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

Abstract

Neuronal ceroid lipofuscinosis type 2 (CLN2) results from biallelic pathogenic variants in the TPP1 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 TPP1 variants.