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Mevalonate kinase deficiency / HIDS
MKD/HIDS is a rare inherited condition that causes episodes of fever and widespread inflammation throughout the body. These episodes often begin in infancy or early childhood and can vary in severity.
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Overview
Mevalonate Kinase Deficiency (MKD) is an inherited autoinflammatory disease, often referred to as Hyperimmunoglobulinemia D Syndrome (HIDS). It is caused by genetic changes in the <i>MVK</i> gene, leading to a deficiency of the mevalonate kinase enzyme. This enzyme plays a crucial role in the mevalonate pathway, which is essential for various cellular processes, including cholesterol synthesis and immune system regulation [PMID:33005819].
The condition is characterised by recurrent episodes of fever and inflammation. These inflammatory attacks typically begin in infancy or early childhood, although onset can sometimes be later. MKD/HIDS is considered a rare disease, meaning its exact prevalence is not well established within the general population. While severity can vary significantly between individuals, the recurrent inflammatory episodes can impact quality of life.
Symptoms & clinical features
The hallmark of MKD/HIDS is recurrent episodes of high fever, which can last from a few days to a week. These fever attacks are often accompanied by a range of other inflammatory symptoms. Individuals may experience abdominal pain, vomiting, and diarrhoea. Swollen and painful joints (arthralgia or arthritis) are also common during attacks, often affecting multiple joints [PMID:11340156].
Skin manifestations can include a rash, which might appear as red spots or nettle-like lesions (urticaria). Swollen lymph nodes (lymphadenopathy) in the neck, armpits, or groin are frequently observed. Headaches and muscle pain are also reported by some individuals during these inflammatory episodes. In more severe cases, particularly in infancy, growth delays or developmental issues may occur, and very rarely, neurological complications can arise, which may be more prominent in severe mevalonic aciduria.
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Affected organs
MKD/HIDS can affect multiple organ systems due to widespread inflammation. The immune system is directly involved, leading to heightened inflammatory responses. The gastrointestinal system is often affected, causing symptoms such as abdominal pain, nausea, vomiting, and diarrhoea during attacks. Joints can become inflamed and painful, impacting mobility.
Skin is also commonly affected, with various rashes appearing during episodes. Lymph nodes throughout the body can swell. In some severe forms of the condition, particularly mevalonic aciduria, there can be impacts on the brain and nervous system, potentially leading to developmental delays, ataxia (problems with coordination), or seizures. The severity of organ involvement can vary greatly between individuals.
Risks & severity
The severity of MKD/HIDS can range from moderate, with relatively mild and infrequent attacks, to severe, with more intense and frequent inflammatory episodes. The condition is often classified into two main forms based on severity: a milder form, known as HIDS, and a more severe form, mevalonic aciduria, which is typically associated with more profound enzyme deficiency and can have neurological involvement. The more severe mevalonic aciduria form often presents earlier and can be life-threatening in infancy due to metabolic crises and neurological complications [PMID:16524330].
Individuals with MKD/HIDS generally experience lifelong recurrent fevers and inflammation, though the frequency and intensity of attacks may sometimes decrease with age. However, some individuals continue to have significant inflammatory burden into adulthood. There is also a small increased risk of developing amyloidosis, a condition where abnormal protein builds up in organs, which can occur due to chronic inflammation over many years, particularly if the disease is not well controlled.
Genetic causes
Mevalonate Kinase Deficiency / HIDS is caused by pathogenic variants in the <i>MVK</i> gene. This gene provides instructions for making the mevalonate kinase enzyme. This enzyme is a critical component of the mevalonate pathway, a biochemical pathway that is essential for the body's production of cholesterol, steroid hormones, and bile acids.
Beyond these well-known functions, the mevalonate pathway also produces isoprenoids, which are vital for various cellular functions, including cell growth, differentiation, and the regulation of the immune system. When the <i>MVK</i> gene has a pathogenic variant, the mevalonate kinase enzyme either has reduced activity or is not produced effectively. This enzyme deficiency disrupts the mevalonate pathway, leading to an accumulation of mevalonic acid and other intermediate products, which is thought to trigger the chronic inflammatory response characteristic of MKD/HIDS.
