A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.

Chronic pain is a major global public health issue causing a severe impact on both the quality of life for sufferers and the wider economy. Despite the significant clinical burden, little progress has been made in terms of therapeutic development. A unique approach to identifying new human-validated analgesic drug targets is to study rare families with inherited pain insensitivity. Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures. This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity. The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain. Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity. Gene expression analyses in dorsal root ganglia from mutant and wild-type mice show altered expression of genes implicated in peripheral pain mechanisms. The ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are therefore potential novel targets for the development of new analgesic drugs.awx326media15680039660001.

Non-truncating LIFR mutation: causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?

We present a Qatari family with two children who displayed a characteristic phenotype of congenital marked pain insensitivity with hypohidrosis and progressive aseptic destruction of joints and vertebrae resembling that of hereditary sensory and autonomic neuropathies (HSANs). The patients, aged 10 and 14, remained of uncertain genetic diagnosis until whole genome sequencing was pursued. Genome sequencing identified a novel homozygous C65S mutation in the LIFR gene that is predicted to markedly destabilize and alter the structure of a particular domain and consequently to affect the functionality of the whole multi-domain LIFR protein. The C65S mutant LIFR showed altered glycosylation and an elevated expression level that might be attributed to a slow turnover of the mutant form. LIFR mutations have been reported in Stüve-Wiedemann syndrome (SWS), a severe autosomal recessive skeletal dysplasia often resulting in early death. Our patients share some clinical features of rare cases of SWS long-term survivors; however, they also phenocopy HSAN due to the marked pain insensitivity phenotype and progressive bone destruction. Screening for LIFR mutations might be warranted in genetically unresolved HSAN phenotypes.

Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia.

OBJECTIVE: Mutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia. METHODS: We sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes. RESULTS: In erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations. CONCLUSIONS: Two novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors.

Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders.

The voltage-gated sodium-channel type IX alpha subunit, known as Na(v)1.7 and encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in action potential production in these cells. Recent genetic studies have identified Na(v)1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in Na(v)1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Na(v)1.7 result in loss of Na(v)1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. This review highlights these recent developments and discusses the critical role of Na(v)1.7 in pain sensation in humans.

Clinical, genomics and networking analyses of a high-altitude native American Ecuadorian patient with congenital insensitivity to pain with anhidrosis: a case report.

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). CASE PRESENTATION: Here, we present clinical and molecular findings in a 9-year-old girl with CIPA. The high-altitude indigenous Ecuadorian patient presented several health problems such as anhidrosis, bone fractures, self-mutilation, osteochondroma, intellectual disability and Riga-Fede disease. After the mutational analysis of NTRK1, the patient showed a clearly autosomal recessive inheritance pattern with the pathogenic mutation rs763758904 (Arg602*) and the second missense mutation rs80356677 (Asp674Tyr). Additionally, the genomic analysis showed 69 pathogenic and/or likely pathogenic variants in 46 genes possibly related to phenotypic heterogeneity, including the rs324420 variant in the FAAH gene. The gene ontology enrichment analysis showed 28 mutated genes involved in several biological processes. As a novel contribution, the protein-protein interaction network analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix involved in the response to stimulus and nervous system development. CONCLUSIONS: This is the first study that associates clinical, genomics and networking analyses in a Native American patient with consanguinity background in order to better understand CIPA pathogenesis.

A kindred with cerebellar ataxia and thermoanalgesia.

OBJECTIVE: To characterise the clinical, neurophysiological, neuropathological and genetic features of a family with cerebellar autosomal dominant ataxia. DESIGN: Patients were submitted to clinical, neuroradiological and neurophysiological examinations. Molecular studies were undertaken to exclude SCAs 1-3, 6-8, 12 and 17. Studies were performed to rule out linkage to SCA4 on chromosome 16, and for all still uncharacterised SCA loci. Neuropathological examination of the proband was performed with immunocytochemistry. RESULTS: These patients presented a late onset cerebellar ataxia with thermoanalgesia and deep sensory loss. Unlike in SCA4, reflexes were preserved. MRI revealed cerebellar, medullar and spinal cord atrophy. Neurophysiological studies showed absence or marked reduction of the sensory nerve action potentials and somatosensory evoked potentials in lower and upper limbs but preservation of the soleus H reflex. No triplet repeat expansion mutations in the studied SCA genes were identified. Our studies ruled out linkage of the disease to the SCA4 locus on chromosome 16 and the remaining reported SCA loci. The neuropathological study of the proband revealed severe loss of Purkinje cells and dentate neurons. The inferior olive and lower cranial nerve nuclei also showed extensive cell loss. Posterior columns and spinocerebellar tracts were demyelinated. Ubiquitin immunoreactive intranuclear inclusions were absent. CONCLUSION: This kind of cerebellar ataxia, associated with thermoanalgesia as well as deep sensory loss with retained reflexes, does not associate to any known SCA loci. Therefore, we identify and describe a new form of late onset dominant spinocerebellar ataxia.

