To evaluate potential biomarkers of disease progression in patients with atypical Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) disease currently undergoing enzyme replacement therapy (ERT) with a recombinant human tripeptidyl peptidase 1 (TPP1) protein.

CLN2 is a rare, inherited infantile neurodegenerative lysosomal storage disorder (LSD) caused by deficiency in TPP1. Atypical cases present in adolescence with seizures, language abnormalities, and behavioral disorders. ERT has shown promise in slowing disease progression, but biomarkers are needed to monitor treatment effects. Candidate biomarkers analyzed included subunit c of mitochondrial ATP synthase (SCMAS), a lysosomal substrate that accumulates in LSDs, and lysosomal-associated membrane glycoprotein 1 (LAMP1), a biomarker of neurodegeneration in related LSDs.

Relative CSF levels of LAMP1 and SCMAS of five atypical CLN2 disease patients were assessed at multiple time points using western blot. Western blot images were analyzed using FIJI image software. Retrospective chart review was conducted and CLN2 Clinical Rating Scale Motor-Language (ML) Domain scores were abstracted. 

SCMAS decreased over time with ERT. LAMP1 increases within the first two years of ERT initiation (Paired T test of first two timepoints P=0.0002, mixed effects analysis P=0.0004). Earlier ERT in sibling pairs stabilized motor and language CLN2 scores and slowed disease progression. 

Atypical CLN2 ERT patients are surpassing the average life expectancy of untreated patients, creating a need to identify biomarkers. SCMAS and LAMP1 may, in combination with thorough clinical evaluation and appropriate scoring systems, be helpful biomarkers to trend disease progression. Language and motor scores expand our understanding of ERT effects on clinical disease progression, specifically within sibling pairs.