Mevalonate Kinase Deficiency as Cause of Periodic Fever in Two Siblings

Mevalonate Kinase Deficiency (MKD) is a rare inborn disease belonging to the family of periodic fever syndromes. The MKD phenotype is characterized by systemic inflammation involving multiple organs, including the nervous system. Current anti-inflammatory approaches to MKD are only partially effective and do not act specifically on neural inflammation. According to the new emerging pharmacology trends, the repositioning of drugs from the indication for which they were originally intended to another one can make mechanistic-based medications easily available to treat rare diseases. According to this perspective, the squalene synthase inhibitor Lapaquistat (TAK-475), originally developed as a cholesterol-lowering drug, might find a new indication in MKD, by modulating the mevalonate cholesterol pathway, increasing the availability of anti-inflammatory isoprenoid intermediates. Using an in vitro model for MKD, we mimicked the blockade of the cholesterol pathway and evaluated the potential anti-inflammatory effect of Lapaquistat. The results obtained showed anti-inflammatory effects of Lapaquistat in association with a low blockade of the metabolic pathway, while this effect did not remain with a tighter blockade. On these bases, Lapaquistat could be configured as an effective treatment for MKD’s mild forms, in which the residual enzymatic activity is only reduced and not almost completely absent as in the severe forms.

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Validation of the new classification criteria for hereditary recurrent fever in an independent cohort: experience from the JIR Cohort Database

Rheumatology ◽

10.1093/rheumatology/keaa031 ◽

2020 ◽

Vol 59 (10) ◽

pp. 2947-2952

Author(s):

Glory Dingulu ◽

Sophie Georgin-Lavialle ◽

Isabelle Koné-Paut ◽

Pascal Pillet ◽

Anne Pagnier ◽

...

Keyword(s):

Periodic Fever ◽

Classification Criteria ◽

Recurrent Fever ◽

Mevalonate Kinase Deficiency ◽

Periodic Syndrome ◽

Mevalonate Kinase ◽

New Classification ◽

Clinical Criteria ◽

Clinical Variables ◽

Independent Cohort

Abstract Objective The new classification criteria for the hereditary recurrent fever (HRF) syndrome [cryopyrin-associated periodic syndrome (CAPS), TNF-α receptor-associated periodic syndrome (TRAPS), FMF and mevalonate kinase deficiency] have been published recently. These criteria define two core sets of criteria for each HRF: mixed criteria, including genetic and clinical variables, and clinical criteria, relying on clinical variables only. Our aim was to validate the criteria for HRF in an independent cohort, the JIR Cohort database, an international repository of systemic inflammatory diseases. Methods We enrolled patients with HRF, periodic fever, adenitis, pharyngitis and aphthous stomatitis syndrome (PFAPA) and syndrome of undefined recurrent fever (SURF). A score ranging from zero to two was attributed to their respective genotypes: zero (no mutation), one (non-confirmatory genotype) or two (confirmatory genotype). The criteria were applied to all patients based on genotype scoring. The treating physician’s diagnosis served as the gold standard for the determination of specificity. Results We included 455 patients. The classification criteria showed excellent specificity for CAPS and TRAPS (98% specificity each), fair specificity for FMF (88%), but poor specificity for mevalonate kinase deficiency (58%). Sub-analysis showed excellent accuracy of the mixed criteria for all four HRFs. Misclassification was mainly attributable to clinical criteria sets, with false-positive patients in all four HRF clinical criteria sets. Conclusion This study represents the final validation step of the HRF classification criteria as recommended by the ACR. Genetic data appear to be necessary to classify patients with HRF correctly.

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An International Delphi Survey for the Definition of New Classification Criteria for Familial Mediterranean Fever, Mevalonate Kinase Deficiency, TNF Receptor–associated Periodic Fever Syndromes, and Cryopyrin-associated Periodic Syndrome

The Journal of Rheumatology ◽

10.3899/jrheum.180056 ◽

2018 ◽

Vol 46 (4) ◽

pp. 429-436 ◽

Cited By ~ 7

Author(s):

Silvia Federici ◽

Federica Vanoni ◽

Eldad Ben-Chetrit ◽

Luca Cantarini ◽

Joost Frenkel ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Periodic Fever ◽

Tumor Necrosis Factor Receptor ◽

Classification Criteria ◽

Delphi Survey ◽

Mevalonate Kinase Deficiency ◽

Evidence Based ◽

Mevalonate Kinase ◽

Clinical Criteria ◽

Mediterranean Fever

Objective.Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF.Methods.Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1.Results.The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor–associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF.Conclusion.Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.

