A novel nonsense variant in the ATL3 gene is associated with disturbed pain sensitivity, numbness of distal limbs and muscle weakness.

Introduction Hereditary sensory neuropathy (HSN) describes as a heterogeneous group of peripheral neuropathies. HSN type 1 (HSN1) is one subtype characterized by distal sensory impairment that occurs in the form of numbness, tingling, or pain. To date, only two variants in the atlastin GTPase 3 (ATL3) gene have been identified that result in hereditary sensory neuropathy type 1F (HSN1F) with autosomal dominantinheritance. Methods We sudied and examined who present with sensory disturbances and muscle weakness in their lower limb. Patients underwent Whole Exome Sequencing and Sanger sequencing was performed in families for validation of detected variant. Results Here, we identified two Iranian families carrying the novel heterozygous stop variant NM_015459.5: c.16C>T, p.Arg6Ter in ATL3 that led to disturbed pain and touch sensitivity. This variant in the ATL3 gene was detected in both families (NM_015459.5: c.16C>T, p.Arg6Ter) by whole-exome sequencing and confirmed by Sanger sequencing. Conclusion In this study, the subjects manifested weakness of distal limb muscles and numbness of the lower extremities. In addition, some unusual features, including hearing problems and inability to sit and walk presented in one of the patients. Eventually, we provide a case-based review of the clinical features associated with HSN1F. Hitherto, only 11 patients with HSN1F have been reported. We compared our findings to previously reported cases, suggesting that the clinical features are generally variable in the HSN1F patients.

Early life oxytocin treatment improves thermo-sensory reactivity and maternal behavior in neonates lacking the autism-associated gene Magel2.

Atypical responses to sensory stimuli are considered as a core aspect and early life marker of autism spectrum disorders (ASD). Although recent findings performed in mouse ASD genetic models report sensory deficits, these were explored exclusively during juvenile or adult period. Whether sensory dysfunctions might be present at the early life stage and rescued by therapeutic strategy are fairly uninvestigated. Here we found that under cool environment neonatal mice lacking the autism-associated gene Magel2 present pup calls hypo-reactivity and are retrieved with delay by their wild-type dam. This neonatal atypical sensory reactivity to cool stimuli was not associated with autonomic thermoregulatory alteration but with a deficit of the oxytocinergic system. Indeed, we show in control neonates that pharmacogenetic inactivation of hypothalamic oxytocin neurons mimicked atypical thermosensory reactivity found in Magel2 mutants. Furthermore, pharmacological intranasal administration of oxytocin to Magel2 neonates was able to rescue both the atypical thermosensory response and the maternal pup retrieval. This preclinical study establishes for the first-time early life impairments in thermosensory integration and suggest a therapeutic potential benefit of intranasal oxytocin treatment on neonatal atypical sensory reactivity for autism.

Reducing monocarboxylate transporter MCT1 worsens experimental diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the most common complications in diabetic patients. Though the exact mechanism for DPN is unknown, it clearly involves metabolic dysfunction and energy failure in multiple cells within the peripheral nervous system. Lactate is an alternate source of metabolic energy that is increasingly recognized for its role in supporting neurons. The primary transporter for lactate in the nervous system, monocarboxylate transporter-1 (MCT1), has been shown to be critical for peripheral nerve regeneration and metabolic support to neurons/axons. In this study, MCT1 was reduced in both sciatic nerve and dorsal root ganglia in wild-type mice treated with streptozotocin (STZ), a common model of type-1 diabetes. Heterozygous MCT1 null mice that developed hyperglycemia following STZ treatment developed a more severe DPN compared to wild-type mice, as measured by greater axonal demyelination, decreased peripheral nerve function, and increased numbness to innocuous low-threshold mechanical stimulation. Given that MCT1 inhibitors are being developed as both immunosuppressive and chemotherapeutic medications, our results suggest that clinical development in patients with diabetes should proceed with caution. Collectively, our findings uncover an important role for MCT1 in DPN and provide a potential lead toward developing novel treatments for this currently untreatable disease.

A touching story.

