsistent and temporary. They are generally considered best for people with mild symptoms and only a few episodes.
Several other medications have been used in people with mevalonate kinase deficiency. Colchicine is a medication that reduces inflammation and has been effective in other periodic fever syndromes, but has, generally, been ineffective in mevalonate kinase deficiency. Statins are another medication that has been tried in affected individuals, but similarly have not proven to be effective.
In 2016, the U.S. Food and Drug Administration (FDA) approved canakinumab (Ilaris) for the treatment of individuals with mevalonate kinase deficiency. Canakinumab is a fully-humanized protein which blocks the cytokine interleukin-1 beta, which contributes to fever episodes. In a recent clinical trial, significantly more people with mevalonate kinase deficiency had complete resolution of symptoms when treated with cankinumab than with placebo. However, more research is necessary to determine the long-term safety and efficacy of canakinumab for people with mevalonate kinase deficiency.
Some affected individuals have been treated with anakinra. Anakinra is an interleukin-1 receptor antagonist; it blocks the activity of interleukin-1. Initial reports suggest that this drug is safe and has shown some benefit in treating individuals with mevalonate kinase deficiency. More research is necessary to determine the long-term safety and effectiveness of anakinra for this disorder.
Some people have been treated with drugs that block the activity of tumor necrosis factor, a specialized protein (cytokine) that is helps to protect the body and is involved in inflammation. These TNF-inhibitors are called etanercept and adalimumab. More research is necessary to determine the long-term safety and effectiveness of these therapies for people with mevalonate kinase deficiency.
Tocilizumab is a drug that suppresses the immune system by blocking a different cytokine called interleukin-6. Tocilizumab has been tried as a treatment for people with mevalonate kinase deficiency. This drug has shown benefit in reducing the frequency and duration of fever episodes. More research is necessary to determine the long-term safety and effectiveness of this therapy.
Genetic counseling is recommended for affected individuals and their families.
The only curative therapy for individuals with mevalonate kinase deficiency is an allogeneic hematopoietic stem transplantation (allogeneic HSCT). However, because of the risk of morbidity and mortality, it is reserved for individuals with serious complications and specific children with mevalonate aciduria. Hematopoietic stem cells are specialized cells found in the bone marrow (the soft spongy material found in long bones). These blood stem cells grow and eventually develop into one of the three main types of blood cells– red blood cells, white blood cells or platelets. During an allogeneic HSCT, an affected individual’s bone marrow is destroyed usually by chemotherapy, radiation, or both and replaced with healthy marrow obtained from a donor. The donor marrow is transplanted intravenously into the body where it travels to the bone marrow and eventually begins producing new blood cells. The best match for a bone marrow transplant is an identical twin or sibling with an identical HLA type. However, in some individuals, a search for an unrelated, matched donor is necessary. According to the medical literature, several children with mevalonate aciduria have undergone allogeneic HCST and had a remission of systemic inflammation and an improvement of neurological symptoms.
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