Hereditary sensory and autonomic neuropathy types IV and V in Japan.

Hereditary sensory and autonomic neuropathy (HSAN) is a group of genetic disorders involving varying sensory and autonomic dysfunction. HSAN types IV and V are characterized by congenital generalized loss of pain and thermal sensation. HSAN type IV is additionally accompanied by decreased sweating and intellectual disability. From 2010 to 2013, we (members of the Japanese Research Group on Congenital Insensitivity to Pain) carried out research on HSAN types IV and V. Research by this group included epidemiological data, examination of clinical findings, solutions of disease etiology, investigation of complications and development of their management. Complications were categorized into musculoskeletal complications, oral/dental complications, dermal complications, ocular complications, complications resulting from impaired thermal control, anesthetic considerations, other complications possibly related to autonomic dysfunction, and abnormal mental development and behavior. Treatment and care for patients with HSAN types IV and V require a wide range of knowledge and experience, and a multidisciplinary team approach. Therefore, we produced the "Guideline of Total Management and Care for Congenital Insensitivity to Pain (Ver.1)" in 2012, to provide information for medical specialists based on our knowledge and experience. This guideline includes medical issues, as well as descriptions of social participation and welfare. This review outlines the situation of HSAN types IV and V in Japan, and the recommendations of treatment and care for patients, mostly based on research conducted by the Japanese Research Group.

From genes to pain: nerve growth factor and hereditary sensory and autonomic neuropathy type V.

Hereditary sensory and autonomic neuropathy type V (HSAN V) is an autosomal recessive disorder characterized by the loss of deep pain perception. The anomalous pain and temperature sensations are due to the absence of nociceptive sensory innervation. The neurotrophin nerve growth factor (NGF), by binding to tropomyosin receptor A (TrkA) and p75NTR receptors, is essential for the development and survival of sensory neurons, and for pain perception during adulthood. Recently a homozygous missense mutation (R100W) in the NGF gene has been identified in HSAN V patients. Interestingly, alterations in NGF signalling, due to mutations in the NGF TRKA gene, have also been involved in another congenital insensitivity to pain, HSAN IV, characterized not only by absence of reaction to painful stimuli, but also anhidrosis and mental retardation. These symptoms are absent in HSAN V patients. Unravelling the mechanisms that underlie the differences between HSAN IV and V could assist in better understanding NGF biology. This review highlights the recent key findings in the understanding of HSAN V, including insights into the molecular mechanisms of the disease, derived from genetic studies of patients with this disorder.

Morbidity characteristics of patients with congenital insensitivity to pain with anhidrosis (CIPA).

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is a congenital autonomic sensory neuropathy. In southern Israel, there are many patients with this disease. We here tried to characterize the different infections acquired by children with CIPA. METHODS: We collected all the available data about CIPA patients in southern Israel in the year 1991-2005, including the lesion types, area in the body where the infection occurs, and the treatment given. RESULTS: The current study included 30 children with CIPA, out of 44 known CIPA patients in southern Israel (68.2%). A total of 382 different episodes of infections, fever, orthopedic lesions, and jaw and mouth lesions led our patients to our outpatient clinic or resulted in hospitalization. CONCLUSION: We found that children with CIPA mainly have infections of the skin and skeleton, and that the most frequent pathogen is Staphylococcus aureus. We also found that a fair amount of these pathogens are resistant to conventional treatment regimens.

Epidemiology of hereditary sensory and autonomic neuropathy type IV and V in Japan.

Hereditary sensory and autonomic neuropathy (HASN) refers to a group of rare congenital disorders characterized by loss of pain sensation and other sensory or autonomic abnormalities. Among them, a relatively large proportion of patients with HSAN type IV, which is accompanied by anhidrosis and intellectual disability, are reported from Israel and Japan. HSAN type V, with normal sweating and mental development, is rarely reported in Japan. In 2009, we founded a research group for congenital insensitivity to pain and performed the first epidemiological survey of HSAN types IV and V in Japan. Questionnaires were sent to a total of 3,488 certified training institutions of five nationwide medical societies comprising pediatricians, neurologists, orthopedic surgeons, and dentists. Answers were obtained from 1,610 institutions, and 192 HSAN patients (152 with type IV and 28 with type V) were reported from 105 institutions. After excluding duplicated patients, we identified a total of 62 current, 36 past, and five deceased patients for HSAN-IV, and a total of 14 current, 13 past, and 0 deceased patients for HSAN-V. Using these figures, we estimated that the number of Japanese patients with HSAN types IV and V as 130-210 and 30-60 patients, respectively. We identified no gender differences, and patients with a family history of the disorder were limited to affected siblings in both conditions. Most patients with HSAN-IV were 5-40 years of age, whereas half of the patients with HSAN-V were 40 years or older.

