In 1984 the internist Prof. dr. Jos van der Meer was the first to describe the so-called hyper-IgD syndrome. Patients suffer from severe periodic attacks of fever without a clear cause, which start early in childhood. A high concentration of the protein immunoglobulin D (IgD) in their blood is characteristic; this is the reason for the name of the disorder. In the last few years, internist-in-training dr. Joost Drenth [translator's note: Joost Drenth graduated as internist in january 2000] has been examining this mysterious syndrome. Recently, he discovered a number of mutations in a gene on chromosome 12, which cause the hyper-IgD syndrome. This has led to a publication in the prestigious journal Nature Genetics this month.
Drenth has examined some 120 patients with the hyper-IgD syndrome: about half of them is Dutch of origin. The other half has been referred to Nijmegen, the Netherlands, by members of an international Study Group, which consists of pediatricians and internists with a special interest in the syndrome.
The main symptom in all patients is the spiking fever, which occurs every four to eight weeks, and lasts three to seven days. The fever attacks usually start in the first months of life, and torment the patient a whole lifetime, although frequency and intensity can diminish at a later age. Apart from this, during fever attacks most patients have painful joints and swollen lymph nodes and they suffer from symptoms like stomachache, diarrhoea, vomiting and headaches.
Last year, Drenth stayed a few months in Généthon, a center for research of genetic disorders in Paris, to study the genetic material of the patients more closely. This was made possible by the Niels Stensen foundation, a fund which supports promising research by young scientists. "The Généthon has very advanced techniques at its disposal to test genetic markers", according to Drenth. "That is the reason why I had localised the gene for the hyper-IgD syndrome within 2 months." The step towards the final unraveling of the gene structure was comparatively easy after that.
It appeared that the gene encodes for the enzyme mevalonate kinase, which is one step in the conversion of mevalonic acid into cholesterol. From the literature it was known that patients with a severe illness, in which the body produces hardly any mevalonate kinase, suffer from fever attacks too. This provides the link with hyper-IgD. And it was shown by the group of Drenth that this enzyme doesn't function properly in HIDS. The function is reduced to an average of seven procent of normal.
The discovery of the genetic defect which causes hyper-IgD, raises a lot of new questions. "The functional link between mevalonate kinase and the hyper-IgD syndrome is still absolutely unclear," says Drenth. "The concentration of cholesterol of the patients is hardly different from the average population. This is also the case for the concentration of mevalonic acid. It's still impossible to directly link mevalonate kinase and the raised concentration of immunoglobulin D in the patients, too."
This discovery does prove that there are at least three different periodic fever syndromes. Apart from the hyper-IgD syndrome, these are the familiar Hibernian fever, which, as the name implies, was first described in an Irish family, and the familial Mediterranean fever, with a few thousands of patients in Israel and surrounding countries. These disorders are caused by a different genetic defect.
The publication in Nature Genetics provides the department of General Internal Medicine [of the University Medical Center St. Radboud of Nijmegen, the Netherlands] with an extra impulse to continue the research into hyper-IgD. Among other things, following studies will focus on the role of fever-inducing cytokines and the effect of drugs, including drugs which lower cholesterol concentration, for this disease.
