Carbidopa for Afferent Baroreflex Failure in Familial Dysautonomia: A Double-Blind Randomized Crossover Clinical Trial.

Afferent lesions of the arterial baroreflex occur in familial dysautonomia. This leads to excessive blood pressure variability with falls and frequent surges that damage the organs. These hypertensive surges are the result of excess peripheral catecholamine release and have no adequate treatment. Carbidopa is a selective DOPA-decarboxylase inhibitor that suppresses catecholamines production outside the brain. To learn whether carbidopa can inhibit catecholamine-induced hypertensive surges in patients with severe afferent baroreflex failure, we conducted a double-blind randomized crossover trial in which patients with familial dysautonomia received high dose carbidopa (600 mg/day), low-dose carbidopa (300 mg/day), or matching placebo in 3 4-week treatment periods. Among the 22 patients enrolled (13 females/8 males), the median age was 26 (range, 12-59 years). At enrollment, patients had hypertensive peaks to 164/116 (range, 144/92 to 213/150 mm Hg). Twenty-four hour urinary norepinephrine excretion, a marker of peripheral catecholamine release, was significantly suppressed on both high dose and low dose carbidopa, compared with placebo (P=0.0075). The 2 co-primary end points of the trial were met. The SD of systolic BP variability was reduced at both carbidopa doses (low dose: 17±4; high dose: 18±5 mm Hg) compared with placebo (23±7 mm Hg; P=0.0013), and there was a significant reduction in the systolic BP peaks on active treatment (P=0.0015). High- and low-dose carbidopa were similarly effective and well tolerated. This study provides class Ib evidence that carbidopa can reduce blood pressure variability in patients with congenital afferent baroreflex failure. Similar beneficial effects are observed in patients with acquired baroreflex lesions.

Usefulness of Blood Pressure Variability Indices Derived From 24-Hour Ambulatory Blood Pressure Monitoring in Detecting Autonomic Failure.

Background Increased blood pressure ( BP ) variability and nondipping status seen on 24-hour ambulatory BP monitoring are often observed in autonomic failure ( ATF ). Methods and Results We assessed BP variability and nocturnal BP dipping in 273 patients undergoing ambulatory BP monitoring at Southwestern Medical Center between 2010 and 2017. SD , average real variability, and variation independent of mean were calculated from ambulatory BP monitoring. Patients were divided into a discovery cohort (n=201) and a validation cohort (n=72). ATF was confirmed by formal autonomic function test. In the discovery cohort, 24-hour and nighttime average real variability, SD , and variation independent of mean did not differ significantly between ATF (n=25) and controls (n=176, all P>0.05). However, daytime SD, daytime coefficient of variation, and daytime variation independent of mean of systolic BP ( SBP ) were all significantly higher in patients with ATF than in controls in both discovery and validation cohorts. Nocturnal BP dipping was more blunted in ATF patients than controls in both cohorts (both P<0.01). Using the threshold of 16 mm Hg, daytime SD SBP yielded a sensitivity of 77% and specificity of 82% in detecting ATF in the validation cohort, whereas nondipping status had a sensitivity of 80% and specificity of 44%. The area under the receiver operator characteristic of daytime SD SBP was greater than the area under the receiver operator characteristic of nocturnal SBP dipping (0.79 [0.66-0.91] versus 0.73 [0.58-0.87], respectively). Conclusions Daytime SD of SBP is a better screening tool than nondipping status in detecting autonomic dysfunction.

Plexopatía braquial bilateral como forma de presentación de la neuropatía hereditaria con parálisis sensible a la presión / Hereditary neuropathy with liability to pressure palsy presenting as a bilateral brachial plexopathy

No disponible

Increased frequency of rhabdomyolysis in familial dysautonomia.

INTRODUCTION: Familial dysautonomia (FD; OMIM # 223900) is an autosomal recessive disease with features of impaired pain and temperature perception and lack of functional muscle spindles. After 3 FD patients presented with rhabdomyolysis in a short time span, we aimed to determine the frequency of rhabdomyolysis is this population. METHODS: This study was a retrospective chart review of 665 FD patients. RESULTS: Eight patients had at least 1 episode of rhabdomyolysis. Two patients had 2 episodes. The average incidence of rhabdomyolysis in FD was 7.5 per 10,000 person-years. By comparison, the average incidence with statins has been reported to be 0.44 per 10,000 person-years. Mean maximum creatine kinase (CK) level was 32,714 ± 64,749 U/L. Three patients had hip magnetic resonance imaging showing gluteal hyperintensities. CONCLUSIONS: Patients with FD have an increased incidence of rhabdomyolysis. We hypothesize that this may result from a combination of absent functional muscle spindles and muscle mitochondrial abnormalities.

