Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy

Department of Neurology, University Medical Center Maastricht, Maastricht, The Netherlands.
Annals of Neurology (Impact Factor: 11.91). 01/2012; 71(1):26-39. DOI: 10.1002/ana.22485
Source: PubMed

ABSTRACT Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I-SFN). We sought to identify a genetic basis for I-SFN by screening patients with biopsy-confirmed idiopathic SFN for mutations in the SCN9A gene, encoding voltage-gated sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons.
Patients referred with possible I-SFN, who met the criteria of ≥2 SFN-related symptoms, normal strength, tendon reflexes, vibration sense, and nerve conduction studies, and reduced intraepidermal nerve fiber density (IENFD) plus abnormal quantitative sensory testing (QST) and no underlying etiology for SFN, were assessed clinically and by screening of SCN9A for mutations and functional analyses.
Twenty-eight patients who met stringent criteria for I-SFN including abnormal IENFD and QST underwent SCN9A gene analyses. Of these 28 patients with biopsy-confirmed I-SFN, 8 were found to carry novel mutations in SCN9A. Functional analysis revealed multiple gain of function changes in the mutant channels; each of the mutations rendered dorsal root ganglion neurons hyperexcitable.
We show for the first time that gain of function mutations in sodium channel Na(V)1.7, which render dorsal root ganglion neurons hyperexcitable, are present in a substantial proportion (28.6%; 8 of 28) of patients meeting strict criteria for I-SFN. These results point to a broader role of Na(V)1.7 mutations in neurological disease than previously considered from studies on rare genetic syndromes, and suggest an etiological basis for I-SFN, whereby expression of gain of function mutant sodium channels in small diameter peripheral axons may cause these fibers to degenerate.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We encountered a 5-year-old girl who had short-lasting, severe, unilateral temporal headaches with ipsilateral lacrimation, nasal congestion and rhinorrhoea, and facial flushing after severe attacks. Family history revealed similar short-lasting, severe headaches in an older brother, younger sister, mother, maternal aunt, and maternal grandfather's brother. We performed routine laboratory examinations and electrophysiological and radiological studies for three children, and whole-exome sequencing to determine the genetic causality in this family. Focal hyperperfusion of the right trigeminal root entry zone was seen during a right-sided attack in one child, while left-sided temporal headache attacks were provoked by bilateral electrical stimulation of the upper extremities in another. We identified a novel SCN9A mutation (NM_002977: c.5218G>C, p.Val1740Leu) in all affected family members, but not in any of the unaffected members. SCN9A encodes the voltage-gated sodium-channel type IX alpha subunit known as Nav1.7. Gain-of-function mutations in Nav1.7 are well known to cause paroxysmal extreme pain disorder (PEPD), a painful Na-channelopathy characterized by attacks of excruciating deep burning pain in the rectal, ocular, or jaw areas. The SCN9A mutation suggests that our patients had a phenotype of PEPD with a predominant symptom of short-lasting, severe, unilateral headache.
    The Journal of Headache and Pain 04/2015; 16(1):35. DOI:10.1186/s10194-015-0519-3 · 3.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Small fiber neuropathy is a syndrome of diverse disease etiology because of multiple pathophysiologic mechanisms with major presentations of neuropathic pain and autonomic symptoms. Over the past decade, there has been substantial progress in the treatments for neuropathic pain, dysautonomia and disease-modifying strategy. In particular, anticonvulsants and antidepressants alleviate neuropathic pain based on randomized clinical trials.
    Expert Review of Neurotherapeutics 02/2015; 15(3):1-9. DOI:10.1586/14737175.2015.1013097 · 2.83 Impact Factor
  • Klinische Neurophysiologie 12/2012; 43(04):254-258. DOI:10.1055/s-0032-1327672 · 0.33 Impact Factor