Retrograde tubing as a rescue treatment for megaoesophagus: a case report.

Familial dysautonomia (FD) is a genetic disease of the autonomous and sensory nervous systems. Severe gastro-oesophageal reflux is common and one of the major complications. Some patients with FD develop megaoesophagus. Oesophageal malfunction, accompanied by oesophageal food and secretion retention, results in recurrent aspiration and other severe respiratory complications. Through a traditional case report, we wish to show how reverse tubing of the oesophagus can lead to significant symptomatic improvement in these patients. Moreover, this technique can serve as an alternative treatment for other oesophageal motility disorders.

Nociception and pain in humans lacking a functional TRPV1 channel.

BACKGROUNDChronic pain is a debilitating illness with currently limited therapy, in part due to difficulties in translating treatments derived from animal models to patients. The transient receptor potential vanilloid 1 (TRPV1) channel is associated with noxious heat detection and inflammatory pain, and reports of adverse effects in human trials have hindered extensive efforts in the clinical development of TRPV1 antagonists as novel pain relievers.METHODSWe examined 2 affected individuals (A1 and A2) carrying a homozygous missense mutation in TRPV1, rendering the channel nonfunctional. Biochemical and functional assays were used to analyze the mutant channel. To identify possible phenotypes of the affected individuals, we performed psychophysical and medical examinations.RESULTSWe demonstrated that diverse TRPV1 activators, acting at different sites of the channel protein, were unable to open the cloned mutant channel. This finding was not a consequence of impairment in the expression, cellular trafficking, or assembly of protein subunits. The affected individuals were insensitive to application of capsaicin to the mouth and skin and did not demonstrate aversive behavior toward capsaicin. Furthermore, quantitative sensory testing of A1 revealed an elevated heat-pain threshold but also, surprisingly, an elevated cold-pain threshold and extensive neurogenic inflammatory, flare, and pain responses following application of the TRPA1 channel activator mustard oil.CONCLUSIONOur study provides direct evidence in humans for pain-related functional changes linked to TRPV1, which is a prime target in the development of pain relievers.FUNDINGSupported by the Israel Science Foundation (368/19); Teva's National Network of Excellence in Neuroscience grant (no. 0394886) and Teva's National Network of Excellence in Neuroscience postdoctoral fellowship.

Uncommon side effects of common drugs in patients with familial dysautonomia.

PURPOSE: Patients with the autosomal recessive disorder of familial dysautonomia typically exhibit exacerbated adverse side effects to many common drugs. We aimed to catalog these adverse effects - with a focus on common drugs that are frequently administered to FD patients and compare their incidences to those within the general population. METHODS: We used data of 595 FD patients from an international database with information on drugs received and adverse effects. To investigate the molecular causes of reported differences in drug responses in FD patients, we used expression microarrays to compare the mRNA expression profiles in peripheral blood leukocytes of FD patients (n = 12) and healthy individuals (n = 10). RESULTS: Several drug classes, including cholinergics, anti-cholinergics, anti-convulsants, methylxanthines, SSRIs, and antibiotics caused either unreported symptoms or elevated rates of adverse events in FD patients. FD patients experienced different or more frequent adverse side effects than the general population in 31/123 drugs. These side effects included blood cell dyscrasias, amenorrhea, gastrointestinal bleeding, and bronchospasm. New findings include enhanced reaction of FD patients to H2 antagonist agents and to serotonin receptor agonists. We also detected eight genes differentially expressed between FD patients and healthy individuals that may underlie the differential drug responses of FD patients. CONCLUSION: We provide evidence that suggests the use of several common drugs should be discontinued or reduced in FD patients.

Respiratory care in familial dysautonomia: Systematic review and expert consensus recommendations.

BACKGROUND: Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. METHODS: We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS: Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. CONCLUSIONS: Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

Characteristics of ataxic gait in familial dysautonomia patients.

