The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry

Abstract

Objective Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study was undertaken to describe the genotype, phenotype, and response to treatment in an international cohort of MKD patients. Methods All MKD cases were extracted from the Eurofever registry (Executive Agency for Health and Consumers project no. 2007332), an international, multicenter registry that retrospectively collects data on children and adults with autoinflammatory diseases. Results The study included 114 MKD patients. The median age at onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n = 112), mucocutaneous involvement (n = 99), lymphadenopathy (n = 102), or musculoskeletal symptoms (n = 89). Neurologic symptoms included headache (n = 43), cerebellar syndrome (n = 2), and mental retardation (n = 4). AA amyloidosis was noted in 5 patients, almost twice as many as expected from findings in previous cohorts. Macrophage activation syndrome occurred in 1 patient. Patients were generally well between attacks, but 10–20% of the patients had constitutional symptoms, such as fatigue, between fever episodes. Patients with p.V377I/p.I268T compound heterozygosity had AA amyloidosis significantly more often. Patients without a p.V377I mutation more often had severe musculoskeletal involvement. Treatment with nonsteroidal antiinflammatory drugs relieved symptoms. Steroids given during attacks, anakinra, and etanercept appeared to improve symptoms and could induce complete remission in patients with MKD. Conclusion We describe the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA amyloidosis is far higher than expected.

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

“…Anakinra given only during attacks resulted in three complete and five partial responses whereas out of the 19 patients who received Anakinra as maintenance therapy, 3 exhibited a complete remission, 13 a partial remission and 3 did not respond. Canakinumab led to complete remission in four patients and partial remission in a patient resistant to all other therapies (Ter Haar et al, 2016). In an open-label, single treatment arm study, 9 HIDS patients received Canakinumab every 6 weeks for 6 months followed by a withdrawal phase lasting up to 6 months and a 24 month-long-term treatment period.…”

Immunotherapeutic Biologic Agents to Treat Autoinflammatory Diseases

“…Reports detail response to anti-IL-1 therapy in FMF [6,14,43]. All these observations confirm response to anti-IL-1 therapy by a spectrum of AutoIDx [3,21,25,43,44]. …”

Effects of Anakinra on Health-Related Quality of Life in a Patient with 1129G>A/928G>A Mutations in MVK Gene and Heterozygosity for the Mutation 2107C>A in CIAS1 Gene

“…Cellular isoprenoid deficiency leads to the activation of monocytes, macrophages, RhoA, and Rac1, with subsequent IL-1β hypersecretion and proinflammatory cellular pyroptosis and apoptosis (2). HIDS is usually associated with high serum IgD (72–88% of patients); during flares, C-reactive protein and erythrocyte sedimentation rate are above the normal range, and neutrophil predominant leukocytosis is frequent (2, 4, 7, 8). Urinary mevalonic acid is often elevated, and mevalonate kinase function is reduced (1.8–28% in HIDS patients, less than 0.5% in MA patients); 3% of HIDS patients have also high serum amyloid A (2).…”