Cerliponase Alfa for the Treatment of Atypical Phenotypes of CLN2 Disease: A Retrospective Case Series

Abstract

Background: The classic phenotype of CLN2 disease (neuronal ceroid lipofuscinosis type 2) typically manifests between ages 2 and 4 years with a predictable clinical course marked by epilepsy, language developmental delay, and rapid psychomotor decline. Atypical phenotypes exhibit variable time of onset, symptomatology, and/or progression. Intracerebroventricular-administered cerliponase alfa (rhTPP1 enzyme) has been shown to stabilize motor and language function loss in patients with classic CLN2 disease, but its impact on individuals with atypical phenotypes has not been described. Methods: A chart review was conducted of 14 patients (8 male, 6 female) with atypical CLN2 phenotypes who received cerliponase alfa. Pre- and posttreatment CLN2 Clinical Rating Scale Motor and Language (ML) domain scores were compared. Results: Median age at first presenting symptom was 5.9 years. First reported symptoms were language abnormalities (6 [43%] patients), seizures (4 [29%]), ataxia/language abnormalities (3 [21%]), and ataxia alone (1 [7%]). Median age at diagnosis was 10.8 years. ML score declined before treatment in 13 (93%) patients. Median age at treatment initiation was 11.7 years; treatment duration ranged from 11 to 58 months. From treatment start, ML score remained stable in 11 patients (treatment duration 11-43 months), improved 1 point in 1 patient after 13 months, and declined 1 point in 2 patients after 15 and 58 months, respectively. There were 13 device-related infections in 8 patients (57%) and 10 hypersensitivity reactions in 6 (43%). Conclusions: Cerliponase alfa is well tolerated and has the potential to stabilize motor and language function in patients with atypical phenotypes of CLN2 disease.

Clinical management and diagnosis of CLN2 disease: consensus of the Brazilian experts group

“…According to a case series with 14 patients with atypical CLN2, ataxia, language regression, seizures, and vision disturbance are the most common clinical manifestation with the progression of the disease. 20 However, only 3% of the South America cohort presented visual impairment in the first year; the mean age for the appearance of this symptom was 11.47 AE 5.04 years old. 13 Cognitive decline was present in 93% of the population of the present study, 7% had it as first symptom and 67% occurred within the 1 st year after the appearance of seizures.…”

Natural History Studies in NCL and Their Expanding Role in Drug Development: Experiences From CLN2 Disease and Relevance for Clinical Trials

“…Many rarer CLN2 genetic variants have been reported whose influence on phenotype and residual TPP1 activity is not well understood; some genetic variants are thought to result in the delayed onset or prolonged course of the disease (15). Atypical CLN2 phenotypes are reported more frequently, with increased ability for genetic testing from different regions in the world (8,10,(15)(16)(17)(18)(19)(20)(21)(22). In Latin America 50% of cases show protracted course of disease with later onset of symptoms and slightly different order of symptom onset (9).…”

Sortilin inhibition treats multiple neurodegenerative lysosomal storage disorders

“…[15][16][17] Only one form of Batten disease, CLN2 disease, has an FDAapproved disease-modifying treatment -an enzyme replacement therapy called cerliponase alfa (Brineura®), which is well-tolerated and stabilizes language and motor abilities but fails to halt gray matter loss in the brain. 18,19 While gene therapy and enzyme replacement therapy offer encouraging results, limitations such as incomplete transduction, patient immune-responses, and bioavailability emphasize an overwhelming need for more effective therapies. 20, 21 4 Small molecule therapeutics have been shown to have some efficacy in LSDs such as Fabry disease, Gaucher disease, and Pompe disease as well as neurogenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease.…”