Presymptomatic treatment of classic late-infantile neuronal ceroid lipofuscinosis with cerliponase alfa

J Schaefers,M H G Dremmen,L J Van Der Giessen,H H Huidekoper,S Sieverdink,E H Jacobs,J M P Van Den Hout,A T Van Der Ploeg,C Klees,J K H Spoor

doi:10.1186/s13023-021-01858-6

Abstract

BackgroundNeuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare rapidly progressive neurodegenerative disorder, resulting in early death. Intracerebroventricular enzyme replacement therapy (ERT) with cerliponase alfa is now available and has shown to delay disease progression in symptomatic patients. It is yet unknown if cerliponase alfa can prevent disease onset in presymptomatic patients.ResultsWe evaluated the effect of 2 years of intracerebroventricular ERT in two siblings with CLN2 disease, one symptomatic (age 47 months) and one presymptomatic (age 23 months) at treatment start, using the CLN2 Clinical Rating Scale (CLN2 CRS), Gross Motor Function Measure-66 (GMFM-66) for motor function, Bayley Scales of Infant and Toddler Development, 3rd Edition, Dutch (BSID-III-NL) for neurocognitive development, brain MRI, and visual evoked potentials (VEP), electroretinogram (ERG) and retinoscopy for visual function. On the CLN2 CRS patient 1 showed a decline from 3 to 2 in the combined motor and language score due to regression in language use (CLN2 CRS total score after 2 years of treatment: 8), whereas a decline of 2 or more points in the combined motor and language score would be expected without treatment. Patient 2 retained the maximum score of 3 in all 4 subdomains (CLN2 CRS total score after 2 years of treatment: 12). The GMFM-66 total score declined from 46 to 39 in patient 1 and showed an age-appropriate increase from 66 to 84 in patient 2. Cognitive-developmental age decreased from 24 to 11 months in patient 1, whereas an increase in cognitive-developmental age from 21 to 39 months was seen in patient 2. Cerebral and cerebellar atrophy observed on MRI in patient 1 at age 42 months (before treatment) was not observed in patient 2 at age 48 months (after 2 years of treatment).ConclusionWe show that cerliponase alfa is able to delay the onset of symptoms when treatment is started in a presymptomatic stage of CLN2 disease. Our results advocate the start of treatment at an early age before symptom onset, but should be confirmed in a larger cohort study.

Highlights

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare rapidly progressive neurodegenerative disorder, resulting in early death
We evaluated treatment outcome after 2 years of treatment with cerliponase alfa in two siblings with CLN2 disease, both heterozygous for the two most common pathogenic Tripeptidyl peptidase (TPP1) variants and with the same environmental factors, and found cerliponase alfa to be effective in slowing down disease progression, and in extending the presymptomatic phase of the disease
This is why the CLN2 CLN2 clinical rating scale (CRS) combined motor and language score was chosen as the primary outcome measure over the CLN2 CRS total score in the pivotal trial [15], since cerliponase alfa is less likely to influence seizure control, as seizures result from existing neurological damage, or affect loss of vision as the retina will not be reached with intracerebroventricular administration

Summary

Introduction

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare rapidly progressive neurodegenerative disorder, resulting in early death. Intracerebroventricular enzyme replacement therapy (ERT) with cerliponase alfa is available and has shown to delay disease progression in symptomatic patients. It is yet unknown if cerliponase alfa can prevent disease onset in presymptomatic patients. Neuronal ceroid lipofuscinosis type 2 (CLN2 disease; OMIM#204500) is an autosomal recessive disease, caused by deficiency of the lysosomal enzyme tripeptidyl peptidase (TPP1; EC 3.4.14.9) [1, 2]. In the classic late-infantile form of CLN2 disease this results in a rapidly progressive neurodegenerative disorder with a highly homogeneous course of disease. Progression and onset of disease is largely homogeneous and predictable for several genotypes [10,11,12]

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