Sindrome de Riley Day, manifestaciones bucales: revisión de la literatura / Riley Day syndrome, oral manifestations: revision of literature

Riley Day es una rara enfermedad o transtorno hereditario que afecta el desarrollo y funcionamiento de los nervios. Ocasiona Insensibilidad al dolor, no tiene cura ni tratamiento paliativo. Se transmite de padres a hijos, la persona debe heredar una copia del gen defectuoso de cada uno de los padres para desarrollar la afecci6n. El odontopediatra debe de estar capacitado para reconocer esta enfermedad, siendo un transtorno hereditario las primeras manifestaciones clínicas y orales se van a dar des de la infancia y van a ir aumentando con la edad; por eso el pro- pósito del presente reporte es describir el caso de un niño de 2 años 4 meses con Riley day, sus manifestaciones clínicas, datos epidemio16gicos y sugerencias de manejo odontologico de los pacientes con esta enfermedad...

Riley Day is a rare hereditary disease or disorder that affects the development and functioning of nerves. It causes insensitivity to pain, has no cure or treatment paliativo. It is transmitted from parent to child, the person must inherit a defective copy of the gene from each parent to develop afeccion. The dentist should be able to recognize this disease, an inherited disorder being the first clinical and oral manifestations are to be given since childhood and will gradually increase with age; therefore the purpose of this report is to describe the case of a 2 years 4 months Riley Day, its clinical manifestations, oral manifestations, epidemiological data and suggestions for dental management of patients with this disease....

Pain insensitivity syndrome misinterpreted as inflicted burns.

We present a case study of a 10-year-old child with severe burns that were misinterpreted as inflicted burns. Because of multiple injuries since early life, the family was under suspicion of child abuse and therefore under supervision of the Child Care Board for 2 years before the boy was burned. Because the boy incurred the burns without feeling pain, we conducted a thorough medical examination and laboratory testing, evaluated detection and pain thresholds, and used MRI to study brain morphology and brain activation patterns during pain between this patient and 3 healthy age- and gender-matched controls. We found elevated detection and pain thresholds and lower brain activation during pain in the patient compared with the healthy controls and reference values. The patient received the diagnosis of hereditary sensory and autonomic neuropathy type IV on the basis of clinical findings and the laboratory testing, complemented with the altered pain and detection thresholds and MRI findings. Hereditary sensory and autonomic neuropathy IV is a very rare congenital pain insensitivity syndrome characterized by the absence of pain and temperature sensation combined with oral mutilation due to unawareness, fractures, and anhidrosis caused by abnormalities in the peripheral nerves. Health care workers should be aware of the potential presence of this disease to prevent false accusations of child abuse.

Onabotulinum toxin A for the treatment of sialorrhea in familial dysautonomia.

Familial dysautonomia is a rare disease affecting the nervous system. Symptoms include speech and movement problems, anterior sialorrhea (drooling) due to hypersalivation as a consequence of poor oropharyngeal coordination; dysphagia and aspiration pneumonia secondary to recurrent posterior sialorrhea. The treatment for sialorrhea in this population is very challenging. Traditional drugs carry a number of side-effects that are difficult to control in this disease. We report the first documented case series of 3 patients with this condition that successfully responded to Onabotulinum toxin A injection into their salivary glands. This is an innovative, safe method for drooling control in this population.

Results of the College of American Pathology/American College of Medical Genetics and Genomics external proficiency testing from 2006 to 2013 for three conditions prevalent in the Ashkenazi Jewish population.

