RESUMEN
A 22-month-old girl of consanguineous parents was admitted with a high-grade fever. She was found to have insensitivity to painful stimuli and an absence of perspiration. She also displayed self-mutilating behaviour and was insensitive to cold/hot water on her body. On examination, there was loss of the tip of the tongue, missing teeth, generalised xerosis, and several ulcers at sites of minor trauma. She also had dysplastic nails and digital ulcers. Sensory examination demonstrated a complete lack of awareness of pain and temperature, vibration and fine touch were intact and lacrimation was normal. Differential diagnoses of hereditary sensory and autonomic neuropathy (HSAN), Lesch-Nyhan syndrome, hypohidrotic ectodermal dysplasia and leprosy were considered. Results of routine blood investigations including serum uric acid were normal. On performing clinical exome sequencing, the diagnosis of congenital insensitivity to pain with anhidrosis (CIPA) of autosomal recessive inheritance was confirmed. A novel, predicted to be pathogenic variant detected at exon 16 of the NTRK1 gene resulting in congenital insensitivity to pain with anhidrosis is reported.Abbreviations: CIPA: congenital Insensitivity to pain with anhidrosis; HSAN: hereditary sensory and autonomic neuropathy; NGF: nerve growth factor; NTRK1: neurotrophic tyrosine kinase receptor 1 gene; TrKA: tropomyosin receptor kinase A.
Asunto(s)
Neuropatías Hereditarias Sensoriales y Autónomas , Receptor trkA , Humanos , Femenino , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Neuropatías Hereditarias Sensoriales y Autónomas/diagnóstico , Neuropatías Hereditarias Sensoriales y Autónomas/complicaciones , Receptor trkA/genética , Lactante , Insensibilidad Congénita al Dolor/genética , Insensibilidad Congénita al Dolor/complicaciones , Insensibilidad Congénita al Dolor/diagnóstico , Hipohidrosis/diagnóstico , Hipohidrosis/genética , Hipohidrosis/complicacionesRESUMEN
RATIONALE: Hereditary sensory and autonomic neuropathy type IV (HSAN IV) may be misdiagnosed because of low awareness among clinical professionals and overlap with other subtypes of congenital insensitivity to pain (CIP). PATIENT: The patient was a 1-year-and-5-months-old boy whose main symptoms were delayed psychomotor development and recurrent fever. Whole-exome sequencing (WES) revealed a compound heterozygous mutation (c. 1927Câ >â T, c. 851-33Tâ >â A) in the NTRK1 gene of the child. Pathological analysis showed decreased autonomic small nerve fibers, sparse hair follicles, and atrophy of the sweat glands. Sweat glands lack innervating nerve fibers. Brain magnetic resonance imaging (MRI) of the patient showed delayed myelination in the brain, slightly enlarged bilateral lateral ventricles, and patchy abnormal signals in the brain. DIAGNOSIS: hereditary sensory and autonomic neuropathy type IV (HSAN IV). INTERVENTION: Inform parents about the illness and take good care of the child. OUTCOMES: The children had less self-harming behavior and no painless fractures during follow-up at 2 years. LESSONS: This report describes the pathological and imaging features and clinical manifestations of a child with HSAN IV in early life to provide a reference for the early diagnosis of the disease. Early diagnosis can help avoid self-mutilation and painless injury and reduce wound infection.
Asunto(s)
Neuropatías Hereditarias Sensoriales y Autónomas , Insensibilidad Congénita al Dolor , Conducta Autodestructiva , Masculino , Humanos , Preescolar , Lactante , Neuropatías Hereditarias Sensoriales y Autónomas/diagnóstico , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Insensibilidad Congénita al Dolor/diagnóstico , Insensibilidad Congénita al Dolor/genética , Fenotipo , MutaciónRESUMEN
BACKGROUND: In this case report, we described the past history, clinical manifestations, genetic characteristics and cognitive evaluation of a boy with congenital insensitivity to pain with anhidrosis (CIPA) who developed autism spectrum disorder (ASD). CASE PRESENTATION: The boy had an early onset of CIPA at the age of 48 months, and was later diagnosed with ASD at 5 years old. Developmental delays in communication, social skills and the presence of maladaptive behaviors were observed in the patient. Professional treatments significantly improved the developmental delays. CONCLUSIONS: This case demonstrated that ASD may develop in children with CIPA, and pediatricians should be aware that if they suspect or identify a child with CIPA that they should also be screened for ASD using similar examination and diagnostic tools as shown in the present report. Moreover, therapeutic interventions for ASD was helpful for the remission of both diseases.
