Mevalonate kinase deficiency

The clinical spectrum of mevalonate kinase deficiency ranges from the relatively mild hyperimmunoglobulinemia D syndrome (HIDS) to the severe mevalonic aciduria (MA). HIDS is characterized by recurrent episodes of high fever, lymphadenopathy, abdominal pain, arthralgia, and skin rashes, often triggered by infections or vaccinations. These episodes typically begin in infancy and last 3–6 days. In contrast, MA presents with more severe and continuous symptoms, including developmental delay, ataxia, dysmorphic features, cataracts, and failure to thrive. The severity correlates with residual enzyme activity: HIDS patients retain about 1–7% of normal activity, while MA patients have less than 1%.

Mutations in the MVK gene, located on chromosome 12q24, lead to reduced or absent mevalonate kinase activity. The enzyme catalyzes the phosphorylation of mevalonic acid to 5-phosphomevalonic acid, a step in the mevalonate pathway that produces isoprenoids, including farnesyl and geranylgeranyl pyrophosphates. Deficiency leads to accumulation of mevalonic acid in urine and blood, and a shortage of isoprenoids, which impairs protein prenylation and triggers the innate immune system, particularly the NLRP3 inflammasome, resulting in excessive interleukin-1β production. This explains the inflammatory episodes. Over 200 pathogenic variants have been reported, with the V377I mutation being the most common in HIDS.

Diagnosis is based on clinical suspicion, elevated urinary mevalonic acid during attacks, and confirmed by genetic testing of the MVK gene. Enzyme assays in fibroblasts or leukocytes can also be used. Management is largely supportive and includes nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids to control acute episodes. Biologic agents targeting interleukin-1, such as anakinra and canakinumab, have shown efficacy in reducing attack frequency and severity. Statins, which inhibit HMG-CoA reductase, have been tried but with mixed results. Early diagnosis and treatment can improve quality of life, though long-term outcomes vary.

Beyond the classic fever episodes, mevalonate kinase deficiency can present with atypical features such as chronic kidney disease, amyloidosis, and even neurological complications like seizures and intellectual disability in severe cases. The condition is also associated with an increased risk of hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome. Notably, the V377I variant is common in the Dutch population, suggesting a founder effect. Additionally, some patients may experience a paradoxical response to vaccinations, with episodes triggered by immunizations. Research into the mevalonate pathway has also linked this deficiency to altered cholesterol synthesis, which may have implications for neurodevelopment.

Autosomal recessive

A pattern of inheritance where two copies of a mutated gene are required to cause the disorder.

Mevalonate pathway

A metabolic pathway that produces cholesterol and other isoprenoids, essential for cell function.

Isoprenoids

A diverse class of organic compounds derived from isoprene units, involved in various cellular processes.

NLRP3 inflammasome

A protein complex that activates inflammatory responses, particularly the production of interleukin-1β.

Hemophagocytic lymphohistiocytosis

A severe systemic inflammatory syndrome characterized by uncontrolled activation of immune cells.