PURPOSE: The purpose of this study was to determine analytic performance of laboratories offering molecular testing for conditions such as Tay-Sachs disease, Canavan disease, and familial dysautonomia, which are prevalent in the Ashkenazi Jewish population. METHODS: The College of American Pathologists and the American College of Medical Genetics and Genomics cosponsor molecular proficiency testing for these disorders. Responses from 2006 to 2013 were analyzed for accuracy (genotyping and interpretations). RESULTS: Between 11 and 36 laboratories participated in each Tay-Sachs disease distribution. Samples tested per month were constant (2,900) from 2006 to 2011 but recently increased. Participants reporting <10 samples tested per month had longer turnaround times (42 vs. 7%, longer than 14 days; P = 0.03). Analytic sensitivity and specificity for US participants were 97.2% (95% confidence interval: 94.7-98.7%) and 99.8% (95% confidence interval: 99.1-99.9%), respectively. Of 11 genotyping errors, 2 were due to sample mix-up. Analytic interpretations were correct in 99.3% of challenges (956/963; 95% confidence interval: 98.5-99.7%). Better performance was found for Canavan disease and familial dysautonomia. International laboratories performed equally well. CONCLUSION: These results demonstrated high analytic sensitivity and specificity along with excellent analytic interpretation performance, confirming the genetics community impression that laboratories provide accurate test results in both diagnostic and screening settings. Proficiency testing can identify potential laboratory issues and helps document overall laboratory performance.

["But I have done the genetic tests...". The obligation to identify genetic carriers and prenatal genetic tests for new mutations].

INTRODUCTION: Genetic tests are developing quickly. Therefore, genetic screening tests which were carried out before the first pregnancy are not always sufficient for the subsequent pregnancies. Familial dysautonomia (FD) is a disabling autosomal recessive disorder affecting Ashkenazi Jews in which the carrier frequency varies from 1:17 to 1:32. In 2001, the FD gene was discovered and the genetic tests were made available in most Israeli hospitals or institutes. In 2008, the FD genetic test was included in the "health basket" by the Israeli Ministry of Health. AIMS: Investigating the reasons for new FD patients born after 2001 as a model for other genetic diseases. METHODS: A retrospective study was performed from medical chart data. RESULTS: Since 2001, forty FD patients were born to Israeli parents. Eleven patients were born to mothers who had undergone genetic tests before 2001, however, they were not informed that new genes had been discovered. This has led to a number of law suits. Furthermore, the FD test was not offered to another woman who had some of the genetic tests performed after 2001. Religious parents of 9 FD patients had married long before the FD genetic test became avaiLable. Four children were born to families who were unaware that there was an FD patient in their extended family. DISCUSSION AND SUMMARY: The burden on the patients, families and the National Health Service for treating FD and other genetic diseases is enormous. Updating new genetic information might prevent new cases. CONCLUSIONS: Before each new pregnancy, it is necessary to update the population about new genetic tests.

Assessing autonomic dysfunction symptoms in children: a pilot study.

As a screening tool to identify symptoms of autonomic dysfunction, the Pediatric Autonomic Symptoms Scale was administered to parents of children with familial dysautonomia, autism spectrum disorders, and age-matched controls. The total scores for the presence of symptoms were compared among the 3 groups for each section and overall. The Pediatric Autonomic Symptoms Scale distinguished controls from children with familial dysautonomia and autism spectrum disorders with scores from each section and overall scores. Familial dysautonomia children scored significantly higher in visceral symptoms, while children with autism spectrum disorders scored significantly higher in psychosocial symptoms. In familial dysautonomia, the concordance for the presence of symptoms within sections and overall scores ranged from 71% to 100%. The concordance for absence of autonomic dysfunction symptoms in controls ranged from 75% to 87.5%. The Pediatric Autonomic Symptoms Scale is comprehensive and can profile autonomic dysfunction in the 2 neurodevelopmental disorders. Its usefulness in other pediatric disorders remains to be studied.

Complicações osteoarticulares da analgesia congênita / Osteoarticular complications of congenital analgesia

Os autores apresentam dois irmãos com diagnóstico de analgesia congênita, com suas características clínicas e evolução. Essa doença é rara, apresenta alta morbidade e gera complicações osteoarticulares de difícil solução. O objetivo dos autores foi ressaltar a importância do diagnóstico tanto para o tratamento de suas afecções secundárias, quanto para seu aspecto jurídico.

The authors present two brothers with congenital pain insensitivity, with their clinical characteristics and evolution. This disease is rare, has high morbidity and originates complex osteoarticular complications. The aim of the authors was to emphasize the value of the diagnosis for a better treatment and to avoid legal problems to the parents.

Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent.