Asunto(s)
Trastorno del Espectro Autista , Neuropatías Hereditarias Sensoriales y Autónomas , Hipohidrosis , Insensibilidad Congénita al Dolor , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/diagnóstico , Canalopatías , Niño , Preescolar , Neuropatías Hereditarias Sensoriales y Autónomas/complicaciones , Neuropatías Hereditarias Sensoriales y Autónomas/diagnóstico , Humanos , Hipohidrosis/complicaciones , Hipohidrosis/diagnóstico , Hipohidrosis/genética , Masculino , Insensibilidad Congénita al Dolor/complicaciones , Insensibilidad Congénita al Dolor/diagnósticoRESUMEN
Background: Congenital insensitivity to pain is a rare autosomal recessive condition characterized by insensitivity to painful stimuli due to absence of sensory and sympathetic post ganglionic neurons in the skin and skeletal system leading to lack of protective sensation and altered joint propioception. This study was performed to assess hand and wrist manifestations of patients with congenital insensitivity to pain in the Maltese Islands. Methods: Records of public and private hospitals were reviewed to identify patients suffering from this condition. A review of notes, patients, and imaging was performed. A Disabilities of the Arm, Shoulder, and Hand score was obtained to assess level of function. Results: Nine patients were identified. Mean age of diagnosis was 8.9 years. Interphalangeal joints were most commonly affected. Multiple spontaneous or posttraumatic fingertip ulceration occurred in 5 patients. Anhidrosis resulted in more protracted ulcers and infections, requiring amputation of distal and middle phalanges due to osteomyelitis. The wrist joint was less commonly involved and showed more complex joint involvement. Conclusion: The hand and wrist are involved in different ways, with fingertip ulceration leading to potential infection and osteomyelitis in the hand, whereas the wrist joint is involved in cases of increased axial loading and load transfer, such as following prolonged use of walking and mobility aids. The latter should be borne in mind during management of lower limb conditions. Hand care and hygiene is important in all patients, especially in cases of anhidrosis due to the increased rate of ulceration and osteomyelitis requiring surgical intervention. Despite the severity of the condition, patients report good overall function.
Asunto(s)
Neuropatías Hereditarias Sensoriales y Autónomas , Hipohidrosis , Insensibilidad Congénita al Dolor , Niño , Humanos , Insensibilidad Congénita al Dolor/diagnóstico , Muñeca , Articulación de la MuñecaRESUMEN
AIM: To describe ocular manifestations in children with congenital insensitivity to pain with and without anhidrosis (CIPA and CIP). METHODS: We reviewed records of eye examinations of 39 children diagnosed with CIPA or CIP. We collected clinical data, with particular attention to ocular surface findings. Corneal sensitivity was tested by presence of a blink reflex upon touching the cornea. Statistical analysis assessed differences in manifestations between the two conditions, and relationships among corneal sensitivity, presence of corneal opacities and visual acuity (VA). RESULTS: CIPA was diagnosed in 32 children and CIP in 7. The median follow-up periods were 50 months (CIPA group) and 94 months (CIP group). Corneal opacities were present in 23% of CIPA eyes and in 57% of CIP eyes. A blink reflex was positive in 52% of CIPA eyes and in 33% of CIP eyes. We recorded VA ≥20/25 in 36% of CIPA eyes, whereas all patients with CIP had VA ≤20/30. For the whole cohort, we found a negative correlation between a preserved blink reflex and the presence of corneal opacities, and a positive correlation between a preserved blink reflex and VA ≥20/25. CONCLUSION: Children with congenital insensitivity to pain are prone to develop corneal scarring. Patients with CIP tend to have more severe ocular surface disease than those with CIPA, probably due to more prevalent loss of corneal sensation. In both groups, a preserved blink reflex correlated with good vision. Affected children should have close follow-up to promptly treat ocular surface disease and prevent vision loss.
