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Clinical Journal of Pain:
doi: 10.1097/AJP.0000000000000075
Original Articles

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

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Abstract

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.

Copyright © 2014 by Lippincott Williams & Wilkins

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