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Background Charcot–Marie–Tooth disease (CMT) is a genetically and clinically heterogeneous group of inherited neuropathies. Monoallelic pathogenic variants in ATP1A1 were associated with axonal and intermediate CMT. ATP1A1 encodes for the catalytic α1 subunit of the Na+/ K+ ATPase. Besides neuropathy, other associated phenotypes are spastic paraplegia, intellectual disability, and renal hypomagnesemia. We hereby report the first demyelinating CMT case due to a novel ATP1A1 variant. Methods Whole-exome sequencing on the patient’s genomic DNA and Sanger sequencing to validate and confirm the segregation of the identified p.P600R ATP1A1 variation were performed. To evaluate functional effects, blood-derived mRNA and protein levels of ATP1A1 and the auxiliary β1 subunit encoded by ATP1B1 were investigated. The ouabain-survival assay was performed in transfected HEK cells to assess cell viability, and two-electrode voltage clamp studies were performed in Xenopus oocytes. Results The variant was absent in the local and global control datasets, falls within a highly conserved protein position, and is in a missense-constrained region. The expression levels of ATP1A1 and ATP1B1 were significantly reduced in the patient compared to healthy controls. Electrophysiology indicated that ATP1A1p.P600R injected Xenopus oocytes have reduced Na+/ K+ ATPase function. Moreover, HEK cells transfected with a construct encoding ATP1A1p.P600R harbouring variants that confers ouabain insensitivity displayed a significant decrease in cell viability after ouabain treatment compared to the wild type, further supporting the pathogenicity of this variant. Conclusion Our results further confirm the causative role of ATP1A1 in peripheral neuropathy and broaden the mutational and phenotypic spectrum of ATP1A1-associated CMT.

The chaperone protein BiP is the master regulator of the unfolded protein response in the endoplasmic reticulum. BiP chaperone activity is regulated by the post-translational modification AMPylation, exclusively provided by FICD. We investigated whether FICD variants identified in patients with motor neuron disease could interfere with BiP activity regulation. Methods Exome sequencing was performed to identify causative pathogenic variants associated with motor neuron diseases. Functional studies were conducted on fibroblasts from patients to explore the molecular mechanism of the disease. Results We identified biallelic variants in FICD causing a neurodegenerative disease of upper and lower motor neurons. Affected individuals harbor a specific missense variant, Arg374His, positioned in the catalytic motif of the enzyme and important for adenosine triphosphate binding. The mutated residue abolishes intramolecular interaction with the regulatory residue Glu234, essential to inhibit AMPylation and to promote de-AMPylation by FICD. Consequently, fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP. Conclusion Loss of BiP chaperone activity in patients likely results in a chronic impairment of the protein quality control system in the endoplasmic reticulum. These findings will guide the development of therapeutic strategies for motoneuron and related diseases linked to proteotoxic stress.

Patel K et al. Diabetic neuropathies. Muscle Nerve 2021. doi: 10.1002/mus.27014 Diabetische Neuropathien sind die häufigsten Nervenerkrankungen in der klinischen Praxis. Das Spektrum reicht von asymptomatischen Formen bis hin zu schwerwiegenden Symptomen. Da hierbei neben dem peripheren Nervensystem auch das Herz-Kreislauf-System und der Magen-Darm-Trakt betroffen sein können, haben Patel und Kollegen nun eine Übersichtsarbeit zu den Subtypen, ihrer Präsentation, Diagnosewerkzeugen und Behandlungsstrategien vorgelegt.

ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.

Neurotherapeutics 18(4), 2425-2435 (2021). doi:10.1007/s13311-021-01141-3, Published by Springer, New York, NY

