Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies

Abstract

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.

Keywords: diabetic neuropathy; molecular inversion probes; neuropathic pain; next generation sequencing; small fiber neuropathy; sodium channel genes variants.

Figure 1

PROPANE study patients analyzed for potentially pathogenic SCG variants by single molecule Molecular Inversion Probe-Next generation sequencing (smMIP-NGS). Between June 2014 and September 2016, patients with painful and painless diabetic peripheral neuropathy (DPN) and idiopathic small fiber neuropathy (SFN), recruited in four different centers, were screened for SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B variants by smMIP-NGS. The variants’ pathogenicity was classified according to current classification guidelines [16]. UK, University of Manchester, United Kingdom; GER, Deutsche Diabetes Forschungsgesellschaft EV, Germany; IT, Fondazione IRCCS Instituto Neurologico “Carlo Besta”, Italy; NET, Maastricht University Medical Center+, the Netherlands; n, number; pts, patients; Painful-DPN, painful-diabetic peripheral neuropathy; Painless-DPN, painless-diabetic peripheral neuropathy; Painful-SFN, painful-idiopathic small fiber neuropathy; Painless-SFN, painless-idiopathic small fiber neuropathy; SCG, sodium channel genes.

Figure 2

Clinical features in patients with painful and painless diabetic peripheral neuropathy (DPN) and painful and painless idiopathic small fiber neuropathy (SFN). (A) Neuropathic Pain Scale (NPS) of painful-DPN (n = 149), painless-DPN (n = 125), painful-SFN (n = 247), and painless-SFN (n = 4) patients. Each item is scored on an 11-point scale (0 = not applicable to the experienced pain, and 10 = in the most severe form applicable to the experienced pain). An NPS score > 3 is considered as a relevant pain quality. (B) SFN symptoms inventory questionnaire (SFN-SIQ) of painful-DPN (n = 152), painless-DPN (n = 172), painful-SFN (n = 266) and painless-SFN (n = 4) patients. The answer options of the SFN-SIQ include ‘never = 1’,‘sometimes = 2’, ‘often = 3’ and ‘always = 4’. A symptom is considered to be present when the score is >1. Statistically significant differences are shown as * for p < 0.05, ** for p < 0.01, and *** p < 0.001. Painful-DPN, painful-diabetic peripheral neuropathy; Painless-DPN, painless-diabetic peripheral neuropathy; Painful-SFN, painful-idiopathic small fiber neuropathy; Painless-SFN, painless-idiopathic small fiber neuropathy.

Figure 3

SCG variant positive patients with painful and painless diabetic peripheral neuropathy and painful and painless idiopathic small fiber neuropathy. (A) Percentage of SCN3A, SCN7A-SCN11A and SCN1B-SFN4B positive painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32) patients with ≥1 variant(s). (B) Percentages of SCN3A, SCN7A-SCN11A and SCN1B-4B positive patients with ≥1 variant(s) corrected for variants that were not specific for a painful or painless diabetic/idiopathic neuropathy. Painful-DPN, painful diabetic peripheral neuropathy; Painless-DPN, painless diabetic peripheral neuropathy; Painful-SFN, painful-idiopathic small fiber neuropathy; Painless-SFN, painless-idiopathic small fiber neuropathy; SCG, sodium channel genes.