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Xue-Rong Leng, Xiao-Hong Qi, Yong-Tao Zhou, Yu-Ping Wang
Familial episodic pain is a rare autosomal-dominant disorder characterized by recurrent attacks of pain. The pathogenesis of familial episodic pain is not very clear so far. Essential tremor is the most common movement disorder, but the identification of essential tremor genes has remained elusive. We studied a four-generation Chinese family with early-onset familial episodic pain and adult onset familial essential tremor. All essential tremor diagnoses were confirmed based on a review of the questionnaires, videotaped neurological examinations and was then reconfirmed by a senior neurologist specializing in movement disorders using published criteria...
June 2017: Journal of Human Genetics
S M Srinivas, V K Gowda, C M Owen, C Moss, R Hiremagalore
Chronic ulcerating lesions on the face are rarely seen in toddlers. Blistering disease, vasculitis, infections and self-mutilation due to neurometabolic disease can usually be excluded on clinical and histological grounds. In the absence of identifiable disease, such lesions are sometimes attributed to child abuse or fabricated illness. We describe three toddlers with chronic mid-face erosions, two from India and one from the UK. One had moderate developmental delay and one had had seizures. The lesions appeared to be self-inflicted, no underlying disease was identified and there was no suspicion of child abuse...
January 2017: Clinical and Experimental Dermatology
Arthur Beyder, Gianrico Farrugia
In the gastrointestinal (GI) tract, abnormalities in secretion, absorption, motility, and sensation have been implicated in functional gastrointestinal disorders (FGIDs). Ion channels play important roles in all these GI functions. Disruptions of ion channels' ability to conduct ions can lead to diseases called ion channelopathies. Channelopathies can result from changes in ion channel biophysical function or expression due to mutations, posttranslational modification, and accessory protein malfunction. Channelopathies are strongly established in the fields of cardiology and neurology, but ion channelopathies are only beginning to be recognized in gastroenterology...
October 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Chongyang Han, Yang Yang, Rene H Te Morsche, Joost P H Drenth, Juan M Politei, Stephen G Waxman, Sulayman D Dib-Hajj
OBJECTIVE: Gain-of-function mutations in Nav1.9 have been identified in three families with rare heritable pain disorders, and in patients with painful small-fibre neuropathy. Identification and functional assessment of new Nav1.9 mutations will help to elucidate the phenotypic spectrum of Nav1.9 channelopathies. METHODS: Patients from a large family with early-onset pain symptoms were evaluated by clinical examination and genomic screening for mutations in SCN9A and SCN11A...
March 2017: Journal of Neurology, Neurosurgery, and Psychiatry
Hiroko Okuda, Atsuko Noguchi, Hatasu Kobayashi, Daiki Kondo, Kouji H Harada, Shohab Youssefian, Hirotomo Shioi, Risako Kabata, Yuki Domon, Kazufumi Kubota, Yutaka Kitano, Yasunori Takayama, Toshiaki Hitomi, Kousaku Ohno, Yoshiaki Saito, Takeshi Asano, Makoto Tominaga, Tsutomu Takahashi, Akio Koizumi
Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence...
2016: PloS One
Voraluck Phatarakijnirund, Steven Mumm, William H McAlister, Deborah V Novack, Deborah Wenkert, Karen L Clements, Michael P Whyte
Congenital insensitivity to pain (CIP) comprises the rare heritable disorders without peripheral neuropathy that feature inability to feel pain. Fracturing and joint destruction are common complications, but lack detailed studies of mineral and skeletal homeostasis and bone histology. In 2013, discovery of a heterozygous gain-of-function mutation in SCN11A encoding voltage-gated sodium channel 1.9 (Nav1.9) established a distinctive CIP in three unrelated patients who suffered multiple painless fractures, self-inflicted mutilation, chronic diarrhea, and hyperhidrosis...
