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Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy.

ABSTRACT: Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis for better patient stratification in clinical trials and to target therapy more appropriately. Here, we examined the relationship between variants in the voltage-gated sodium channel NaV1.7 and NeuP in a deeply phenotyped cohort of patients with DPN. Although no rare variants were found in 78 participants with painless DPN, we identified 12 rare NaV1.7 variants in 10 (out of 111) study participants with painful DPN. Five of these variants had previously been described in the context of other NeuP disorders and 7 have not previously been linked to NeuP. Those patients with rare variants reported more severe pain and greater sensitivity to pressure stimuli on quantitative sensory testing. Electrophysiological characterization of 2 of the novel variants (M1852T and T1596I) demonstrated that gain of function changes as a consequence of markedly impaired channel fast inactivation. Using a structural model of NaV1.7, we were also able to provide further insight into the structural mechanisms underlying fast inactivation and the role of the C-terminal domain in this process. Our observations suggest that rare NaV1.7 variants contribute to the development NeuP in patients with DPN. Their identification should aid understanding of sensory phenotype, patient stratification, and help target treatments effectively.

SUBMITTER: Blesneac I

PROVIDER: S-EPMC5828379 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy.

Blesneac Iulia I Themistocleous Andreas C AC Fratter Carl C Conrad Linus J LJ Ramirez Juan D JD Cox James J JJ Tesfaye Solomon S Shillo Pallai R PR Rice Andrew S C ASC Tucker Stephen J SJ Bennett David L H DLH

Pain 20180301 3

Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis for better patient stratification in clinical trials and to target therapy more appropriately. Here, we examined the relationship between variants in the ...[more]

PMID: 29176367

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Project description:Background Diabetic peripheral neuropathy is a common long-term complication of diabetes. Accumulating evidence suggests that vascular impairment plays important roles in the pathogenesis of diabetic peripheral neuropathy, while the mechanism remains unclear. We recently reported that transient receptor potential ankyrin 1 (TRPA1) is sensitized by hypoxia, which can contribute to cold hypersensitivity. In this study, we investigated the involvement of TRPA1 and vascular impairment in painful diabetic peripheral neuropathy using streptozotocin-induced diabetic model mice. Results Streptozotocin-induced diabetic model mice showed mechanical and cold hypersensitivity with a peak at two weeks after the streptozotocin administration, which were likely to be paralleled with the decrease in the skin blood flow of the hindpaw. Streptozotocin-induced cold hypersensitivity was significantly inhibited by an antagonist HC-030031 (100 mg/kg) or deficiency for TRPA1, whereas mechanical hypersensitivity was unaltered. Consistent with these results, the nocifensive behaviors evoked by an intraplantar injection of the TRPA1 agonist allyl isothiocyanate (AITC) were enhanced two weeks after the streptozotocin administration. Both streptozotocin-induced cold hypersensitivity and the enhanced AITC-evoked nocifensive behaviors were significantly inhibited by a vasodilator, tadalafil (10 mg/kg), with recovery of the decreased skin blood flow. Similarly, in a mouse model of hindlimb ischemia induced by the ligation of the external iliac artery, AITC-evoked nocifensive behaviors were significantly enhanced three and seven days after the ischemic operation, whereas mechanical hypersensitivity was unaltered in TRPA1-knockout mice. However, no difference was observed between wild-type and TRPA1-knockout mice in the hyposensitivity for current or mechanical stimulation or the deceased density of intraepidermal nerve fibers eight weeks after the streptozotocin administration. Conclusion These results suggest that TRPA1 sensitization during diabetic vascular impairment causes cold, but not mechanical, hypersensitivity in the early painful phase of diabetic peripheral neuropathy. However, TRPA1 may play little or no role in the progression of diabetic peripheral neuropathy.

Project description:There are no data on physician-patient communication in painful diabetic peripheral neuropathy (pDPN) in the Asia-Pacific region. The objective of this study was to examine patient and physician perceptions of pDPN and clinical practice behaviors in five countries in South-East Asia. Primary care physicians and practitioners, endocrinologists, diabetologists, and patients with pDPN completed separate surveys on pDPN diagnosis, impact, management, and physician-patient interactions in Hong Kong, Malaysia, the Philippines, Taiwan, and Thailand. Data were obtained from 100 physicians and 100 patients in each country. The majority of physicians (range across countries, 30-85%) were primary care physicians and practitioners. Patients were mostly aged 18-55 years and had been diagnosed with diabetes for >5 years. Physicians believed pDPN had a greater impact on quality of life than did patients (ranges 83-92% and 39-72%, respectively), but patients believed pDPN had a greater impact on items such as sleep, anxiety, depression, and work than physicians. Physicians considered the diagnosis and treatment of pDPN a low priority, which may be reflected in the generally low incidence of screening (range 12-65%) and a lack of awareness of pDPN. Barriers to treatment included patients' lack of awareness of pDPN. Both physicians and patients agreed that pain scales and local language descriptions were the most useful tools in helping to describe patients' pain. Most patients were monitored upon diagnosis of pDPN (range 55-97%), but patients reported a shorter duration of monitoring compared with physicians. Both physicians and patients agreed that it was patients who initiated conversations on pDPN. Physicians most commonly referred to guidelines from the American Diabetes Association or local guidelines for the management of pDPN. This study highlights important differences between physician and patient perceptions of pDPN, which may impact on its diagnosis and treatment. For a chronic and debilitating complication like pDPN, the physician-patient dialogue is central to maximizing patient outcomes. Strategies, including education of both groups, need to be developed to improve communication.FundingPfizer.

Dataset Information

Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy.

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Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy.

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