Animal and cellular models of familial dysautonomia

Lefcort, Frances; Mergy, Marc; Ohlen, Sarah B.; Ueki, Yumi; George, Lynn

doi:10.1007/s10286-017-0438-2

Cited by 27 publications

(34 citation statements)

References 71 publications

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“…Examples of this would be congenital central hypoventilation and familial dysautonomia (hereditary sensory and autonomic neuropathy type 3), the latter a rare genetic disease characterized by afferent baroreflex and chemoreflex failure and resulting in a very high incidence of sudden unexpected death during sleep [15]. Although rare, these genetic disorders represent interesting models to understand the interactions between sleep and the autonomic nervous system, which can be further studied in animal and cellular models of the disease [11].These mechanisms are not mutually exclusive. Not infrequently, patients with functional disorders affecting the…”

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confidence: 99%

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Autonomic dysfunction in sleep disorders: introduction to the series

Palma

2018

Clin Auton Res

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Sleep is a fascinating and enigmatic phenomenon occurring, with varying patterns, in virtually all known animal species. This issue of Clinical Autonomic Research features a series of manuscripts authored by renowned experts in the field which focus on the connections between the autonomic nervous system and sleep. Although sleep is not traditionally considered a function regulated by the autonomic nervous system, it is evident that there are overlapping areas in the central nervous system (CNS) that regulate both systems, resulting in interesting and relevant interactions that can potentially impact morbidity and mortality. These interactions are concisely summarized in the review by Fink and colleagues [6], which highlights how specific CNS nuclei play a critical role in regulating cardiovascular autonomic function during both rapid eye movement (REM) and non-REM sleep.The sleep-autonomic interactions can occur, broadly speaking, under three different scenarios, which are not mutually exclusive and can overlap:(1) A common etiology impairs both the autonomic and sleep systems. The α-synucleinopathies, disorders caused by the abnormal accumulation of misfolded α-synuclein, are a very good example of this scenario, as reviewed by Chiaro and colleagues in this issue [5]. Progressive α-synuclein-mediated neurodegeneration of specific brainstem nuclei can result in REM sleep behavior disorder (RBD), a distinctive parasomnia in which patients act out and scream in their dreams. Conversely, α-synuclein-related neurodegeneration of peripheral and central autonomic areas can result in autonomic failure. Consequently, the co-existence of RBD and autonomic failure in patients with pure autonomic failure (PAF) [12], Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) is not infrequent. Interestingly, the presence of RBD and autonomic failure are now well-recognized prodromal markers of PD/DLB and MSA [2, 10]. Moreover, the coexistence of RBD and autonomic failure in patients without overt motor or cognitive deficits carries a very risk of phenoconversion to PD/DLB or MSA [10, 14]. Identifying sleep and autonomic abnormalities in patients is, therefore, highly relevant as the presence of these abnormalities has diagnostic, prognostic and therapeutic implications. (2) Failure of sleep-related cardio-respiratory control mechanisms and impaired arousal response cause or aggravate autonomic dysfunction. In this context, autonomic dysfunction can occur in sleep apnea, as reviewed by Fink and colleagues [6], or in the sudden infant death syndrome, as explained by Horne in her authoritative review [9]. These disorders can potentially result in prolonged hypoxia during sleep, cardiac arrhythmias and death. (3) A disorder in which autonomic dysfunction causes or aggravates a sleep disorder. Examples of this would be congenital central hypoventilation and familial dysautonomia (hereditary sensory and autonomic neuropathy type 3), the latter a rare genetic disease characterized by afferent baroref...

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confidence: 99%

“…. Although rare, these genetic disorders represent interesting models to understand the interactions between sleep and the autonomic nervous system, which can be further studied in animal and cellular models of the disease [11].…”

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confidence: 99%

Autonomic dysfunction in sleep disorders: introduction to the series

Palma

2018

Clin Auton Res

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“…Mutants and knockdowns for tRNA-modifying enzymes present a plethora of phenotypes [3]. Elongator Complex (EC) has been shown to be involved in other cellular activities besides tRNA modification [17][18][19][20][21][22][23][24][25][26][27][28]. It is not clear whether these functions in which the complex is involved are consequences of impaired translation or are bona fide novel functions acquired during evolution.…”

Section: Discussionmentioning

confidence: 99%

Elongator Subunit 3 (Elp3) Is Required for Zebrafish Trunk Development

Rojas-Benítez

Allende

2020

IJMS

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Transfer RNAs (tRNAs) are the most post-transcriptionally modified RNA species. Some of these modifications, especially the ones located in the anti-codon loop, are required for decoding capabilities of tRNAs. Such is the case for 5-methoxy-carbonyl-methyl-2-thio-uridine (mcm5s2U), synthetized by the Elongator complex. Mutants for its sub-units display pleiotropic phenotypes. In this paper, we analyze the role of elp3 (Elongator catalytic sub-unit) in zebrafish development. We found that it is required for trunk development; elp3 knock-down animals presented diminished levels of mcm5s2U and sonic hedgehog (Shh) signaling activity. Activation of this pathway was sufficient to revert the phenotype caused by elp3 knockdown, indicating a functional relationship between Elongator and Shh through a yet unknown molecular mechanism.

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“…Developing a standardized rating scale to grade CT scan findings specific for FD will be a future objective. Development of animal models reproducing the respiratory disorders of patients with FD [92, 93] and improved controlled clinical studies to evaluate the response to therapeutic interventions will allow us to understand the actual impact of potential treatments. An international collaborative effort is needed to enable sufficient power to assess the impact of standard treatments.…”

Section: Future Directionsmentioning

confidence: 99%

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

Kazachkov

Palma

Norcliffe‐Kaufmann

et al. 2018

Respiratory Medicine

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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, noninvasive 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.

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Animal and cellular models of familial dysautonomia

Cited by 27 publications

References 71 publications

Autonomic dysfunction in sleep disorders: introduction to the series

Autonomic dysfunction in sleep disorders: introduction to the series

Elongator Subunit 3 (Elp3) Is Required for Zebrafish Trunk Development

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

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