Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients
Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients
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DOI：
10.1093/brain/awp211
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发表时间：
2009-10-01
期刊：
影响因子：
14.5
通讯作者：
Koenig, M.
中科院分区：
文献类型：
--
作者：
Anheim, M.;Monga, B.;Koenig, M.
共济失调伴眼用不能2型（AOA 2）是一种常染色体隐性遗传疾病，由于senataxin基因突变，引起进行性小脑共济失调伴周围神经病变、小脑萎缩、偶发性眼用不能和甲胎蛋白（AFP）血清水平升高。我们收集了67例先前报道的和58例新的共济失调患者，这些患者因疑似AOA 2而接受了senataxin基因测序。来自全球15个国家的90例患者被确诊为AOA 2，发现了25个新的senataxin基因突变，在AOA 2患者中，诊断时AFP血清水平中位数为31.0 μ g/l，高于AOA 2阴性患者的AFP血清水平中位数：13.8 μ g/l，P = 0.0004;本身高于正常水平（3.4 μ g/l，范围为0.5 - 17.2 μ g/l），因为AFP升高是可能的选择标准之一。AOA 2患者中97.5%的患者出现多发性神经病，96%的患者出现小脑萎缩，51%的患者出现偶发性眼用不能，20.5%的患者出现锥体束征，14%的患者出现头震颤，13.5%的患者出现肌张力障碍，12.3%的患者出现斜视，9.5%的患者出现舞蹈病。所有患者均无周围神经病变和小脑萎缩。发病年龄和偶尔出现眼用不能与疾病进展率呈负相关（分别为P = 0.03和P = 0.009），而斜视与疾病进展率呈正相关（P = 0.03）。AFP水平升高以及小脑萎缩似乎在疾病过程中是稳定的，并且大多发生在疾病发作时或之前。诊断时AFP水平正常的两名患者中，一名在4年后AFP水平较高，而另一名则处于临界水平。在仅对AFP水平>= 7 μ g/l的非弗里德赖希共济失调非共济失调-毛细血管扩张共济失调患者进行senataxin基因测序的情况下，AOA 2诊断缺失的概率为0.23%，而AFP水平>= 7 μ g/l的非弗里德赖希共济失调非共济失调-毛细血管扩张共济失调患者受AOA 2影响的概率为46%。因此，选择AFP水平高于7 μ g/l的患者进行senataxin基因测序是AOA 2诊断的良好策略。与解旋酶结构域外的错义突变以及缺失和无义突变相比，senataxin基因解旋酶结构域内的错义突变更频繁出现锥体征和肌张力障碍，且疾病较轻（分别为P = 0.001、P = 0.008和P = 0.01）。大多数患者缺乏锥体束征可能是由于严重的运动神经病造成的掩蔽。
Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 mu g/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 mu g/l, P = 0.0004; itself higher than the normal level (3.4 mu g/l, range from 0.5 to 17.2 mu g/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level >= 7 mu g/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels >= 7 mu g/l is 46%. Therefore, selection of patients with an AFP level above 7 mu g/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.