Abstract：
BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), classically presenting as a triad of early-onset cerebellar ataxia, lower extremity spasticity and peripheral neuropathy, is caused by mutations in SACS gene which encodes the protein sacsin.
OBJECTIVE: To provide new insight into the occurrence of SACS mutations in South India.
METHODS: Patients with three cardinal features of ARSACS-peripheral neuropathy, cerebellar ataxia, and pyramidal tract signs were included. Nine patients were clinically identified and genetically evaluated. Mutation screening of SACS by targeted sequencing of 40 recessive ataxia genes panel by next-generation sequencing was conducted. Additional investigations included magnetic resonance imaging (MRI), fundoscopy, optical coherence tomography (OCT) and nerve conduction studies (NCS). Functional disability was assessed by the Spinocerebellar Degeneration Functional Score.
RESULTS: Two hundred and fifteen cerebellar ataxia patients were screened, and 9 patients with cerebellar ataxia with spasticity, peripheral neuropathy and MRI brain characteristics, consistent with a clinical diagnosis of ARSACS were identified, of which 7 patients were identified to have mutation in the SACS gene and are detailed hereafter. Age of presentation ranged from 20 to 55 years (29.8 ± 11.9) with a mean disease duration of 12.7 years (SD-7.65, range 5-22 years). All except one had onset of symptoms in the form of an ataxic gait noticed before 20 years of age. Additional features were subnormal intelligence (4/7), slow and hypometric saccades (1/7), seizures (1/7), kyphoscoliosis (1/7) and dysmorphic facies (1/7). SDFS was 3 in 5/7 patients signifying moderate disability with independent ambulation. MRI showed cerebellar atrophy with predominant atrophy of the superior vermis (7/7), horizontal linear T2 hypointensities in the pons(7/7), hyperintensities where lateral pons merges with the middle cerebellar peduncle (MCP) (7/7) well seen in fluid-attenuated inversion recovery (FLAIR) images, thickening of MCP (3/7), symmetric lateral thalamic hyperintensities (6/7), posterior fossa arachnoid cyst (4/7),thinning of posterior mid-body of corpus callosum (7/7), marginal mineralisation of the basal ganglia (7/7), bilateral parietal atrophy (7/7) and thinning of corticospinal tract on diffusion tensor imaging (DTI) (7/7). We identified pathogenic homozygous frameshift mutations in the SACS gene in six patients (including two siblings), while one patient had a heterozygous pathogenic deletion.
CONCLUSIONS: This is the largest series of genetically confirmed ARSACS patients from India highlighting the clinical, ophthalmological, imaging and genetic features of this cohort.
OBJECTIVE: To provide new insight into the occurrence of SACS mutations in South India.
METHODS: Patients with three cardinal features of ARSACS-peripheral neuropathy, cerebellar ataxia, and pyramidal tract signs were included. Nine patients were clinically identified and genetically evaluated. Mutation screening of SACS by targeted sequencing of 40 recessive ataxia genes panel by next-generation sequencing was conducted. Additional investigations included magnetic resonance imaging (MRI), fundoscopy, optical coherence tomography (OCT) and nerve conduction studies (NCS). Functional disability was assessed by the Spinocerebellar Degeneration Functional Score.
RESULTS: Two hundred and fifteen cerebellar ataxia patients were screened, and 9 patients with cerebellar ataxia with spasticity, peripheral neuropathy and MRI brain characteristics, consistent with a clinical diagnosis of ARSACS were identified, of which 7 patients were identified to have mutation in the SACS gene and are detailed hereafter. Age of presentation ranged from 20 to 55 years (29.8 ± 11.9) with a mean disease duration of 12.7 years (SD-7.65, range 5-22 years). All except one had onset of symptoms in the form of an ataxic gait noticed before 20 years of age. Additional features were subnormal intelligence (4/7), slow and hypometric saccades (1/7), seizures (1/7), kyphoscoliosis (1/7) and dysmorphic facies (1/7). SDFS was 3 in 5/7 patients signifying moderate disability with independent ambulation. MRI showed cerebellar atrophy with predominant atrophy of the superior vermis (7/7), horizontal linear T2 hypointensities in the pons(7/7), hyperintensities where lateral pons merges with the middle cerebellar peduncle (MCP) (7/7) well seen in fluid-attenuated inversion recovery (FLAIR) images, thickening of MCP (3/7), symmetric lateral thalamic hyperintensities (6/7), posterior fossa arachnoid cyst (4/7),thinning of posterior mid-body of corpus callosum (7/7), marginal mineralisation of the basal ganglia (7/7), bilateral parietal atrophy (7/7) and thinning of corticospinal tract on diffusion tensor imaging (DTI) (7/7). We identified pathogenic homozygous frameshift mutations in the SACS gene in six patients (including two siblings), while one patient had a heterozygous pathogenic deletion.
