title: Expanding spectrum of neurologic manifestations in patients with NLRP3 low-penetrance mutations.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Clinical Neuroimmunology (E.S., M.K., L.-A.G., R.H., T.K.), Institute of Clinical Radiology (B.E.-W.), and Department of Rheumatology (M.W.), Ludwig-Maximillians University, Munich, Germany; Department of Neuroimmunology (E.S.), Center of Brain Research, Vienna, Austria; Institute of Laboratory Medicine and Human Genetics (P.L.), Singen, Germany; Comprehensive Pneumology Center (M.F.) (Ludwig-Maximilians University Munich, Asklepios Kliniken Gauting, Helmholtz Zentrum München, Germany); and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schuh
authors.affiliation: Institute of Clinical Neuroimmunology (E.S., M.K., L.-A.G., R.H., T.K.), Institute of Clinical Radiology (B.E.-W.), and Department of Rheumatology (M.W.), Ludwig-Maximillians University, Munich, Germany; Department of Neuroimmunology (E.S.), Center of Brain Research, Vienna, Austria; Institute of Laboratory Medicine and Human Genetics (P.L.), Singen, Germany; Comprehensive Pneumology Center (M.F.) (Ludwig-Maximilians University Munich, Asklepios Kliniken Gauting, Helmholtz Zentrum München, Germany); and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.affiliation: Institute of Clinical Neuroimmunology (E.S., M.K., L.-A.G., R.H., T.K.), Institute of Clinical Radiology (B.E.-W.), and Department of Rheumatology (M.W.), Ludwig-Maximillians University, Munich, Germany; Department of Neuroimmunology (E.S.), Center of Brain Research, Vienna, Austria; Institute of Laboratory Medicine and Human Genetics (P.L.), Singen, Germany; Comprehensive Pneumology Center (M.F.) (Ludwig-Maximilians University Munich, Asklepios Kliniken Gauting, Helmholtz Zentrum München, Germany); and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Ertl-Wagner
authors.affiliation: Institute of Clinical Neuroimmunology (E.S., M.K., L.-A.G., R.H., T.K.), Institute of Clinical Radiology (B.E.-W.), and Department of Rheumatology (M.W.), Ludwig-Maximillians University, Munich, Germany; Department of Neuroimmunology (E.S.), Center of Brain Research, Vienna, Austria; Institute of Laboratory Medicine and Human Genetics (P.L.), Singen, Germany; Comprehensive Pneumology Center (M.F.) (Ludwig-Maximilians University Munich, Asklepios Kliniken Gauting, Helmholtz Zentrum München, Germany); and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Witt
authors.affiliation: Institute of Clinical Neuroimmunology (E.S., M.K., L.-A.G., R.H., T.K.), Institute of Clinical Radiology (B.E.-W.), and Department of Rheumatology (M.W.), Ludwig-Maximillians University, Munich, Germany; Department of Neuroimmunology (E.S.), Center of Brain Research, Vienna, Austria; Institute of Laboratory Medicine and Human Genetics (P.L.), Singen, Germany; Comprehensive Pneumology Center (M.F.) (Ludwig-Maximilians University Munich, Asklepios Kliniken Gauting, Helmholtz Zentrum München, Germany); and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Krumbholz
authors.affiliation: Institute of Clinical Neuroimmunology (E.S., M.K., L.-A.G., R.H., T.K.), Institute of Clinical Radiology (B.E.-W.), and Department of Rheumatology (M.W.), Ludwig-Maximillians University, Munich, Germany; Department of Neuroimmunology (E.S.), Center of Brain Research, Vienna, Austria; Institute of Laboratory Medicine and Human Genetics (P.L.), Singen, Germany; Comprehensive Pneumology Center (M.F.) (Ludwig-Maximilians University Munich, Asklepios Kliniken Gauting, Helmholtz Zentrum München, Germany); and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Frankenberger
authors.affiliation: Institute of Clinical Neuroimmunology (E.S., M.K., L.-A.G., R.H., T.K.), Institute of Clinical Radiology (B.E.-W.), and Department of Rheumatology (M.W.), Ludwig-Maximillians University, Munich, Germany; Department of Neuroimmunology (E.S.), Center of Brain Research, Vienna, Austria; Institute of Laboratory Medicine and Human Genetics (P.L.), Singen, Germany; Comprehensive Pneumology Center (M.F.) (Ludwig-Maximilians University Munich, Asklepios Kliniken Gauting, Helmholtz Zentrum München, Germany); and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.
authors.forename: Lisa-Ann
authors.initials: LA
authors.lastname: Gerdes
authors.affiliation: Institute of Clinical Neuroimmunology (E.S., M.K., L.-A.G., R.H., T.K.), Institute of Clinical Radiology (B.E.-W.), and Department of Rheumatology (M.W.), Ludwig-Maximillians University, Munich, Germany; Department of Neuroimmunology (E.S.), Center of Brain Research, Vienna, Austria; Institute of Laboratory Medicine and Human Genetics (P.L.), Singen, Germany; Comprehensive Pneumology Center (M.F.) (Ludwig-Maximilians University Munich, Asklepios Kliniken Gauting, Helmholtz Zentrum München, Germany); and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hohlfeld
authors.affiliation: Institute of Clinical Neuroimmunology (E.S., M.K., L.-A.G., R.H., T.K.), Institute of Clinical Radiology (B.E.-W.), and Department of Rheumatology (M.W.), Ludwig-Maximillians University, Munich, Germany; Department of Neuroimmunology (E.S.), Center of Brain Research, Vienna, Austria; Institute of Laboratory Medicine and Human Genetics (P.L.), Singen, Germany; Comprehensive Pneumology Center (M.F.) (Ludwig-Maximilians University Munich, Asklepios Kliniken Gauting, Helmholtz Zentrum München, Germany); and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Kümpfel