Familial dysautonomia

Felicia B Axelrod MD (Dr. Axelrod, Co-Director of the Dysautonomia Treatment and Evaluation Center at New York University Langone Medical Center, has no relevant financial relationships to disclose.)
Louis H Weimer MD, editor. (Dr. Weimer of Columbia University has received consulting fees from Roche.)
Originally released May 31, 2000; last updated January 10, 2014; expires January 10, 2017

This article includes discussion of familial dysautonomia, hereditary sensory and autonomic neuropathy type 3, HSAN type 3, and Riley-Day syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Familial dysautonomia is an HSAN disorder characterized by both sensory and autonomic dysfunction, resulting in decreased pain and temperature perception as well as protein perturbations in various organ systems. Four unique features associated with this particular HSAN type are absence of overflow emotional tearing, afferent baroreflex failure, hyperadrenergic vomiting crises, and optic neuropathy. The author of this article has been providing treatment and conducting research that has resulted in decreased morbidity and improved survival. In 2001, the familial dysautonomia gene was identified as IKBKAP. The most common mutation is a missplicing mutation that results in decreased production of IKAP protein. As a result, population screening is feasible, and research is starting to provide understanding of how the genetic error results in the complex phenotype. In addition, efforts are focused on correcting the missplicing defect in IKBKAP and enhancing the production of normal IKAP. Four compounds, tocotrienol, epigallocatechin gallate, phosphatidylserine, and kinetin, have been shown to modify genetic expression in cell culture, but only kinetin is presently being assessed in clinical trials.

Key points

• Mutations in the IKBKAP gene cause familial dysautonomia, and more than 99% of individuals with familial dysautonomia are homozygous for a splicing mutation in intron 20, suggesting there was a founder effect in the Ashkenazi Jewish population.

• Familial dysautonomia mutations lead to tissue-specific reductions in normal IKAP/hELP1 protein, with subsequent downregulation of genes involved in neurogenic differentiation and migration of neural crest cells that eventually impacts the sensory and sympathetic systems.

• Sensory perturbations include decreased pain and temperature perception, but sensitivity to visceral pain is intact.

• The autonomic disturbances are pervasive and impose the greatest impediments to function and survival.

• Four unique features associated with this particular HSAN type are absence of overflow emotional tearing, afferent baroreflex failure, hyperadrenergic vomiting crises, and optic neuropathy.

• Although the gene has been identified and there are early reports of agents that may be able to modify genetic expression in cell culture, the mainstay of treatment remains preventative and supportive.

Historical note and terminology

Familial dysautonomia is the most extensively described of the group of disorders known as hereditary sensory and autonomic neuropathies, which are generally characterized by widespread sensory dysfunction and variable autonomic dysfunction (Axelrod 2002; Hilz 2002). In Riley and colleagues' original report of familial dysautonomia in 1949, it was described as "central autonomic dysfunction with defective lacrimation” (Riley et al 1949). In acknowledgment of this original report, the eponym “Riley-Day syndrome” was commonly employed. When numerical classification was suggested, familial dysautonomia was designated as HSAN type 3 (Dyck 1966). However, now that consistent neuropathology and the specific genetic mutations are known, the disorder is usually termed familial dysautonomia (Axelrod 2002; Axelrod 2004; Axelrod 2006).

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