Thuppanattumadam Ananthasubramanian Sangeeth, Padmanabha Hansashree, Ravindranadh C M, Kenchiah Raghavendra, Bhatia Saloni, Santhoshkumar Rashmi, Kumar Tumulu Seetam, Sukrutha Ramya, Arunachal Gautham, Karthik K, Nagappa Madhu, Nashi Saraswati, Mahale Rohan, Viswananthan L G, Pooja M, Nagaraj A R, Ravi Shekar J, Yasha T C, Mahadevan Anita, Sinha Sanjib
Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India.
Department of Human Genetics, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India.
J Neurol Sci. 2025 Jan 15;468:123338. doi: 10.1016/j.jns.2024.123338. Epub 2024 Dec 9.
Neuronal ceroid lipofuscinoses (NCLs) are progressive, autosomal recessive lysosomal storage disorders primarily affecting children, marked by seizures, cognitive decline, motor regression, and visual impairment. Limited genetic data exist for South Asian populations, with most studies relying on enzymatic assays or electron microscopy. This study explores the genetic spectrum of NCL and genotype-phenotype correlations in a cohort from South India.
A retrospective analysis was conducted on 56 genetically confirmed NCL patients diagnosed between January 2018 and June 2024 at a specialized neurological center in South India. Genetic analysis using next-generation sequencing (NGS) were performed, with variants classified as per ACMG guidelines. Clinical, electroencephalographic (EEG), imaging, and electron microscopy (EM) findings were reviewed, and genotype-phenotype correlations were analyzed.
The cohort (33 males, 23 females) had a median age of onset of 36 months and a median disease duration of 65.5 months. Eight genetic subtypes were identified, with predominant mutations in TPP1 (19.64%), CLN6, MFSD8, and CLN8 (16.07% each). Seizures (75%), regression of milestones (87.5%), visual impairment (33.9%), and ataxia (57.1%) were common. EEG abnormalities were found in 76.3%, MRI revealed cerebellar atrophy in 89.13%, and thalamic T2 hypo-intensity in 91.3%. EM showed curvilinear and fingerprint profiles. Of the identified variants, 31 were previously reported, while 29 were novel.
This is the largest single-center NCL cohort in South Asia, highlighting a diverse genetic spectrum and significant novel variants, underscoring the importance of genetic testing for diagnosis and future therapies.
神经元蜡样脂褐质沉积症（NCLs）是一种进行性常染色体隐性溶酶体贮积症，主要影响儿童，其特征为癫痫发作、认知衰退、运动功能倒退和视力损害。关于南亚人群的遗传数据有限，大多数研究依赖酶分析或电子显微镜检查。本研究探讨了印度南部一个队列中NCL的遗传谱及基因型-表型相关性。
对2018年1月至2024年6月期间在印度南部一家专业神经中心确诊的56例经基因确诊的NCL患者进行回顾性分析。采用下一代测序（NGS）进行基因分析，并根据美国医学遗传学与基因组学学会（ACMG）指南对变异进行分类。对临床、脑电图（EEG）、影像学和电子显微镜（EM）检查结果进行回顾，并分析基因型-表型相关性。
该队列（33名男性，23名女性）的中位发病年龄为36个月，中位病程为65.5个月。共鉴定出8种遗传亚型，主要突变发生在TPP1（19.64%）、CLN6、MFSD8和CLN8（各16.07%）。癫痫发作（75%）、发育里程碑倒退（87.5%）、视力损害（33.9%）和共济失调（57.1%）较为常见。76.3%的患者脑电图异常，89.13%的患者MRI显示小脑萎缩，91.3%的患者丘脑T2低信号。EM显示出曲线形和指纹样形态。在鉴定出的变异中，31个此前已有报道，29个为新变异。
这是南亚最大的单中心NCL队列，突出了多样的遗传谱和大量新变异，强调了基因检测对诊断和未来治疗的重要性。