A slide taped to a window at the Woods Hole Marine Biology Laboratory was my first introduction to the touch receptor neurons of the nematode Caenorhabditis elegans. Studying these cells as a postdoc with Sydney Brenner gave me a chance to work with John Sulston on a fascinating set of neurons. I would never have guessed then that 43 years later I would still be excited about learning their secrets.

Impaired mechanical, heat, and cold nociception in a murine model of genetic TACE/ADAM17 knockdown.

TNF-α-converting enzyme, a member of the ADAM (A disintegrin and metalloproteinase) protease family and also known as ADAM17, regulates inflammation and regeneration in health and disease. ADAM17 targets are involved in pain development and hypersensitivity in animal models of inflammatory and neuropathic pain. However, the role of ADAM17 in the pain pathway is largely unknown. Therefore, we used the hypomorphic ADAM17 (ADAM17ex/ex) mouse model to investigate the importance of ADAM17 in nociceptive behavior, morphology, and function of primary afferent nociceptors. ADAM17ex/ex mice were hyposensitive to noxious stimulation, showing elevated mechanical thresholds as well as impaired heat and cold sensitivity. Despite these differences, skin thickness and innervation were comparable to controls. Although dorsal root ganglia of ADAM17ex/ex mice exhibited normal morphology of peptidergic and nonpeptidergic neurons, a small but significant reduction in the number of isolectin ß-4-positive neurons was observed. Functional electrical properties of unmyelinated nociceptors showed differences in resting membrane potential, afterhyperpolarization, and firing patterns in specific subpopulations of sensory neurons in ADAM17ex/ex mice. However, spinal cord morphology and microglia activity in ADAM17ex/ex mice were not altered. Our data suggest that ADAM17 contributes to the processing of painful stimuli, with a complex mode of action orchestrating the function of neurons along the pain pathway.-Quarta, S., Mitric, M., Kalpachidou, T., Mair, N., Schiefermeier-Mach, N., Andratsch, M., Qi, Y., Langeslag, M., Malsch, P., Rose-John, S., Kress, M. Impaired mechanical, heat, and cold nociception in a murine model of genetic TACE/ADAM17 knockdown.

Increased fronto-hippocampal connectivity in the Prrxl1 knockout mouse model of congenital hypoalgesia.

Despite the large number of studies addressing how prolonged painful stimulation affects brain functioning, there are only a handful of studies aimed at uncovering if persistent conditions of reduced pain perception would also result in brain plasticity. Permanent hypoalgesia induced by neonatal injection of capsaicin or carrageenan has already been shown to affect learning and memory and to induce alterations in brain gene expression. In this study, we used the Prrxl1 model of congenital mild hypoalgesia to conduct a detailed study of the neurophysiological and behavioral consequences of reduced pain experience. Prrxl1 knockout animals are characterized by selective depletion of small diameter primary afferents and abnormal development of the superficial dorsal laminae of the spinal cord, resulting in diminished pain perception but normal tactile and motor behaviour. Behavioral testing of Prrxl1 mice revealed that these animals have reduced anxiety levels, enhanced memory performance, and improved fear extinction. Neurophysiological recordings from awake behaving Prrxl1 mice show enhanced altered fronto-hippocampal connectivity in the theta- and gamma-bands. Importantly, although inflammatory pain by Complete Freund Adjuvant injection caused a decrease in fronto-hippocampal connectivity in the wild-type animals, Prrxl1 mice maintained the baseline levels. The onset of inflammatory pain also reverted the differences in forebrain expression of stress- and monoamine-related genes in Prrxl1 mice. Altogether our results suggest that congenital hypoalgesia may have an effect on brain plasticity that is the inverse of what is usually observed in animal models of chronic pain.

Bilateral congenital corneal anesthesia in a patient with SCN9A mutation, confirmed primary erythromelalgia, and paroxysmal extreme pain disorder.

The SCN9A gene codes for the sodium voltage-gated channel NaV 1.7. Gain of function mutations cause pain disorders such as primary erythromelalgia, paroxysmal extreme pain disorder, and small fiber neuropathy. Loss of function mutations lead to congenital insensitivity to pain. We report the case of a 6-year-old girl with a SCN9A mutation who presented with both gain of function and loss of function phenotypes, including congenital corneal anesthesia.

