Neuropathic pain (NP) has important clinical and socioeconomic consequences for individuals and society. Increasing evidence indicates that genetic factors make a significant contribution to NP, but ...genome-wide association studies (GWASs) are scant in this field and could help to elucidate susceptibility to NP.
To identify genetic variants associated with NP susceptibility.
This genetic association study included a meta-analysis of GWASs of NP using 3 independent cohorts: ie, Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS); Generation Scotland: Scottish Family Health Study (GS:SFHS); and the United Kingdom Biobank (UKBB). Data analysis was conducted from April 2018 to December 2019.
Individuals with NP (ie, case participants; those with pain of ≥3 months' duration and a Douleur Neuropathique en 4 Questions score ≥3) and individuals with no pain (ie, control participants) with or without diabetes from GoDARTS and GS:SFHS were identified using validated self-completed questionnaires. In the UKBB, self-reported prescribed medication and hospital records were used as a proxy to identify case participants (patients recorded as receiving specific anti-NP medicines) and control participants.
GWAS was performed using linear mixed modeling. GWAS summary statistics were combined using fixed-effect meta-analysis. A total of 51 variants previously shown to be associated with NP were tested for replication.
This study included a total of 4512 case participants (2662 58.9% women; mean SD age, 61.7 10.8 years) and 428 489 control participants (227 817 53.2% women; mean SD age, 62.3 11.5 years) in the meta-analysis of 3 cohorts with European descent. The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3 (rs369920026; odds ratio OR for having NP, 1.68; 95% CI, 1.40-2.02; P = 1.30 × 10-8), and a suggestive variant at 13q14.2 near CAB39L (rs7992766; OR, 1.09; 95% CI, 1.05-1.14; P = 1.22 × 10-7). These mitochondrial phosphate carriers and calcium binding genes are expressed in brain and dorsal root ganglia. Colocalization analyses using expression quantitative loci data found that the suggestive variant was associated with expression of CAB39L in the brain cerebellum (P = 1.01 × 10-14). None of the previously reported variants were replicated.
To our knowledge, this was the largest meta-analyses of GWAS to date. It found novel genetic variants associated with NP susceptibility. These findings provide new insights into the genetic architecture of NP and important information for further studies.
Small fiber neuropathy usually presents with gradual and progressive chronic length‐dependent pain. Acute small fiber neuropathy is rarely reported. Three patients with acute onset neuropathic pain ...after Oxford‐AstraZeneca ChAdOx1‐S vaccination are described. Two patients were identified at the Oxford University NHS Foundation Trust, Oxford, UK and one patient in Red de Salud UC Christus, Santiago, Chile. All patients underwent a clinical assessment that included a detailed neurological examination, laboratory investigations, nerve conduction studies, thermal threshold testing, and skin biopsy for intra‐epidermal nerve fiber density. Patients seen in Oxford underwent MRI of the brain and spinal cord. Cerebrospinal analysis was not performed. Neuropathic symptoms (burning pain, dysaesthesias) developed in the hands and feet within 2 weeks of vaccination. On clinical examination, there was pinprick and thermal hyposensitivity in the area of neuropathic pain. Laboratory investigation, nerve conduction tests, sympathetic skin responses, and MRI showed no relevant abnormalities. Thermal thresholds were abnormal and intra‐epidermal nerve fiber density in the lower leg was reduced. In two cases symptoms persist after several months. Three cases of definite acute small fiber neuropathy after Oxford‐AstraZeneca ChAdOx1‐S vaccination are described. At follow up, neuropathic pain was present in two of the patients.
We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (
D
IV). The identified ...mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype–phenotype correlation profile for
SCN9A
and highlight a new region of Nav1.7 that is implicated in PEM.
Chronic pain (CP) is a common and often debilitating disorder that has major social and economic impacts. A subset of patients develop CP that significantly interferes with their activities of daily ...living and requires a high level of healthcare support. The challenge for treating physicians is in preventing the onset of refractory CP or effectively managing existing pain. To be able to do this, it is necessary to understand the risk factors, both genetic and environmental, for the onset of CP and response to treatment, as well as the pathogenesis of the disorder, which is highly heterogenous. However, studies of CP, particularly pain with neuropathic characteristics, have been hindered by a lack of consensus on phenotyping and data collection, making comparisons difficult. Furthermore, existing cohorts have suffered from small sample sizes meaning that analyses, especially genome-wide association studies, are insufficiently powered. The key to overcoming these issues is through the creation of large consortia such as DOLORisk and PAINSTORM and biorepositories, such as UK Biobank, where a common approach can be taken to CP phenotyping, which allows harmonisation across different cohorts and in turn increased study power. This review describes the approach that was used for studying neuropathic pain in DOLORisk and how this has informed current projects such as PAINSTORM, the rephenotyping of UK Biobank, and other endeavours. Moreover, an overview is provided of the outputs from these studies and the lessons learnt for future projects.
