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Expanding spectrum of neurologic manifestations in patients with NLRP3 low-penetrance mutations

Neurol Neuroimmunol Neuroinflamm. 2015 May 14;2(4):e109. doi: 10.1212/NXI.0000000000000109. eCollection 2015.

Authors/Editors: Schuh E, Lohse P, Ertl-Wagner B, Witt M, Krumbholz M, Frankenberger M, Gerdes LA, Hohlfeld R, Kümpfel T.
Publication Date: 2015



To evaluate the frequency of the cryoporin/NLRP3 low-penetrance mutations V198M and Q703K in patients who reported at least 2 symptoms compatible with cryopyrin-associated periodic syndromes (CAPS) and to characterize the phenotype in mutation-positive patients.

The frequency of the V198M and Q703K mutations was investigated in a selected cohort of 108 patients from our neuroimmunology department. We describe the clinical, neurologic, immunologic, and neuroradiologic features of the mutation carriers.

Seventeen patients (16%) tested positive for either of the 2 mutations (V198M: n = 2; Q703K: n = 15). Eleven patients (65%) had severe headache syndromes. Six of these 11 patients were diagnosed with migraine. Nine patients (53%) had a concomitant diagnosis of multiple sclerosis (MS). In 3 patients, we identified additional family members with the respective mutation as well as the diagnosis of MS. Severe recurrent cranial nerve (CN) affection was the hallmark feature in 7 of the 8 (88%) non-MS mutation carriers. Brain MRI showed abnormalities in all but 2 patients (88%) and detected CN inflammation in 4 patients. Interleukin-6 was elevated in the CSF of 2 patients in the non-MS cohort during acute CAPS episodes with severe CNS inflammation. 5 of 9 treated patients (56%) responded to anti-interleukin-1 therapy.

CAPS constitute rare but treatable and commonly misdiagnosed autoinflammatory syndromes. Our data expand the spectrum of CAPS-associated neurologic manifestations. They also broaden our concept of autoimmunity and autoinflammation by linking CAPS and MS.

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