Gain-of-function Naᵥ1.8 mutations in painful neuropathy Faber, Catharina G; Lauria, Giuseppe; Merkies, Ingemar S. J ...
Proceedings of the National Academy of Sciences - PNAS,
11/2012, Letnik:
109, Številka:
47
Journal Article
Recenzirano
Painful peripheral neuropathy often occurs without apparent underlying cause. Gain-of-function variants of sodium channel Na ᵥ1.7 have recently been found in ∼30% of cases of idiopathic painful ...small-fiber neuropathy. Here, we describe mutations in Na ᵥ1.8, another sodium channel that is specifically expressed in dorsal root ganglion (DRG) neurons and peripheral nerve axons, in patients with painful neuropathy. Seven Na ᵥ1.8 mutations were identified in 9 subjects within a series of 104 patients with painful predominantly small-fiber neuropathy. Three mutations met criteria for potential pathogenicity based on predictive algorithms and were assessed by voltage and current clamp. Functional profiling showed that two of these three Na ᵥ1.8 mutations enhance the channel’s response to depolarization and produce hyperexcitability in DRG neurons. These observations suggest that mutations of Na ᵥ1.8 contribute to painful peripheral neuropathy.
Objective:
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 NaV1.7, which is preferentially expressed in small diameter peripheral axons.
Methods:
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.
Results:
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.
Interpretation:
We show for the first time that gain of function mutations in sodium channel NaV1.7, 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 NaV1.7 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. ANN NEUROL 2012;71:26–39
Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small-caliber nerve fibers of unknown etiology ...with limited treatment options. Functional variants of voltage-gated sodium channel Nav1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium channel Nav1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Nav1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Nav1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN.
ABSTRACT
Introduction: The impact of small‐fiber neuropathy (SFN) on patients' quality of life (QOL) has not been studied extensively. Our aim was to determine the impact of SFN on QOL and examine ...possible determinants. Methods: We examined a total of 265 patients diagnosed with SFN. The SFN Symptoms Inventory Questionnaire (SFN‐SIQ), the pain Visual Analog Scale (VAS), and the generic SF‐36 Health Survey were assessed. Regression studies were undertaken to evaluate determinants of functioning. Results: SFN patients demonstrated a severe overall reduction in QOL. The biggest deficits were in Role Functioning–Physical, Body Pain, and Physical Component Summary (PCS) scores. VAS scores, changed sweating pattern, dry mouth, and age were the strongest predictors for PCS, explaining 32% of the QOL decrease. Conclusions: SFN leads to a reduction in overall QOL. The presence of pain and some autonomic symptoms explained only a small portion of the findings. Muscle Nerve 49:329–336, 2014
Small fiber neuropathy (SFN) is a common cause of neuropathic pain in peripheral neuropathies. Good accessibility of diagnostics and treatment is necessary for an accurate diagnosis and treatment of ...SFN. Evidence is lacking on the quality performance of the diagnostic SFN service in the Netherlands. Our aim was to determine the patient satisfaction and -accessibility of the diagnostic SFN service, and to identify areas for improvement.
In a single-center, prospective, survey-based cohort study, 100 visiting patients were asked to fill in the SFN patient satisfaction questionnaire (SFN-PSQ), with 10 domains and 51 items. Cut-off point for improvement was defined as ≥ 25% dissatisfaction on an item. A chi-square test and linear regression analyses was used for significant differences and associations of patient satisfaction.
From November 2020 to May 2021, 98 patients with SFN-related complaints filled in the online SFN-PSQ within 20 minutes. In 84% of the patients SFN was confirmed, average age was 55.1 (52.5-57.8) years and 67% was female. High satisfaction was seen in the domains 'Waiting List Period', Chest X-ray', 'Consultation with the Doctor or Nurse Practitioner (NP)', 'Separate Consultation with the Doctor or NP about Psychological Symptoms', and 'General' of the SFN service. Overall average patient satisfaction score was 8.7 (IQR 8-10) on a 1-to-10 rating scale. Main area for improvement was shortening the 8-week period for receiving the results of the diagnostic testing (p < 0.05). General health status was statistically significant associated with patient satisfaction (p < 0.05).
