👤 Norihisa Monji

Neuronal ceroid lipofuscinosis (NCL) is a heterogeneous group of lysosomal disorders characterized by progressive psychomotor regression, visual impairment, and intractable seizures. Genetically, NCL type 3 (CLN3) is associated with variants in the gene encoding a lysosomal transmembrane protein. To date, few Japanese patients with CLN3 have been reported. Thus, their neurodevelopmental and clinical features remain unclear. Here, we report the clinical course of a genetically confirmed Japanese patient with CLN3. A 17-year-old Japanese boy was diagnosed with retinitis pigmentosa at age 7. Visual impairment progressed over a 10-year follow-up period. Generalized tonic-clonic seizures also began at age 7. Developmental regression was recognized at age 13, with an accelerated decline in motor and communication skills following a COVID-19 infection at age 17. Tube feeding and gastrostomy were initiated for dysphagia and recurrent respiratory infections. Serial MRI revealed progressive cerebral and cerebellar atrophy. Lymphopenia (351-1467/μL) was present from age 9; peripheral blood smear revealed vacuolated lymphocytes. Exome sequencing identified a heterozygous CLN3 variant, NM₀₀₁₀₄₂₄₃₂.2:c.295-2A > C. SpliceAI suggested exon 6 skipping and/or an 80-bp deletion, leading to nonsense-mediated mRNA decay. Manual inspection using Integrated Genomic Viewer revealed a second variant (c.178₁₈₀delinsACATCCTTAGCCACAAGAG) missed initially. Trio Sanger sequencing confirmed compound heterozygosity: NM₀₀₁₀₄₂₄₃₂.2:c.[295-2A > C]; [178₁₈₀delinsACATCCTTAGCCACAAGAG] p.[?]; [His60Thrfs∗10]. A review of 430 genetically confirmed CLN3 patients (1989-2025) identified no hematologic abnormalities. This Japanese CLN3 patient developed visual impairment 7-8 years before systemic deterioration. Retinal degeneration, together with vacuolated peripheral lymphocytes, may provide early diagnostic clues for CLN3 in Japanese patients. Show less