Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran.
Department of Pediatrics Center, Growth and Development Research Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.
Cerebellum. 2023 Aug;22(4):640-650. doi: 10.1007/s12311-022-01430-3. Epub 2022 Jun 22.
Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.
常染色体隐性痉挛性共济失调型夏格诺（ARSACS）现在在世界各国都越来越被发现，可能是最常见的常染色体隐性共济失调之一。在这里，我们从 2019 年 5 月至 2021 年 5 月招募的 137 名早发性共济失调患者的大型队列中选择了携带 SACS 变异体（ARSACS 的致病基因）的患者，并将其转介至共济失调诊所。对 137 名患者中的 111 名（81%）进行了基因研究，得出的诊断率为 72.9%（81 例）。确定了 10 例 ARSACS 的分子诊断患者。我们研究了所有确诊 ARSACS 患者的表型和影像学谱。我们还估计了该队列中 ARSACS 的频率，并描述了他们的临床和遗传发现，包括七个新变异体以及新的神经影像学发现。虽然 ARSACS 的经典临床三联征是进行性小脑共济失调、痉挛和感觉运动性多神经病，但并非所有患者都有此特征。我们所有患者均检测到感觉运动轴索性脱髓鞘神经病，但 50%（5/10）的患者无痉挛和伸性跖反射。在所有患者中，脑磁共振成像（MRI）显示桥脑（桥脑条纹）和前上小脑萎缩的对称性线性低信号以及丘脑周围高信号环（丘脑环）。尽管先前有报道称 ARSACS 存在颅后窝蛛网膜囊肿，但我们首次报告了两名患者的前颞部蛛网膜囊肿，表明蛛网膜囊肿可能是 ARSACS 的一种相关影像学特征。我们还通过呈现 8 种致病性和 1 种意义不明的变异体（VUS）序列变异体，扩展了 ARSACS 的分子谱，其中 7 种以前没有报道过。MetaDome 服务器证实，所识别的 VUS 变异体位于 SACS 编码的 sacsin 蛋白的不耐受区域内。