CONCLUSIONS: This is the largest series of genetically confirmed ARSACS patients from India highlighting the clinical, ophthalmological, imaging and genetic features of this cohort.
摘要：
背景：Charlevoix-Saguenay常染色体隐性遗传性痉挛性共济失调（ARSACS），典型地表现为早发性小脑共济失调的三联征，下肢痉挛和周围神经病变，是由编码蛋白sacsin的SACS基因突变引起的。
目的：为印度南部SACS突变的发生提供新的见解。
方法：具有ARSACS-周围神经病变三种主要特征的患者，小脑共济失调,包括锥体束体征。对9名患者进行了临床鉴定和遗传评估。通过下一代测序对40个隐性共济失调基因组进行靶向测序对SACS进行突变筛选。其他研究包括磁共振成像（MRI），眼底镜检查,光学相干断层扫描（OCT）和神经传导研究（NCS）。通过脊髓小脑变性功能评分评估功能障碍。
结果：筛查了两百十五名小脑共济失调患者，和9例小脑共济失调伴痉挛的患者，周围神经病和MRI脑特征，与ARSACS的临床诊断一致，其中7例患者被鉴定为SACS基因突变，并在下文详述。就诊年龄为20至55岁（29.8±11.9），平均病程为12.7年（SD-7.65，范围5-22年）。除一名患者外，所有患者均在20岁之前以共济失调步态形式出现症状。其他特征是智力低于正常(4/7)，缓慢和高测量扫视（1/7），癫痫发作（1/7），脊柱侧后凸（1/7）和异形相（1/7）。SDFS为5/7例患者中的3例，表示中度残疾并独立行走。MRI显示小脑萎缩，占优势的是上疣萎缩（7/7），脑桥中的水平线性T2低张力(7/7)，在流体衰减的反转恢复（FLAIR）图像中可见的外侧脑桥与小脑中梗（MCP）（7/7）合并的高强度，MCP增厚（3/7），对称外侧丘脑高强度（6/7），后颅窝蛛网膜囊肿（4/7），call体后部中体变薄（7/7），基底神经节的边缘矿化（7/7），在弥散张量成像（DTI）（7/7）上，双侧顶叶萎缩（7/7）和皮质脊髓束变薄。我们在6名患者（包括2名兄弟姐妹）中发现了SACS基因的致病性纯合移码突变，而一名患者有杂合子致病基因缺失。
结论：这是来自印度的最大的一系列经基因证实的ARSACS患者，眼科,该队列的影像学和遗传特征。
目的：为印度南部SACS突变的发生提供新的见解。
方法：具有ARSACS-周围神经病变三种主要特征的患者，小脑共济失调,包括锥体束体征。对9名患者进行了临床鉴定和遗传评估。通过下一代测序对40个隐性共济失调基因组进行靶向测序对SACS进行突变筛选。其他研究包括磁共振成像（MRI），眼底镜检查,光学相干断层扫描（OCT）和神经传导研究（NCS）。通过脊髓小脑变性功能评分评估功能障碍。
结果：筛查了两百十五名小脑共济失调患者，和9例小脑共济失调伴痉挛的患者，周围神经病和MRI脑特征，与ARSACS的临床诊断一致，其中7例患者被鉴定为SACS基因突变，并在下文详述。就诊年龄为20至55岁（29.8±11.9），平均病程为12.7年（SD-7.65，范围5-22年）。除一名患者外，所有患者均在20岁之前以共济失调步态形式出现症状。其他特征是智力低于正常(4/7)，缓慢和高测量扫视（1/7），癫痫发作（1/7），脊柱侧后凸（1/7）和异形相（1/7）。SDFS为5/7例患者中的3例，表示中度残疾并独立行走。MRI显示小脑萎缩，占优势的是上疣萎缩（7/7），脑桥中的水平线性T2低张力(7/7)，在流体衰减的反转恢复（FLAIR）图像中可见的外侧脑桥与小脑中梗（MCP）（7/7）合并的高强度，MCP增厚（3/7），对称外侧丘脑高强度（6/7），后颅窝蛛网膜囊肿（4/7），call体后部中体变薄（7/7），基底神经节的边缘矿化（7/7），在弥散张量成像（DTI）（7/7）上，双侧顶叶萎缩（7/7）和皮质脊髓束变薄。我们在6名患者（包括2名兄弟姐妹）中发现了SACS基因的致病性纯合移码突变，而一名患者有杂合子致病基因缺失。
结论：这是来自印度的最大的一系列经基因证实的ARSACS患者，眼科,该队列的影像学和遗传特征。