Defined by dysfunction or degeneration of Aδ and C fibers, small fiber neuropathies (SFNs) entail a relevant health burden. In 50% of cases, the underlying cause cannot be identified or treated. In 100 individuals (70% female individuals; mean age: 44.8 years) with an idiopathic, skin biopsy-confirmed SFN, we characterized the symptomatic spectrum and measured markers of oxidative stress (vitamin C, selenium, and glutathione) and inflammation (transforming growth factor beta, tumor necrosis factor alpha), as well as neurotoxic 1-deoxy-sphingolipids. Neuropathic pain was the most abundant symptom (95%) and cause of daily life impairment (72%). Despite the common use of pain killers (64%), the painDETECT questionnaire revealed scores above 13 points in 80% of patients. In the quantitative sensory testing (QST), a dysfunction of Aδ fibers was observed in 70% and of C fibers in 44%, affecting the face, hands, or feet. Despite normal nerve conduction studies, QST revealed Aβ fiber involvement in 46% of patients' test areas. Despite absence of diabetes mellitus or mutations in SPTLC1 or SPTLC2 , plasma 1-deoxy-sphingolipids were significantly higher in the sensory loss patient cluster when compared with those in patients with thermal hyperalgesia ( P0.01) or those in the healthy category ( P0.1), correlating inversely with the intraepidermal nerve fiber density (1-deoxy-SA: P0.05, 1-deoxy-SO: P0.01). Patients with arterial hypertension, overweight (body mass index25 kg/m 2 ), or hyperlipidemia showed significantly lower L-serine (arterial hypertension: P0.01) and higher 1-deoxy-sphingolipid levels (arterial hypertension: P0.001, overweight: P0.001, hyperlipidemia: P0.01). Lower vitamin C levels correlated with functional Aβ involvement ( P0.05). Reduced glutathione was lower in patients with Aδ dysfunction ( P0.05). Idiopathic SFNs are heterogeneous. As a new pathomechanism, plasma 1-deoxy-sphingolipids might link the metabolic syndrome with small fiber degeneration.

ZusammenfassungVon weltweit mehr als 400 Mio. Menschen mit Diabetes mellitus entwickeln bis zu 50% im Laufe ihrer Erkrankung eine Neuropathie. Trotz oder gerade wegen dieser Häufigkeit darf jedoch nicht jede Neuropathie, die in Koinzidenz mit einem Diabetes mellitus auftritt, unkritisch als diabetische Neuropathie diagnostiziert werden. Eine präzise Ausschluss- und Ausmaßdiagnostik ist entscheidend, um andere behandelbare Erkrankungen wie z. B. die Chronisch Inflammatorische Demyelinisierende Polyradikuloneuropathie oder die hereditäre Transthyretin-Amyloidose nicht zu übersehen. Einfache, nicht-invasive, preiswerte und allzeit verfügbare Screeningmethoden stellen Anamnese und klinische Untersuchung dar. Ergänzend ist in frühen Erkrankungsstadien die Quantitativ Sensorische Testung hilfreich zur Eingrenzung einer Small Fiber-Dysfunktion. Sind, typischerweise im Verlauf, große Nervenfasern geschädigt, so ist das charakteristische elektrophysiologische Bild das einer längenabhängigen, axonalen, sensibel betonten oder sensomotorischen Neuropathie. Die Nervensonografie kann zur Unterscheidung von autoimmun-demyelinisierenden Neuropathien hilfreich sein. Moderne Untersuchungsverfahren wie die MR-Neurografie können auch proximale Nervenabschnitte bis auf Faszikelebene darstellen, sind allerdings nur an wenigen Zentren verfügbar. Haut- und Nervenbiopsien sind v. a. bei untypischen Verläufen zur Abgrenzung von Differenzialdiagnosen hilfreich. Diabetische Neuropathien können zu einer erheblichen Reduktion von Lebensqualität und Lebensdauer führen. Zur frühest- und bestmöglichen ursächlichen und symptomatischen Therapieeinleitung ist eine präzise Diagnostik essentiell.

Genetic pain loss includes congenital insensitivity to pain (CIP), hereditary sensory neuropathies and, if autonomic nerves are involved, hereditary sensory and autonomic neuropathy (HSAN). This heterogeneous group of disorders highlights the essential role of nociception in protecting against tissue damage. Patients with genetic pain loss have recurrent injuries, burns and poorly healing wounds as disease hallmarks. CIP and HSAN are caused by pathogenic genetic variants in >20 genes that lead to developmental defects, neurodegeneration or altered neuronal excitability of peripheral damage-sensing neurons. These genetic variants lead to hyperactivity of sodium channels, disturbed haem metabolism, altered clathrin-mediated transport and impaired gene regulatory mechanisms affecting epigenetic marks, long non-coding RNAs and repetitive elements. Therapies for pain loss disorders are mainly symptomatic but the first targeted therapies are being tested. Conversely, chronic pain remains one of the greatest unresolved medical challenges, and the genes and mechanisms associated with pain loss offer new targets for analgesics. Given the progress that has been made, the coming years are promising both in terms of targeted treatments for pain loss disorders and the development of innovative pain medicines based on knowledge of these genetic diseases.