Prevalencia del dolor neuropático (DN), según DN4, en atención primaria / Prevalence of Neuropathic Pain according to the NP4 test in Primary Care

Introducción. El médico de atención primaria suele ser el primero en atender a pacientes con dolor neuropático. Se pretende evaluar la prevalencia del dolor neuropático, su manejo terapéutico y la caracterización clínica de estos pacientes. Material y métodos. Estudio epidemiológico, observacional y transversal realizado en centros de atención primaria de España. Registro de los primeros 25 pacientes ≥ 18 años con dolor de cualquier tipo (total 16.115) e inclusión de los 5 primeros con alto componente neuropático identificados mediante DN4 y confirmados clínicamente (3.836 evaluables). Se valoró la intensidad e impacto del dolor sobre las actividades diarias y la satisfacción con el tratamiento. Resultados. El 45,7% de los pacientes presentaron dolor neuropático según DN4. La edad media era 59 años y un 60% eran mujeres. Los pacientes utilizaban una media global de 2,4 fármacos los 3 meses previos al estudio, principalmente antiinflamatorios no esteroideos (AINE) (53%) y analgésicos no opioides (51%). Las puntuaciones de la intensidad del dolor e interferencia sobre las actividades diarias fueron ambas 6,2. La opinión general del SATMED-Q fue 47,3/100 que está 1,4 puntos por debajo de la obtenida por la población general española. Conclusiones. El dolor neuropático, según cuestionario DN4, es muy prevalente en los centros de atención primaria españoles. El manejo de estos pacientes con AINE y analgésicos no opioides no es adecuado, ya que no están recomendados para este tipo de dolor, y aun siendo tratados con más de 2 fármacos, los pacientes continúan presentando un dolor moderado con interferencia sobre sus actividades (AU)

Background. Primary Care Physicians are usually the first to see patients with neuropathic pain. The aim of this study is to assess the prevalence of neuropathic pain, its therapeutic management, and to clinically characterize these patients. Material and methods. An epidemiological, observational, cross-sectional study was carried out in Spanish Primary Care settings. The first 25 patients older than 18 years with any type of pain (a total of 16,115) were registered, and the first 5 with a high neuropathic pain component according to the NP4 test, and was clinically confirmed (n= 3,836) were included in the study. Pain intensity and impact on daily activities, as well as overall satisfaction with treatment were assessed. Results. A total of 45.7% of patients had neuropathic pain according to NP4 test. The median age was 59 years, and 60% were women. Patients took a mean of 2.4 drugs, with NSAIDs (53%) and non-opioid analgesics (51%) being the most common. The scores for Pain intensity and interference in daily activities were both 6.2. The overall opinion of the SATMED-Q test was 47.3/100, which was 1.4 points lower than the standardised score according to Spanish population. Conclusions. Neuropathic pain according to NP4 test is highly prevalent in Spanish Primary Care settings. The management of these patients with NSAIDs and non-opioid analgesics is not appropriate, as they are not recommended for this kind of pain. Although they were being treated with more than 2 analgesics, they still referred to high pain intensity, interference in daily activities, and a low general opinion of the treatment (AU)

Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

Autonomic peripheral neuropathy.

Most generalized peripheral polyneuropathies are accompanied by clinical or subclinical autonomic dysfunction. There is a group of peripheral neuropathies in which the small or unmyelinated fibers are selectively targeted. In these neuropathies, autonomic dysfunction is the most prominent manifestation. The features associated with an autonomic neuropathy include impairment of cardiovascular, gastrointestinal, urogenital, thermoregulatory, sudomotor, and pupillomotor autonomic function.

Asistencia neurológica neonatal en un hospital de referencia regional / Neurological care for newborn infants in a regional referral hospital