[Congenital insensitivity to pain]. / L'insensibilité congénitale à la douleur.

Congenital insensitivity to pain (CIP) is a rare syndrome with various clinical expressions, characterized by a dramatic impairment of pain perception since birth. In the 1980s, progress in nerve histopathology allowed to demonstrate that CIP was almost always a manifestation of hereditary sensory and autonomic neuropathies (HSAN) involving the small-calibre (A-delta and C) nerve fibres which normally transmit nociceptive inputs along sensory nerves. Identification of the genetic basis of several clinical subtypes has led to a better understanding of the mechanisms involved, emphasizing in particular the crucial role of nerve growth factor (NGF) in the development and survival of nociceptors. Recently, mutations of the gene coding for the sodium channel Nav1.7--a voltage-dependent sodium channel expressed preferentially on peripheral nociceptors and sympathetic ganglia--have been found to be the cause of CIP in patients showing a normal nerve biopsy. This radical impairment of nociception mirrors the hereditary pain syndromes associated with "gain of function" mutations of the same ion channel, such as familial erythromelalgia and paroxysmal extreme pain disorder. Future research with CIP patients may identify other proteins specifically involved in nociception, which might represent potential targets for chronic pain treatment. Moreover, this rare clinical syndrome offers the opportunity to address interesting neuropsychological issues, such as the role of pain experience in the construction of body image and in the empathic representation of others' pain.

Arthritis in a child secondary to congenital insensitivity to pain and self-aggression. Why and when pain is good?

A 9 year-old female child presented with recurrent arthritis of ankles, left knee and unequal leg length. Clinical examination revealed mild valgus deformity in her left knee with grade 2 effusion, arthritis of both ankles and deformity in her left wrist. Examination of the affected joints showed no evidence of tenderness upon active or passive movements and the patient did not show any limping upon gait analysis. Past history of the patient revealed evidence of previous dislocation of her left hip and previous fibular fracture. Revision of her previous x-rays showed left hip dislocation, fracture left fibula and fracture of right metatarsal bone after repetitive trauma which pass unnoticed. Recent x-ray of her left knee showed osteochondral injury. Laboratory investigations were done to rule out common causes of childhood arthritis and revealed: ESR 12 1st hours, CRP negative, negative rheumatoid factor, and negative ANA. Neurological evaluation of the patient documented congenital insensitivity to pain and EMG studies confirmed evidence of sensory neuropathy. Traumatic arthritis resulting from congenital insensitivity to pain with self-aggression is rarely encountered in children but should be considered in the differential diagnosis specially if radiological features point to repetitive trauma with attempts of healing.

Congenital insensitivity to pain with anhidrosis in a 2-month-old boy.

In a 2-month-old boy with congenital insensitivity to pain and anhidrosis, the initial symptom was recurrent fever of unknown origin. After eruption of the first teeth, self-mutilation of the tongue was limited by extraction of the teeth. Unmyelinated fibers were essentially lacking, and the number of small myelinated fibers was decreased in sural nerve. This case is the youngest to be diagnosed and the first one in which nerve biopsy clearly showed the characteristic findings.

[Structural and ultrastructural quantitative study of skin and nerve biopsies in the diagnosis of congenital indifference to pain]. / Contribution a l'etude quantitative structurale et ultra-structurale de biopsies cutanees et nerveuse dans le diagnostic de l'indifference congenitale a la douleur.

The muscolo-cutaneous nerve, and skin biopsies from 3rd and 5th finger-tips and the back were studied in a 8-year-old girl with congenital indifference to pain, and in a control child of the same age. The tips of the fingers, and the toes were the most damaged areas. The diameters of myelinated and unmyelinated fibers of the nerve in the sick child and the control child were compared. A loss of 54% of myelinated fibers and 33% of unmyelinated fibers was observed. In the skin, the loss of myelinated fibers was 82% in the 3rd finger-tip, 78% in the 5th, and 35% in the back, and of unmyelinated fibers, 97%, 87%, and 8%, respectively. Eighty four per cent of free endings were absent in the 3rd finger-tip and they were completely absent in the 5th. As for Meissner's corpuscles, 97% were absent in the 3rd finger, and 75% in the 5th. The absence of degenerating fibers and the unimodal distribution of unmyelinated fibers raise the problem of the nosological position of this case of congenital indifference to pain, as compared to the sensory neuropathies.

