Expanding the genotypic landscape of the neuronal ceroid lipofuscinoses: clinical and molecular findings from a tertiary-care center in Argentina.

PURPOSE: To characterize the clinical, neurophysiological, neuroimaging, and molecular features of pediatric patients with neuronal ceroid lipofuscinoses (NCLs) from a tertiary-care center in Argentina and to expand the genotypic spectrum of NCLs in an underrepresented population.

METHODS: We retrospectively analyzed 19 children with genetically confirmed NCL evaluated between 2000 and 2025. Clinical data, electroencephalographic (EEG), neuroimaging, electroretinographic (ERG), and visual evoked potential (VEP) findings were reviewed. Molecular diagnosis was established using a targeted next-generation sequencing panel, and variants were classified according to ACMG/AMP recommendations.

RESULTS: Mean age at disease onset was 3.7 years. CLN7 disease was the most frequent subtype (36.8%), followed by CLN2 disease (31.6%) and CLN5 disease (10.5%). Neurodevelopmental impairment was the most common presenting feature, followed by seizures and visual deterioration. All patients exhibited progressive neurological decline characterized by developmental regression, increasing seizure burden, cognitive deterioration, and motor impairment. CLN2 disease patients showed a relatively homogeneous late-infantile phenotype, whereas CLN7 disease patients displayed marked phenotypic variability, including infantile-, late-infantile-, and juvenile-onset presentations. EEG recordings demonstrated diffuse background slowing and multifocal epileptiform abnormalities, while no patient exhibited a photoparoxysmal response to low-frequency intermittent photic stimulation. Brain MRI commonly revealed cerebral and/or cerebellar atrophy and white matter abnormalities. Twenty distinct variants were identified, including four novel variants. Recurrent pathogenic variants in MFSD8 and TPP1 were observed in multiple unrelated families.

CONCLUSION: This study expands the molecular and phenotypic spectrum of NCLs and provides one of the largest detailed descriptions of pediatric NCLs from Argentina. The predominance of CLN7 disease contrasts with previous regional and international reports, highlighting potential population-specific genetic characteristics and the importance of generating local epidemiological data. Improved access to genetic testing and greater representation of Latin American populations in international registries are essential to facilitate earlier diagnosis, optimize therapeutic opportunities, and improve care for affected patients.