Familial Dysautonomia: Mechanisms and Models

Abstract

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.

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

“…T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1)(2)(3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells.…”

“…The latter loss may ultimately lead to blindness (4,5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3,6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3,6).…”

“…More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3,6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3,6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7).…”

Animal and cellular models of familial dysautonomia

“…Familial dysautonomia (FD; OMIM 223900; also called Riley-Day Syndrome) is classified as one of the hereditary sensory and autonomic neuropathies (HSAN Type III) and afflicts Jews of eastern European, Ashkenazi, descent; 1:18 – 1:32 Ashkenazi Jews are carriers of the mutant haplotype [1, 2]. Its hallmark features are the consequence of a depletion of sensory and autonomic neurons, which manifests as reduced pain and temperature sensation, cardiovascular instability, gastrointestinal incoordination, respiratory dysfunction and frequent autonomic “crises” marked by vomiting, nausea, hypertension, tachycardia, and blotching – the consequences of unrestrained release of catecholamines in plasma [1, 3, 4].…”

“…Its hallmark features are the consequence of a depletion of sensory and autonomic neurons, which manifests as reduced pain and temperature sensation, cardiovascular instability, gastrointestinal incoordination, respiratory dysfunction and frequent autonomic “crises” marked by vomiting, nausea, hypertension, tachycardia, and blotching – the consequences of unrestrained release of catecholamines in plasma [1, 3, 4]. With close supervision, now more than 50% of patients can reach age 30 [4] with the most common cause of death being sudden death during sleep.…”