March 2016: Bone
Enrico Leipold, Andrea Hanson-Kahn, Miya Frick, Ping Gong, Jonathan A Bernstein, Martin Voigt, Istvan Katona, R Oliver Goral, Janine Altmüller, Peter Nürnberg, Joachim Weis, Christian A Hübner, Stefan H Heinemann, Ingo Kurth
Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na(+) channel NaV1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the NaV1.9 diseases has yet to be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) in NaV1.9, which leads to cold-aggravated peripheral pain in humans. Electrophysiological analysis reveals that p.V1184A shifts the voltage dependence of channel opening to hyperpolarized potentials thereby conferring gain-of-function characteristics to NaV1...
2015: Nature Communications
Michael S Nahorski, Ya-Chun Chen, C Geoffrey Woods
Erroneous activation of the pain-sensing system, as in chronic or neuropathic pain, represents a major health burden with insufficient treatment options. However, the study of genetic disorders rendering individuals completely unable to feel pain offers hope. All causes of congenital painlessness affect nociceptors, evolutionarily conserved specialist neurons able to sense all type of tissue damage. The discovery of new genes essential for sensing pain (SCN11A, PRDM12, and CLTCL1) has provided unexpected insights into the biological mechanisms that drive distinct stages of nociception...
November 2015: Trends in Neurosciences
J R F Hockley, W J Winchester, D C Bulmer
BACKGROUND: Visceral pain is a common symptom for patients with gastrointestinal (GI) disease. It is unpleasant, debilitating, and represents a large unmet medical need for effective clinical treatments. Recent studies have identified NaV 1.9 as an important regulator of afferent sensitivity in visceral pain pathways to mechanical and inflammatory stimuli, suggesting that NaV 1.9 could represent an important therapeutic target for the treatment of visceral pain. This potential has been highlighted by the identification of patients who have an insensitivity to pain or painful neuropathies associated with mutations in SCN11A, the gene encoding voltage-gated sodium channel subtype 1...
March 2016: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Monica Coll, Catarina Allegue, Sara Partemi, Jesus Mates, Bernat Del Olmo, Oscar Campuzano, Vincenzo Pascali, Anna Iglesias, Pasquale Striano, Antonio Oliva, Ramon Brugada
Sudden unexpected death in epilepsy (SUDEP) is defined as the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥ 30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder...
March 2016: International Journal of Legal Medicine
Patrícia Abrantes, Maria M Santos, Inês Sousa, Joana M Xavier, Vânia Francisco, Tiago Krug, João Sobral, Mafalda Matos, Madalena Martins, António Jacinto, Domingos Coiteiro, Sofia A Oliveira
Subarachnoid hemorrhage (SAH) is a life-threatening event that most frequently leads to severe disability and death. Its most frequent cause is the rupture of a saccular intracranial aneurysm (IA), which is a blood vessel dilation caused by disease or weakening of the vessel wall. Although the genetic contribution to IA is well established, to date no single gene has been unequivocally identified as responsible for IA formation or rupture. We aimed to identify IA susceptibility genes in the Portuguese population through a pool-based multistage genome-wide association study...
2015: PloS One
R Oliver Goral, Enrico Leipold, Ehsan Nematian-Ardestani, Stefan H Heinemann
SCN11A encodes the voltage-gated sodium channel NaV1.9, which deviates most strongly from the other eight NaV channels expressed in mammals. It is characterized by resistance to the prototypic NaV channel blocker tetrodotoxin and exhibits slow activation and inactivation gating. Its expression in dorsal root ganglia neurons suggests a role in motor or pain signaling functions as also recently demonstrated by the occurrence of various mutations in human SCN11A leading to altered pain sensation syndromes. The systematic investigation of human NaV1...
December 2015: Pflügers Archiv: European Journal of Physiology
Ruoyuan Yin, Dong Liu, Mark Chhoa, Chi-Ming Li, Yi Luo, Maosheng Zhang, Sonya G Lehto, David C Immke, Bryan D Moyer
The nine members of the voltage-gated sodium channel (Nav) family mediate inward sodium currents that depolarize neurons and lead to action potential firing. Increased Nav expression and function in sensory ganglia may drive ectopic action potentials and result in neuropathic pain. Using patch-clamp electrophysiology and molecular biology techniques, experiments were performed to elucidate the contribution of Nav channels to sodium currents in rat dorsal root ganglion (DRG) neurons following the L5/L6 spinal nerve ligation (SNL) model of neuropathic pain...