Objetivo: Conocer la incidencia de la patología neurológica en el período neonatal en el Hospital Universitario “Miguel Servet” de Zaragoza, centro de referencia para Aragón, La Rioja y soria. Pacientes y métodos: Se revisan los casos de patología neurológica puesta de manifiesto durante el período neonatal, estudiados en nuestro hospital (en hospitalización y consultas externas) en un periodo de 5 años (desde enero de 1996 hasta diciembre de 2000). Resultados: Se han evaluado 205 niños con patología neurológica en el período neonatal, 118 niños (57,56%) y 87 niñas (42,44%). La tasa de incidencia de neonatos afectados de patología neurológica en el período neonatal está por encima de 6,76 por 1.000 al año. Ingresaron en la unidad neonatal 199 niños (97,07%), y en la unidad de cuidados intensivos neonatales 123 (60%); 136 (66,34%)provenían del propio hospital, y 26 (12,68%) derivados de clínicas privadas de la ciudad. La media de días de ingreso fue de 30 (rango: 1-80). Continúan siendo visitados en las consultas externas de nuestro hospital 96 niños (46,83%). Conclusiones: Existe una importante demanda de asistencia neuropediátrica en el período neonatal, con ingresos prolongados y una elevada necesidad de cuidados intensivos. La patología neurológica neonatal genera, durante los primeros años de vida, las intervenciones y el seguimiento de profesionales de servicios sanitarios, educativos y sociales, que trabajan de forma coordinada en programas de atención temprana, en los que es fundamental la participación de neonatólogos y neuropediatras

Objective: The incidence of neurological disorders during the neonatal period was studied at Miguel Servet University Children´s Hospital in Zaragoza, Spain, a referral center for Aragon, Rioja and Soria. Material and methods: Those newborns with an identified neurological disorder at Miguel Servet University Children´s Hospital in Zaragoza were studied, in both the inpatient and outpatient setting, over a five-year period from (January 1996 to December 2000). Results: the authors evaluated 205 children, 118 boys (57,56%) and 87 girls (42,44%), who has presented a neurological disorder during the neonatal period. The incidence was over 6,76 per thousand per year. One hundred ninety-nine (97,07%) were admitted to the Neonatal Unit, and 123 (60%) to the Neonatal Intensive Care Unit. One hundred thirty-six (66,34%) had been born in the hospital, 26 (12,68%) had been referred from private clinics in the city of Zaragoza and the remainder from others centers. The hospital stay ranged between 1 and 180 days, with a mean length of 30 days. Ninety-six children (46,83%) were still being followed in the outpatient services of the hospital at this writing. Conclusions: There is a great demand for neurological care during the neonatal period, with prolonged hospital stays and a frequent need for intensive care. During the first few years of life, the neonatal neurological disorder requires interventions and follow-up involving different professionals from the health care, educational and social services, who must work in a coherent and coordinated way, in early intervention programs, in which the participation of neonatologists and pediatric neurologists is essential

Novel mutation in the HSN2 gene in a Korean patient with hereditary sensory and autonomic neuropathy type 2.

Hereditary sensory and autonomic neuropathies (HSAN) are a group of clinically and genetically heterogeneous disorders that are associated with sensory dysfunction. Among these, HSAN type 2 (HSAN2; MIM 201300) is a rare recessive disease that is characterized by an early age of onset with distal and proximal sensory loss, dysfunction of the autonomic nervous system, loss of the tendon reflex, the presence of various mutilations, and the slow progression of the disease over time. The authors report a Korean patient with the clinical features of HSAN2, who was compound heterozygous for two loss-of-function mutations in the HSN2 gene: c.217C > T (Gln73X) and c.1134_1135insT (Asp379fsX1). The Gln73X mutation was a novel mutation while the Asp379fsX1 mutation has recently been reported in a Japanese patient with HSAN2. These results expanded the spectrum of mutations of the HSN2 gene by identifying a novel truncating mutation in a Korean patient and further support the hypothesis that HSN2 is a causative gene for HSAN2.

Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians.

BACKGROUND: Hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM 201300) is a rare recessive neuropathy typically diagnosed in the first decade. The 1973 study of a French Canadian family led to the definition of HSAN2. OBJECTIVES: To demonstrate that the apparent higher prevalence of HSAN2 in Quebec is due to the presence of two HSN2 mutations and that carriers of different mutations appear to have a similar phenotype. METHODS: Through attending physicians, the authors recruited French Canadian patients with HSAN2. Exclusion of linkage to the known HSAN loci and linkage to the HSAN2 was performed using standard methods. Sequencing of the HSN2 gene was used to uncover the causal mutations. RESULTS: A large cluster of HSAN2 patients comprising 16 affected individuals belonging to 13 families was identified. The mode of inheritance is clearly autosomal recessive. All patients originated from southern Quebec, and 75% are from the Lanaudière region. Whereas linkage to the HSAN1, 3, and 4 loci was excluded, linkage to the 12p13.33 HSAN2 locus was confirmed. Sequencing of the HSN2 gene uncovered two French Canadian mutations and a novel nonsense mutation in a patient of Lebanese origin, all predicted to lead to truncations of the HSN2 protein. The comparison of clinical variables between patients with different genotypes does not suggest any difference in phenotype. CONCLUSIONS: Two founder mutations are responsible for the apparently higher prevalence of HSAN2 in French Canadians. Genotype-phenotype correlation does not suggest any significant clinical variability.