HIV-associated sensory neuropathy (HIV-SN) is the most frequent manifestation of HIV disease. It often presents with significant neuropathic pain and is associated with previous exposure to ...neurotoxic nucleoside reverse transcriptase inhibitors. However, HIV-SN prevalence remains high even in resource-rich settings where these drugs are no longer used. Previous evidence suggests that exposure to indinavir, a protease inhibitor commonly used in antiretroviral therapy, may link to elevated HIV-SN risk. Here, we investigated whether indinavir treatment was associated with the development of a "dying back" axonal neuropathy and changes in pain-relevant limb withdrawal and thigmotactic behaviours. After 2 intravenous injections of indinavir (50 mg/kg, 4 days apart), adult rats developed hind paw mechanical hypersensitivity, which peaked around 2 weeks post first injection (44% reduction from baseline). At this time, animals also had (1) significantly changed thigmotactic behaviour (62% reduction in central zone entries) comparing with the controls and (2) a significant reduction (45%) in hind paw intraepidermal nerve fibre density. Treatment with gabapentin, but not amitriptyline, was associated with a complete attenuation of hind paw mechanical hypersensitivity observed with indinavir treatment. Furthermore, we found a small but significant increase in microglia with the effector morphology in the lumbar spinal dorsal horn in indinavir-treated animals, coupled with significantly increased expression of phospho-p38 in microglia. In summary, we have reported neuropathic pain-related sensory and behavioural changes accompanied by a significant loss of hind paw skin sensory innervation in a rat model of indinavir-induced peripheral neuropathy that is suitable for further pathophysiological investigation and preclinical evaluation of novel analgesics.
Heterologous prime/boost regimens have the potential for raising high levels of immune responses. Here we report that DNA priming followed by a recombinant modified vaccinia Ankara (rMVA) booster ...controlled a highly pathogenic immunodeficiency virus challenge in a rhesus macaque model. Both the DNA and rMVA components of the vaccine expressed multiple immunodeficiency virus proteins. Two DNA inoculations at 0 and 8 weeks and a single rMVA booster at 24 weeks effectively controlled an intrarectal challenge administered 7 months after the booster. These findings provide hope that a relatively simple multiprotein DNA/MVA vaccine can help to control the acquired immune deficiency syndrome epidemic.
Membrane metallo‐endopeptidase (MME), also known as neprilysin (NEP), has been of interest for its role in neurodegeneration and pain due to its ability to degrade β‐amyloid and substance‐P, ...respectively. In addition to its role in the central nervous system, MME has been reported to be expressed in the peripheral system, specifically in the inner and outer border of myelinating fibers, in the Schmidt‐Lantermann cleft and in the paranodes. Recently, mutations of this gene have been associated with Charcot‐Marie‐Tooth Type 2 (CMT2). Peripheral nerve morphometry in mice lacking MME previously showed minor abnormalities in aged animals in comparison to CMT2 patients. We found that MME expression was dysregulated after nerve injury in a Neuregulin‐1 dependent fashion. We therefore explored the hypothesis that MME may have a role in remyelination. In the naïve state in adulthood we did not find any impairment in myelination in MME KO mice. After nerve injury the morphological outcome in MME KO mice was indistinguishable from WT littermates in terms of axon regeneration and remyelination. We did not find any difference in functional motor recovery. There was a significant difference in sensory function, with MME KO mice starting to recover response to mechanical stimuli earlier than WT. The epidermal reinnnervation, however, was unchanged and this altered sensitivity may relate to its known function in cleaving the peptide substance‐P, known to sensitise nociceptors. In conclusion, although MME expression is dysregulated after nerve injury in a NRG1‐dependent manner this gene is dispensable for axon regeneration and remyelination after injury.
Main points
MME is dysregulated after nerve injury in a NRG1‐dependent manner.
MME is dispensable for regeneration/remyelination after injury.
Increased sensitivity in MME mice could be related to nociceptor sensitization.
Nitrous oxide is increasingly being used as a recreational drug. Prolonged use of nitrous oxide can have disabling neurological sequelae due to functional inactivation of vitamin B₁₂. We present ...three cases illustrating the neurological complications of using nitrous oxide. Two of these patients received nitrous oxide as a consequence of repeated hospital attendance and the third via 'Whippit' canisters used in cream dispensers, which are now widely available. Two patients developed sensorimotor peripheral neuropathy with demyelinating features with no clinical or imaging evidence of myelopathy, emphasising that not all patients develop subacute combined degeneration of the spinal cord (the typical presentation of functional vitamin B12 deficiency). The diagnosis was based upon the history of nitrous oxide use and raised levels of homocysteine and/or methylmalonic acid. All patients were treated with parenteral vitamin B12 with partial recovery, though two were left significantly disabled.
This review summarizes the major recent developments in understanding of pathogenic mechanisms in inflammatory and paraproteinaemic neuropathies.
In the inflammatory neuropathies, there has been a ...particular focus on antibody-mediated disease affecting the nodal/paranodal regions. Disruption of electrical integrity at these sites on the axonal membrane can cause conduction block without other electrophysiological features of demyelination, which has led to calls for a revision in the classification of axonal versus demyelinating neuropathies to include the new category of 'nodo-paranodopathies'. There has likewise been an expansion in knowledge regarding the diverse disease mechanisms of the paraproteinaemic neuropathies. These also include disease mediated by antibodies binding to peripheral nerve antigens, but additionally encompass immune complex deposition, cellular infiltration, and cytokine production.
An increasing range of laboratory tests for antibodies, growth factors, and cytokines are proposed as useful in the management of inflammatory and paraproteinaemic neuropathies. Furthermore, the traditional electrodiagnostic classification into axonal and demyelinating neuropathy may not always accurately reflect the underlying disease process. Understanding how these paraclinical tests aid in identifying the underlying disease has relevance to the practising clinician both in terms of diagnosis and for the selection of rational treatments.
Using a composite diagnostic-neuroimaging approach, this study shows the modulatory effects of pleasant cooling on pain-related cortical regions in a subject suffering from inherited erythromelalgia.
...We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Nav1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject.
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