Asunto(s)
Opacidad de la Córnea , Insensibilidad Congénita al Dolor , Niño , Córnea , Estudios de Seguimiento , Humanos , Insensibilidad Congénita al Dolor/complicaciones , Insensibilidad Congénita al Dolor/diagnóstico , Trastornos de la VisiónRESUMEN
PURPOSE: To report the findings of a comprehensive eye examination from an individual with congenital insensitivity to pain because of loss-of-function mutations in the SCN9A gene. METHODS: Ophthalmologic examination and confocal microscopy were performed on a patient with congenital insensitivity to pain. RESULTS: A 39-year-old man with compound heterozygous mutations in the SCN9A gene underwent examination. Cochet-Bonnet esthesiometry readings averaged 38 mm (SD 8 mm) in the right eye and 55 mm (SD 7 mm) in the left eye. Other corneal findings included mild conjunctival lissamine green staining, nonvisually significant corneal scars, mild anterior basement membrane dystrophy, and a tear breakup time of 3 seconds in each eye. In vivo confocal microscopy of the corneal subbasal nerve plexus revealed relatively normal corneal nerve morphology, but a reduction in corneal nerve fiber density. CONCLUSIONS: An individual with loss-of-function mutations in SCN9A had reduced corneal nerve fiber density but normal corneal mechanoreception.
Asunto(s)
Enfermedades de la Córnea/diagnóstico , Microscopía Confocal/métodos , Fibras Nerviosas/patología , Insensibilidad Congénita al Dolor/diagnóstico , Sensación/fisiología , Adulto , Enfermedades de la Córnea/etiología , Enfermedades de la Córnea/fisiopatología , ADN/genética , Análisis Mutacional de ADN , Humanos , Masculino , Mecanorreceptores/fisiología , Mutación , Canal de Sodio Activado por Voltaje NAV1.7/genética , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Insensibilidad Congénita al Dolor/complicaciones , Insensibilidad Congénita al Dolor/metabolismo , Lágrimas/metabolismoRESUMEN
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare condition with protean manifestations. Occasionally, these diseases may present with musculoskeletal problems. Here we report a case of young child who presented with joint problems in our clinic. Since the child had a number of musculoskeletal manifestations her diagnosis was difficult and delayed. She was given supportive treatment and a team of doctors from different specialties was involved in her management.
Asunto(s)
Artritis Juvenil , Canalopatías , Hipohidrosis , Insensibilidad Congénita al Dolor , Artritis Juvenil/complicaciones , Artritis Juvenil/diagnóstico , Niño , Femenino , Humanos , Dolor , Insensibilidad Congénita al Dolor/complicaciones , Insensibilidad Congénita al Dolor/diagnósticoRESUMEN
Paul Ferdinand Schilder was born in Vienna in 1886 and died in New York in 1940. Today he is remembered particularly as a psychoanalyst and a psychotherapist. His research in neuroscience, however, was also both comprehensive and innovative. For example, he is considered to be the first to describe Schilder's disease, which was named after him. This article focuses on pain asymbolia, which was also first described by Schilder, and is currently little known and considered to be rarely encountered. Pain asymbolia is a central impairment of pain experience with no negative affective-emotional component. The basis of Schilder's discovery and the differential diagnosis of pain asymbolia was the detailed examination of eleven medical cases between 1928 and 1930. His publications on the condition are characterized by meticulousness, progressive thinking and critical reflection. He nosologically assigned pain asymbolia to the group of agnosias and integrated it into the concept of body image, which was a central issue in his entire scientific work. This article additionally addresses the question of whether Schilder's assumptions are still valid today and what consequences might arise from this.
