Hyper IgD Syndrome Mevalonate Kinase Deficiency
What is HIDS/MKD?
HIDS and MKD refer to the same periodic fever syndrome, with HIDS being the milder form. They are genetic diseases characterised by repeated attacks of fever. Hyper IgD refers to elevated levels of IgD in the blood, which are found in part of the patients. MKD refers to the enzyme mevalonate kinase, of which the activity is reduced in the cells of the body.
From birth, the MVK gene is damaged and this causes the disease. Mevalonate kinase (MVK) is an enzyme, a protein that facilitates a chemical reaction necessary for normal health. That reaction is the conversion of mevalonic acid to phosphomevalonic acid. In patients, both available copies of the MVK gene are damaged, which means there is a lack of active mevalonate kinase enzyme. The mevalonic acid accumulates in the body and ends up in the urine. More importantly, the production of certain fats (isoprenoids) is deficient. As a result, the body mistakenly acts as if there is a bacterial infection and produces inflammatory agents, such as interleukin-1beta. This causes fever and inflammatory symptoms in the blood and tissues.
HIDS/MKD is caused by a defect in the MVK gene. It is a hereditary disease that is inherited in an autosomal recessive manner. This means that the disease is not gender-specific. This type of inheritance means that an individual will only get the disease if both genes are abnormal. In other words, the gene that comes from the mother, as well as the gene that comes from the father. Both parents are usually carriers of the disease. That is, both parents have one healthy and one abnormal gene. In that case, the chance that their child is affected is 25%.
The child has the disease because the genes that cause the disease are affected.
There is a pattern of symptoms with fever recurring regularly (every 2 to 12 weeks), with flares lasting 3 to 7 days. The symptoms during these fever attacks include: headache, sore throat, abdominal pain, vomiting, diarrhoea, sore swollen lymph nodes, joint pains, rash, loss of appetite and an overall feeling of malaise. Elevated levels of inflammation are found in the blood, but no bacteria or viruses are found.
In the most severely affected patients, problems of the nervous system (developmental delay, coordination disorders) or the eyes (cataracts, retinal damage) may also occur.
Course of the disease
HIDS/MKD is a life-long disease. In general, the frequency and severity of the flares decrease as the child grows older. Unfortunately, the episodes will never disappear completely.
A very rare, but serious complication of HIDS/MKD is the development of amyloidosis. Amyloid is an inflammatory protein that deposits in certain organs, such as the intestines, skin, heart, but also the kidneys. This protein deposition causes the affected internal organ to function less well. In the case of the kidneys, this may eventually lead to kidney failure and require dialysis or a transplant. This dangerous complication is believed to be well-preventable by preventing the inflammation, for example with interleukin-1 receptor antagonist.
The diagnosis is made through chemical determinations and/or genetic analysis. The concentration of Mevalonic Acid in the urine is examined. The genetic analysis looks for mutations of the MVK gene.
Treatment depends on the severity of the disease. Sometimes simple remedies such as paracetamol and anti-inflammatory drugs, such as indometacin, diclofenac or ibuprofen, are sufficient. Sometimes, the flares can be treated with corticosteroids such as prednisone, but if this drug is used too often or for too long, there may be unpleasant side effects. Children for which simple remedies do not work, are often treated with medication that blocks the inflammatory protein interleukin-1beta. Canakinumab and anakinra are medicines that block interleukin-1. Canakinumab is extremely expensive but very effective: in 2/3 of the patients, the episodes can disappear completely and the remainder patients experience a strong decrease in the number of episodes. It must be injected under the skin every 4-8 weeks. Anakinra has been studied less well. It is less expensive but must be injected daily.
Side effects of interleukin-1 receptor antagonist.
Interleukin-1 is important for the immune system to fight infections. This is why the main side effects of canakinumab and anakinra are an increased risk of bacterial infections, such as ear infections, pneumonia and impetigo. It is therefore very important that children treated with these drugs are fully vaccinated. Infections should also be treated promptly with antibiotics.
The other important side effect is pain at the injection site. This occurs especially with anakinra.
HIDS/MKD is a life-long disease. However, over the years the symptoms/episodes may decrease. Also, an interleukin-1 receptor antagonist can significantly reduce the episodes, but living with this condition remains difficult because the patient never knows exactly when he/she will have another episode and how long it will last. If the inflammation cannot be controlled, amyloidosis will likely be preventable by using this medication. Many HIDS/MKD patients suffer from fatigue. In very rare cases, retinal damage (“retinitis pigmentosa”) can lead to loss of vision.