Sodium Channel Mutations in Idiopathic Small Fiber Neuropathy
Sodium Channel Mutations in Idiopathic Small Fiber Neuropathy
Abstract & Commentary
By Joshua Weaver, MD, and Norman Latov, MD, PhD. Dr. Weaver is a Clinical Neurophysiology Fellow, and Dr. Latov is Professor of Neurology and Neuroscience, and Director of the Peripheral Neuropathy Clinical and Research Center, Weill Cornell Medical College.
Dr. Weaver reports no financial relationships relevant to this field of study. Dr. Latov has served as consultant to Grifols, Novartis, CSL Behring, Pfizer, Octapharma, Baxter Biotherapeutics, Elan Pharmaceuticals, Depomed, and Eisai Inc. He owns stock in Therapath LLC, and is beneficiary of a licensing agreement between Cornell University and Teva Pharmaceuticals for a patent related to the use of MSR1 antibodies in inflammatory diseases.
Synopsis: Gain-of-function mutations in a voltage-gated sodium channel, Nav1.7 that renders dorsal root ganglion neurons hyperexcitable, are present in approximately one quarter of patients with idiopathic small fiber neuropathy. Such mutations might be responsible for the degeneration of small nerve fibers and associated symptoms.
Source: Faber CG, et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012;71:26-39.
Small fiber neuropathy (SFN) is a relatively common disorder that affects small somatic and/or autonomic nerves. Known causes include diabetes, vitamin B12 deficiency, and Sjogren's syndrome among others, although the condition is idiopathic in most cases.
Nav1.7 is a voltage-gated sodium channel expressed in the ganglia and axons of small-diameter peripheral nerves. Gain-of-function mutations in the SCN9A gene encoding Nav1.7 have been associated with Paroxysmal Extreme Pain Disorder (PEPD)1 or Inherited Erythromelalgia (IEM),2 while loss of function mutations of Nav1.7 are associated with insensitivity to pain.3
Patients with idiopathic SFN were recruited from the Masstricht University Medical Center in the Netherlands. Eligibility criteria included normal nerve conduction studies and reduced intraepidermal nerve fiber density on skin biopsy. Patients with an associated systemic disorder were excluded.
Complementary DNA from exons in the SCN9A gene coding for Nav1.7 from each subject was amplified, sequenced, and compared to controls to identify sequence variations. Functional analysis of the Nav1.7 mutation was done via voltage clamp (to assess channel function) and current clamp (to assess dorsal root ganglion neuron firing properties). Of 28 patients tested, eight (28.6%) were found to have mutations in the SCN9A gene. All were heterozygous for the mutation, and all mutations were missense. All eight patients reported skin hyperesthesia and burning feet, and seven patients reported autonomic dysfunction with dry eyes, dry mouth, orthostatic dizziness, and palpitations.
Seven unique mutations were identified (two unrelated patients shared the same mutation); all were gain of function mutations rendering dorsal root ganglion hyperexcitable.
Commentary
This is the first study to show that missense mutations in the voltage-gated sodium channel Nav1.7 (distinct from those found previously associated with IEM and PEPD) are present in a large proportion of patients with idiopathic SFN.
The study paves the way for a better understanding of the etiology of SFN, and may lead to better treatment options for patients suffering with pain. As these investigations proceed, additional pain syndromes are being identified and linked to Nav1.7 mutations,4,5 and at least one study has shown phenotypic variability for a given mutation within the same family.6 Treatment options recently have focused on medications that affect sodium channel functioning, such as mexiletine (a lidocaine derivative),7 and new sodium channel blockers are being developed that may more effectively treat these pain syndromes.8
Limitations of Faber et al's study include possible selection bias and the lack of diversity among the cohort (all Dutch Caucasians from the same academic center) making it harder to relate to the general population. Larger studies with more diverse patient populations need to be done to confirm and expand these findings. Studies evaluating Nav1.7 mutations in the general population (including asymptomatic patients and those that meet less strict criteria of small fiber neuropathy) will be needed to assess the prevalence and degree of penetrance of Nav1.7 mutations. Future drug trials assessing the efficacy of sodium channel blockers in treating patients with Nav1.7 mutations and SFN will be of particular interest.
References
1. Fertleman CR, et al. SCN9A mutations in paroxysmal extreme pain disorder: Allelic variants underlie distinct channel defects and phenotypes. Neuron 2006;52:767-774.
2. Yang Y, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet 2004;41:171-174.
3. Goldberg Y, et al. Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet 2007;71:311-319.
4. Dabby R, et al. Chronic non-paroxysmal neuropathic pain Novel phenotype of mutation in the sodium channel SCN9A gene. J Neurol Sci 2011;301:90-92.
5. Hoeijmakers JG, et al. Small nerve fibres, small hands and small feet: A new syndrome of pain, dysautonomia and acromesomelia in a kindred with a novel Nav1.7 mutation. Brain 2012 Jan 26 [Epub ahead of print].
6. Estacion M, et al. Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of Nav1.7. Mol Pain 2011;7:92.
7. Choi JS, et al. Mexiletine-responsive erythromelalgia due to a new Nav1.7 mutation showing use-dependent current fall-off. Exp Neurol 2009;216:383-389.
8. Goldberg YP, et al. Treatment of Nav1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker. Pain 2012;153:80-85.
Small fiber neuropathy (SFN) is a relatively common disorder that affects small somatic and/or autonomic nerves. Known causes include diabetes, vitamin B12 deficiency, and Sjogren's syndrome among others, although the condition is idiopathic in most cases.Subscribe Now for Access
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