Publications

Objective: To examine the incidence of nonsynonymous missense variants in SCN9A (NaV1.7), SCN10A (NaV1.8), and SCN11A (NaV1.9) in patients with painful and nonpainful peripheral neuropathy.

Methods: Next-generation sequencing was performed on 457 patient DNA samples provided by the Peripheral Neuropathy Research Registry (PNRR). The patient diagnosis was as follows: 278 idiopathic peripheral neuropathy (67% painful and 33%nonpainful) and 179 diabetic distal polyneuropathy (77% painful and 23% nonpainful).

Results: We identified 36 (SCN9A), 31 (SCN10A), and 15 (SCN11A) nonsynonymous missense variants, with 47.7% of patients carrying a low-frequency (minor allele frequency ,5%) missense variant in at least 1 gene. The incidence of previously reported gain-of-function missense variants was low (#3%), and these were detected in patients with and without pain. There were no significant differences in missense variant allele frequencies of any gene, or SCN9A haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient SCN9A and SCN11A missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For SCN10A, there was a significant increase in the alternate allele frequency of the common variant p.V1073A and low-frequency variant pS509P in PNRR patients compared with EVS-EA and the 1000 Genomes European reference populations.

Conclusions: These results suggest that identification of a genetically defined subpopulation for testing of NaV1.7 inhibitors in patients with peripheral neuropathy is unlikely and that additional factors, beyond expression of previously reported disease “mutations,” are more important for the development of painful neuropathy than previously discussed. Neurol Genet 2017;3:e207; doi: 10.1212/NXG.0000000000000207

The Peripheral Neuropathy Research Registry (PNRR) is a prospective cohort of peripheral neuropathy (PN) patients focused on idiopathic axonal peripheral neuropathy. Patients with diabetic, human immunodeficiency virus‐, and chemotherapy‐induced peripheral neuropathies are enrolled as comparison groups. The PNRR is a multi‐center collaboration initiated and funded by the Foundation for Peripheral Neuropathy (FPN) with the objective to recruit a well characterized cohort of patients with different phenotypes and symptoms in each diagnostic category, and to advance research through development of biomarkers and identification of previously unknown causes of PN. The overall goal of the initiative is to find disease‐altering treatments and better symptom relief for patients. We present the study design, types of data collected, and characteristics of the first 1150 patients enrolled. We also discuss ongoing analyses on this dataset, including untargeted‐omics methodologies.

Pyridoxine (vitamin B6) toxicity is known to cause a length-dependent, sensory predominant axonal polyneuropathy. There is debate regarding the threshold at which intake levels can cause neurological symptoms through pyridoxine toxicity. We asked if elevated plasma vitamin B6 levels were related to outcome measures in a well-characterized cohort of patients with chronic idiopathic axonal polyneuropathy (CIAP). We included 261 patients enrolled in the Peripheral Neuropathy Research Registry who had a complete dataset including a plasma vitamin B6 value. Patients with vitamin B6 deficiency (0-4.9 μg/L) were excluded. We performed a chi-square test for independence and analyzed the logistic relation of elevated plasma B6 level to nerve conduction studies (NCS), neurological examination findings, and patient-reported symptoms controlling for age and time elapsed since neuropathy symptom onset. Plasma B6 level was not related to neuropathy severity. There was no logistic relation of elevated plasma B6 level to NCS results, examination features including toe strength, vibration sense, and deep tendon reflexes, or patient-reported numbness or pain intensity. This study suggests that moderately elevated plasma B6 levels, even in the 100 to 200 μg/L range, are not associated with significantly worse neuropathy signs or symptoms. Although standard supplementation of B6 does not appear to have a major negative affect on CIAP, this study does not directly answer whether stopping supplementation will have a beneficial effect. Very few patients in the study had vitamin B6 levels >300 μg/L, suggesting that screening for vitamin B6 toxicity may be left to the discretion of the physician.

Background and aims: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain.

Methods: We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein-protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping.

Results: In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini-Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini-Hochberg adjusted p-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified.

Interpretation: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.

Background and aims: Peripheral neuropathy (PN) is a common neurological condition in elderly adults. Vitamin D deficiency has been associated with diabetic and chemotherapy-induced neuropathy, but its role in idiopathic PN, in which no underlying cause of neuropathy can be identified, has not been investigated. Methods: Two hundred thirty patients with idiopathic PN enrolled in the Peripheral Neuropathy Research Registry (PNRR) at Johns Hopkins University School of Medicine had vitamin D testing information on record. Linear and logistic regressions were used to investigate the relationship between absolute vitamin D level or vitamin D insufficiency (<20 ng/mL) and both the severity of neuropathy as measured by the reduced total neuropathy score (TNSr) and severity of neuropathic pain. Results: Sixteen (7%) patients were vitamin D insufficient (<20 ng/mL). Controlling for factors known to correlate with severity of neuropathy, there was no correlation between absolute vitamin D levels and TNSr (correlation coefficient 0.01, 95% CI -0.03 to 0.07, p = .59) and no association between vitamin D insufficiency and TNSr (correlation coefficient 0.3, 95% CI -2.8 to 3.4, p = .86). Vitamin D insufficiency was not associated with the presence of neuropathic pain (OR 4.1, 95% CI 0.6-26.0, p = .13), and there was no correlation between vitamin D levels and pain score (correlation coefficient 0.01, 95% CI -0.02 to 0.03, p = .59). Interpretation: In a single-center cohort of patients with idiopathic PN, there was no correlation between vitamin D levels and the severity of neuropathy or neuropathic pain.