ZusammenfassungHintergrundDie Hälfte aller Diabetiker ist von einer diabetischen Neuropathie betroffen. Mikroangiopathie, dysfunktionale Schwann-Zell-Interaktion, Akkumulation toxischer Metabolite und inflammatorische Prozesse führen gemeinsam zur Nervenschädigung.Ziel der ArbeitAus- und Überblick zum aktuellen Kenntnisstand der Pathophysiologie mit aktuellen und zukünftigen Therapieimplikationen.MethodenLiteraturrecherche (1990–2020).ErgebnisseKlinisch führend sind sensible und autonome Symptome, Paresen können jedoch auftreten. Komplikationen wie stumme Myokardinfarkte oder das diabetische Fußsyndrom können lebensbedrohlich verlaufen und zu schwerer Behinderung führen. In ihrer Pathophysiologie unterscheiden sich Neuropathien bei Typ-1- und Typ-2-Diabetikern durch die Gegenwart zusätzlicher Risikofaktoren des metabolischen Syndroms. Die intensivierte ist der konventionellen Insulintherapie im Hinblick auf die Neuropathierisikoreduktion überlegen. Orale Antidiabetika sind nach Nebenwirkungsprofil auszuwählen. Metformin kann zu einem iatrogenen Vitamin-B12-Mangel führen. Zur Behandlung neuropathischer Schmerzen besitzt der Kalziumkanalblocker Pregabalin die höchste Empfehlungsstufe. Das Trizyklikum Amitriptylin gilt als ähnlich wirksam, ist aber bei autonomer Dysfunktion sowie kognitiven Einschränkungen kontraindiziert. Alternativ ist der Serotonin-Noradrenalin-Wiederaufnahmehemmer Duloxetin zur symptomatischen Therapie der diabetischen Neuropathie zugelassen. Umstritten sind weitere, zum Teil nicht zugelassene Medikamente wie α‑Liponsäure, Epalrestat und L‑Serin.SchlussfolgerungenDie diabetische Neuropathie ist häufig und komplikationsreich. Ein gutes Verständnis der Pathophysiologie kann zur Entwicklung neuer Therapiestrategien beitragen.

ZusammenfassungDie neuropathische Osteo(arthro-)pathie, auch Charcot-Fuß genannt, ist eine progressive, nicht-infektiöse Schwellung mit Überwärmung und Demineralisierung, gefolgt von Knochendestruktion und Deformierung, die in ca. 75% unilateral auftritt und in einer Defektheilung zum Stillstand kommt. Resultierende Fehlstellungen können zu neuropathischen Ulzera führen, die sich infizieren und Amputationen erforderlich machen können. Die häufigste, aber nicht einzige Ursache ist der Diabetes mellitus. Etwa 2% aller Diabetiker entwickeln einen Charcot-Fuß. Der pathophysiologische „Charcot-Prozess“ ist komplex, scheint aber untrennbar mit der vorausgehenden Neuropathie verbunden zu sein. Die C- und Aδ- Fasern sind im Rahmen der diabetischen Neuropathie früh und häufig geschädigt, was ein Ungleichgewicht an CGRP, VIP, Substanz P und weiteren Transmittern erklärt. Störungen der Knocheninnervation verschieben das Verhältnis von Knochenan- und -abbau, von OPG und RANKL zugunsten des Abbaus. Demnach stellt die Fehlregulation nozizeptiver Nervenfasern auf molekularer Ebene eine pathophysiologische Brücke zwischen Diabetes mellitus und neurogener Inflammation dar.

Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients.After unremarkable whole-exome sequencing (WES) analysis, we performed repeat-primed PCR to detect intronic RFC1 expansions in 12 HSAN families, who all presented with chronic cough.In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared with RFC1-/- cases, RFC1+/+ cases presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the RFC1+/+ cohort and cerebellar ataxia was a common feature (21%).We demonstrate that RFC1 is a frequent cause of (WES-negative) HSAN with chronic cough and ataxia. The diagnostic yield of RFC1 repeat-primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy-ataxia spectrum.

