Enzyme replacement therapy for CLN2 disease

BACKGROUND AND PURPOSE: Neuronal ceroid lipofuscinoses (NCL) are a group of neurodegenerative disorders. Recently, enzyme replacement therapy (ERT) was approved for CLN2, a subtype of NCL. The aim of this study was to quantify brain volume loss in CLN2 disease of patients on ERT in comparison to a natural history cohort using magnetic resonance imaging (MRI).

MATERIALS AND METHODS: Nineteen (13 female, 6 male) patients with CLN2 disease at one UK center were studied using serial 3D T1-weighted MRI (follow-up time, 1 to 9 years). Brain segmentation was done using FreeSurfer. Volume measurements for supratentorial grey and white matter, deep grey matter (basal ganglia/thalami), lateral ventricles, and cerebellar grey and white matter were recorded. The volume change over time was analyzed using a linear mixed-effects model excluding scans before treatment start. Comparison was made to a published natural history cohort of 12 patients (8 female, 4 male) which was reanalyzed using the same method.

RESULTS: Brain volume loss of all segmented brain regions was much slower in treated patients compared to the natural history cohort. For example, supratentorial grey matter volume in treated patients decreased by 3±0.74% (p<0.001) annually compared to an annual volume loss of 16.8±1.5% (p<0.001) in the natural history cohort.

CONCLUSIONS: Our treatment cohort showed a significantly slower rate of brain parenchymal volume loss compared to a natural history cohort in several anatomical regions. Our results complement prior clinical data which found a positive response to ERT. We demonstrate that automated MRI volumetry is a sensitive tool to monitor treatment response in children with CLN2 disease.

ABBREVIATIONS: NCL = Neuronal Ceroid Lipofuscinosis, CLN2 = Neuronal Ceroid Lipofuscinosis type 2, TPP1 = tripeptidyl peptidase 1, ERT = enzyme replacement therapy, EMA = European Medicines Agency, ICV = intra-cerebro-ventricular reservoir.