PO:19:286 | Genetic testing reveals an unexpected case of mevalonate kinase deficiency in a 37-year-old patient with AA renal amyloidosis and good response to colchicine

Francesca Crisafulli¹, Paolo Airò², Federica Mescia³, Gianmarco Lugli³, Gianfranco Savoldi⁴, Claudia Izzi^3|5, Federico Alberici³, Marco Cattalini⁶, Franco Franceschini¹, Micol Frassi². | ¹Rheumatology and Clinical Immunology Unit, ASST Spedali Civili and University of Brescia, Brescia, Italy; ²Rheumatology and Clinical Immunology Unit, ASST Spedali Civili of Brescia, Brescia, Italy; ³U.O Nefrologia, ASST Spedali Civili di Brescia e Università degli Studi di Brescia, Brescia, Italy; ⁴Medical genetics Laboratory, Laboratory Department ASST Spedali Civili di Brescia, Brescia, Italy; ⁵Struttura Complessa di Genetica Clinica, ASST Spedali Civili di Brescia, Brescia, Italy; ⁶Pediatrics Clinic, University of Brescia and ASST Spedali Civili of Brescia, Brescia, Italy.

Mevalonate kinase deficiency (MKD) is a rare genetic autoinflammatory disease usually diagnosed in pediatric age.

Case presentation. A 37-year-old male, born in Pakistan from consanguineous parents was first evaluated in March 2024 at the Nephrology Unit, where he was admitted for abdominal pain, peripheral and periorbital edema. Scrotal edema, peritoneal and pleural effusions were observed. Laboratory tests revealed: nephrotic syndrome (24h proteinuria max 12.4 g/day, albumin 1.8 g/dL); mild renal impairment (creatinine 1.5 mg/dL); hypogammaglobulinemia (IgG 1.37 g/L); raised levels of CRP (19 mg/L, normal value <5) and serum amyloid A (SAA; 286 mg/L, normal value <8). ANA, antiENA, antidsDNA, antiPLA2R, anti-phospholipid antibodies, cryoglobulins, C3, C4, serum and urine immunofixation, serum IgA were negative or in normal range. Renal biopsy showed amyloidosis (with glomerular, arteriolar and interstitial involvement) positively stained for AA. He reported hospital admission at the age of 2 with no clear diagnosis. Since infancy to 2007, he experienced periodic fever with abdominal pain, occurring approximately once a month and lasting 2-3 days. In the suspect of familial Mediterranean fever (FMF), colchicine was started (1 mg/day) and next generation sequencing (NGS) analysis of genes potentially linked to periodic fever was performed. Moreover, treatment with furosemide, canrenone, ramipril, statin, ezetimibe, dapaglifozin and warfarin (for catheter-associated deep vein thrombosis) was started. Two months after discharge, clinical condition improved (no more edema nor abdominal pain); SAA normalized; proteinuria decreased to 7 g/day. A clinical diagnosis of FMF was confirmed (Tel-Hashomer and Eurofever/Printo criteria). During the follow-up, due to creatinine and liver enzymes increase, a treatment adjustment was necessary, including colchicine reduction (0.5 mg/day). This resulted in an improvement of renal and hepatic function but a slight elevation of SAA. Proteinuria progressively decreased (3 g/24h). Soon after, the NGS result became available, demonstrating a homozygous variant (N205D; likely pathogenic according to ACMG standard) of the MVK gene. Canakinumab (150 mg/4 weeks) was started in November with initial good response.

Conclusions. In the here presented case, clinical features and response to colchicine treatment initially led to clinical diagnosis of FMF but, unexpectedly, NGS revealed MVK gene mutation. Few cases of MKD presenting with AA amyloidosis in adult patients were so far described (1), but none of them responded to colchicine therapy. This case highlights the usefulness of genetic testing even in apparently well-defined cases, contributing to a better understanding of a rare disease such as MKD.

References: 1 Rodrigues F, et al., Semin Arthritis Rheum. 2020 Dec;50(6):1370-1373.