A profile of childhood neuropathies at a university hospital in Oman.

OBJECTIVE: To analyze all cases of childhood neuropathies (under 14 years of age) and report on their profile, pattern, clinical features and management. METHODS: Children with acute flaccid paralysis, longstanding weakness of extremities, neuroregression and children receiving anti cancer drugs with symptoms suggestive of neuropathy were evaluated for evidence of peripheral neuropathy. The evaluation of children with acute flaccid paralysis was a prospective study from January 1992 through to December 2000. The rest of the patients were studied retrospectively from the hospital medical records, pediatric neurology outpatient clinic and the neurophysiology laboratory, Sultan Qaboos University Hospital, Al-Khod, Oman RESULTS: Eighty-two (39 Male: 43 Female) children were found to have peripheral neuropathy. Acute Guillain-Barré [corrected] syndrome was the most common with 37 children (45.1%), followed by genetic neuropathies [hereditary motor and sensory neuropathy with 17 (20.7%), hereditary sensory and autonomic neuropathy with 2 (2.4%), hereditary spastic paraplegia associated neuropathy with 9 (11%) and metachromatic leucodystrophy with 9 (11%)]. Chronic inflammatory demyelinating neuropathy was seen in 5 (6.1%) and vincristine induced neuropathy in 3 (3.5%) children. CONCLUSION: Acute Guillain-Barré [corrected] syndrome is the most common neuropathy amongst the acquired neuropathies. The treatable neuropathies constituted 54.7% (45 children) and the preventable genetic neuropathies accounted for the remaining 45.3% (37 children)

El dolor neuropático: un problema científico y terapéutico / No disponible

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Prevalencia de neuropatía sensorial distal en artritis reumatoide / The prevalence of sensitive distal neuropathy in rheumatoid arthritis

Objetivo. Determinar la prevalencia de neuropatía sensorial distal (NSD) en pacientes con artritis reumatoide (AR). Tipo de estudio. Encuesta descriptiva prolectiva. Sitio de estudio. HE CMN "El Fénix" IMSS. Mérida Yucatán, México. Material y métodos. Pacientes con AR según criterios del ACR sin enfermedades predisponentes para neuropatía periférica fueron sometidos a estudios de neuroconducción (velocidad de conducción nerviosa y latencias distales sensitivas) y examen clínico. Resultados. Se estudiaron 58 pacientes (50 mujeres y 8 varones) con edad media de 42 años (variabilidad 16-74, con tiempo de evolución media de 9.3 años (variabilidad 0.5-38 años). Treinta y ocho de los pacientes (65 por ciento) fueron positivos a factor reumatoide (FR), y al tiempo de la encuesta, 32 (55 por ciento) se encontraban activos. Se diagnosticó NSD en 2 pacientes (3.4 por ciento), ambos con FR positivos, inactivos de la enfermedad, con evolución mayor de 9 años y sin síntomas neurológicos. Conclusión. La NSD tuvo prevalencia de AR de 3.4 por ciento, no se relaciona con actividad de la enfermedad, cursa asintomática y parece presentarse en pacientes de larga evolución

[Connection between microalbuminuria and subclinical cardiovascular autonomic neuropathy in diabetic children]. / A microalbuminuria és a szubklinikai cardiovascularis autonom neuropathia összefüggésének vizsgálata diabeteses gyermekekben.

Cardiovascular tests were investigated in 16 microalbuminuric, in 20 normoalbuminuric diabetic children and a control group of 20 healthy children. Comparing to the control group, in both of two diabetic groups a similar increase in resting heart rate (74.5 +/- 2.5/min vs. 87.8 +/- 3.5/min, p less than 0.01, and 83.6 +/- 3.2/min, p less than 0.05) and a decrease in hyperventilatory arrhythmia (32.3 +/- 1.2/min vs. 20.1 +/- 0.8/min, p less than 0.01, and 17.2 +/- 0.8/min, p less than 0.01) was observed. In the diabetic group with microalbuminuria in comparison with both the control group and the normoalbuminuric group there was a lower standing/lying heart rate ratio (1.02 +/- 0.03 vs. 1.30 +/- 0.05, p less than 0.01, and 1.22 +/- 0.05, p less than 0.05), a pronounced orthostatic decrease in blood pressure (15.1 +/- 0.3 mmHg vs. 2.0 +/- 0.1 mmHg, p less than 0.001, and 5.0 +/- 0.2 mmHg, p less than 0.01) and a diminished increase in blood pressure during sustained handgrip (6.3 +/- 0.2 mmHg vs. 14.0 +/- 0.3 mmHg, p less than 0.01, and 12.2 +/- 0.3 mmHg, p less than 0.05). The occurrence of cases with distinct autonomic dysfunction (3 or more abnormal cardiovascular tests) proved to be more frequent in the group with microalbuminuria than in the diabetic group with normal albumin excretion (6/16 vs. 1/20, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Vitreous involvement in familial amyloidotic neuropathy: a genealogical and genetic study.