Movement disorders 37(2), 401-404 (2022). doi:10.1002/mds.28835, Published by Wiley, New York, NY

Mutations in PLEKHG5, a pleckstrin homology domain containing member of the GEF family, are associated with distal spinal muscular atrophy and intermediate Charcot-Marie-Tooth disease. Here, we describe an isolated case with distal intermediate neuropathy with scapular winging. By whole exome sequencing, we identified the homozygous PLEKHG5 Arg97Gln missense mutation, located in the N-terminal region of the protein. This mutation resides between a zinc-finger motif and a RBD domain, involved in binding rnd3, a RhoA effector protein. We conclude that based on the characteristic phenotype presented by the patient and the supportive genetic findings, the PLEKHG5 mutation is the causative variant.

Neurological research and practice 3, 57 (2021). doi:10.1186/s42466-021-00155-8, Published by BioMed Central, [London]

ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.

ZusammenfassungDie elektrophysiologische Untersuchung von Hirnstammreflexen ist eine funktionelle Methode, die Rückschlüsse auf Läsionen in unterschiedlichen Bereichen des Hirnstamms und beteiligter Hirnnerven ermöglicht. Wie relevant ist diese Diagnostik im Zeitalter der MR-Bildgebung noch im klinischen Alltag? Der Artikel befasst sich mit der Durchführung, den anatomischen Hintergründen und den daraus entstehenden Rückschlussmöglichkeiten verschiedener Läsionslokalisationen für den Blinkreflex, Masseterreflex und Kieferöffnungsreflex. Zudem wird der heutige Stellenwert sowie die diagnostische Bedeutung diskutiert.

Die Ursachen neuropathischer Schmerzen sind vielfaltig und bleiben in vielen Fallen unklar. In den vergangenen Jahren konnten mehrere Schmerzsyndrome auf Veranderungen in Natriumkanalgenen zuruckgefuhrt werden, sodass diese Gruppe seltener Erkrankungen in der Differenzialdiagnostik neuropathischer Schmerzen zunehmend zu berucksichtigen ist. Auswertung von themenbezogener Literatur, Diskussion eigener Erfahrungen sowie Berucksichtigung bestehender Leitlinien. Veranderungen in der elektrischen Erregbarkeit der schmerzleitenden Nervenfasern durch pathogene Varianten der Natriumkanale fuhren zu Krankheitsbildern wie der Small-fiber-Neuropathie und verschiedenen Schmerzsyndromen. Die Gruppe dieser genetischen Erkrankungen wird besprochen und in die Differenzialdiagnostik des neuropathischen Schmerzes eingeordnet. Therapiekonzepte werden dargestellt und die bislang vorwiegend experimentellen Ansatze zur gezielten Modulation der Natriumkanale diskutiert. Die Behandlung von Patienten mit chronischen neuropathischen Schmerzen erfordert interdisziplinare Zusammenarbeit und gestaltet sich aufgrund eines unbefriedigenden Therapieansprechens oft schwierig. Zunehmende Erkenntnisse zu seltenen, genetisch bedingten Ionenkanalerkrankungen konnen zukunftig dazu beitragen, dass die pharmakologische Beeinflussung dieser zentralen Vermittler des Schmerzempfindens neue Impulse in der Schmerztherapie setzt.

With emerging treatment approaches, it is crucial to correctly diagnose and monitor hereditary and acquired polyneuropathies. This study aimed to assess the validity and accuracy of magnet resonance imaging (MRI)-based muscle volumetry.Using semi-automatic segmentations of upper- and lower leg muscles based on whole-body MRI and axial T1-weighted turbo spin-echo sequences, we compared and correlated muscle volumes, and clinical and neurophysiological parameters in demyelinating Charcot-Marie-Tooth disease (CMT) (n = 13), chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 27), and other neuropathy (n = 17) patients.The muscle volumes of lower legs correlated with foot dorsiflexion strength (p &lt, 0.0001), CMT Neuropathy Score 2 (p &lt, 0.0001), early gait disorders (p = 0.0486), and in CIDP patients with tibial nerve conduction velocities (p = 0.0092). Lower (p = 0.0218) and upper (p = 0.0342) leg muscles were significantly larger in CIDP compared to CMT patients. At one-year follow-up (n = 15), leg muscle volumes showed no significant decrease.MRI muscle volumetry is a promising method to differentiate and characterize neuropathies in clinical practice.

