Clinical, Pathological, and Molecular Findings in a Mexican Patient With Neuronal Ceroid Lipofuscinosis Type 2: Support for Pathogenicity of the c.1226 G>T Variant and for Presence of Cherry-Red Spot in This Disease

Neuronal ceroid lipofuscinosis type 2 (CLN2) results from biallelic pathogenic variants in the <i>TPP1</i> gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase 1. We report an autopsy case of CLN2 characterized at molecular level. The patient exhibited a spectrum of neurologic symptoms including epilepsy, behavioral alterations, cognitive regression, motor impairment, and visual loss. In fundus exam, a cherry-red spot was observed. She died at 7 years old, autopsy demonstrated severe atrophy of the brain and cerebellum with neuronal loss and gliosis. Neurons were distended by autofluorescent ceroid lipofuscin of 2 types: fine granular deposits and coarse round bodies. In addition, electron microscopy study revealed characteristic curvilinear profiles. After autopsy, a germline molecular test was performed that found the c.1226 G>T variant in a homozygous state. This variant has been referenced in a single undetailed report and is classified as of uncertain significance. Our findings support that cherry-red spot can be present in CLN2 and confirm the pathogenicity of the c.1226 G>T variant. Current management of CLN2 includes enzyme replacement that requires early diagnosis, which can be facilitated by clinical delineation of the disease and appropriate classification and public reporting of <i>TPP1</i> variants.