HYPER-IgD SYNDROME/MEVALONATE KINASE DEFICIENCY

Mevalonate aciduria (MA) and hyper-IgD-and-periodic fever syndrome (HIDS) represent the two ends of the spectrum of clinical symptoms of mevalonate kinase deficiency (MKD). The severity of symptoms, in each case, depends on the remaining mevalonate kinase activity; in HIDS it is approximately 10%, in MA <0.5%.

HIDS is one of the rare congenital periodic fever syndromes; a few hundred cases of HIDS are thought to occur worldwide. The disease is inherited in an autosomal recessive manner and almost exclusively manifests in early childhood, usually in the first year of life. Febrile episodes usually occur every 4-8 weeks and last approximately 3-7 days. In up to 50% of cases, they are triggered by certain factors, usually vaccinations, stress, and infections. The relapses are typically accompanied by cervical lymphadenopathy, arthritis/arthralgias, measles-like exanthema, and abdominal pain with diarrhea and vomiting. In most cases, the specific symptoms are preceded by severe headaches and chills. The development of amyloidosis is very rare. There is usually a continuous elevation of IgD (and IgA) serum concentrations above 100 IU/ml, but in about 20% of cases, especially in young children, IgD levels may be within the normal range. Currently, there are no approved guidelines for the treatment of HIDS. In addition to non-steroidal anti-inflammatory drugs, corticosteroids are used during febrile episodes. In severe courses of the disease, treatment with IL1 blockers seems to be most promising.

Symptoms of MA include psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphia, progressive loss of vision, and recurrent fevers. Life expectancy is often limited.

Both diseases are caused by mutations in the MVK gene, which encodes mevalonate kinase, a key enzyme in cholesterol biosynthesis. The relationship between a defect in cholesterol biosynthesis and autoinflammatory disease pattern is still unclear. In about 80% of HIDS patients, the mutation V377I in exon 11 is present in a homozygous form or in combination with a second mutation.

References

Gattorno et al. 2019, Ann Rheum Dis 78:1025 / Martorana et al. 2017, Front Immunol 8:344 / van der Burgh et al. 2013, Clin Immunol 147:197 / Mandey et al. 2006, Hum Mut 27:796