Extended genealogical studies stretching back to the 17th century were performed concerning the heredity patterns of vitreous involvement in Swedish patients with familial amyloidotic polyneuropathy (FAP). FAP is an autosomal dominant inherited disorder, characterized by extracellular deposition of amyloid and a clinical syndrome of peripheral and autonomic neuropathy. In addition, some patients show typical vitreous opacities. All patients had their origin in a restricted geographical area. Some main patterns arose from this study: 1) Patients who had vitreous opacities as the first symptom of FAP seem to form a separate group, with a distinct age of onset distribution; 2) The familial occurrence of vitreous opacities raises the possibility that other familial factors modify the expression of the FAP gene; 3) The mean age of onset for vitreous opacities is lower for homozygous than for heterozygous patients.

Molecular genetics of amyloid neuropathy in Europe.

The Portuguese type of familial amyloid polyneuropathy (FAP type I), a disabling autosomal dominant disorder with onset in early adult life, is caused by a point mutation in the transthyretin (TTR; previously known as prealbumin) gene. DNA analysis in thirteen European families (one British, two French, one Italian, one Greek, and eight Cypriot) showed that members of all those from Cyprus and Greece, and one from France, carried the FAP type I mutation. Patients from seven of these ten kindreds were not known to have a genetic disease before this study, which demonstrated the mutation in 16 of 43 clinically unaffected relatives. 2 of these were aged over 50 years. TTR gene analysis has useful applications in genetic counselling, including prenatal diagnosis, in identifying the cause of seemingly sporadic cases of amyloid neuropathy, and in epidemiological studies of FAP.

Hereditary motor and sensory neuropathies: a genetic and epidemiological study in the province of Turin, Italy.

A clinical, genetic and epidemiological study of hereditary motor and sensory neuropathies (HMSN) was performed in the province of Turin, Italy. The patients were allocated to 5 groups, according to genetic and electroneurographic features. The high proportion of males among recessive and sporadic cases in the present series may suggest the existence of a recessive X-linked form of the disease. The crude prevalence rate was 3.18 (+/- 0.72)/100.000 population for all cases. The slow progression rate and the frequently mild symptoms of the disease, already suggested in literature, are confirmed by the analysis of the survival curves of the cases.

Descriptive epidemiology of selected neuromuscular disorders in Benghazi, Libya.

A 3-year intensive search for selected neuromuscular disorders in Benghazi, yielded 34 patients with Duchenne's muscular dystrophy (25 index cases), 19 with limb-girdle muscular dystrophy (13 index cases), 4 with facioscapulohumeral muscular dystrophy (3 index cases), 3 with opthalmoplegia-plus (all index cases), 13 with polymyositis, 41 with hereditary motor and sensory neuropathy (HMSN) (17 index cases) and 27 with Guillain-Barré Syndrome (GBS). The age-adjusted prevalence rates, on 31 December 1985, per 100,000 population were 6 for Duchenne dystrophy, 3.7 for limb-girdle dystrophy, 0.8 for facioscapulohumeral dystrophy, 0.6 for opthalmoplegia-plus and 7.9 for HMSN (6.4 and 1.5 for Types I and II, respectively). The adjusted average annual incidence of polymyositis was 8.8/mill population; the peak incidence was observed in females in the age-group 20-40. A mean age-adjusted incidence rate for GBS of 1.7/100,000 population per year has been found. The peak age-specific incidence of GBS occurred in the third decade; the sex-dependent difference in the incidence was not significant. No indigenous forms of the disease were encountered and the clinical features differed little from the descriptions in literature. The large family size and high rate of consanguineous marriages contribute to the high frequency of familial disorders, especially those with autosomal recessive inheritance.

Prevalence of hereditary motor and sensory neuropathy in Cantabria.

One hundred and forty-four patients with hereditary motor and sensory neuropathy (HMSN) were selected from within a defined area (Cantabria) in Northern Spain, from 1974 to 1984. The series comprises 49 index cases and 95 affected relatives. The prevalence ratio was 28.2 cases per 100,000. The results of the study indicate that the majority of the cases were hereditary as a dominant trait. The prevalence for the Type I HMSN cases did not differ from that of Type II cases. Previous population-surveys of these disorders are compared.