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Molecular Analysis of Cluster Headache

Zarrilli, Federica ScD, PhD*; Tomaiuolo, Rossella MD, PhD†,‡; Ceglia, Carlo ScD, PhD†,‡; Lombardo, Barbara ScD, PhD†,‡; Izzo, Barbara ScD, PhD‡,§; Castaldo, Giuseppe MD, PhD†,‡; Pastore, Lucio MD, PhD†,‡; De Simone, Roberto MD

doi: 10.1097/AJP.0000000000000075
Original Articles

Objectives: Cluster headache (CH) is characterized by severe, recurrent, unilateral attacks of extreme intensity and brief duration. Variants in a myriad of genes were studied in sporadic CH patients, often with conflicting results.

Methods: We studied gene mutations in some candidate genes, hypocretin receptor 2, Clock, and alcohol dehydrogenase 4 (ADH4), in 54 unrelated sporadic CH patients and in 200 controls in 8 kindreds/families that included more affected and nonaffected cases. Furthermore, we performed the whole-genome scanning by comparative genomic hybridization, searching for rearrangements associated with DNA gain or loss in a subset of sporadic and familial CH and control participants.

Results: The analysis of candidate genes revealed that only allele and genotype frequency of the 2 ADH4 mutations resulted significantly between sporadic CH and controls; the same mutations were homozygous in CH patients from 2 families. The comparative genomic hybridization analysis revealed 2 novel rearrangements that involved the intron regions of thyrotropin-releasing hormone-degrading enzyme and neurexin 3 (NRXN3) genes, respectively. The first arrangement was present either in CH or in controls, whereas the second one was specifically found in some sporadic and familial CH cases.

Conclusions: Our data (although obtained on a small number of cases) confirm the genetic heterogeneity of CH, suggesting that mutations in the ADH4 gene and a novel rearrangement involving NRXN3 gene might be related to CH in a subset of cases.

*Dipartimento di Bioscienze e Territorio, Università del Molise, Isernia, Italy

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy

§Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli Federico II, Naples, Italy

Dipartimento di Neuroscienze e Scienze Riproduttive e Odontostomatologiche, Università di Napoli Federico II, Naples, Italy

CEINGE-Biotecnologie Avanzate, Naples, Italy

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Supported by a grant from Regione Campania (DGRC 1901/2009) and by POR Campania FSE 2007-13, Project CREME. It was a contribution of Campania region (public administration) aimed to fund research and diagnostics in the field of genes related to human disorders. The authors declare no conflict of interest.

Reprints: Giuseppe Castaldo, MD, PhD, CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, I-80145, Naples, Italy (e-mail:

Received November 15, 2013

Received in revised form February 13, 2014

Accepted January 15, 2014

© 2015 by Lippincott Williams & Wilkins