INTRODUCTION AND OBJECTIVES: Progressive ataxic gait is a common symptom in individuals with Familial Dysautonomia (FD). At least 50% of adults with FD require assistance with walking. Our aims were to describe the medical condition of individuals with FD (ii) compare their gait characteristics to healthy individuals, and (iii) assess correlations between gait measures, presence of unstable gait pattern and frequency of falls. METHODS: Twelve subjects with FD (7 males, age 25.3±10.6 years) and 16 healthy participants (6 males, age 35.9±11.9 years) were recruited. Gait kinematics, gait symmetry, dynamic muscle activity, and foot deep vibration sensation were recorded. RESULTS: Ataxic gait degrees were: severe (6 out of 12), moderate (4 out of 12) and low (2 out of 12). The number of falls correlated with base width asymmetry. Crouch gait was noted in 3 out of 12 of the subjects. CONCLUSIONS: In-depth quantitative gait analysis of individuals with FD revealed ataxic gait. The ataxic pattern might be a result of combined neurological deficiencies and osseous deformities. Increasing the base of support of patients with FD might increase the symmetry of the base width during gait and decrease the number of falls. Additionally, perturbation treatment and dynamic balance exercises may be recommended in order to improve compensatory strategies. Future investigation of this population should include quantification of osseous rotations of the lower limb in order to fully understand its effect on their gait pattern and falls.

Genetic Polymorphisms in the ESR1 and VDR Genes Do Not Correlate With Osteoporosis in Patients With Familial Dysautonomia.

One of the major clinical manifestations of familial dysautonomia (FD)-a rare, neurodegenerative, autosomal-recessive disorder-is a high incidence and early onset of osteoporotic bone fractures. Early diagnosis is essential to initiate preventative therapy in at-risk patients and thus improve quality of life. However, the current lack of understanding of the complex relationship between FD and osteoporosis etiology precludes early diagnosis, and as such, accurate predictors of osteoporosis development in FD patients remain to be determined. It has been previously reported that a restriction fragment length polymorphism in the gene encoding the vitamin D receptor (VDR) and the number of thymine-adenine (TA) repeats in the gene encoding the estrogen receptor alpha (ESR1) may each be associated with determinants of bone mineral density and may thus predict the development of osteoporosis across a number of non-FD populations. In this study, we aimed to examine the correlation between osteoporosis and the presence of these genetic polymorphisms and to establish whether they could be used as predictive markers of osteoporosis development in the context of FD. The correlations between osteoporosis and either the BsmI restriction site polymorphism in VDR or the (TA)n repeat polymorphism in ESR1 were analyzed in 73 and 67 genotyped patients, respectively. Osteoporosis was defined as a bone mineral density greater than 2.5 (T-score) or greater than 2 (Z-score) standard deviations below the mean, as measured by dual-energy X-ray absorptiometry of the spine or hip. In both instances, no statistically significant difference in the frequency of polymorphism could be detected between FD patients with and without osteoporosis. Neither polymorphism can serve as a predictive marker for the development of osteoporosis in FD patients.

Tocotrienol Treatment in Familial Dysautonomia: Open-Label Pilot Study.

Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy, primarily presented in Ashkenazi Jews. The most common mutation in FD patients results from a single base pair substitution of an intronic splice site in the IKBKAP gene which disrupts normal mRNA splicing and leads to tissue-specific reduction of IKBKAP protein (IKAP). To date, treatment of FD patients remains preventative, symptomatic and supportive. Based on previous in vitro evidence that tocotrienols, members of the vitamin E family, upregulate transcription of the IKBKAP gene, we aimed to investigate whether a similar effects was observed in vivo. In the current study, we assessed the effects of tocotrienol treatment on FD patients' symptoms and IKBKAP expression in white blood cells. The initial daily doses of 50 or 100 mg tocotrienol, doubled after 3 months, was administered to 32 FD patients. Twenty-eight FD patients completed the 6-month study. The first 3 months of tocotrienol treatment was associated with a significant increase in IKBKAP expression level in FD patients' blood. Despite doubling the dose after the initial 3 months of treatment, IKBKAP expression level returned to baseline by the end of the 6-month treatment. Clinical improvement was noted in the reported clinical questionnaire (with regard to dizziness, bloching, sweating, number of pneumonia, cough episodes, and walking stability), however, no significant effect was observed in any clinical measurements (weight, height, oxygen saturation, blood pressure, tear production, histamine test, vibration threshold test, nerve conduction, and heart rate variability) following Tocotrienol treatment. In conclusion, tocotrienol treatment appears significantly beneficial by clinical evaluation for some FD patients in a few clinical parameters; however it was not significant by clinical measurements. This open-label study shows the complexity of effect of tocotrienol treatment on FD patients' clinical outcomes and on IKBKAP expression level compared to in vitro results. A longitudinal study with an increased sample size is required in the future to better understand tocotrienol affect on FD patients.

TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability.

BACKGROUND: TECPR2 was first described as a disease causing gene when the c.3416delT frameshift mutation was found in five Jewish Bukharian patients with similar features. It was suggested to constitute a new subtype of complex hereditary spastic paraparesis (SPG49). RESULTS: We report here 3 additional patients from unrelated non-Bukharian families, harboring two novel mutations (c.1319delT, c.C566T) in this gene. Accumulating clinical data clarifies that in addition to intellectual disability and evolving spasticity the main disabling feature of this unique disorder is autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events. CONCLUSION: We suggest that the disease should therefore be classified as a new subtype of hereditary sensory-autonomic neuropathy. The discovery of additional mutations in non-Bukharian patients implies that this disease might be more common than previously appreciated and should therefore be considered in undiagnosed cases of intellectual disability with autonomic features and respiratory symptoms regardless of demographic origin.

Familial Dysautonomia (FD) Human Embryonic Stem Cell Derived PNS Neurons Reveal that Synaptic Vesicular and Neuronal Transport Genes Are Directly or Indirectly Affected by IKBKAP Downregulation.

A splicing mutation in the IKBKAP gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we found new molecular insights for the IKAP role and the impact of the FD mutation in the human PNS lineage by using a novel and unique human embryonic stem cell (hESC) line homozygous to the FD mutation originated by pre implantation genetic diagnosis (PGD) analysis. We found that IKBKAP downregulation during PNS differentiation affects normal migration in FD-hESC derived neural crest cells (NCC) while at later stages the PNS neurons show reduced intracellular colocalization between vesicular proteins and IKAP. Comparative wide transcriptome analysis of FD and WT hESC-derived neurons together with the analysis of human brains from FD and WT 12 weeks old embryos and experimental validation of the results confirmed that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation in FD neurons. Moreover we show that kinetin (a drug that corrects IKBKAP alternative splicing) promotes the recovery of IKAP expression and these IKAP functional associated genes identified in the study. Altogether, these results support the view that IKAP might be a vesicular like protein that might be involved in neuronal transport in hESC derived PNS neurons. This function seems to be mostly affected in FD-hESC derived PNS neurons probably reflecting some PNS neuronal dysfunction observed in FD.

Laughter is not always funny: breath-holding spells in familial dysautonomia.

Familial dysautonomia (FD) is a genetic disease characterized by primary autonomic dysfunction including parasympathetic hypersensitivity. Breath-holding spells (BHS) are believed to be caused by autonomic dysregulation mediated via the vagus nerve and increased in patients with a family history of BHS. Details and understanding of its pathophysiology are lacking. In this retrospective study of patients with FD, the incidence of BHS was higher at 53.3%, compared with previous studies in normal children. Laughter as a precipitating factor for BHS has not been previously reported in FD and occurred in 10% of patients in this study. Lower lung volumes, chronic lung disease, chronic CO2 retention, and inadequate autonomic compensation occur in those with FD leading to a higher incidence and severity of BHS when crying or laughing. Thus, FD may be a good model for understanding manifestations of the autonomic nervous system dysfunction and contribute to our knowledge of BHS mechanisms.

IKAP deficiency in an FD mouse model and in oligodendrocyte precursor cells results in downregulation of genes involved in oligodendrocyte differentiation and myelin formation.

The splice site mutation in the IKBKAP gene coding for IKAP protein leads to the tissue-specific skipping of exon 20, with concomitant reduction in IKAP protein production. This causes the neurodevelopmental, autosomal-recessive genetic disorder - Familial Dysautonomia (FD). The molecular hallmark of FD is the severe reduction of IKAP protein in the nervous system that is believed to be the main reason for the devastating symptoms of this disease. Our recent studies showed that in the brain of two FD patients, genes linked to oligodendrocyte differentiation and/or myelin formation are significantly downregulated, implicating IKAP in the process of myelination. However, due to the scarcity of FD patient tissues, these results awaited further validation in other models. Recently, two FD mouse models that faithfully recapitulate FD were generated, with two types of mutations resulting in severely low levels of IKAP expression. Here we demonstrate that IKAP deficiency in these FD mouse models affects a similar set of genes as in FD patients' brains. In addition, we identified two new IKAP target genes involved in oligodendrocyte cells differentiation and myelination, further underscoring the essential role of IKAP in this process. We also provide proof that IKAP expression is needed cell-autonomously for the regulation of expression of genes involved in myelin formation since knockdown of IKAP in the Oli-neu oligodendrocyte precursor cell line results in similar deficiencies. Further analyses of these two experimental models will compensate for the lack of human postmortem tissues and will advance our understanding of the role of IKAP in myelination and the disease pathology.

