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  • Updated 02.17.2021
  • Released 05.31.2000
  • Expires For CME 02.17.2024

Familial dysautonomia

Introduction

Overview

Familial dysautonomia is an autosomal recessive hereditary sensory and autonomic neuropathy (HSAN) disorder characterized by both sensory and autonomic dysfunction, resulting in decreased pain and temperature perception as well as pervasive manifestations of autonomic dysregulation. Four unique features associated with this particular HSAN type are absence of overflow emotional tearing, afferent baroreflex failure, hyperadrenergic vomiting crises, and optic neuropathy. In 2001, the familial dysautonomia gene was identified as an inhibitor of kappa light polypeptide gene enhancer in B-cells (IKBKAP). The most common mutation is a missplicing mutation that results in decreased production of IKK complex-associated protein (IKAP) protein. As a result, population screening is feasible, and research is starting to provide an 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 was advanced to human 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 (05; 51). In Riley and colleagues’ original report of familial dysautonomia in 1949, it was described as "central autonomic dysfunction with defective lacrimation” (85). 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 (37). However, now that consistent neuropathology and the specific genetic mutations are known, the disorder is usually termed familial dysautonomia (05; 06; 08).

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