Familial dysautonomia.

Familial dysautonomia (FD) is an autosomal recessive hereditary sensory and autonomic neuropathy (HSAN, type 3) expressed at birth with profound sensory loss and early death. The FD founder mutation in the ELP1 gene arose within the Ashkenazi Jews in the sixteenth century and is present in 1:30 Jews of European ancestry. The mutation yield a tissue-specific skipping of exon 20 and a loss of function of the elongator-1 protein (ELP1), which is essential for the development and survival of neurons. Patients with FD produce variable amounts of ELP1 in different tissues, with the brain producing mostly mutant transcripts. Patients have excessive blood pressure variability due to the failure of the IXth and Xth cranial nerves to carry baroreceptor signals. Neurogenic dysphagia causes frequent aspiration leading to chronic pulmonary disease. Characteristic hyperadrenergic "autonomic crises" consisting of brisk episodes of severe hypertension, tachycardia, skin blotching, retching, and vomiting occur in all patients. Progressive features of the disease include retinal nerve fiber loss and blindness, and proprioceptive ataxia with severe gait impairment. Chemoreflex failure may explain the high frequency of sudden death in sleep. Although 99.5% of patients are homozygous for the founder mutation, phenotypic severity varies, suggesting that modifier genes impact expression. Medical management is currently symptomatic and preventive. Disease-modifying therapies are close to clinical testing. Endpoints to measure efficacy have been developed, and the ELP1 levels are a good surrogate endpoint for target engagement. Early intervention may be critical for treatment to be successful.