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Le sindromi autoinfiammatorie: quando non è solo PFAPA

Medico e Bambino ◽

10.53126/meb40221 ◽

2021 ◽

Vol 40 (4) ◽

pp. 221-225

Author(s):

ALBERTO TOMMASINI ◽

LOREDANA LEPORE

Keyword(s):

Periodic Fever ◽

Mevalonate Kinase Deficiency ◽

Inflammatory Disorder ◽

Mevalonate Kinase ◽

Red Flags ◽

Periodic Fever Syndromes ◽

Hereditary Periodic Fever Syndromes ◽

Hereditary Periodic Fever ◽

Fever Syndromes ◽

Mediterranean Fever

PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis) is the most common self-inflammatory disorder in children. The diagnosis of PFAPA is easy, based on Thomas criteria, and the prognosis is good. Differential diagnosis with hereditary periodic fever syndromes (Familial Mediterranean Fever, Mevalonate Kinase Deficiency, TRAPS and CAPS) should be considered only in the presence of red flags such as early onset, severe abdominal complaints, arthritis and severe rashes. Some patients may present distinct clinical entities with periodic fevers that neither meet PFAPA criteria nor hereditary periodic fever syndromes genotypes. Subjects with these “Undifferentiated Periodic Fever” may respond to glucocorticoids or colchicines or to anakinra in the most severe cases and still have an undetermined prognosis.

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An Atypical Presentation of Mevalonate Kinase Deficiency in Response to Colchicine Treatment

Molecular Syndromology ◽

10.1159/000518825 ◽

2021 ◽

pp. 1-6

Author(s):

Merve Koç Yekedüz ◽

Neslihan Doğulu ◽

Ümmühan Öncül ◽

Engin Köse ◽

Serdar Ceylaner ◽

...

Keyword(s):

Periodic Fever ◽

Mevalonic Acid ◽

Colchicine Treatment ◽

Recurrent Fever ◽

Mevalonate Kinase Deficiency ◽

Mevalonate Kinase ◽

Atypical Presentation ◽

Genetic Investigation ◽

Duration Of Treatment ◽

Inflammatory Drugs

Mevalonate kinase deficiency (MKD) is a periodic fever syndrome. Nonsteroidal anti-inflammatory drugs, corticosteroids, and anakinra are the most common treatments. However, colchicine is considered insufficient in disease control. In this case report, we present an 8-month-old infant with an atypical presentation of MKD. She had recurrent fever episodes, diarrhea, and lethargy. Elevated mevalonic acid was not detected in the urine. However, the genetic investigation showed a novel pathogenic heterozygous c.925G>C (p.Gly309Arg) variant and a heterozygous c.1129G>A (p.Val377Ile) mutation in the <i>MVK</i> gene. The patient was treated with colchicine for 8 months. During treatment, no further fever episode had been observed. It should be kept in mind that mevalonic acid excretion may not be present in the urine with mild MKD. Colchicine may be a reasonable option in mild MKD patients for a longer duration of treatment due to favorable adverse event profiles.

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O007. Register of hereditary auto-inflammatory diseases in a pediatric rheumatology unit

Rheumatology ◽

10.1093/rheumatology/keab723.006 ◽

2021 ◽

Vol 60 (Supplement_5) ◽

Author(s):

M Souali ◽

F Semlali ◽

G Benbrahim ◽

A Sakhi ◽

N Mikou ◽

...

