• Janneke G J Hoeijmakers, Chongyang Han, Ingemar S J Merkies, Lawrence J Macala, Giuseppe Lauria, Monique M Gerrits, Sulayman D Dib-Hajj, Catharina G Faber, and Stephen G Waxman.
• Neuroscience and Regeneration Research Centre, VA Connecticut Healthcare System, 950 Campbell Avenue, Building 34, West Haven, CT 06516, USA.
• Brain. 2012 Feb 1;135(Pt 2):345-58.

AbstractThe Na(V)1.7 sodium channel is preferentially expressed within dorsal root ganglion and sympathetic ganglion neurons and their small-diameter peripheral axons. Gain-of-function variants of Na(V)1.7 have recently been described in patients with painful small fibre neuropathy and no other apparent cause. Here, we describe a novel syndrome of pain, dysautonomia, small hands and small feet in a kindred carrying a novel Na(V)1.7 mutation. A 35-year-old male presented with erythema and burning pain in the hands since early childhood, later disseminating to the feet, cheeks and ears. He also experienced progressive muscle cramps, profound sweating, bowel disturbances (diarrhoea or constipation), episodic dry eyes and mouth, hot flashes, and erectile dysfunction. Neurological examination was normal. Physical examination was remarkable in revealing small hands and feet (acromesomelia). Blood examination and nerve conduction studies were unremarkable. Intra-epidermal nerve fibre density was significantly reduced compared to age- and sex-matched normative values. The patient's brother and father reported similar complaints including distal extremity redness and pain, and demonstrated comparable distal limb under-development. Quantitative sensory testing revealed impaired warmth sensation in the proband, father and brother. Genetic analysis revealed a novel missense mutation in the SCN9A gene encoding sodium channel Na(V)1.7 (G856D; c.2567G > A) in all three affected subjects, but not in unaffected family members. Functional analysis demonstrated that the mutation hyperpolarizes (-9.3 mV) channel activation, depolarizes (+6.2 mV) steady-state fast-inactivation, slows deactivation and enhances persistent current and the response to slow ramp stimuli by 10- to 11-fold compared with wild-type Na(V)1.7 channels. Current-clamp analysis of dorsal root ganglion neurons transfected with G856D mutant channels demonstrated depolarized resting potential, reduced current threshold, increased repetitive firing in response to suprathreshold stimulation and increased spontaneous firing. Our results demonstrate that the G856D mutation produces DRG neuron hyperexcitability which underlies pain in this kindred, and suggest that small peripheral nerve fibre dysfunction due to this mutation may have contributed to distal limb under-development in this novel syndrome.

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