Familial dysautonomia

Cohen, Philip; Solomon, Nathaniel H.

doi:10.1016/s0022-3476(55)80171-0

Cited by 47 publications

(9 citation statements)

References 9 publications

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“…The similar proportion of amplitude decrement for the early and late components, approximately 50%, indicates that both peripheral trigeminal afferents and central pathways within the brainstem are affected in a similar proportion, as occurred with the latencies of these responses. This is in line with pathology samples in FD showing involvement of brainstem reticular formation (Cohen et al, 1955, Brown et al, 1964) and marked reduction in the number of sensory neurons in the trigeminal ganglia (Brown et al, 1964, Aguayo et al, 1971, Pearson et al, 1971, Pearson et al, 1975, Pearson et al, 1978b), as well as the decreased sensory nerve action potentials in the limbs (Hilz et al, 2000). Impairment of the efferent neurons, as suggested by the slightly decreased orbicularis oculi CMAP and masseter EMG amplitudes, is unlikely to fully explain the marked decrease in reflex amplitudes.…”

Section: Discussionsupporting

confidence: 86%

“…In support of this, brainstem auditory evoked potentials in children with FD were reported to have increased latencies of waves III and V and durations of I–III and III–V intervals, which can only be explained by concomitant peripheral and central lesions throughout the auditory neuronal pathway (Lahat et al, 1992). Furthermore, post-mortem neuropathology studies in patients with FD showed involvement of cranial nerves (including the trigeminal peripheral fibers) and brainstem reticular formation (Cohen et al, 1955, Brown et al, 1964). …”

Section: Discussionmentioning

confidence: 99%

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Brainstem reflexes in patients with familial dysautonomia

Gutiérrez¹,

Norcliffe‐Kaufmann

Kaufmann

2015

Clinical Neurophysiology

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Objective Several distinctive clinical features of patients with familial dysautonomia (FD) including dysarthria and dysphagia suggest a developmental defect in brainstem reflexes. Our aim was to characterize the neurophysiological profile of brainstem reflexes in these patients. Methods We studied the function of sensory and motor trigeminal tracts in 28 patients with FD. All were homozygous for the common mutation in the IKAP gene. Each underwent a battery of electrophysiological tests including; blink reflexes, jaw jerk reflex, masseter silent periods and direct stimulation of the facial nerve. Responses were compared with 25 age-matched healthy controls. Results All patients had significantly prolonged latencies and decreased amplitudes of all examined brainstem reflexes. Similar abnormalities were seen in the early and late components. In contrast, direct stimulation of the facial nerve revealed relative preservation of motor responses. Conclusions The brainstem reflex abnormalities in FD are best explained by impairment of the afferent and central pathways. A reduction in the number and/or excitability of trigeminal sensory axons is likely the main problem. Significance These findings add further evidence to the concept that congenital mutations of the elongator-1 protein (or IKAP) affect the development of afferent neurons including those carrying information for the brainstem reflex pathways.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Brainstem reflexes in patients with familial dysautonomia

Gutiérrez¹,

Norcliffe‐Kaufmann

Kaufmann

2015

Clinical Neurophysiology

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“…Yet CNS perturbations have been demonstrated in autopsy, pathology and imaging studies on FD patients, in EEG recordings, and as manifested in psychometric exams (Engel and Aring, 1945; Cohen and Solomon, 1955; Brown et al, 1964; Sak et al, 1967; Ochoa, 2003, 2004; Axelrod et al, 2010; Norcliffe-Kaufmann et al, 2016; Dietrich and Dragatsis, 2016). Our study is the first to directly investigate the CNS pathophysiology of an animal model for FD, and the results demonstrate that Ikbkap is required for the normal development, function and survival of several CNS subpopulations.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical symptoms involving the CNS include visual impairment (Mendoza-Santiesteban et al, 2012, 2014; Ueki et al, 2016), high anxiety levels, learning impairments (Day, 1979; Sak et al, 1967; Welton et al, 1979; Clayson et al, 1980; Axelrod et al, 2012; Norcliffe-Kaufmann et al, 2016), seizures, decreased motor nerve conduction, deficits in brain stem reflexes (Gutiérrez et al, 2015) and abnormal electroencephalogram (EEG) activity (Niedermeyer et al, 1967; Ochoa, 2003). Neuroimaging studies [magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI)] demonstrate both white and gray matter microstructural damage in FD brains (Axelrod et al, 2010), and pathological studies have revealed enlarged 4th ventricles associated with atrophy in the medulla (Engel and Aring, 1945; Cohen and Solomon, 1955; Brown et al, 1964). Most patients die due to sudden death during sleep or respiratory failure (Axelrod, 2006).…”

Section: Introductionmentioning

confidence: 99%

The Familial Dysautonomia disease gene,Ikbkap/Elp1, is required in the developing and adult central nervous system

Chaverra

George

Mergy

et al. 2017

Disease Models &Amp; Mechanisms

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Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement for Ikbkap in the CNS of mice. The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap in the CNS. Here, we report, using a novel mouse line in which Ikbkap is deleted solely in the nervous system, that not only is Ikbkap widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that, in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that includes impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap that extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed.

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“…In all four cases, demyelination of the reticular formation of the pons and medulla were consistent findings. In addition, demyelination of spinothalamic tracts, and loss of cranial nerve nuclei of the brain stem were also reported in two cases (Aring and Engel, 1945; Cohen and Solomon, 1955; Brown et al , 1964). Other abnormalities, including thalamic degeneration and brain abscesses were observed in only two cases, but appeared to be secondary to episodes of hypoxia or inflammation (Solitare, 1991).…”

Section: Clinical Aspects and Pathological Findingsmentioning

confidence: 93%

Familial Dysautonomia: Mechanisms and Models

Dietrich

Dragatsis

2016

Genet. Mol. Biol.

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Hereditary Sensory and Autonomic Neuropathies (HSANs) compose a heterogeneous group of genetic disorders characterized by sensory and autonomic dysfunctions. Familial Dysautonomia (FD), also known as HSAN III, is an autosomal recessive disorder that affects 1/3,600 live births in the Ashkenazi Jewish population. The major features of the disease are already present at birth and are attributed to abnormal development and progressive degeneration of the sensory and autonomic nervous systems. Despite clinical interventions, the disease is inevitably fatal. FD is caused by a point mutation in intron 20 of the IKBKAP gene that results in severe reduction in expression of IKAP, its encoded protein. In vitro and in vivo studies have shown that IKAP is involved in multiple intracellular processes, and suggest that failed target innervation and/or impaired neurotrophic retrograde transport are the primary causes of neuronal cell death in FD. However, FD is far more complex, and appears to affect several other organs and systems in addition to the peripheral nervous system. With the recent generation of mouse models that recapitulate the molecular and pathological features of the disease, it is now possible to further investigate the mechanisms underlying different aspects of the disorder, and to test novel therapeutic strategies.

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Familial dysautonomia

Cited by 47 publications

References 9 publications

Brainstem reflexes in patients with familial dysautonomia

Brainstem reflexes in patients with familial dysautonomia

The Familial Dysautonomia disease gene,Ikbkap/Elp1, is required in the developing and adult central nervous system

Familial Dysautonomia: Mechanisms and Models

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