- MVK mevalonate kinaseThe MVK gene provides instructions for the mevalonate kinase enzyme, which plays a crucial role in the production of cholesterol and other essential cellular substances.
Inheritance pattern
MKD/HIDS follows an autosomal recessive pattern of inheritance. This means that an individual must inherit two altered copies of the <i>MVK</i> gene - one from each parent - to develop the condition. If a person inherits only one altered copy of the <i>MVK</i> gene, they are considered a 'carrier' and typically do not show symptoms of MKD/HIDS.
For parents who are both carriers of an <i>MVK</i> pathogenic variant, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered copies and develop MKD/HIDS. There is a 50% (1 in 2) chance that their child will be a carrier, and a 25% (1 in 4) chance that their child will inherit two normal copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of MKD/HIDS is typically suspected based on an individual's clinical symptoms, particularly recurrent fever episodes accompanied by characteristic inflammatory signs. Blood tests during an attack often show elevated inflammatory markers, such as C-reactive protein (CRP) and serum amyloid A (SAA). A distinctive feature of HIDS is usually elevated levels of immunoglobulin D (IgD) in the blood, often above 100 mg/L, though this is not always present in younger children or milder cases [PMID:11340156].
Definitive diagnosis requires genetic testing to identify pathogenic variants in the <i>MVK</i> gene. This can be performed through targeted gene sequencing or broader genomic approaches. In the NHS Genomic Medicine Service, genetic testing for autoinflammatory conditions is typically accessed via an R-code, and referral to a clinical geneticist or immunology specialist is usually required to initiate this process.
Management & lifestyle
The management of MKD/HIDS focuses on reducing the frequency and severity of inflammatory attacks and managing symptoms during episodes. There is no cure for the underlying genetic cause, so treatment aims to control the inflammatory response. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to manage fever and pain during attacks.
For more severe or frequent attacks, specific anti-inflammatory medications may be considered. These include biological therapies that target key inflammatory cytokines, such as anakinra (an IL-1 receptor antagonist) or canakinumab (an anti-IL-1β monoclonal antibody), which have shown effectiveness in preventing or reducing the severity of attacks in many individuals [PMID:33005819]. Treatment decisions are made by specialist clinicians, often within multidisciplinary teams, considering the individual's specific symptoms and disease severity.
UK care pathway
In the UK, individuals suspected of having MKD/HIDS would typically be referred to a specialist in immunology, rheumatology, or clinical genetics. If a genetic cause is suspected, they would be assessed for eligibility for genomic testing through the NHS Genomic Medicine Service. This usually involves a referral to a clinical genetics service or a specialist with access to the national Genomic Laboratory Networks.
Genetic testing for autoinflammatory conditions, including MKD/HIDS, is listed within the National Genomic Test Directory under specific R-codes (e.g., R151 for 'Autoinflammatory disorders'). A genetic counsellor can provide essential support, explaining the inheritance pattern, the implications of a diagnosis for the individual and their family, and discussing testing options for relatives.
Frequently asked questions
What triggers MKD/HIDS attacks?
Attacks can sometimes be triggered by stress, infections, vaccinations, or physical exertion, though often there is no clear trigger. The body's own immune system essentially overreacts, leading to inflammation.
Is MKD/HIDS contagious?
No, MKD/HIDS is not contagious. It is a genetic condition, meaning it is caused by an alteration in a person's genes and cannot be spread from person to person.
Can MKD/HIDS affect fertility or pregnancy?
MKD/HIDS typically does not directly affect fertility. However, managing the condition during pregnancy requires careful planning with specialist doctors to ensure the health of both the mother and the baby.
Are there dietary restrictions for MKD/HIDS?
Generally, there are no specific dietary restrictions for MKD/HIDS. However, a balanced diet is important for overall health. Some individuals might find certain foods aggravate their symptoms, but this is highly individual and should be discussed with a healthcare professional.
Will my children inherit MKD/HIDS?
MKD/HIDS is inherited in an autosomal recessive pattern. If you have MKD/HIDS, it means you have two altered copies of the <i>MVK</i> gene. For your children to inherit the condition, your partner would also need to be a carrier or have MKD/HIDS themselves. Genetic counselling can provide specific risk assessments for your family.