The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P.

摘要: Individuals with congenital insensitivity to pain (CIP) have never felt despite possessing an anatomically normal peripheral nervous system and intelligence.1 In 2006/7, biallelic null mutations in the transmembrane voltage-gated sodium channel NaV1.7/SCN9A were discovered as a cause of CIP.2, 3 Recently, new form CIP was reported two isolated unrelated cases. Both had recurrent injuries self-mutilations secondary feeling no pain, identical de novo heterozygous p.L811P variants NaV1.9, encoded by SCN11A.4 We now identified further case variant c.2432T>C (p.(L811P)) report that all complex extended phenotype, see Table 1. Table 1 A comparison phenotype each individual due SCN11A/NaV1.9 p.L811P The presenting feature three failure thrive intestinal dysmotility. Consequent upon this, multiple hospital admissions investigations required parenteral nutrition. Abnormal gut peristalsis found; however, biopsies repeatedly normal. All continuing problems diarrhoea and/or constipation. All severe pruritus, scratching themselves sufficiently full-thickness skin loss cervical area during infancy (see Figure 1). Remarkably this at same location seen transgenic Scn11a-mutant mice.4 Ulceration itching may be hyperhidrosis, only reduced following use cyprohepatidine, which lead clear reduction sweating. Hyperhidrosis persisted throughout life, increased on exertion raised ambient temperatures. cried blushed normally, none any abnormal cardiovascular findings nor emotional liability. Figure 1 Neck mutation age 1 year 5 months. A large contiguous healing region is shown. This caused child scratching, mostly while awake. excoriated for 6 months intense ... Motor milestones delayed, consequences persisting hypotonia mild muscle weakness. No clinical or significant neurophysiological signs neuropathy observed. Two individuals adopted bizarre dystonia-like postures extremes joint positions, awake asleep. All slow wound healing, patient particular Staphylococci cultured from lesions. apparent selective immunity staphylococcal infections also hereditary autonomic sensory types 4 5, NTRK1 NGF, respectively. No felt, example, painless bone fractures self-amputation tongue tip lips, defecation produced discomfort. Furthermore, whereas temperature within range could perceived, variations such gust cold wind distinctly unpleasant. These experiences ‘pain' describe. NaV1.9 strongly expressed enteric plexus nociceptor/temperature sensing neurons, show are present. Therefore mainly nerve dysfunction not its absence. The causes pattern effects neuronal subtype activity: it excitatory (NaV1.9 knockout mice activity5), sweat glands leading hyperhidrosis ano-rectal nociceptors showing these innervations functioning; but inhibitory most infective inflammation (which occur neuropathies where small unmyelinated nerves absent). NaV1.9–CIP unique clearly clinically distinguishable NaV1.7–CIP, accompanied anosmia gastrointestinal motility disturbances contrast channelopathies, NTRK1-associated type (also termed ‘congenital anhidrosis') characterized variable degree intellectual disability lack gland innervation, resulting anhidrosis febrile episodes owing poor thermoregulation. pathophysiological basis illustrated families dominant episodic syndrome missense adult onset painful neuropathy.6, 7 including gain-of-function properties level suggest neuron hyperexcitability.4, 6, Yet contrary physiological outcome depending variant, is, versus abolished perception, remains puzzling. One explanation might effect size respective NaV1.9 function determines consequences. This recent insight human pathology suggests agonists antagonists therapeutic potentials. Information regarding SCN11A (p.Leu811Pro) ({"type":"entrez-nucleotide","attrs":{"text":"NM_014139.2","term_id":"115583666","term_text":"NM_014139.2"}}NM_014139.2) available: OMIM Mutation ID 604385.0001 http://omim.org/entry/604385#0001; ClinVar: http://www.ncbi.nlm.nih.gov/clinvar/RCV000074494/ Patient consent been obtained.