Eberhardt E, Namer B, Neureiter A, Körner J, Jørum E , et al.
Pain •
Spontaneous activity of peripheral sensory nerve fibers is one of the main drivers of neuropathic pain. It can be assessed in microneurography recordings of patients' C fibers and in patch-clamp recordings of dissociated dorsal root ganglia from humans and rodents. In microneurography of human C fibers, a distinct subgroup of neurons, the so-called mechano-insensitive (CMi) or sleeping nociceptors, shows spontaneous activity during neuropathic pain. It was shown before that sensory neurons from patient-derived induced pluripotent stem cells (iSNs) can be used to model this increased spontaneous activity in vitro, suggesting that a disease relevant cell type is generated with this approach. The origin of the spontaneous activity in human C fibers is not fully understood. Derived sensory neurons offer the unique possibility to study patient-derived, single-cell function, allowing for identification of potential mechanisms underlying spontaneous C-fiber activity. Here, we identify 4 distinct functional subtypes of iSNs from healthy donors and a patient suffering from the neuropathic pain syndrome inherited erythromelalgia using patch-clamp recordings. Similar to microneurography recordings from the same patient, spontaneous activity is restricted to 1 functional subgroup that shows tonic firing behavior and seems to be especially prone to develop neuronal hyperexcitability. We demonstrate that spontaneous activity correlates with a reduced voltage threshold of action potential generation and increased spontaneous depolarizing fluctuations of the membrane potential. Our findings reveal that only the tonically firing functional subclass of iSNs shows spontaneous activity and suggest that these neurons may be related to the pathologically active CMi fibers identified during microneurography recordings in patients with pain.
Le Cann K, Meents JE, Sudha Bhagavath Eswaran V, Dohrn MF, Bott R , et al.
Channels (Austin, Tex.) •
Mutations in the voltage-gated sodium channel Nav1.7 are linked to human pain. The Nav1.7/N1245S variant was described before in several patients suffering from primary erythromelalgia and/or olfactory hypersensitivity. We have identified this variant in a pain patient and a patient suffering from severe and life-threatening orthostatic hypotension. In addition, we report a female patient suffering from muscle pain and carrying the Nav1.7/E1139K variant. We tested both Nav1.7 variants by whole-cell voltage-clamp recordings in HEK293 cells, revealing a slightly enhanced current density for the N1245S variant when co-expressed with the β1 subunit. This effect was counteracted by an enhanced slow inactivation. Both variants showed similar voltage dependence of activation and steady-state fast inactivation, as well as kinetics of fast inactivation, deactivation, and use-dependency compared to WT Nav1.7. Finally, homology modeling revealed that the N1245S substitution results in different intramolecular interaction partners. Taken together, these experiments do not point to a clear pathogenic effect of either the N1245S or E1139K variant and suggest they may not be solely responsible for the patients' pain symptoms. As discussed previously for other variants, investigations in heterologous expression systems may not sufficiently mimic the pathophysiological situation in pain patients, and single nucleotide variants in other genes or modulatory proteins are necessary for these specific variants to show their effect. Our findings stress that biophysical investigations of ion channel mutations need to be evaluated with care and should preferably be supplemented with studies investigating the mutations in their context, ideally in human sensory neurons.
Huppke P, Wegener E, Gilley J, Angeletti C, Kurth I , et al.
Experimental neurology •
We identified a homozygous missense mutation in the gene encoding NAD synthesizing enzyme NMNAT2 in two siblings with childhood onset polyneuropathy with erythromelalgia. No additional homozygotes for this rare allele, which leads to amino acid substitution T94M, were present among the unaffected relatives tested or in the 60,000 exomes of the ExAC database. For axons to survive, axonal NMNAT2 activity has to be maintained above a threshold level but the T94M mutation confers a partial loss of function both in the ability of NMNAT2 to support axon survival and in its enzymatic properties. Electrophysiological tests and histological analysis of sural nerve biopsies in the patients were consistent with loss of distal sensory and motor axons. Thus, it is likely that NMNAT2 mutation causes this pain and axon loss phenotype making this the first disorder associated with mutation of a key regulator of Wallerian-like axon degeneration in humans. This supports indications from numerous animal studies that the Wallerian degeneration pathway is important in human disease and raises important questions about which other human phenotypes could be linked to this gene.
The causes for neuropathic pain are manifold and remain unexplained in the majority of cases. In recent years a growing number of pain syndromes have been attributed to mutations in genes encoding voltage-gated sodium channels. Hence, this group of rare diseases should be considered in the differential diagnostics of neuropathic pain. Evaluation of topic-related literature and discussion of own experiences as well as consideration of current guidelines. Alterations in the electrical excitability of nociceptive neurons by pathogenic mutations in sodium channels lead to disease patterns, such as small fiber neuropathy and various pain syndromes. This article summarizes the knowledge on these genetic diseases and discusses the differential diagnosis of neuropathic pain. Current treatment concepts are presented and the predominantly experimental approaches to targeted modulation of sodium channels are discussed. The treatment of patients with chronic neuropathic pain requires interdisciplinary cooperation and is often difficult due to an unsatisfactory treatment response. Increasing knowledge on rare genetically determined channelopathies can contribute to the development of novel pharmaceuticals since ion channels are central players in the processing of pain.
Skeik N, Rooke TW, Davis MD, Davis DM, Kalsi H , et al.
Vascular medicine (London, England) •
Erythromelalgia is a rare clinical syndrome characterized by intermittent heat, redness, swelling and pain more commonly affecting the lower extremities. Symptoms are mostly aggravated by warmth and are eased by a cold temperature. In some cases, symptoms can be very severe and disabling. Erythromelalgia can be classified as either familial or sporadic, with the familial form inherited in an autosomal dominant manner. Recently, there has been a lot of progress in studying Na(v)1.7 sodium channels (expressed mostly in the sympathetic and nociceptive small-diameter sensory neurons of the dorsal root ganglion) and different mutations affecting the encoding SCN9A gene that leads to channelopathies responsible for some disorders, including primary erythromelalgia. We present a severe case of progressive primary erythromelalgia caused by a new de novo heterozygous missense mutation (c.2623C>G) of the SCN9A gene which substitutes glutamine 875 by glutamic acid (p.Q875E). To our knowledge, this mutation has not been previously reported in the literature. We also provided a short literature review about erythromelalgia and Na(v) sodium channelopathies.