Asunto(s)
Insensibilidad Congénita al Dolor , Diagnóstico Diferencial , Emociones , Historia del Siglo XX , Humanos , Masculino , Dolor , Insensibilidad Congénita al Dolor/diagnóstico , Insensibilidad Congénita al Dolor/historiaRESUMEN
Congenital insensitivity to pain is an umbrella term used to describe a group of rare genetic diseases also classified as hereditary sensory autonomic neuropathies. These conditions are intriguing, with the potential to shed light on the poorly understood relationship concerning nociception and the experience of pain. However, the term congenital insensitivity to pain is epistemologically incorrect and is the product of historical circumstances. The term conflates pain and nociception and, thus, prevents researchers and caregivers from grasping the full dimensions of these conditions. The aims of this article were to review the epistemological problems surrounding the term, to demonstrate why the term is inaccurate and to suggest a new term, namely, congenital nociceptor deficiency. The suggested term better reflects the nature of the conditions and incorporates current understandings of nociception. PERSPECTIVE: The umbrella term congenital insensitivity to pain conflates pain and nociception, which is epistemologically unacceptable. We suggest a new term, namely, congenital nociceptor deficiency, that overcomes this problem and is concordant with current neurobiological knowledge.
Asunto(s)
Nocicepción/fisiología , Insensibilidad Congénita al Dolor/diagnóstico , Percepción del Dolor/fisiología , Humanos , Insensibilidad Congénita al Dolor/fisiopatologíaRESUMEN
Congenital analgesia is a rare condition, reporting in the international literature in rare cases since 1932, when it was first described. Its cause has been the subject of development of multiple theories and studies through the years. Currently various studies and experiments as its origin point mutation in the gene encoding SC9NA sodium channels, which have an important role in nociceptive transmission signals in the human body. The purpose of this study is to present two cases that were valued in the department of pediatric orthopedics at UMAE HTYOLV, patients whose insensitivity to pain has produced significant injuries that were once cause for valuation of the hospital.
La analgesia congénita es un padecimiento poco frecuente, en la literatura internacional se ha reportado en contados casos desde 1932, año en el que fue descrita por primera vez. Su causa ha sido motivo del desarrollo de múltiples teorías y numerosos estudios a través de los años. Actualmente diversos estudios y experimentos apuntan como origen la mutación en el gen SCN9A que codifica para los canales de sodio, los cuales tienen un papel muy importante en la transmisión de señales nociceptivas en el cuerpo humano. El motivo del presente estudio es dar a conocer dos casos que fueron valorados en el servicio de ortopedia pediátrica de la UMAE HTYOLV, pacientes en quienes la falta de sensibilidad al dolor ha producido lesiones importantes que fueron en su momento motivo de valoración por parte del hospital.
Asunto(s)
Insensibilidad Congénita al Dolor , Niño , Humanos , Insensibilidad Congénita al Dolor/complicaciones , Insensibilidad Congénita al Dolor/diagnóstico , Heridas y LesionesRESUMEN
Resumen: La analgesia congénita es un padecimiento poco frecuente, en la literatura internacional se ha reportado en contados casos desde 1932, año en el que fue descrita por primera vez. Su causa ha sido motivo del desarrollo de múltiples teorías y numerosos estudios a través de los años. Actualmente diversos estudios y experimentos apuntan como origen la mutación en el gen SCN9A que codifica para los canales de sodio, los cuales tienen un papel muy importante en la transmisión de señales nociceptivas en el cuerpo humano. El motivo del presente estudio es dar a conocer dos casos que fueron valorados en el servicio de ortopedia pediátrica de la UMAE HTYOLV, pacientes en quienes la falta de sensibilidad al dolor ha producido lesiones importantes que fueron en su momento motivo de valoración por parte del hospital.
Abstract: Congenital analgesia is a rare condition, reporting in the international literature in rare cases since 1932, when it was first described. Its cause has been the subject of development of multiple theories and studies through the years. Currently various studies and experiments as its origin point mutation in the gene encoding SC9NA sodium channels, which have an important role in nociceptive transmission signals in the human body. The purpose of this study is to present two cases that were valued in the department of pediatric orthopedics at UMAE HTYOLV, patients whose insensitivity to pain has produced significant injuries that were once cause for valuation of the hospital.
