MVK – Hyperimmunoglobulinemia D with Periodic Fever Syndrome

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is an autosomal recessive autoinflammatory disorder characterized by recurrent episodes of fever, lymphadenopathy, arthralgia, diarrhea, abdominal pain, and skin rash. HIDS is caused by biallelic pathogenic variants in the mevalonate kinase gene (MVK) (MVK), leading to deficient mevalonate kinase activity and dysregulated isoprenoid biosynthesis in innate immune cells. The association between MVK and HIDS (Hyperimmunoglobulinemia D and periodic fever syndrome) is well established through extensive clinical and functional studies.

Genetic Evidence

Multiple case series and cohort studies have identified more than 100 unrelated probands with two MVK variants presenting with HIDS phenotypes, meeting autosomal recessive inheritance criteria. In a German surveillance study, 16 MVK mutation-positive children were identified across two ascertainment arms, with recurrent fever episodes beginning in infancy and median attack duration of 4.5 days (PMID:22038276). Over 11 distinct MVK mutations were reported, with p.Val377Ile observed in 81% of alleles. A South Indian case series described ten patients from six families, identifying a founder haplotype with p.Val377Ile and a splice variant c.226+2del in compound heterozygosity (PMID:32822427). Segregation analysis in multiplex families supports pathogenicity, with at least 19 additional affected relatives co-segregating MVK variants.

Variant Spectrum and Phenotypic Spectrum

The variant spectrum includes missense (e.g., c.1129G>A (p.Val377Ile)), splice-site (c.226+2del), frameshift, and stop-gain mutations. Founder and recurrent alleles such as p.Val377Ile are prevalent in European and South Indian populations. Phenotypic variability ranges from classic HIDS to severe mevalonic aciduria, with symptom onset in infancy but documented diagnosis beyond preschool age. Partial or absent clinical manifestations in homozygous p.Val377Ile carriers indicate incomplete penetrance.

Functional Evidence

Biochemical studies demonstrate that pathogenic MVK mutations markedly reduce enzyme activity (<1–7% residual for HIDS) and protein stability, confirmed by recombinant expression and fibroblast assays (PMID:10401001, PMID:11325608). Sensitive UPLC-MS/MS quantification of mevalonate-5-phosphate provides precise enzymatic activity measurements, revealing a 53% decrease for the V261A variant (PMID:25982894). Peripheral blood mononuclear cells from MVK-deficient patients accumulate unprenylated Rab GTPases, correlating inversely with residual enzyme activity and offering a robust biomarker (PMID:31474985).

Conflicting and Modifier Evidence

Heterozygous carriers of low‐penetrance MVK variants or combined MVK/TNFRSF1A genotypes may exhibit atypical or attenuated phenotypes, underscoring modifier effects and incomplete penetrance. Some individuals homozygous for p.Val377Ile remain asymptomatic despite severely reduced enzyme activity, suggesting additional genetic or environmental modifiers.

Clinical Integration and Utility

The definitive association between MVK and HIDS is supported by extensive genetic, segregation, and functional data. Enzymatic assays and prenylation biomarkers enable differential diagnosis from other periodic fever syndromes. Genetic testing for MVK variants, especially recurrent alleles like c.1129G>A (p.Val377Ile), informs prognosis and targeted therapy, including biologics such as etanercept and canakinumab, which have shown symptom reduction in small cohorts. Early genetic diagnosis facilitates timely intervention and improves patient management.

Key Take-home: MVK pathogenic variants cause HIDS through loss of enzyme function and impaired protein prenylation; genetic testing and functional assays provide definitive diagnosis and guide targeted therapy.

References

• Rheumatology International • 2012 • Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children. PMID:22038276
• PLOS One • 2020 • Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome. PMID:32822427
• Human Molecular Genetics • 1999 • Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria. PMID:10401001
• Biochimica et Biophysica Acta • 2001 • Characterization of mevalonate kinase V377I, a mutant implicated in defective isoprenoid biosynthesis and HIDS/periodic fever syndrome. PMID:11325608
• Clinical Biochemistry • 2015 • Quantification of mevalonate-5-phosphate using UPLC-MS/MS for determination of mevalonate kinase activity. PMID:25982894
• Frontiers in Immunology • 2019 • Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency. PMID:31474985

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