Abstract：
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.
摘要：
家族性自主神经障碍（FD）是一种常染色体隐性遗传性感觉和自主神经病变（HSAN，3型）在出生时表现为严重的感觉丧失和早期死亡。ELP1基因的FD创始人突变出现在16世纪的德系犹太人中，并存在于欧洲血统的1:30犹太人中。突变产生外显子20的组织特异性跳跃和延伸因子1蛋白（ELP1）的功能丧失，这对神经元的发育和存活至关重要。FD患者在不同组织中产生不同数量的ELP1，大脑主要产生突变的转录本。由于IXth和Xth颅神经未能携带压力感受器信号，患者的血压变异性过大。神经性吞咽困难引起频繁的误吸,导致慢性肺病。特征性高肾上腺素能“自主神经危机”，包括严重高血压的快速发作，心动过速,皮肤斑点,干涩,所有患者都会出现呕吐。该疾病的进展特征包括视网膜神经纤维丢失和失明，和本体性共济失调伴严重步态障碍。化学反射失败可以解释睡眠中猝死的高频率。尽管99.5％的患者是创始人突变的纯合子，表型严重程度各不相同，表明修饰基因影响表达。医疗管理目前是对症和预防性的。疾病改善疗法接近临床试验。已经开发了衡量疗效的终点，ELP1水平是目标参与的良好替代终点。早期干预可能是治疗成功的关键。