Muscle involvement in congenital insensitivity to pain with anhidrosis.

A patient with congenital insensitivity to pain with anhidrosis, who had characteristic clinical features and biopsied sural nerve, is presented. Nerve pathology findings indicated a loss of the small myelinated and unmyelinated fibers. Biopsied muscle disclosed a marked variation in fiber size, some small fibers with central nuclei, and a small number of small angulated fibers, consistent with neurogenic and myogenic changes. Many patients with congenital insensitivity to pain with anhidrosis had muscle weakness and absent or decreased deep tendon reflexes with normal nerve conduction velocity. We confirmed that lack of small myelinated fibers in motor neurons resulted in a striking change of muscle in our patient.

Congenital insensitivity to pain with anhidrosis (hereditary sensory and autonomic neuropathy type IV)

Congenital insensitivity to pain with anhidrosis (CIPA, hereditary sensory and autonomic neuropathy type IV) is an exceedingly rare disease. Only 31 cases have been reported. We report a 4-year-old girl with CIPA and include a complete review of the literature. CIPA is a severe autosomal recessive condition that leads to self-mutilation in the first months of life and to bone fractures, multiple scars, osteomyelitis, joint deformities, and limb amputation as the children grow older. Mental retardation is common. Death from hyperpyrexia occurs within the first 3 years of life in almost 20% of the patients. Ultrastructural and morphometric studies of the peripheral nerves demonstrate a loss of the unmyelinated and small myelinated fibers. The actual physiopathologic mechanism of this developmental disorder remains unknown.

Congenital insensitivity to pain with anyhydrosis: morphological studies of skin and peripheral nerves.

Two male siblings born to consanguineous parents, with the diagnosis of congenital insensitivity to pain with anhydrosis are evaluated. The patients presented with unexplained bouts of fever, self-mutilation, repeated trauma and inability to sweat. Physical examination revealed both siblings to be insensitive to pain and temperature. The electron microscopic study of the skin was unremarkable whereas sural nerve biopsies yielded an essential lack of unmyelinated fibers.

[Familial indifference to pain with somatosensory asymmetry: possible central anomaly]. / Forme familiale d'insensibilité à la douleur avec asymétrie de la somesthésie: anomalie centrale?

A family of seven siblings is described. The mother and six siblings have been examined, the eldest and youngest of whom suffer from congenital indifference to pain , although both were ticklish, and itched. The functions examined included somatosensory perception thresholds and autonomic functions; perception thresholds were greatly raised in the painfree subjects and to a lesser extent in some other family members, asymmetrically in all cases, being higher in the dominant hand. Painfree Subject 1 also underwent cerebrospinal fluid analysis at age 16, which showed normal B-endorphin levels but undetectable enkephalins. Electrophysiological tests when a child demonstrated notably that most (raised) measured values were lowered by naloxone. Light microscopic sural nerve biopsy performed on painfree Subject 1 in childhood did not suggest any abnormalities other than a thickened nerve sheath. Threshold asymmetry has not been observed in large numbers of subjects without neurological deficits. There were no significant autonomic changes in any tested family member, though there was some asymmetry. It is suggested that the findings may imply a congenital anomaly of the central nervous system which accounts for the somatosensory, biochemical, and electrophysiological abnormalities.

[Hereditary sensory and autonomic neuropathies. The neurophysiological and pathological aspects of two cases with congenital insensitivity to pain]. / Neuropatías sensitivas autonómicas hereditarias. Dos casos con insensibilidad congenita al dolor; aspectos neurofisiológicos y patológicos.

AIM: Two patients suffering from congenital insensitivity to pain were studied. They corresponded to types IV and V of the 'hereditary sensory and autonomic neuropathies' (HSAN) classification. CASE REPORTS: The first case showed important autonomic dysfunctions, such as anhidrosis, hyperthermia, skin and bone trophic impairment, and mental retardation; the second one only exhibited alterations in pain and temperature sensibilities. In both, chronic indolent corneal ulcers were also present. Conventional neurophysiological evaluation of the neuromuscular system was normal, but an afferent disturbance of the blink reflex (BR) was evident in both. The sympathetic skin response was absent in the HSAN type IV case and normal in the HSAN type V. Notable reduction of the small myelinated fibres, associated to almost no unmyelinated fibres in the first case, were found in the sural nerve biopsies. CONCLUSIONS: So far there haven't been described BR abnormalities in patients with congenital insensitivity to pain, which should be related to a trigeminal sensory impairment, which could explain the corneal ulcers that suffered these cases. BR studies should be included in the neurophysiological evaluation of the suspected small fibre neuropathies even when there are no facial symptoms shown.