Chicago Center for Jewish Genetics Disorders - Ashkenazi Disorders: Familial Dysautonomia

Ashkenazi Disorders: Mendelian

Gene: The gene causing familial dysautonomia is IKBKAP, which is located at 9q31. This encodes a protein involved in the development and maintenance of the sensory and autonomic nervous systems.

Mutations and testing: Two mutations have been seen in all of the cases of familial dysautonomia tested for at this time. The major mutation is IVS2+6T-C and it accounts for more than 99.5% of mutant alleles seen thus far. This mutation creates an alternative splice site in the message RNA, resulting in varying levels of wild-type message expressed in a tissue-specific manner, with the deleted message seen only in the brain. In other words, the major mutation doesn't cause complete inactivation of the IKBKAP protein in all tissues of the body, only in the brain. The other mutation, the so-called "minor mutation," is R696P. As of 2007, only four patients have been reported to have the minor mutation. Each of these patients is a compound heterozygote for the major mutation and the minor mutation. No homozygotes for the minor mutation have been identified.

Traits: Familial dysautonomia (FD) is associated with poor development, progressive degeneration of the sensory and autonomic nervous system, and high mortality rate. Marked and progressive depletion of unmyelinated sensory and autonomic neurons has been seen in patients with FD, and is believed to start early in fetal life. FD is clinically characterized by seven main features: absence of fungiform papillae on tongue, absence of flare after injection of intradermal histamine, hypotonia in infancy, decreased or absent deep-tendon reflexes, absence of overflow emotional tears (alacrima), pupillary hypersensitivity, and Ashkenazi Jewish heritage. Other common characteristics include: gastrointestinal dysfunction, such as reflux and vomiting; abnormal respiratory responses to low levels of oxygen and high levels of carbon dioxide in the blood; scoliosis; poor coordination; sensory impairment with regard to pain, heat, and cold; inappropriate sweating and lack of temperature control; and postural hypotension. At this time only 60% of patients live to 20 years of age, due to cardiovascular, pulmonary, and gastrointestinal problems.

Treatment: Treatment is supportive only. Artificial tears can be helpful, as well as medications to help control abnormal blood pressure, nausea, and vomiting.

Other: As of August 2004, the American College of Obstetrics and Gynecology considers FD carrier screening to be standard of care for Ashkenazi Jewish couples. It should be offered to all persons of Ashkenazi Jewish descent who are pregnant or planning a pregnancy.

Familial Dysautonomia from Geneclinics.org
http://www.genetests.org/profiles/fd

Reviewed by Joel Charrow, MD, Head, Division of Genetics, Birth Defects and Metabolism, Children’s Memorial Hospital, 8/07.

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This page last updated on September 7, 2007.