Introduction
Central nervous system (CNS) involvement is common in cryopyrin-associated periodic syndromes (CAPS), especially in children. Neurological manifestations of the low-penetrance cryopyrin mutations V198M and Q703K encoded by exon 3 of the NLRP3 gene have not been investigated so far.
Objectives
To determine the frequency of the V198M and Q703K substitutions in adult patients with possible inflammatory CNS disease and at least two symptoms compatible with CAPS and to describe the clinical phenotype of mutation-positive patients.
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Methods
94 unrelated, consecutive patients with possible inflammatory CNS disease and at least two symptoms compatible CAPS were prospectively screened for the V198M and Q703K mutations. In addition, the clinical, laboratory, and MRI features of mutation carriers were assessed.
Results
15 patients (16%; 12 females) were identified to carry one of the two low-penetrance mutations in exon 3 of the NLRP3 gene (V198M: n= 2; Q703K: n =13). CAPS-associated systemic symptoms consisted of recurrent inflammation of the eyes, arthralgias, myalgias, urticarial rash, abdominal pain, and severe fatigue. CNS manifestation included optic nerve inflammation and/or atrophy, cranial nerve palsy, migraine, recurrent meningitis, and sensoneurinal hypacusis. Eight patients (53%) fulfilled the diagnostic criteria for multiple sclerosis (MS) according to the McDonald criteria. Brain magnetic resonance imaging (MRI) showed abnormalities in all but one patient.
Conclusion
So far, the V198M and Q703K mutations have been only rarely described in association with MS or CNS inflammation. We observed a a surprisingly high frequency of these two low-penetrance mutations in the cohort studied, leading to a heterogeneous pattern of CNS manifestations in affected patients. Thus, molecular genetic testing should be considered in patients with an unusual CNS inflammation and/or MS, who report additional symptoms compatible with CAPS.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Competing interests
T. Kümpfel Grant / Research Support from: TK has received grant support by Novartis Pharma, E. Schuh: None declared, R. Hohlfeld: None declared, P. Lohse: None declared