Keyword(s):

Clinical Features ◽

Periodic Fever ◽

Diagnostic Delay ◽

Chronic Recurrent Multifocal Osteomyelitis ◽

Recurrent Fever ◽

Mevalonate Kinase Deficiency ◽

Mevalonate Kinase ◽

Genetic Syndromes ◽

Mediterranean Fever ◽

Wells Syndrome

Abstract Background Autoinflammatory diseases (AID) are a group of genetic syndromes resulting from an excessive activation of the innate immune system, caused by mutations in genes regulating the inflammatory pathways and can involve several organs. The aim of this study is to evaluate the clinical, paraclinical, epidemiogical and genetic data of Moroccan patients with confirmed AID, in order to allow a first experience of AID registry in our unit. Material We have retrospectively analyzed 30 cases of patients in our unit over a period of 13 years (between 2006 and 2019), according to inclusion criterias (recurrent fever > 3 episodes and a CRP > 40mg/L) and having excluded immune deficiency, autoimmune disease, neoplasia and infectious diseases. Results The mean age of our patients at 1st consultation was 6.9 years (with extremes ranging from 8 months to 14 years). Consanguinity was reported in 16 cases, and unknown in one case of an adopted child. The patients were classified as follows: 66% of cases with Familial Mediterranean Fever (FMF) including 1 case with a characteristic phenotype of Marshall/Periodic Fever Aphtous Pharyngitis Adenitis (PFAPA) syndrome, 16% of cases with Mevalonate Kinase Deficiency (MKD), 10% of cases with Chronic Recurrent Multifocal Osteomyelitis (CRMO), 1 patient with Familial Pustular Psoriasis (FPP) and another symptomatic patient with Muckle Wells syndrome. An association with Henoch Schonlein purpura was reported in 30% of cases and with periarteritis nodosa in 1 case in FMF patients. The mean diagnostic delay was 3 years (with extremes ranging from 1 month to 12 years). The main clinical features found in our patients included fever (83%), abdominal pain (90%), arthralgia (83%), arthritis (46%), adenopathies (40%), aphtous (30%) and other specific signs. Genetic analysis revealed that M694V was the most frequent mutation (60%), followed by A744S (15%), E148Q (10%), K695R (10%) and P369S/ R408Q (5%) in all FMF patients, and V337I found in 1 patient with MKD while the 4 others were confirmed basing on a high rate of urinary mevalonic acid. CRMO patients were confirmed by radiological and histological analysis. The case of FPP was confirmed histologically by skin biopsy and the patients with Muckle Wells and PFAPA syndroms were diagnosed basing on characteristic clinical features. Therapeutically, all FMF patients were treated with colchicine in addition of corticosteroids in 1 case of PFAPA syndrome. Patients with MKD received targeted therapy (Anakinra, Etanercept) and Ibuprofen in 1 case. CRMO patients were treated with targeted therapy and NSAIDs. The case of FPP was treated with Methotrexate combined with Etanercept and the patient with Muckel Wells Syndrome received corticosteroid therapy combined with Azathioprine and then Anakinra. The clinical and biological evolution was considered favorable in 76% of cases, partial in 13% of cases and 3 death cases were reported. Conclusion AIDs remain rare genetic syndromes whose lack of knowledge explains the late diagnostic delay. Therefore, it is necessary for any pediatrician to know how to evoke an AID in front of recurrent fever with free intervals, clinical features and inflammatory syndrome, in order to choose the optimal treatment as well as to make the genetic counseling. Abbreviations AID: Auto-Inflammatory Disease CAPS: Cryopyrin Associated Periodic Syndromes CARD14: Caspase Recruitment Domain Family Member 14 CIAS1: Cold-Induced Autoinflammatory Syndrome 1 CRMO: Chronic Recurrent Multifocal Osteomyelitis CRP: C-Reactive Protein CT scan: Computerized Tomography scan DNA: DeoxyriboNucleic Acid ESR: Erythrocyte Sedimentation Rate FMF: Familial Mediterranean Fever FPP: Familial Pustular Psoriasis IL-1β: Interleukine-1beta IL-17A: Interleukine 17A MEFV: Mediterranean fever gene MKD: Mevalonate Kinase Deficiency MVK: Mevalonate Kinase MW: Muckle Wells NALP3: NAcht Leucine-rich repeat Protein 3 NLRP3: NOD-like receptor family, pyrin domain containing 3 NSAID: Non-Steroidal Anti Inflammatory Drugs PFAPA: Periodic Fever Aphtous Pharyngitis Adenitis PRINTO: Pediatric Rheumatology INternational Trials Organization SAA: Serum Amyloid A TRAPS: TNF Receptor Associated Periodic Syndroms TNF: Tumor Necrosis Factor

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