An atypical case of SCN9A mutation presenting with global motor delay and a severe pain disorder.

INTRODUCTION: Erythromelalgia due to heterozygous gain-of-function SCN9A mutations usually presents as a pure sensory-autonomic disorder characterized by recurrent episodes of burning pain and redness of the extremities. METHODS: We describe a patient with an unusual phenotypic presentation of gross motor delay, childhood-onset erythromelalgia, extreme visceral pain episodes, hypesthesia, and self-mutilation. The investigation of the patient's motor delay included various biochemical analyses, a comparative genomic hybridization array (CGH), electromyogram (EMG), and muscle biopsy. Once erythromelalgia was suspected clinically, the SCN9A gene was sequenced. RESULTS: The EMG, CGH, and biochemical tests were negative. The biopsy showed an axonal neuropathy and neurogenic atrophy. Sequencing of SCN9A revealed a heterozygous missense mutation in exon 7; p.I234T. CONCLUSIONS: This is a case of global motor delay and erythromelalgia associated with SCN9A. The motor delay may be attributed to the extreme pain episodes or to a developmental perturbation of proprioceptive inputs.

HDAC inhibitors restore C-fibre sensitivity in experimental neuropathic pain model.

BACKGROUND AND PURPOSE: Hypoesthesia is a clinical feature of neuropathic pain. The feature is partly explained by the evidence of epigenetic repression of Nav 1.8 sodium channel in the dorsal root ganglion (DRG). EXPERIMENTAL APPROACH: We investigated the possibility of trichostatin A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to reverse the unique C-fibre sensitivity observed following partial ligation of sciatic nerve in mice. KEY RESULTS: Nerve injury-induced down-regulation of DRG Nav 1.8 sodium channel and C-fibre-related hypoesthesia were reversed by TSA, VPA and SAHA treatments, which inhibit histone deacetylase (HDAC), and increase histone acetylation at the regulatory sequence of Nav 1.8. CONCLUSIONS AND IMPLICATIONS: Taken together, these studies provide the evidence that hypoesthesia and underlying down-regulation of Nav 1.8, negative symptoms observed in nerve injury-induced neuropathic pain models are regulated by an epigenetic chromatin remodelling through HDAC-related machineries.

Genome-wide association study of sensory disturbances in the inferior alveolar nerve after bilateral sagittal split ramus osteotomy.

BACKGROUND: Bilateral sagittal split ramus osteotomy (BSSRO) is a common orthognatic surgical procedure. Sensory disturbances in the inferior alveolar nerve, including hypoesthesia and dysesthesia, are frequently observed after BSSRO, even without distinct nerve injury. The mechanisms that underlie individual differences in the vulnerability to sensory disturbances have not yet been elucidated. METHODS: The present study investigated the relationships between genetic polymorphisms and the vulnerability to sensory disturbances after BSSRO in a genome-wide association study (GWAS). A total of 304 and 303 patients who underwent BSSRO were included in the analyses of hypoesthesia and dysesthesia, respectively. Hypoesthesia was evaluated using the tactile test 1 week after surgery. Dysesthesia was evaluated by interview 4 weeks after surgery. Whole-genome genotyping was conducted using Illumina BeadChips including approximately 300,000 polymorphism markers. RESULTS: Hypoesthesia and dysesthesia occurred in 51 (16.8%) and 149 (49.2%) subjects, respectively. Significant associations were not observed between the clinical data (i.e., age, sex, body weight, body height, loss of blood volume, migration length of bone fragments, nerve exposure, duration of anesthesia, and duration of surgery) and the frequencies of hypoesthesia and dysesthesia. Significant associations were found between hypoesthesia and the rs502281 polymorphism (recessive model: combined χ² = 24.72, nominal P = 6.633 × 10⁻7), between hypoesthesia and the rs2063640 polymorphism (recessive model: combined χ² = 23.07, nominal P = 1.563 × 10⁻6), and between dysesthesia and the nonsynonymous rs2677879 polymorphism (trend model: combined χ² = 16.56, nominal P = 4.722 × 10⁻5; dominant model: combined χ² = 16.31, nominal P = 5.369 × 10⁻5). The rs502281 and rs2063640 polymorphisms were located in the flanking region of the ARID1B and ZPLD1 genes on chromosomes 6 and 3, whose official names are "AT rich interactive domain 1B (SWI1-like)" and "zona pellucida-like domain containing 1", respectively. The rs2677879 polymorphism is located in the METTL4 gene on chromosome 18, whose official name is "methyltransferase like 4". CONCLUSIONS: The GWAS of sensory disturbances after BSSRO revealed associations between genetic polymorphisms located in the flanking region of the ARID1B and ZPLD1 genes and hypoesthesia and between a nonsynonymous genetic polymorphism in the METTL4 gene and dysesthesia.

TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells.

Transient receptor potential (TRP) channels TRPC3 and TRPC6 are expressed in both sensory neurons and cochlear hair cells. Deletion of TRPC3 or TRPC6 in mice caused no behavioural phenotype, although loss of TRPC3 caused a shift of rapidly adapting (RA) mechanosensitive currents to intermediate-adapting currents in dorsal root ganglion sensory neurons. Deletion of both TRPC3 and TRPC6 caused deficits in light touch and silenced half of small-diameter sensory neurons expressing mechanically activated RA currents. Double TRPC3/TRPC6 knock-out mice also showed hearing impairment, vestibular deficits and defective auditory brain stem responses to high-frequency sounds. Basal, but not apical, cochlear outer hair cells lost more than 75 per cent of their responses to mechanical stimulation. FM1-43-sensitive mechanically gated currents were induced when TRPC3 and TRPC6 were co-expressed in sensory neuron cell lines. TRPC3 and TRPC6 are thus required for the normal function of cells involved in touch and hearing, and are potential components of mechanotransducing complexes.

Deletion of 8q24 in an adult with mild dysmorphic features, developmental delay, and ketotic hypoglycemia.

We present a 56-year-old female with a history of carbohydrate intolerance and ketotic hypoglycemia, dysmorphic features, mild developmental delay, lymphedema, altered pain sensation, and frequent fractures, who was found to have a heterozygous 8.09 Mb deletion of chromosome 8q24.11q24.13 containing more than 39 genes, as well as a duplication of 20q11.23 containing one gene. The deleted region overlaps that of two previously reported patients, who share a subset of clinical characteristics with the patient described here. Some of this patient's clinical features are consistent with the loss of genes in the deleted region. The diagnostic work-up of this patient clearly demonstrates the evolution of genetic testing techniques.

Two novel SCN9A mutations causing insensitivity to pain.

The sensation of pain is important and there may be serious consequences if it is missing. Recently, the genetic basis for a channelopathy characterised by a congenital inability to experience pain has been described and channelopathy-associated insensitivity to pain has been proposed as a suitable name for this condition. Different mutations in the SCN9A gene causing loss of function of the voltage-gated sodium channel Nav1.7 have been reported in patients with this rare disease. Here we describe a woman with insensitivity to pain with two novel mutations in the SCN9A gene, coding for the Nav1.7 channel. We also discuss the finding of anosmia which apparently is a common feature in these patients.

Impaired pain sensation in mice lacking prokineticin 2.

Prokineticins (PKs), consisting of PK1 and PK2, are a pair of newly identified regulatory peptides. Two closely related G-protein coupled receptors, PKR1 and PKR2, mediate the signaling of PKs. PKs/PKRs participate in the regulation of diverse biological processes, ranging from development to adult physiology. A number of studies have indicated the involvement of PKs/PKRs in nociception. Here we show that PK2 is a sensitizer for nociception. Intraplantar injection of recombinant PK2 resulted in a strong and localized hyperalgesia with reduced thresholds to nociceptive stimuli. PK2 mobilizes calcium in dissociated dorsal root ganglion (DRG) neurons. Mice lacking the PK2 gene displayed strong reduction in nociception induced by thermal and chemical stimuli, including capsaicin. However, PK2 mutant mice showed no difference in inflammatory response to capsaicin. As the majority of PK2-responsive DRG neurons also expressed transient receptor potential vanilloid (TRPV1) and exhibited sensitivity to capsaicin, TRPV1 is likely a significant downstream molecule of PK2 signaling. Taken together, these results reveal that PK2 sensitize nociception without affecting inflammation.