2016: International Journal of Neuroscience
Stephen G Waxman, Ingemar S J Merkies, Monique M Gerrits, Sulayman D Dib-Hajj, Giuseppe Lauria, James J Cox, John N Wood, C Geoffrey Woods, Joost P H Drenth, Catharina G Faber
Human studies have firmly implicated voltage-gated sodium channels in human pain disorders, and targeted and massively parallel genomic sequencing is beginning to be used in clinical practice to determine which sodium channel variants are involved. Missense substitutions of SCN9A, the gene encoding sodium channel NaV1.7, SCN10A, the gene encoding sodium channel NaV1.8, and SCN11A, the gene encoding sodium channel NaV1.9, produce gain-of-function changes that contribute to pain in many human painful disorders...
November 2014: Lancet Neurology
Brigitte A Brouwer, Ingemar S J Merkies, Monique M Gerrits, Stephen G Waxman, Janneke G J Hoeijmakers, Catharina G Faber
Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage-gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where NaV 1.7, NaV 1.8, and NaV 1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain-of-function SCN9A mutations...
June 2014: Journal of the Peripheral Nervous System: JPNS
Erin Greaves, Kelsey Grieve, Andrew W Horne, Philippa T K Saunders
CONTEXT: Ovarian suppression is a common treatment for endometriosis-associated pelvic pain. Its exact mechanism of action is poorly understood, although it is assumed to reflect reduced production/action of estrogens. OBJECTIVE: The objective of the study was to measure the expression of mRNAs encoded by nociceptive genes in the peritoneum of women with chronic pelvic pain (CPP) with or without endometriosis and to investigate whether estrogens alter nociceptive gene expression in human sensory neurons...
September 2014: Journal of Clinical Endocrinology and Metabolism
David L H Bennett, C Geoffrey Woods
The discovery of genetic variants that substantially alter an individual's perception of pain has led to a step-change in our understanding of molecular events underlying the detection and transmission of noxious stimuli by the peripheral nervous system. For example, the voltage-gated sodium ion channel Nav1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A, which encodes Nav1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and small-fibre neuropathy...
June 2014: Lancet Neurology
Jianying Huang, Chongyang Han, Mark Estacion, Dymtro Vasylyev, Janneke G J Hoeijmakers, Monique M Gerrits, Lynda Tyrrell, Giuseppe Lauria, Catharina G Faber, Sulayman D Dib-Hajj, Ingemar S J Merkies, Stephen G Waxman
Sodium channel Nav1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in sodium channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral sodium channels Nav1.7 and Nav1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown...
June 2014: Brain: a Journal of Neurology
Nancy Osorio, Sergiy Korogod, Patrick Delmas
Voltage-gated sodium (Nav) channels play a central role in gastrointestinal physiology because they transmit depolarizing impulses in enteric neurons, thereby enabling the coordination of intestinal motility. However, little is known about the ion channel machinery that specifies firing pattern of enteric neurons. Here, we used in situ patch-clamp recording of myenteric neurons from mice to define functionally the Nav channel subtypes responsible for the electrical signature of myenteric neurons. We found that mouse myenteric neurons exhibit two types of tetrodotoxin-resistant Na(+) currents: an early inactivating Na(+) current (INaT) and a persistent Na(+) current (INaP)...
April 9, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Beate St Pourcain, David H Skuse, William P Mandy, Kai Wang, Hakon Hakonarson, Nicholas J Timpson, David M Evans, John P Kemp, Susan M Ring, Wendy L McArdle, Jean Golding, George Davey Smith
BACKGROUND: Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence. METHODS: Social-communication difficulties were ascertained at ages 8, 11, 14 and 17 years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N ≤ 5,628) using mother-reported Social Communication Disorder Checklist scores...
February 24, 2014: Molecular Autism
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