Asunto(s)
Humanos , Niño , Insensibilidad Congénita al Dolor/complicaciones , Insensibilidad Congénita al Dolor/diagnóstico , Heridas y LesionesRESUMEN
BACKGROUND: Hereditary sensory and autonomic neuropathy type VIII is a rare autosomal recessive inherited disorder. Chen et al. recently identified the causative gene and characterized biallelic mutations in the PR domain-containing protein 12 gene, which plays a role in the development of pain-sensing nerve cells. Our patient's family was included in Chen and colleagues' study. We performed a literature review of the PubMed library (January 1985 to December 2016) on hereditary sensory and autonomic neuropathy type I to VIII genetic disorders and their orofacial manifestations. This case report is the first to describe the oral manifestations, and their treatment, of the recently discovered hereditary sensory and autonomic neuropathy type VIII in the medical and dental literature. CASE PRESENTATION: We report on the oral manifestations and dental management of an 8-month-old white boy with hereditary sensory and autonomic neuropathy-VIII over a period of 16 years. Our patient was homozygous for a mutation of PR domain-containing protein 12 gene and was characterized by insensitivity to pain and thermal stimuli, self-mutilation behavior, reduced sweat and tear production, absence of corneal reflexes, and multiple skin and bone infections. Oral manifestations included premature loss of teeth, associated with dental traumata and self-mutilation, severe soft tissue injuries, dental caries and submucosal abscesses, hypomineralization of primary teeth, and mandibular osteomyelitis. CONCLUSIONS: The lack of scientific knowledge on hereditary sensory and autonomic neuropathy due to the rarity of the disease often results in a delay in diagnosis, which is of substantial importance for the prevention of many complications and symptoms. Interdisciplinary work of specialized medical and dental teams and development of a standardized treatment protocols are essential for the management of the disease. There are many knowledge gaps concerning the management of patients with hereditary sensory and autonomic neuropathy-VIII, therefore more research on an international basis is needed.
Asunto(s)
Proteínas Portadoras/genética , Caries Dental/complicaciones , Caries Dental/genética , Neuropatías Hereditarias Sensoriales y Autónomas/complicaciones , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Proteínas del Tejido Nervioso/genética , Pérdida de Diente/complicaciones , Pérdida de Diente/genética , Adolescente , Análisis Mutacional de ADN , Dentadura Parcial Fija , Predisposición Genética a la Enfermedad , Neuropatías Hereditarias Sensoriales y Autónomas/patología , Neuropatías Hereditarias Sensoriales y Autónomas/fisiopatología , Humanos , Lactante , Masculino , Limitación de la Movilidad , Mucosa Bucal/lesiones , Aparatos Ortopédicos , Insensibilidad Congénita al Dolor/complicaciones , Insensibilidad Congénita al Dolor/diagnóstico , Insensibilidad Congénita al Dolor/genética , Automutilación/complicaciones , Automutilación/genética , Factores de Tiempo , Pérdida de Diente/cirugíaRESUMEN
Terminal and interstitial deletions of the distal segment of the long arm of chromosome 4 (Cr4q del) are not common genetic disorders. The severity of the phenotype is correlated with the size of the deletion because small deletions have little clinical impact, whereas large deletions are usually associated with multiple congenital anomalies, postnatal growth failure, and moderate to severe intellectual disability. Alteration in pain tolerance has not been included among these features, also in case of large deletions. The purpose of this report is to document a case of a child affected by interstitial Cr4q del, expressing pain insensitivity as clinical feature not previously described. We also offer a discussion on genetic disorders featuring pain insensitivity/indifference. CASE REPORT: A Caucasian girl aged 12 came to our observation for a developmental delay with multiple congenital abnormalities and moderate intellectual disability (IQ 47). A de novo interstitial Cr4 del between band q31.3 and q32.2 (Cr4 del q31.3 to q32.2) was found. The child also expresses no evidence of pain perception to injures which normally evoke pain. Consequently, she is affected by severe disability caused by painless injuries and self-injurious behaviours, such as excessive self-rubbing and scratching. The neurological examination manifested high pain threshold with preserved tactile sensitivity. CONCLUSIONS: This is the first report of pain insensitivity in a patient with a specific genetic deletion involving the interstitial region of the distal long arm of Cr4. Moreover, this report could serve as a useful model to better understand mechanisms of pain perception and its modulation.
Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 4 , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Insensibilidad Congénita al Dolor/genética , Anomalías Múltiples/diagnóstico , Niño , Discapacidades del Desarrollo/diagnóstico , Femenino , Humanos , Discapacidad Intelectual/diagnóstico , Insensibilidad Congénita al Dolor/diagnósticoRESUMEN
Terminal and interstitial deletions of the distal segment of the long arm of chromosome 4 (Cr4q del) are not common genetic disorders. The severity of the phenotype is correlated with the size of the deletion because small deletions have little clinical impact, whereas large deletions are usually associated with multiple congenital anomalies, postnatal growth failure, and moderate to severe intellectual disability. Alteration in pain tolerance has not been included among these features, also in case of large deletions. The purpose of this report is to document a case of a child affected by interstitial Cr4q del, expressing pain insensitivity as clinical feature not previously described. We also offer a discussion on genetic disorders featuring pain insensitivity/indifference. Case report. A Caucasian girl aged 12 came to our observation for a developmental delay with multiple congenital abnormalities and moderate intellectual disability (IQ 47). A de novo interstitial Cr4 del between band q31.3 and q32.2 (Cr4 del q31.3 to q32.2) was found. The child also expresses no evidence of pain perception to injures which normally evoke pain. Consequently, she is affected by severe disability caused by painless injuries and self-injurious behaviours, such as excessive self-rubbing and scratching. The neurological examination manifested high pain threshold with preserved tactile sensitivity. Conclusions. This is the first report of pain insensitivity in a patient with a specific genetic deletion involving the interstitial region of the distal long arm of Cr4. Moreover, this report could serve as a useful model to better understand mechanisms of pain perception and its modulation.
Asunto(s)
Humanos , Femenino , Niño , Anomalías Múltiples/genética , Cromosomas Humanos Par 4 , Insensibilidad Congénita al Dolor/genética , Discapacidades del Desarrollo/genética , Deleción Cromosómica , Discapacidad Intelectual/genética , Anomalías Múltiples/diagnóstico , Insensibilidad Congénita al Dolor/diagnóstico , Discapacidades del Desarrollo/diagnóstico , Discapacidad Intelectual/diagnósticoRESUMEN
BACKGROUND: Congenital insensitivity to pain and anhidrosis (CIPA) is a rare clinical condition characterized by the absence of normal subjective and objective responses to noxious stimuli in patients with intact central and peripheral nervous systems. CASE PRESENTATIONS: Two patients with CIPA are reported. The first patient was a 13-year-old girl who presented to our hospital with multiple joint destructions secondary to osteomyelitis. The second patient was a 10-year-old boy who presented with multiple hand lesions and right leg osteomyelitis. Our patients were treated with multiple debridements and intravenous antibiotics according to our hospital protocol. CONCLUSION: Early recognition of the disease is important. The treatment for this condition is focused more on the prevention of bone injuries and joint infection, as opposed to a cure. There are no standard techniques or guidelines available to treat this rare disease. Overall, effective CIPA treatment is built around family education and patient training.
Asunto(s)
Osteomielitis/diagnóstico , Osteomielitis/etiología , Insensibilidad Congénita al Dolor/complicaciones , Insensibilidad Congénita al Dolor/diagnóstico , Adolescente , Antibacterianos/administración & dosificación , Niño , Terapia Combinada/métodos , Desbridamiento/métodos , Femenino , Humanos , Hipohidrosis/complicaciones , Hipohidrosis/diagnóstico , Hipohidrosis/terapia , Masculino , Osteomielitis/terapia , Insensibilidad Congénita al Dolor/terapiaRESUMEN
BACKGROUND: Congenital insensitivity to pain (CIP) is a rare extreme phenotype characterised by an inability to perceive pain present from birth due to lack of, or malfunction of, nociceptors. PRDM12 has recently been identified as a new gene that can cause CIP. The full phenotype and natural history have not yet been reported. METHODS: We have ascertained five adult patients and report their clinical features. RESULTS: Based on our findings, and those of previous patients, we describe the natural history of the PRDM12-CIP disorder, and derive diagnostic and management features to guide the clinical management of patients. CONCLUSIONS: PRDM12-CIP is a distinct and diagnosable disorder, and requires specific clinical management to minimise predictable complications.
