Ceroid lipofuscinosis type 2 disease: Effective presymptomatic therapy—Oldest case of a presymptomatic enzyme therapy

Abstract

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, lysosomal storage disorder that causes pediatric onset neurodegenerative disease. It is characterized by mutations in the TPP1 gene. Symptoms begin between 2 and 4 years of age with loss of previously acquired motor, cognitive, and language abilities. Cerliponase alfa, a recombinant human TPP1 enzyme, is the only approved therapy. We report the first presymptomatic cerliponase alfa intraventricular treatment in a familial case of CLN2 related to a classical TPP1 variant. Sister 1 presented with motor, cognitive, and language decline and progressive myoclonic epilepsy since the age of 3 years, evolved with severe diffuse encephalopathy, received no specific treatment, and died at 11 years. Sister 2 had a CLN2 presymptomatic diagnosis and has been treated with cerliponase since she was 12 months old. She is now 6 years 8 months and has no CLN2 symptom except one generalized seizure 1 year ago. No serious adverse event has occurred. Repeated Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition standardized index scores are heterogeneous in the extremely low to low average ranges. Mean length of utterances, a global index of sentence complexity, showed a delay, but a gradual improvement. The reported case enhances the major contribution of presymptomatic diagnosis and significant middle‐term treatment benefit for patients with CLN2.

CLINICAL NOTE

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, autosomal recessive lysosomal storage disorder that causes fatal pediatric onset progressive neurodegenerative disease. CLN2 is characterized by mutations in the TPP1 gene leading to a loss of tripeptidyl peptidase‐1 [1]. Symptoms begin insidiously between 2 and 4 years of age with successive loss of previously acquired motor, cognitive, and language abilities, then seizures and progressive myoclonic epilepsy, and vision loss. Cerliponase alfa is a recombinant human TPP1 enzyme and the first approved enzyme replacement therapy. This treatment has resulted in less decline in motor and language function [2, 3]. No child with early (1 year old) presymptomatic treatment has ever been reported in the literature.

We report the first presymptomatic cerliponase alfa intraventricular treatment in a familial case of classical CLN2 related to a homozygous TPP1 variant (c.1094G>A or p.Cys365Tyr, multiple reports for classical pathogenicity in ClinVar).

Sister 1 had no medical history and developed normally until the age of 3 years except for a language delay. She presented progressive ataxia and language regression and epilepsy. At age 4 years, she had a CLN2 Disease Motor‐Language Clinical Rating Scale (CLN2‐CRS‐ML) of 1/6, frequent seizures, and vision loss [4]. The symptoms followed the typical medical course of this disease, and she died at age 11 years.

For sister 2, molecular diagnosis was performed before birth and confirmed by deficient TPP1 activity in the first month of life. An Ommaya ventricular reservoir was implanted when she was 10 months old. Cerliponase intraventricular treatment (Brineura, BioMarin Pharmaceutical, Novato, CA, USA) began at age 12 months, 200 mg for the four first infusions and then 300 mg every 2 weeks for 4 h. Paracetamol and antihistamine drugs were administered 30 min before each infusion. No serious adverse event occurred. She started walking at 14 months of age and had first words at 12 months. At last evaluation, she was 6.5 years old and had been going to school in regular education with a personal human support for 1 year. She has no ataxia and understands and speaks French, with no regression. She has no myoclonus. She had a brief tonic–clonic generalized seizure at 5 and a half years, with a valproic acid treatment since and no recurrence. She has no symptoms as assessed by the maximal CLN2‐CRS‐ML score (6/6) [4]. Results of psychometric evaluation (Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition) are shown in Figure 1 [5]. We show an improvement of 16 points in full‐scale intelligence quotient between 33 months and 72 months (Figure 1a). To assess the productive use of language acquisition, standardized repeated recorded play sessions with a child psychiatrist (L.O.) in an ecological context were assessed. Mean length of utterances in words and in morphemes, a global index of sentence complexity for French, showed a late acquisition but a gradual progression from 33 months until 72 months (Figure 1b) [6]. Until age 6 years, she did not exhibit any sign of retinal dystrophy. Brain magnetic resonance imaging was normal. Electroencephalography (EEG) was normal before the age of 66 months and before the first seizure. Awake and sleep EEG at 6.5 years (under valproic acid treatment) showed age‐related posterior rhythm and physiological figures, but slow waves and spikes in parietotemporal regions, diffuse spike and waves without clinical correlate, and a photoparoxysmal response at flash frequencies of 6–40 Hz but no flash‐per‐flash response at low frequencies [7].

FIGURE 1.

Psychometric results. (a) Mean Length of Utterances scores for words (MLU‐w) and morphemes (MLU‐m) according to age. (b) Results of the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition scale according to age. FRI, Fluid reasoning Index; FSIQ, full‐scale intelligence quotient; NA, not available; PSI, processing speed index; VAI, verbal acquisition index; VCI, verbal comprehension index; VSI, visual spatial index; WMI, working memory index.

In the historical cohort described by Nickel et al. in 140 patients, the most common first symptoms of the disease were seizures (70%) and language difficulty (57%) [8]. The median age at first clinical symptom was 35 months (interquartile range = 24–38.5). The same evolution, with no asymptomatic child at 5 years, is reported in a large observational study of the natural history (DEM‐CHILD registry) [1, 7]. Finally, at the same age of 6 years, comparison between the two sisters shows a CLN2‐CRS‐ML of 1/6 for sister 1 and 6/6 for treated sister 2.

Neuropsychological tests results suggested borderline cognitive impairment for language, visual–spatial skills, and short‐term memory from first evaluation and low average fluid reasoning and psychomotor speed performances from 5 years old (Figure 1). Due to quarantine requirements (COVID‐19 pandemic), the child had partial schooling between ages 3 and 4 years, and the lack of school inclusion can also have influenced the results, that is, the fluctuation in language acquisition. However, cognitive regression has not yet been observed, and moreover productive language improved steadily.

The reported cases enhance the major contribution of presymptomatic diagnosis and safety, significant middle‐term treatment benefit for patients with CLN2. Thus, although not proven, we anticipate long‐term benefit for this devastating and neurodegenerative disease.

AUTHOR CONTRIBUTIONS

Delphine Breuillard: Conceptualization; investigation; writing – original draft; writing – review and editing; formal analysis; data curation. Lisa Ouss: Conceptualization; investigation; writing – original draft; writing – review and editing; formal analysis; data curation. Marie Thérèse Le Normand: Conceptualization; writing – original draft; investigation; writing – review and editing; data curation; formal analysis. Timothée de Saint Denis: Investigation; validation. Christine Barnerias: Investigation. Matthieu P. Robert: Investigation; writing – original draft; writing – review and editing; validation; formal analysis; data curation. Monika Eisermann: Investigation; writing – review and editing. Nathalie Boddaert: Investigation; validation. Catherine Caillaud: Investigation; validation. Nadia Bahi‐Buisson: Investigation; validation; conceptualization. Isabelle Desguerre: Conceptualization; investigation; writing – original draft; writing – review and editing; validation; supervision. Mélodie Aubart: Conceptualization; investigation; writing – original draft; writing – review and editing; validation; supervision; formal analysis; data curation.

CONFLICT OF INTEREST STATEMENT

None declared.

PATIENT CONSENT

Legally authorized representatives of the children consented to participate in the report according to French law.

Breuillard D, Ouss L, Le Normand MT, et al. Ceroid lipofuscinosis type 2 disease: Effective presymptomatic therapy—Oldest case of a presymptomatic enzyme therapy. Eur J Neurol. 2024;31:e16324. doi: 10.1111/ene.16324

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.