Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Medicale (INSERM)-U964, Centre National de la Recherche Scientifique (CNRS)-Unité Mixte de Recherché (UMR) 7104, Université de Strasbourg, Illkirch, France.
JAMA Neurol. 2018 Apr 1;75(4):495-502. doi: 10.1001/jamaneurol.2017.4373.
Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels.
To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016.
The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations.
The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001).
The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.
重要性：眼动性运动不能伴共济失调 1 型（AOA1）是一种常染色体隐性小脑共济失调，由 aprataxin 基因（APTX）的突变引起，其特征为早发性小脑共济失调、眼动性运动不能、轴索性运动神经病和最终白蛋白血清水平下降。
目的：提高 AOA1 的临床、生物标志物和分子描绘能力，并提供基因型-表型相关性。
设计、地点和参与者：本回顾性分析纳入了 2002 年 1 月 1 日至 2014 年 12 月 31 日期间在一个单一遗传学实验室连续诊断为 AOA1 的所有患者的临床、生物学（特别是疾病的生物标志物）、电生理、影像学和分子数据。数据分析于 2015 年 1 月 1 日至 2016 年 1 月 31 日进行。
主要结局和测量：AOA1 的临床、生物学和分子谱以及基因型-表型相关性。
结果：在 51 个家族中，确认了 80 名患者（46 名男性[58%]和 34 名女性[42%]；发病年龄的平均值[标准差]，7.7[7.4]岁）患有 AOA1，包括 57 名新患者（8 名新突变）和 23 名先前描述过的患者。33 名患者（41%）存在甲胎蛋白（AFP）升高；50 名（63%）患者存在低白蛋白血症。AOA1 患者的中位 AFP 水平（6.0ng/mL；范围，1.1-17.0ng/mL）高于无共济失调患者（3.4ng/mL；范围，0.8-17.2ng/mL；P<.01）。白蛋白水平降低（ρ=-0.532）和 AFP 水平升高（ρ=0.637）与疾病持续时间相关。最初报道局限于葡萄牙创始人单倍型的 p.Trp279*突变，在 53 名 AOA1（66%）患者中被发现，这些患者的种族来源广泛。49 名患者（61%）存在眼动性运动不能；74 名（93%）患者存在多发性神经病；78 名（98%）患者存在小脑萎缩。眼动性运动不能与共济失调的严重程度和突变类型相关，与缺失或截断突变（83%）相比，存在至少 1 个错义变异的患者更常见（17%；P<.01）。至少存在 1 个错义突变的患者发病年龄较高（17.7[11.4]比 5.2[2.6]岁；P<.001）。
结论和相关性：在相当一部分患者中，AFP 水平略有升高，可能成为 AOA1 的新生物标志物。眼动性运动不能可能是 AOA1 的一种可选表现，与更严重的疾病相关。p.Trp279*突变是白人人群中最常见的 APTX 突变。APTX 错义突变可能与较轻的表型相关。
