Microsoft word - mkd.doc

Pædiatric Rheumatology
InterNational Trials
Mevalonate kinase Deficiency (MKD) (or Hyper IgD syndrome)

What is it?
Mevalonate kinase deficiency is a genetic disease. It is an inborn error of the body’s chemistry.
Patients suffer from recurrent bouts of fever, accompanied by a variety of symptoms. These
include painful swelling of lymph nodes (especially in the neck), skin rash, headache, sore
throat, ulcers in the mouth, abdominal pain, vomiting, diarrhea, joint pain and joint swelling.
Severely affected individuals can develop life threatening fever attacks in infancy,
developmental delay, impaired vision and kidney damage. In many affected individuals, a blood
component, immunoglobulin D (IgD), is elevated, giving rise to the alternative name of “hyper
IgD periodic fever syndrome”.

How common is it?
The disease affects people of all ethnic groups, but is relatively common among the Dutch. The
frequency of the disease, even in The Netherlands, is very low. World-wide the disorder has
been recognized in just … people. Fever attacks start before the age of six years in the vast
majority of patients, usually in infancy. Mevalonate kinase deficiency can affect both boys and
girls equally.

What are the causes of the disease?
Mevalonate kinase deficiency is a genetic disease. The responsible gene is called MKD. The
gene produces a protein, mevalonate kinase. Mevalonate kinase is an enzyme, a protein that
enables a chemical reaction that is required 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, resulting in insufficient activity of the mevalonate kinase enzyme. This results in
accumulation of mevalonic acid , which will appear in the urine. Clinically, the result is
recurrent fever. The worse the damage to the MVK-gene, the more severe the disease tends to
be. Although the cause is genetic, fever attacks can sometimes be provoked by vaccinations,
viral infections, injury or emotional stress.

Is it inherited?
Mevalonate kinase deficiency is inherited as an autosomal recessive disease. This means that to
have Mevalonate kinase deficiency one needs two mutated genes, one from the mother and the
other from the father. So both parents are carriers (a carrier has only one mutated copy, but not
the disease) rather than patients. For such a couple, the risk of having another son or daughter
with mevalonate kinase deficiency is 1:4.

Why has my child got this disease? Can it be prevented?
The child has the disease because it has mutations in both copies of the gene that produces
Mevalonate kinase. The disease cannot be prevented. In very severely affected families,
antenatal diagnosis can be considered
Is it contagious?
No, it is not.

What are the main symptoms?
The main symptom is fever, often starting with shaking chills. Fever lasts about 3-6 days and
recurs at irregular intervals (weeks to months). The bouts of fever are accompanied by a variety
of symptoms. These may include painful swelling of lymph nodes (especially in the neck), skin
rash, headache, sore throat, ulcers in the mouth, abdominal pain, vomiting, diarrhea, joint pain
and joint swelling. Severely affected individuals can develop life threatening fever attacks in
infancy, developmental delay, impaired vision and kidney damage.
Is the disease the same in every child?
It is not the same in every child. Moreover, the type, duration and severity of attacks may be
different each time, even in the same child.

Is the disease in children different from the disease in adults?
As patients grow up, the fever attacks tend to become fewer and milder However, some disease
activity will remain in most if not all affected individuals. Some adult patients develop
amyloidosis, which is organ damage due to abnormal protein deposition.

How is it diagnosed?
The diagnosis can be made chemical studies or by genetic analysis.
Chemically, the abnormally high mevalonic acid can be detected in urine. Specialized
laboratories can also measure the activity of the mevalonate kinase enzyme in blood or skin
Genetic analysis is performed on DNA from the patient, in which the damage to the MVK genes
(mutations) can be identified.
Measurement of serum IgD concentration is no longer considered a diagnostic test for
mevalonate kinase deficiency.

What is the importance of tests?
a) Blood tests: The laboratory tests, as mentioned before, are important in diagnosing
mevalonate kinase deficiency. Tests like erythrocyte sedimentation rate (ESR), CRP, serum
Amyloid-A-protein (SAA), whole blood count and fibrinogen are ordered during an attack to see
the extent of inflammation.
These are repeated after the child becomes symptom-free, to observe if the results are back to
normal, or near normal.
b) Urine test: A sample of urine is also tested for the presence of protein and red blood cells.
There may be temporary changes during attacks. Patients with amyloidosis will have persistent
levels of protein in urine tests.
Can it be treated or cured?
It cannot be cured and neither is there a proven effective treatment to control disease activity.

What are the treatments?
The treatments for mevalonate kinase deficiency include non steroidal anti-inflammatory drugs
such as indomethacin, corticosteroids, such as prednisolone, statins, such as simvastatin, and
biologicals, such as etanercept (Enbrel®) or anakinra (Kineret®). None of these drugs appears to
be uniformly effective, but all of them appear to help in some patients. Proof of their efficacy
and safety in mevalonate kinase deficiency is still lacking.

What are the side effects of drug therapy?
This depends on the drug that is used. NSAID’s can give rise to headaches, stomach ulcers and
kidney damage, corticosteroids and biologicals increase susceptibility to infections. In addition,
corticosteroids may cause a wide variety of side effects.

How long should treatment last for?
There are no hard data to support life-long therapy. Given the normal tendency to improvement
as patients grow up, it is probably wise to attempt drug withdrawal in patients whose disease
appears to be quiescent.
What about unconventional or complementary therapies?
There are no published reports of effective complementary remedies
What kind of periodic check-ups are necessary?
Children being treated should have blood and urine tests for at least twice yearly.

How long will the disease last for?
It is a life-long disease, although with age, symptoms may get milder.

What is the long term prognosis (predicted outcome and course) of the disease?

Mevalonate kinase deficiency is a life-long disease, although with age, symptoms may get
milder. Very rarely, patients develop organ damage, especially to the kidneys, due to
amyloidosis. Very severely affected patients, may develop mental impairment and night-
Is it possible to recover completely?
No, because it is a genetic disease.
Everyday life
How could the disease affect the child and family’s daily life?
Frequent attacks disrupt normal family life and may interfere with the parents’ or patient’s job.
There is often considerable delay before the correct diagnosis is made, which gives rise to
parental anxiety and sometimes to unnecessary medical procedures.

What about school?
Frequent attacks cause problems with school attendance. With effective treatment, this is less of
a problem.
The teachers should be informed about the disease and what to do in case an attack starts at

What about sports?
There is no restriction to sports. However, frequent absence from matches and training sessions
may hamper participation in competitive team sports.

What about diet?
There is no specific diet.
Can climate influence the course of the disease?
No, it cannot.

Can the child be vaccinated?

Yes, the child can be and should be vaccinated, even though this may provoke fever attacks.

What about sexual life, pregnancy, birth control?
Patients with mevalonate kinase deficiency can enjoy normal sexual acivity and have children of
their own. During pregnancy attacks tend to decrease. The chance of marrying a partner who
carries mevalonate kinase deficiency is extremely small, except when the partner comes from the
same extended family as the patient. When the partner is no carrier of mevalonate kinase
deficiency, their children cannot get mevalonate kinase deficiency.


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