Channels 15(1), 208-228 (2021). doi:10.1080/19336950.2020.1870087, Published by Taylor & Francis, Abingdon, Oxon

Journal of neurochemistry : JNC 156(6), 802-818 (2021). doi:10.1111/jnc.15233, Published by Wiley-Blackwell, Oxford

Guideline development on motor neuron disease (MND) in Germany is driven mainly by the German Neurological Society and German Association for Muscle Diseases. Greater research funding, a national strategy, and programs on MND are still lacking. General and specialized palliative care home services, palliative care units, or hospice care are accessible for all MND patients in Germany. Assistive technologies can be ordered by treating physicians in experienced centers. In symptomatic patients, qualified neurologists can request genetic testing of about five to ten genes per year. Withholding or withdrawing mechanical ventilation in end-of-life situations of MND can be described as “passive help in dying,” and the German Ethics Council recommends use of the term “letting die.” Palliative sedation therapy is allowed in Germany, euthanasia is prohibited.

PURPOSE OF REVIEW Hereditary motor neuropathies (HMN) comprise a broad genotypic and phenotypic spectrum of rare, progressively disabling diseases manifesting with length-dependent muscle weakness and atrophy. To date, more than half of the cases cannot be genetically explained. To provide symptomatic and disease-modifying treatments in the future, a better understanding of disease mechanisms is required. RECENT FINDINGS By whole exome and genome sequencing, the discovery of several novel genes (SCO2, TDRKH, SPTAN1, CADM3, and SORD) involved in the pathogenesis of HMN has now relevantly changed the pathophysiological knowledge. This recent success in causative understanding has mainly been driven by the development of functional models including cell culture, animal, and patient-derived induced pluripotent stem cell platforms. These models have an important impact on therapeutic advances including broader approaches to prevent or reverse axonal degeneration and individualized gene silencing attempts using sequence-specific RNA degradation mechanisms. SUMMARY In rare diseases such as HMN, the recent development of genetic sequencing and data interpretation methods has enabled a broader diagnostic approach, whereas treatment strategies are becoming more individualized. Significant milestones have been reached in the discovery of new genes, the establishment of functional disease models, and the preclinical development of mechanistic-based therapies.

Half of all diabetics are affected by a diabetic neuropathy. Microangiopathy, dysfunctional Schwann cell interactions, accumulation of toxic metabolites, and inflammatory processes all contribute to nerve damage.Overview and perspectives of the pathophysiology as well as the current and future treatment implications.Literature search (1990-2020).Clinically predominant are sensory and autonomic symptoms; however, muscle weakness can occur as well. Complications such as unrecognized myocardial infarctions and the diabetic foot syndrome are potentially life-threatening and can cause major disability. The pathophysiology of neuropathies in type 1 and type 2 diabetes mellitus differs due to additional risk factors of the metabolic syndrome. To reduce the risk of neuropathy, an intensive insulin therapy is superior compared to the conventional insulin therapy. Oral antidiabetic drugs should be chosen based on individual risk profiles. Metformin can cause an iatrogenic vitamin B12 deficiency. In the treatment of neuropathic pain, the calcium channel blocker pregabalin has the highest recommendation level. The tricyclic antidepressant amitriptyline is considered to be equally effective, but it is contraindicated in autonomic dysregulation and cognitive impairment. Alternatively, the serotonin-norepinephrine reuptake inhibitor duloxetine is approved for the symptomatic treatment of diabetic neuropathies. Controversially discussed medications include alpha-lipoic acid, epalrestat, and L‑serine.The diabetic neuropathy is frequent and causes severe complications. A good understanding of the underlying pathophysiology can contribute to the development of novel treatment strategies in the future.

Journal of neurology 268(10), 3610-3625 (2021). doi:10.1007/s00415-020-09962-6, Published by Steinkopff, [Darmstadt]

This editorial highlights a study by Rodriguez, Sanchez-Moran et al. (2019) in the current issue of the Journal of Neurochemistry, in which the authors describe a microcephalic boy carrying the novel heterozygous de novo missense mutation c.560A> G; p.Asp187Gly in Cdh1/Fzr1 encoding the APC/C E3-ubiquitin ligase cofactor CDH1. A functional characterization of mutant APC/CCDH1 confirms an aberrant division of neural progenitor cells, a condition known to determine the mouse brain cortex size. These data suggest that APC/CCDH1 may contribute to the regulation of the human brain size.

Muscle nerve 61(5), 600-607 (2020). doi:10.1002/mus.26827, Published by Wiley, New York, NY [u.a.]

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.