What is Mevalonate Kinase Deficiency or Hyper IgD Syndrome?
Mevalonate kinase deficiency or syndrome with hyper IgD is a rare disease characterised by recurrent episodes of fever and inflammation
Mevalonate kinase deficiency (MKD) is a genetically transmitted disease
It belongs to the group of autoinflammatory diseases, which are rare diseases characterised by recurrent episodes of fever and inflammation.
Mevalonate kinase deficiency is most common in Northern Europe, especially among the Dutch, but all populations can be affected.
In some people affected by the disease, a type of antibody present in the blood (immunoglobulin D) may be elevated.
This is why this disease is also called ‘hyperIgD syndrome’.
Mevalonate kinase deficiency is caused by alterations (mutations) in a gene located on chromosome number 12
It contains the information necessary for the production of a protein called mevalonate kinase.
Mevalonate kinase is one of the factors involved in the control of inflammation.
This protein serves to transform a substance in the body called mevalonic acid into another substance, phosphomevalonic acid.
When the gene is mutated, the protein produced is altered, mevalonic acid cannot be transformed and accumulates in the blood, appearing in the urine during fever episodes.
The malfunctioning of this process results in persistent inflammation and thus disease.
Mevalonate kinase deficiency is transmitted as an autosomal recessive character
It means that in order to be ill, patients must have inherited mutations in both genes for the production of mevalonate kinase: either the one inherited on the maternal chromosome 12 or the one inherited on the paternal chromosome 12.
Both parents are ‘healthy carriers’ of the disease, i.e. they possess an altered copy of the gene that causes the disease, but do not show symptoms.
Mevalonate kinase deficiency (MKD) usually manifests itself before the age of 3 years
It is characterised by recurrent febrile episodes that occur with varying frequency, onset rapidly and lasting 4 to 7 days.
Fever is almost always associated with:
- Enlargement of the lymph nodes in the neck;
- Appearance of mouth ulcers;
- Widespread rash over the whole body;
Gastrointestinal symptoms such as vomiting and diarrhoea.
Almost always, patients also present with pain or swelling of the joints during these manifestations.
Acute episodes of illness may start spontaneously or be triggered by infections, stress (both physical and psychological) and sometimes vaccinations.
The disease is suspected on the basis of the patient’s history and medical examination.
If performed during febrile episodes, blood tests show a marked increase in inflammation indices (increased white blood cells, ESR, CRP, serum amyloid A) and urine examination shows elevated levels of mevalonic acid.
If they are performed outside the acute episode, however, the indices of inflammation may be slightly altered or completely normal and mevalonic acid in the urine is absent.
The diagnosis is confirmed by molecular gene analysis.
This genetic analysis is performed in specialised genetic laboratories and is therefore not available in all laboratories.
It is important that the result of the genetic test be interpreted by doctors with experience in this field, because not all mutations found in the gene cause disease.
There are in fact some ‘harmless’ mutations (so-called polymorphisms), which do not cause any problems and are also found in healthy people.
Carriers of such polymorphisms, even if present in duplicate, are to all intents and purposes healthy and not sick.
If the genetic analysis is misinterpreted, there is therefore a risk that people who are not actually ill will be considered ill.
The disease is treated using biological drugs directed against a molecule, called interleukin-1, normally involved in inflammation.
Due to mutations in the gene for mevalonate kinase, interleukin 1 is overproduced by the immune system.
It is precisely the excessive production of interleukin 1 that is responsible for the inflammation in mevalonate kinase deficiency.
The biological drugs currently used are anakinra and canakinumab, which block interleukin 1 activity.
Treatment, whatever it is, must be continued for life. If the therapy is discontinued, attacks recur.
The disease cannot be prevented.
If treatment is followed correctly and above all regularly, patients do not develop any complications and have an excellent quality of life without any limitations.
If the disease is not diagnosed in time or the therapy is not followed correctly, patients with mevalonate kinase deficiency are at risk of developing a dreaded complication called amyloidosis.
Amyloidosis consists of the accumulation of amyloid protein that is deposited in various organs and tissues (kidney, heart, etc.) and can impair their function.
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