Neurol Sci DOI 10.1007/s10072-014-1919-x

LETTER TO THE EDITOR

Familiar Mediterranean fever and multiple sclerosis: an unreported association in the Italian population? Margherita Russo • Antonino Naro • Vincenzo Dattola • Romina Gallizzi • Rocco Salvatore Calabro` • Maria Buccafusca

Received: 13 May 2014 / Accepted: 4 August 2014 Ó Springer-Verlag Italia 2014

Sir, Familial Mediterranean fever (FMF) is an inherited disease characterized by recurrent self-limited attacks of fever, polyserositis, and secondary amyloidosis, rarely involving central nervous system (CNS). It is an ethnically restricted genetic disease, commonly found among Mediterranean populations, rarely in Italians [1]. The FMF gene (MEFV) has been mapped to chromosome 16p 13.3, being the E148Q, M680I, M694V, and V726A the most common variants [1]. Most FMF patients have homozygous mutations in the MEFV encoding for the protein pyrin, which is predominantly expressed in polymorphonuclear leukocytes and cytokine-activated monocytes. Hence, mutations of genes like MEFV may produce proinflammatory conditions and promote the development of a variety of autoimmuneinflammatory diseases, including multiple sclerosis (MS) [1]. Since the reported patients carrying the FMF/MS association mostly came from the middle-eastern areas, herein we describe for the first ever time an Italian young female with this intriguing association.

M. Russo (&)  A. Naro  R. S. Calabro` IRCCS Centro Neurolesi Bonino-Pulejo, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy e-mail: [email protected]

Case A 24-year-old female comes to our observation for paresthesia in the left upper limb, followed after two months by motor impairment in lower limbs. Family and personal history was unremarkable, but at the age of 10 she was diagnosed with FMF with MEFV homozygous M680I-G/C and V726A mutations, after having presented episodes of arthralgias and gastrointestinal symptoms, successfully treated with colchicine. Physical examination was negative, whereas neurological examination showed tetrahyperreflexia, mild left hemiparesis and hypoesthesia. Hematochemical tests, including autoimmune screening, were normal, as well as cerebrospinal fluid investigation. Evoked potentials evaluation showed an increased left somatosensory central conduction time and an increased right P100 latency. A brain magnetic resonance imaging (MRI) showed more than nine hyperintense lesions in T2 weighted and FLAIR sequences, mainly involving corpus callosum, centrum semiovale and periventricular white matter; some lesions were hypointense in T1weighted images, and four of these presented a post-gadolinium enhancement. In addition, a spinal cord MRI evidenced two T2 hyperintense lesions at C2 and C4 level. According to current McDonald criteria, the diagnosis of MS was posed. The patient was treated with high i.v. doses of steroids, with a mild recovery, and then with beta-interferon (INF-b) for around 3 years. As she then showed a clinical and neuroimaging worsening, she was prescribed Natalizumab, with nearly stable clinical picture at 7-year follow-up.

V. Dattola  M. Buccafusca Department of Neuroscience, Faculty of Medicine, Messina, Italy

Discussion

R. Gallizzi Department of pediatrics, Faculty of Medicine, Messina, Italy

To the best of our knowledge, this is the first description of an association between FMF and MS in an Italian patient.

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This relationship is still a matter of debate and the impact of MEFV mutations on the clinical course of MS is not yet fully understood. Several studies showed a correlation between the M694V variant in MEFV and disease severity in MS, which can be explained through an increase in inflammatory damage [2]. On the other hand, a recent study indicates that MEFV gene mutations do not affect the neurological prognosis in MS patients [3]. Our patient showed common FMF mutation, i.e. homozygous M680IG/C and a V726A, that code for the protein pyrin. The pyrin domain is a member of the six-helix bundle, deathdomain super-family. Thus, in patients with lack of pyrin protein—or its activity—there is no suppression or inhibition of inflammatory process, thereby leading to a fullblown attack. Pyrin is implicated in the maturation and secretion of the proinflammatory cytokine IL-1b, which is a main mediator of fever and systemic inflammation [4]. Moreover, IL-1 plays a significant role in the regulation of the T cells, and it is considered an essential cytokine for the T-helper cell differentiation that are involved in the MS pathogenesis [4]. In MS, the proinflammatory cytokine IL1b is also present in the CNS, because it is expressed by microglial cells and infiltrating monocyte/macrophages throughout the white matter and around the lesions. Thus, IL-1b is likely to play a part in MS pathogenesis. It is worthy to remember that MS and FMF share some analogies: recurrence of attacks, inflammatory reactions, intra-

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individual variability in terms of frequency and severity of periodic attacks. According to our findings, we would underline the importance of MEF genetic analysis in those MS patients complaining unusual symptoms like recurrent and episodic fever, abdominal pain and diffuse arthralgia. Indeed, many cases of association between MS and FMF may be to date misdiagnosed, especially in the Italian population, where FMF seems to be not so common even if Italians belong to the Mediterranean ethnic group.

References 1. Unal A, Dursun A, Emre U, Tascilar NF, Ankaralin H (2010) Evaluation of common mutations in the Mediterranean fever gene in multiple sclerosis patients: is it a susceptibility gene? J Neurol Sci 294:38–42 2. Alpayci M, Bozan N, Erdem S, Gunes M, Erden M (2012) The possible underlying pathophysiological mechanisms for development of multiple sclerosis in familial Mediterranean fever. Med Hypotheses 78:717–720 3. Terzi M, Taskın E, Unal Akdemir N, Bagcı H, Onar M (2014) The relationship between familial mediterranean fever gene (MEFV) mutations and clinical and radiological parameters in multiple sclerosis patients. Int J Neurosci. doi:10.3109/00207454.2014.913170 4. Zhao R, Zhou H, Su SB (2013) A critical role for interleukin-1b in the progression of autoimmune diseases. Int Immunopharmacol 17:658–669

Familiar Mediterranean fever and multiple sclerosis: an unreported association in the Italian population?

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