Asunto(s)
Proteínas Portadoras/genética , Proteínas del Tejido Nervioso/genética , Insensibilidad Congénita al Dolor/diagnóstico , Insensibilidad Congénita al Dolor/genética , Dolor/diagnóstico por imagen , Dolor/genética , Adulto , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
An emerging class of mitochondrial disorders is caused by mutations in nuclear genes affecting mitochondrial dynamics and function. One of these is the DNM1L gene encoding the dynamin-related protein 1 (DRP1), which is pivotal in the mitochondrial fission process. Here, we describe a patient with a novel dominant-negative, de novo DNM1L mutation, which expands the clinical spectrum. The patient reported here exhibits a chronic neurological disorder, characterized by postnatal microcephaly, developmental delay, and pain insensitivity. Muscle biopsy disclosed decreased respiratory chain complex IV activity. Exome sequencing showed a de novo heterozygous c.1084G>A (p.G362S) mutation. Subsequent studies of patient skin fibroblasts showed markedly impaired mitochondrial fission and a partial respiratory chain defect while peroxisomal morphology remained intact. Human foreskin fibroblasts over-expressing the mutant DNM1L gene displayed aberrant mitochondrial morphology. © 2016 Wiley Periodicals, Inc.
Asunto(s)
GTP Fosfohidrolasas/genética , Heterocigoto , Microcefalia/genética , Proteínas Asociadas a Microtúbulos/genética , Enfermedades Mitocondriales/genética , Dinámicas Mitocondriales/genética , Proteínas Mitocondriales/genética , Mutación , Insensibilidad Congénita al Dolor/genética , Alelos , Biomarcadores , Preescolar , Dinaminas , Exoma , Estudios de Asociación Genética , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Potencial de la Membrana Mitocondrial/genética , Microcefalia/diagnóstico , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Enfermedades Mitocondriales/diagnóstico , Insensibilidad Congénita al Dolor/diagnóstico , FenotipoRESUMEN
Loss of pain perception can result from neurodevelopmental defects, degeneration of nociceptive fibers, or altered excitability of sensory neurons. Hereditary neurodegeneration leading to pain loss is classified as sensory and autonomic neuropathy (HSAN). Mutations in approximately 15 genes have been identified in the group of HSAN disorders. Hallmark of the disease is a liability to injury because of impaired acute pain as a warning system to prevent harm. The clinically overlapping "congenital insensitivity to pain (CIP)" is caused by mutations in voltage-gated sodium channels, which control the excitability of nociceptors. However, mutations in the latter genes can also result in disorders with increased pain susceptibility. This review summarizes the clinical presentation of HSAN and pain-related channelopathies and discusses the underlying disease mechanisms.
Asunto(s)
Canalopatías/diagnóstico , Neuropatías Hereditarias Sensoriales y Autónomas/diagnóstico , Insensibilidad Congénita al Dolor/diagnóstico , Umbral del Dolor/fisiología , Canales de Sodio Activados por Voltaje/genética , Canalopatías/genética , Canalopatías/patología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Genotipo , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Neuropatías Hereditarias Sensoriales y Autónomas/fisiopatología , Humanos , Degeneración Nerviosa/genética , Degeneración Nerviosa/fisiopatología , Nociceptores/fisiología , Insensibilidad Congénita al Dolor/genética , Insensibilidad Congénita al Dolor/fisiopatología , Canales de Sodio Activados por Voltaje/fisiologíaRESUMEN
Hereditary sensory and autonomic neuropathy (HSAN) IV is a rare autosomal recessive disorder which is characterized by a decrease in the number of myelinated and non-myelinated nerve fibers of peripheral nerves which causes diminished or absent pain sensation leading to increase in self-mutilative habits. A retrospective study of eight cases ranging from age group of 4 to 17 years for oral and digital signs and symptoms is presented. All the patients showed congenital insensitivity to pain and anhidrosis. Oral self-mutilations, such as autoextraction of teeth and severe bite injuries (with resultant scarring) of the finger tips and oral soft tissues (tongue, lip, and buccal mucosa) were found in most patients. Our study suggests that early diagnosis and specific treatment plan are important for prevention of characteristic of the oral as well as digital trauma associated with this disorder.