Phenotyping Extreme Neuropathic Pain Patients

We recruited patients with extreme neuropathic pain phenotypes, both sensory loss and gain, from secondary care clinics in the UK, located in Oxford, London, Salford and Newcastle. Study participants with a history of lifestyle-altering sensory disorder, either pain or loss of sensation, for greater than 3 months were invited to participate. The criteria for clinical case definitions are shown in Table 1.^{19 (link)} We excluded patients with a known underlying genetic cause of chronic pain, e.g. Fabry’s disease and SCN9A congenital erythromelalgia (genetic pre-screening for these disorders was not mandatory), pregnancy, coincident major psychiatric disorders, poor or no English language skills, patients with documented central nervous system lesions, or patients with insufficient mental capacity to provide informed consent or to complete phenotyping. Description of the clinical phenotyping can be found in the summary NIHR Bioresource paper by Turro et al.^{19 (link)} and is briefly described here.
Study participants attended a single appointment that included a clinical assessment, screening for neuropathic pain and specialized investigations to investigate distal symmetrical polyneuropathy. A detailed medical and drug history was taken, followed by a structured upper and lower limb neurological examination to detect clinical signs of distal symmetrical polyneuropathy.^{20 ,21 (link)} DN4 questionnaire was used as a screening tool for neuropathic pain.^{22 (link)} Confirmatory tests included nerve conduction studies,^{23 (link)} skin biopsy for intra-epidermal nerve fibre density^{24 ,25 (link)} and thermal thresholds in the area of neuropathic pain.^{26 (link)} Study participants’ pain was assessed and graded (Supplementary Fig. 2) according to published guidelines.^{27 (link)}Whole-blood samples were collected and sent to the NIHR BioResource laboratory in Cambridge. A detailed description of the DNA sequencing, WGS data-processing pipeline and identification of relevant gene variants can be found in Turro et al.^{19 (link)} and relevant aspects are summarized below.
All participants provided written informed consent in accordance with the Declaration of Helsinki. The study was approved by the East of England Cambridge South national research ethics committee (REC) reference 13/EE/0325.