Late infantile neuronal ceroid lipofuscinosis type 6 (CLN6) in Three Children from El salvador: a case series

Rationale Neuronal Ceroid Lipofuscinosis (NCL) is a group of rare, genetic, neurodegenerative disorders with fatal outcomes. Disease-causing variants occur in more than a dozen genes and produce distinct ages of onset and clinical courses. CLN6-related disease typically presents in the late-infantile period with motor regression, cognitive decline, progressive visual impairment, and drug-resistant epilepsy. We describe a case series of three children with genetically confirmed CLN6 disease from the Department of Morazán, El Salvador. Methods We retrospectively reviewed the clinical histories, examinations, EEGs, and brain MRIs of three patients (two brothers and one unrelated girl) from the Department of Morazán, El Salvador, evaluated jointly by child neurologists from the United States and El Salvador. Clinical data collected included age and character of disease onset, seizure semiology and treatment response, and ophthalmological findings. Diagnosis was suspected clinically and confirmed by next-generation sequencing (NGS) gene-panel testing (Invitae Epilepsy Panel, Invitae Corporation); there was no copy-number/deletion-duplication analysis included. Parental segregation testing was offered but could not be completed due to cost; segregation of the variant with disease was therefore not confirmed. Results Three patients were diagnosed with CLN6. All patients live in the Department of Morazan, located in the northeastern part of El Salvador (close to Honduras). All three patients had normal development, until the onset of unrelenting motor regression. The boys had an onset of symptoms at the age of 4 years and the girl at age of 5 years. This was followed by cognitive regression, progressive visual impairment, and the onset of drug-resistant epilepsy (DRE) 1 year after onset of symptoms. Initial MRI of the brain of one out of three patients was reviewed and reported as normal, and two out of three already showed cerebral atrophy. EEGs showed a slow background with fragmented and generalized spike wave discharges, and photoparoxysmal responses were present in all patients. Individual clinical, EEG, MRI, and genetic findings are summarized in Table 1. Genetic testing identified the same homozygous CLN6 missense variant, NM_017882.3:c.368G>A (p.Gly123Asp), in all three patients; American College of Medical Genetics and Genomics (ACMG) classification as likely pathogenic. Conclusion These three cases add clinical and molecular data on late-infantile CLN6 disease from a previously undocumented region of Central America. Based on a structured literature search, these appear to be the first molecularly confirmed cases of CLN6 disease reported from El Salvador; this cannot be considered a definitive claim given the possibility of undiagnosed or unpublished cases. Given the small sample size and the inclusion of two siblings, these findings cannot establish disease prevalence or a founder effect in this population; this remains a hypothesis for future investigation.