A good reflection of the high patient satisfaction and -accessibility of the SFN-service is shown, with important points for improvement. These results could help hospitals widely to optimize the logistic and diagnostic pathway of SFN analysis, benchmarking patient satisfaction results among the hospitals, and to improve the quality of care of comparable SFN services.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Small‐fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ and unmyelinated C fibers. SFN is clinically dominated by neuropathic pain and autonomic complaints, leading to a significant ...reduction in quality of life. According to international criteria, the diagnosis is established by the assessment of intraepidermal nerve fiber density and/or quantitative sensory testing. SFN is mainly associated with autoimmune diseases, sodium channel gene variants, diabetes mellitus, and vitamin B12 deficiencies, although in more than one half of patients no etiology can be identified. Recently, gain‐of‐function variants in the genes encoding for the Nav1.7, Nav1.8 and Nav1.9 sodium channel subunits have been discovered in SFN patients, enlarging the spectrum of underlying conditions. Sodium channel gene variants associated with SFN can lead to a diversity of phenotypes, including different pain distributions and presence or absence of autonomic symptoms. This suggests that SFN is part of a clinical continuum. New assessments might contribute to a better understanding of the cellular and molecular substrates of SFN and might provide improved diagnostic methods and trial designs in the future. Identification of the underlying mechanisms may inform the development of drugs that more effectively address neuropathic pain and autonomic symptoms of SFN.
OBJECTIVE:To determine the minimum incidence and minimum prevalence rates of small-fiber neuropathy (SFN) in a well-defined region in the southern part of the Netherlands.
METHODS:In this ...cross-sectional study with retrospective data collection, we used data of patients diagnosed with pure SFN at our Small Fiber Neuropathy Center between January 2006 and December 2011 to calculate minimum incidence and prevalence rates.
RESULTS:A total of 88 patients were diagnosed with SFN (mean age 56.9 years, SD 11.8, range 34–81; 44.3% women, 55.7% men). The overall minimum incidence over 2010 and 2011 was 11.73 (95% confidence interval 7.12–18.22) cases/100,000 inhabitants/year. The overall minimum prevalence was 52.95 (95% confidence interval 42.47–65.23) cases/100,000. Incidence and prevalence rates were higher in men than in women, as were the rates in elderly patients compared with younger patients.
CONCLUSIONS:The minimum incidence and prevalence rates of SFN are presented. We found that SFN is more frequently seen in men and more often diagnosed in elderly patients. These rates probably are an underestimation and are expected to increase in the coming years, since the awareness of SFN is increasing worldwide.
A previously published Rasch-built activity and participation scale specifically designed for patients with myotonic dystrophy type 1 (DM1) was criticized for having been constructed in a relatively ...small cohort of patients and containing items too broadly phrased for DM1 patients, thus hampering its clinical use.
We report the results of the reconstructed Rasch-built DM1 activity and participation scale for clinical use (DM1-ActivC) through Rasch analyses using an expanded questionnaire containing 146 more simply phrased activity and participation inquiries completed by 340 patients with DM1.
Through stepwise investigation including data quality control, model fit, response category ordering, local dependency and item bias, we succeeded in reconstructing the DM1-ActivC consisting of 25 items that showed good Rasch model fit, including construct convergent validity, items' weights and persons' locations reliability, and unidimensionality.
The DM1-ActivC scale has been reconstructed and fulfills all modern clinimetric requirements. Its use is recommended in future longitudinal trials in patients with DM1 to determine its responsiveness.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Resolving the genetic architecture of painful neuropathy will lead to better disease management strategies. We aimed to develop a reliable method to re-sequence multiple genes in a large cohort of ...painful neuropathy patients at low cost. In this study, we compared sensitivity, specificity, targeting efficiency, performance and cost effectiveness of Molecular Inversion Probes-Next generation sequencing (MIPs-NGS) and TruSeq® Custom Amplicon-Next generation sequencing (TSCA-NGS). Capture probes were designed to target nine sodium channel genes (SCN3A, SCN8A-SCN11A, and SCN1B-SCN4B). One hundred sixty-six patients with diabetic and idiopathic neuropathy were tested by both methods, 70 patients were validated by Sanger sequencing. Sensitivity, specificity and performance of both techniques were comparable, and in agreement with Sanger sequencing. The average targeted regions coverage for MIPs-NGS was 97.3% versus 93.9% for TSCA-NGS. MIPs-NGS has a more versatile assay design and is more flexible than TSCA-NGS. The cost of MIPs-NGS is >5 times cheaper than TSCA-NGS when 500 or more samples are tested. In conclusion, MIPs-NGS is a reliable, flexible, and relatively inexpensive method to detect genetic variations in a large cohort of patients. In our centers, MIPs-NGS is currently implemented as a routine diagnostic tool for screening of sodium channel genes in painful neuropathy patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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