背景:术语先天性眼运动性失用症(COMA),由Cogan于1952年创造,指定无能力启动自愿的眼球运动,执行快速的视线转移,所谓的扫视。虽然被一些作者认为是一个恶学实体,越来越多的证据表明,COMA仅仅是一种具有病因异质性的神经系统症状.2016年,我们报告了一项观察性研究,纳入21例确诊患有COMA的患者。对这21名受试者的神经影像学特征进行彻底的重新评估后,发现其中11名受试者中存在先前未识别的磨牙征(MTS),从而导致Joubert综合征(JBTS)的诊断重新分配。另外两名患者的特定MRI特征表明Poretti-Boltshauser综合征(PTBHS)和肾小管病。在八个病人中,没有获得更精确的诊断.我们进行了该队列研究,旨在澄清每位患者COMA的明确遗传基础。
结果:使用候选基因方法,分子遗传小组或外显子组测序,我们检测到21例COMA患者中17例的致病分子遗传变异.在这11名受试者中,有9名因神经影像学新发现的MTS而被诊断为JBTS,我们在已知与JBTS相关的五个不同基因中发现了致病突变,包括KIAA0586,NPHP1,CC2D2A,MKS1和TMEM67。在两个没有MTSMRI的个体中,在NPHP1和KIAA0586中检测到致病变异,分别诊断为JBTS4型和23型。三名患者在SUFU中携带杂合截断变体,代表新鉴定的JBTS形式的第一个描述。通过检测LAMA1和TUBA1A的致病变异证实了PTBHS和肾小管病的临床诊断,分别。一名MRI正常的患者,ATM的双等位基因致病变异表明变异共济失调毛细血管扩张症。外显子组测序未能揭示其余四名受试者的致病遗传变异,其中两个在MRI上有清晰的MTS。
结论:我们的研究结果表明,在COMA中存在明显的病因异质性,在我们的队列中检测到81%(17/21)的致病突变,9个不同的基因受到影响,主要与JBTS相关的基因。我们提供了COMA的诊断算法。
The term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosological entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational
study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recognized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti-Boltshauser syndrome (PTBHS) and a tubulinopathy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient.
Using a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identified forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causative variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI.
Our findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA.