Familial Dysautonomia

Abstract

Familial dysautonomia (FD, Riley-Day syndrome, hereditary sensory and autonomic neuropathy type III) can be considered a genetic model for understanding how perturbations in the autonomic nervous system and the sensory system can compromise cognition and alter behavior. Even in the original description of FD, the psychological and behavioral aspects of the disorder were attributed to central autonomic dysfunction (Riley et al. 1949). Five children with “central autonomic dysfunction with defective lacrimation” were described as exhibiting “undue reaction to mild anxiety” associated with physical manifestations of excessive sweating and salivation, red blotching of the skin, and transient but marked arterial hypertension. In addition, all the children had “constantly diminished production of tears.” Thus, from its earliest description it was appreciated that FD represented a disorder in which central, as well as peripheral, disturbance of autonomic function was associated with changes in behavior. Familial dysautonomias’ impact on cognitive functioning, however, was not immediately apparent. Although intelligence has been reported to be generally within the normal range (Welton et al. 1979), many patients exhibit delays in social, emotional, and/or cognitive domains, which for some patients is quite extreme. As survival has improved for the FD population (Axelrod et al. 2002), an adult FD population has evolved and progressive degeneration has been appreciated both clinically (Axelrod et al. 1981) and neuropathologically (Pearson, Axelrod, and Dancis 1974). In addition, the progressive nature of the disorder appears to include neuropsychological issues as patients report difficulty concentrating (Welton et al. 1979), depression, anxiety, and even phobias (Clayson, Welton, and Axelrod 1980). Thus, in FD the autonomic and sensory nervous systems appear to play a role in the development of normal cognition and behavior, as well as in sustaining homeostasis of these functions. Familial dysautonomia is a recessive disorder caused by IKBKAP gene mutations with a carrier rate as high as one in 27 in the Ashkenazi Jewish population (Anderson et al. 2001; Slaugenhaupt et al. 2001). Prior to identification of the gene in 2001, diagnosis was based on clinical criteria utilizing the ethnic bias for this disorder, as well as on a constellation of signs attributed to sensory and autonomic dysfunctions (Axelrod 2004; Axelrod 2007).