Congenital indifference to pain and deletion of chromosome 10q-: new association.

We describe a case of a de novo terminal deletion of the long arm of chromosome 10 with the novel feature of congenital indifference to pain in a 2-year 10-month-old boy. Relative indifference to pain defined by a lack of emotional response to pain has not been described previously in association with the terminal deletion of the long arm of chromosome 10.

Bilateral corneal anesthesia associated with diaphragmatic paralysis, ovarian failure, and developmental delay.

PURPOSE: To describe two siblings with bilateral corneal anesthesia associated with multiple systemic abnormalities. DESIGN: Interventional case report. METHODS: A 38-year-old Hispanic woman was seen for bilateral corneal ulcers, exposure keratitis, hemorrhagic retinopathy, and multiple systemic abnormalities. A younger sibling with similar but milder findings was also examined. Medical and genetic evaluation was investigated in these two siblings with bilateral decreased sensation and multiple abnormalities from a consanguineous union. RESULTS: Examination of the patient showed bilateral corneal anesthesia, and multiple systemic abnormalities included diaphragmatic paralysis, ovarian failure, multiple thrombotic cerebrovascular accidents, pedal edema, mandibular hypoplasia, and developmental delay. Milder findings were seen in a sibling. Corneal ulcers were stabilized after treatment that included bandage contact lens, pressure patching, topical antibiotics, and tarsorrhaphy. CONCLUSIONS: The combination of corneal anesthesia and systemic abnormalities, with parental consanguinity, suggests an inherited syndrome.

Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity.

The capsaicin receptor transient receptor potential V1 (TRPV1; also known as vanilloid receptor 1) is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. It has been reported that extracellular ATP potentiates the TRPV1 currents evoked by capsaicin or protons and reduces the temperature threshold for its activation through metabotropic P2Y receptors in a PKC-dependent pathway, suggesting that TRPV1 activation could trigger the sensation of pain at normal body temperature in the presence of ATP. Here, we show that ATP-induced thermal hyperalgesia was abolished in mice lacking TRPV1, suggesting the functional interaction between ATP and TRPV1 at a behavioral level. However, thermal hyperalgesia was preserved in P2Y1 receptor-deficient mice. Patch-clamp analyses using mouse dorsal root ganglion neurons indicated the involvement of P2Y2 rather than P2Y1 receptors. Coexpression of TRPV1 mRNA with P2Y2 mRNA, but not P2Y1 mRNA, was determined in the rat lumbar DRG using in situ hybridization histochemistry. These data indicate the importance of metabotropic P2Y2 receptors in nociception through TRPV1.

[Keratopathy as a sign of multifocal congenital sensory polyneuropathy. A case report]. / Keratopathie als Zeichen einer multifokalen kongenitalen sensiblen Polyneuropathie. Eine Fallbeschreibung.

PATIENT: A 63-year-old female with bilateral recurrent corneal ulcerations for 10 years, suffered from vascularisation of the cornea and absence of corneal sensitivity. Other symptoms were multifocal hypoaesthesia with hypalgesia of hands and legs, generalised lack of deep tendon reflexes, absence of somato-sensory evoked potentials (SSEP) and of sensory nerve action potentials (SNAP) in these regions. A sural biopsy demonstrated extreme lack of myelinated fibres. Acquired causes for polyneuropathy were excluded. THERAPY: Subsequent to local ocular treatment we carried out a perforating corneal transplantation of the left eye because of corneal scars. This had to be repeated 2 years later because of vascularisation of the transplant. The visual function of the left eye could be stabilised at values between 0.2 and 1/50. CONCLUSION: Anamnesis and clinical symptoms of the patient are compatible with the diagnosis of hereditary sensory neuropathy type II (HSN II) affecting the trigeminal nerves. In patients with neuropathy and impaired corneal sensitivity, a favourable prognosis may be achieved by a corneal transplant.