Mevalonate Kinase Deficiency

Mevalonate kinase deficiency (MKD) is an autosomal recessive autoinflammatory disease from MVK mutations, presenting as hyper-IgD syndrome (HIDS, partial deficiency) or mevalonic aciduria (severe).

• Prevalence about 1 per million, with origin in the Netherlands and Northern Europe.

• Deficiency of isoprenoid products leads to pyrin inflammasome activation and IL-1 beta release.

• HIDS: onset in infancy (median 6 months), attacks every 4 to 6 weeks lasting 3 to 7 days, triggered by vaccination, infection, stress.

• Mevalonic aciduria: neurodevelopmental delay, cerebellar ataxia, dysmorphism, failure to thrive, retinitis pigmentosa.

• Complications: amyloidosis (rare), macrophage activation syndrome.

• Recurrent fever with cervical lymphadenopathy, abdominal pain, vomiting, diarrhoea, aphthous ulcers, arthralgia/arthritis, maculopapular rash, splenomegaly.

• Attacks begin in the first year of life, may become less frequent with age.

• Mevalonic aciduria: severe developmental and neurological features.

• During attacks: raised CRP, ESR, leucocytosis, elevated SAA, high urinary mevalonic acid excretion (diagnostic marker).

• Serum IgD (above 100 IU/mL) supportive but neither sensitive nor specific; IgA often raised.

• MVK gene sequencing (biallelic mutations; V377I most common) and enzyme activity assay (reduced 1 to 10% in HIDS).

• Exclude PFAPA, FMF, TRAPS, infection, malignancy.

• Acute attacks: NSAIDs (naproxen 5 to 10 mg/kg twice daily), short prednisolone 1 to 2 mg/kg for 1 to 3 days at onset.

• Prophylaxis for frequent or severe attacks: anakinra 1 to 2 mg/kg SC daily or on demand, canakinumab 150 mg (4 mg/kg) every 4 weeks (effective in a majority), etanercept 0.8 mg/kg weekly (partial benefit).

• Statins (simvastatin 40 mg) inhibit HMG CoA reductase and may worsen disease in some, or help in others; not used as standard.

• Mevalonic aciduria: anti-IL-1 therapy, haematopoietic stem cell transplantation in severe disease.

• Monitor for amyloidosis (proteinuria) and macrophage activation (ferritin, cytopenias).

• Genetic counselling; avoid unnecessary vaccination at trigger time but continue the schedule.