Genetic spectrum of neuronal ceroid lipofuscinosis & its genotype-phenotype correlation -A single centre experience of 56 cases.

Abstract

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.