A novel TRPA1 variant is associated with carbamazepine-responsive cramp-fasciculation syndrome

M. J. Nirenberg, R. Chaouni, T. M. Biller, R. M. Gilbert, C. Paisán-Ruiz

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Cramp-fasciculation syndrome (CFS) is a rare muscle hyperexcitability syndrome that presents with muscle cramps, fasciculations, and stiffness, as well as pain, fatigue, anxiety, hyperreflexia, and paresthesias. Although familial cases have been reported, a genetic etiology has not yet been identified. We performed whole-exome sequencing followed by validation and cosegregation analyses on a father-son pair with CFS. Both subjects manifested other hypersensitivity-hyperexcitability symptoms, including asthma, gastroesophageal reflux, migraine, restless legs syndrome, tremor, cold hyperalgesia, and cardiac conduction defects. Most symptoms improved with carbamazepine, consistent with an underlying cation channelopathy. We identified a variant in the transient receptor potential ankyrin A1 channel (TRPA1) gene that selectively cosegregated with CFS and the other hypersensitivity-hyperexcitability symptoms. This variant (c.2755C>T) resulted in a premature stop codon at amino acid 919 (p.Arg919*) in the outer pore of the channel. TRPA1 is a widely distributed, promiscuous plasmalemmal cation channel that is strongly implicated in the pathophysiology of the specific hypersensitivity-hyperexcitability symptoms observed in these subjects. Thus, we have identified a novel TRPA1 variant that is associated with CFS as part of a generalized hypersensitivity-hyperexcitability disorder. These findings clarify the diverse functional roles of TRPA1, and underscore the importance of this channel as a potential therapeutic target.

Original languageEnglish
Pages (from-to)164-168
Number of pages5
JournalClinical Genetics
Issue number1
StatePublished - Jan 2018


  • TRPA1
  • asthma
  • cardiac
  • channelopathy
  • cramp
  • fasciculation
  • gastrointestinal
  • migraine
  • pain


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