Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive lysosomal neurodegenerative disorders. Among late-infantile onset forms (after 18 months of age), type 2 (CLN2 disease) is the most frequent. This study assessed the incidence and disease burden at diagnosis of CLN2 disease in France. This was a nationwide, population-based, retrospective study including all patients identified with CLN2 disease in the French Hospital Discharge Database (Programme de Médicalisation des Systèmes d'Information, PMSI) from January 2015 to December 2023. After a 2-year washout period to exclude prevalent patients, 51 children were considered to have been diagnosed with CLN2 disease over 7 years (2017-2023). Based on national birth statistics, this corresponds to an incidence of 0.99 cases of CLN2 disease per 100,000 live births. Median age at diagnosis was 5 years (interquartile range, 3-8), with a mean diagnostic delay of 19.1 ± 19.8 months from the first coded symptoms. Epilepsy (90.2 %) and intellectual disability (86.3 %) were the most frequently coded comorbidities. Of the 51 children, 84.3 % were hospitalized via emergency care, and 45.1 % required intensive care. Overall, 13 deaths (25.5 %) were reported, with median age at death of 9 years. This is the first nationwide epidemiological assessment of CLN2 disease in France. The results demonstrate substantial diagnostic delays and disease burden, underscoring the need for earlier diagnosis and referral to expert centers to optimize care and offer genetic counseling to parents before conceiving subsequent offspring.

The classical late-infantile form of neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a fatal lysosomal disorder characterized by progressive motor decline and premature death. A CLN2 cynomolgus macaque (Macaca fascicularis) model closely replicates the late-stage clinical and pathological features of human CLN2. To evaluate motor deterioration in this model, we conducted two behavioral assessments-the CLN2 Macaque Clinical Rating Scale and the Apple test-from the pre-onset stage in one macaque. Hypokinesia was observed as the first symptom at 22 months of age, followed by a marked decline in forelimb movement from 27 months. These simple, non-invasive, and cost-effective tests are valuable tools for monitoring disease progression and may facilitate the future clinical evaluation of therapeutic strategies for CLN2.

Classic late infantile neuronal ceroid lipofuscinosis (CLN2) is caused by a biallelic mutations of the TPP1 gene. Vision loss begins around age four years, resulting in blindness by age seven to ten years. Intracerebroventricular cerliponase alfa (Brineura; BioMarin) is indicated to slow the loss of ambulation in pediatric patients with CLN2. However, treated children continue to experience visual loss. Intravitreal cerliponase alfa allows the enzyme to target tissues in the eye, offering a treatment option. We developed a pathway for same-day administration of both intravitreal and intracerebroventricular cerliponase alfa using a preparation technique that takes advantage of the overfill in the vial. The intravitreal injection of cerliponase alfa is given every 4 weeks. The patient arrives and is registered for both procedures. Sterile technique is used to compound the intracerebroventricular infusion and the intravitreal injections. The intravitreal injection is performed under anesthesia using sterile technique in each eye. The dose of cerliponase alfa injected is 0.2 mg diluted in 0.05 mL of artificial cerebrospinal fluid. The intracerebroventricular infusion is then administered per standard protocol in the infusion center. We believe our pathway can be applied at all centers that are currently administering intracerebroventricular cerliponase alfa and that have the ophthalmologic expertise available to administer intravitreal injections.

CLN2 and CLN3 diseases, the most common types of Batten disease (also known as neuronal ceroid lipofuscinosis), are childhood dementias associated with progressive loss of speech, language and feeding skills. Here we delineate speech, language, non-verbal communication and feeding phenotypes in 33 individuals (19 females) with a median age of 9.5 years (range 3-28 years); 16 had CLN2 and 17 CLN3 disease; 8/15 (53%) participants with CLN2 and 8/17 (47%) participants with CLN3 disease had speech and language impairments prior to genetic diagnosis. At the time of study all participants, bar one, had language impairments. The remaining participant with typical language was tested at age 3 years, following pre-symptomatic enzyme replacement therapy (ERT) from age 9 months. CLN2 and CLN3 disease had different profiles. For CLN2 disease, all affected individuals showed language impairment with dysarthria; older individuals with classical disease progressively became non-verbal. For CLN3 disease, the presentation was more heterogeneous. Speech impairment was evident early in the disease course, with dysarthria (13/15, 87%), often manifesting as neurogenic stuttering (5/15, 33%). Participants with CLN2 disease had comparable expressive and receptive language skills (p > 0.99), yet participants with CLN3 disease had stronger expressive language than receptive language skills (p = 0.004). Speech, cognitive and language impairment and adaptive behaviour showed progressive decline in both diseases. Individuals with pre-symptomatic ERT or atypical CLN2 disease were less impaired. Challenging behaviours were common in CLN3 (11/17, 65%), but less frequent in CLN2 (4/16, 25%) disease. Individuals with Batten disease require tailored speech therapy incorporating communication partner training utilising environment adaptations and informal communication behaviours.

Ceroid lipofuscinosis type 2 (CLN2) is caused by biallelic pathogenic variants in the TPP1 gene, encoding lysosomal tripeptidyl peptidase 1 (TPP1). The classical late-infantile phenotype has an age of onset between 2 and 4 years and is characterized by psychomotor regression, myoclonus, ataxia, blindness, and shortened life expectancy. Vision loss occurs due to retinal degeneration, usually when severe neurological symptoms are already evident.Intracerebroventricular enzyme replacement therapy (ICV-ERT) using recombinant human TPP1 (rhTPP-1) was shown to slow the neurological decline; however, it does not prevent loss of vision. Intravitreal rhTPP-1 (IVT-ERT) was described to halt retinal degeneration in a canine CLN2 model and a compassionate-use study in humans.We report on the clinical and ophthalmological outcome in an early-treated patient homozygous for a pathogenic variant in TPP1 known to be associated with severe CLN2 retinopathy.He was started on ICV-ERT at the age of 40 months and 4 weekly IVT-ERT in one eye at the age of 60 months. The other eye served as untreated control.Baseline best corrected visual acuity (BCVA) was 0.5 with mild bull's eye maculopathy evident in both eyes. After 24 months of IVT-ERT, BCVA in the treated eye was 0.2 with bull's eye maculopathy sparing outer retinal layers, whereas the untreated eye had progressed to endstage retinopathy and BCVA <0.02. No intraocular side effects occurred.Our results provide further evidence that IVT-ERT appears to be safe and markedly delays retinal degeneration preserving visual function and increasing the patient's quality of life, especially if started early.