Natural history of five children with surfactant protein C mutations and interstitial lung disease.

Interstitial lung diseases in infants and children are uncommon and may be caused by specific inborn errors of surfactant metabolism. Five children with open lung biopsy diagnosed interstitial lung disease were followed (mean of 27.2 years) and evaluated for surfactant protein gene mutations. Four of the children were originally diagnosed as desquamative interstitial pneumonitis and one as chronic interstitial pneumonitis. All had good response to chloroquine or hydroxychloroquine treatment for periods of 7-38 months. Lung function tests, incremental exercise tests, and rentgenological studies were performed in the children. Surfactant protein gene mutations were searched in all the patients and in part of their families. Three of the patients, aged now 32, 29, and 37 years, feel well and have normal lung function, while two of the patients, both females, aged 28 and 37 years, conduct normal activities of daily living, have healthy children but have clinical, physiological and rentgenological evidence of restrictive lung disease. All five patients were found to have surfactant protein C gene (SFTPC) mutations, three of them with the most common mutation (p.I73T) and the other two with new mutations of surfactant protein C gene (p.I38F and p.V39L). We conclude that detection of surfactant protein mutations should be attempted in all children presenting with interstitial lung disease. Furthermore, treatment with hydroxychloroquine should be considered in children with SFTPC mutations. Prospective evaluation of hydroxychloroquine therapy in a greater number of patients is needed.

Dynamic changes in IKBKAP mRNA levels during crisis of familial dysautonomia patients.

UNLABELLED: Familial dysautonomia is a neurodegenerative, genetic disorder caused by an autosomal recessive mutation in the IKBKAP gene, which encodes the IkB kinase complex-associated protein. Familial dysautonomia patients have recurrent crises characterized by bouts of nausea, vomiting, hypertension, tachycardia, sweating, blotching and personality changes. The dysautonomia crisis is usually triggered by stressful physiological or emotional events, however the pathophysiology of the crisis is not yet fully clear and little is known about the molecular mechanisms involved in onset and consequences of the crisis. OBJECTIVE: We have investigated the dysautonomia crisis by evaluating the expression of the familial dysautonomia gene - IKBKAP, in patients during different crisis stages. METHOD: Baseline IKBKAP mRNA levels in white blood cells were evaluated in thirteen FD patients (fourteen crisis events) and compared to mRNA levels at the onset, during, and after recovery from the crisis. RESULTS: We have found a significant decrease in IKBKAP mRNA level during the crisis, which is restored to a baseline level after recovery from the crisis. CONCLUSION: We speculate that the familial dysautonomia crisis pathophysiology might be related, at least in part, to the down regulation of the IKBKAP gene. Yet, it is still unclear whether the down regulation in IKBKAP mRNA is caused by the physiological stress events which have triggered the crisis or whether this molecular change is a consequence of the crisis.

Lack of migraine in headaches of familial dysautonomia patients.

Familial Dysautonomia (FD) is an autosomal recessive genetic disease where autonomic and sensory functions are defective affecting many body systems including the vascular. Plasma level of the neurotransmitter Calcitonin Gene Related Peptide (CGRP) is decreased in FD patients. This compound has been implicated to take part in the pathogenesis of migraine. We aimed to evaluate the symptoms of headaches in FD patients and to test the hypothesis that these patients will have a low incidence of migrainous headache. Sixty-five FD patients were evaluated by a medical headache questionnaire. Mean age was 23.73 + 10.82 years (mean 21 years) and there were 37 males (57 %).Thirty-eight patients (58.5 %) described having episodic headache conforming to criteria of tension headache, and in 17 of those 38 (44.7 %) headache were dependent on changes in blood pressure, except from one patient who had complaints that matched diagnosis of acephalic migraine. None of the patients had symptoms compatible with migraine or cluster headache. Results show that the headache is a very common complaint in FD, there is lack of migraine symptoms in this group. This might be attributed to defective sensory innervation and deficiency of CGRP. FD could be regarded as a human model for CGRP deficiency when studying the pathogenesis of migraine.