Many recessive genetic disorders are found at a higher incidence in people of Ashkenazi Jewish (AJ) descent than in the general population. The American College of Medical Genetics and the American College of Obstetricians and Gynecologists have recommended that individuals of AJ descent undergo carrier screening for Tay Sachs disease, Canavan disease, familial dysautonomia, mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia type C, Bloom syndrome, and Gaucher disease. Although these recommendations have led to increased test volumes and number of laboratories offering AJ screening, well-characterized genomic reference materials are not publicly available. The Centers for Disease Control and Prevention-based Genetic Testing Reference Materials Coordination Program, in collaboration with members of the genetic testing community and Coriell Cell Repositories, have developed a panel of characterized genomic reference materials for AJ genetic testing. DNA from 31 cell lines, representing many of the common alleles for Tay Sachs disease, Canavan disease, familial dysautonomia, mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia type C, Bloom syndrome, Gaucher disease, and glycogen storage disease, was prepared by the Repository and tested in six clinical laboratories using three different PCR-based assay platforms. A total of 33 disease alleles was assayed and 25 different alleles were identified. These characterized materials are publicly available from Coriell and may be used for quality control, proficiency testing, test development, and research.

Pregabalin: a new approach to treatment of the dysautonomic crisis.

Nausea and dysautonomic crises severely limit function and quality of life for a large number of individuals with familial dysautonomia. We treated a small cohort of 15 patients with familial dysautonomia who suffered frequent dysautonomic crises with pregabalin. Nausea and overt crises markedly decreased in 13 (87%) of these patients and the overall assessments of benefit were extremely favorable, suggesting that pregabalin may be a potentially useful therapeutic agent for this disorder.

Advanced electrocardiographic predictors of mortality in familial dysautonomia.

OBJECTIVE: To identify electrocardiographic predictors of mortality in patients with familial dysautonomia (FD). METHODS: Ten-minute resting high-fidelity 12-lead electrocardiograms (ECGs) were obtained from 14 FD patients and 14 age/gender-matched healthy subjects. Multiple conventional and advanced ECG parameters were studied for their ability to predict mortality over a subsequent 4.5-year period, including representative parameters of heart rate variability (HRV), QT variability (QTV), T-wave complexity, signal averaged ECG, and 3-dimensional ECG. RESULTS: Four of the 14 FD patients died during the follow-up period, three with concomitant pulmonary disorder. Of the ECG parameters studied, increased non-HRV-correlated QTV and decreased HRV were the most predictive of death. Compared to controls as a group, FD patients also had significantly increased ECG voltages, JTc intervals and waveform complexity, suggestive of structural heart disease. CONCLUSION: Increased QTV and decreased HRV are markers for increased risk of death in FD patients. When present, both markers may reflect concurrent pathological processes, especially hypoxia due to pulmonary disorders and sleep apnea.

[Molecular and cellular characterization ion of IKAP protein and the Elongator complex. Implications for familial dysautonomia]. / Caractérisation moléculaire et cellulaire des fonctions de la protéine IKAP et du complexe Elongator: implications pour la dysautonomie familiale.

Familial dysautonomia (FD), a severe neuro-developmental and neurodegenerative genetic disorder, is caused by mutations of IKBKAP encoding a subunit of Elongator. FD patients have decreased expression of IKAP in a tissue-specific manner and consequently impaired Elongator function. The biological roles of human IKAP/Elongator remained elusive for a while. However, recent data based on the generation of cellular loss of function models of IKAP through RNA interference strongly suggest a role for this protein in transcriptional elongation. Other data also provide evidence for a role of Elongator in tRNA modifications. Importantly, cells depleted for IKAP have defects in cell motility because of impaired transcriptional elongation of some genes coding for proteins involved in cell migration. Therefore, cell motility deficiency seen in IKAP depleted cells may underlie the neuropathology of FD patients.

Pediatric autonomic disorders.

The scope of pediatric autonomic disorders is not well recognized. The goal of this review is to increase awareness of the expanding spectrum of pediatric autonomic disorders by providing an overview of the autonomic nervous system, including the roles of its various components and its pervasive influence, as well as its intimate relationship with sensory function. To illustrate further the breadth and complexities of autonomic dysfunction, some pediatric disorders are described, concentrating on those that present at birth or appear in early childhood.