["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.

Dead sea water intoxication.

Near drowning in the Dead Sea is associated with both respiratory manifestations and severe electrolyte abnormalities. It is often difficult to distinguish between the contributions of sea water aspiration or ingestion to clinical manifestations. We present a unique case of accidental ingestion of a large amount of Dead Sea water through a gastrostomy tube in which a patient with familial dysautonomia presented with severe electrolyte disturbances. Forced diuresis with large amounts of intravenous fluids resulted in clinical and biochemical improvement. Full recovery was achieved after 2 days of treatment.

Hereditary sensory autonomic neuropathy caused by a mutation in dystonin.

In 4 infants with a new lethal autonomic sensory neuropathy with clinical features similar to familial dysautonomia as well as contractures, we identified a deleterious mutation in the DST gene, using homozygosity mapping followed by exome sequencing. DST encodes dystonin, a cytoskeleton linker protein, and the mutation results in an unstable transcript. Interestingly, dystonin is significantly more abundant in cells of familial dysautonomia patients with IKBKAP (I-κ-B kinase complex-associated protein) mutation compared to fibroblasts of controls, suggesting that upregulation of dystonin is responsible for the milder course in familial dysautonomia. Homozygosity mapping followed by exome sequencing is a successful approach to identify mutated genes in rare monogenic disorders.

IKAP/Elp1 involvement in cytoskeleton regulation and implication for familial dysautonomia.

Deficiency in the IKAP/Elp1 protein leads to the recessive sensory autosomal congenital neuropathy which is called familial dysautonomia (FD). This protein was originally identified as a role player in transcriptional elongation being a subunit of the RNAPII transcriptional Elongator multi-protein complex. Subsequently, IKAP/Elp1 was shown to play various functions in the cytoplasm. Here, we describe experiments performed with IKAP/Elp1 downregulated cell lines and FD-derived cells and tissues. Immunostaining of the cytoskeleton component α-tubulin in IKAP/Elp1 downregulated cells revealed disorganization of the microtubules (MTs) that was reflected in aberrant cell shape and process formation. In contrast to a recent report on the decrease in α-tubulin acetylation in IKAP/Elp1 downregulated cells, we were unable to observe any effect of IKAP/Elp1 deficiency on α-tubulin acetylation in the FD cerebrum and in a variety of IKAP/Elp1 downregulated cell lines. To explore possible candidates involved in the observed aberrations in MTs, we focused on superior cervical ganglion-10 protein (SCG10), also called STMN2, which is known to be an MT destabilizing protein. We have found that SCG10 is upregulated in the IKAP/Elp1-deficient FD cerebrum, FD fibroblasts and in IKAP/Elp1 downregulated neuroblastoma cell line. To better understand the effect of IKAP/Elp1 deficiency on SCG10 expression, we investigated the possible involvement of RE-1-silencing transcription factor (REST), a known repressor of the SCG10 gene. Indeed, REST was downregulated in the IKAP/Elp1-deficient FD cerebrum and IKAP/Elp1 downregulated neuroblastoma cell line. These results could shed light on a possible link between IKAP/Elp1 deficiency and cytoskeleton destabilization.

Phosphatidylserine increases IKBKAP levels in familial dysautonomia cells.

Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from abnormal development and progressive degeneration of the sensory and autonomic nervous system. The mutation observed in almost all FD patients is a point mutation at position 6 of intron 20 of the IKBKAP gene; this gene encodes the IκB kinase complex-associated protein (IKAP). The mutation results in a tissue-specific splicing defect: Exon 20 is skipped, leading to reduced IKAP protein expression. Here we show that phosphatidylserine (PS), an FDA-approved food supplement, increased IKAP mRNA levels in cells derived from FD patients. Long-term treatment with PS led to a significant increase in IKAP protein levels in these cells. A conjugate of PS and an omega-3 fatty acid also increased IKAP mRNA levels. Furthermore, PS treatment released FD cells from cell cycle arrest and up-regulated a significant number of genes involved in cell cycle regulation. Our results suggest that PS has potential for use as a therapeutic agent for FD. Understanding its mechanism of action may reveal the mechanism underlying the FD disease.