Recognizing Lipofuscinosis as a Guide in Antiepileptic Treatment: Clinical Description of the First Mexican Case With Neuronal Ceroid Lipofuscinosis Type 7 (NCL7).

Neuronal ceroid lipofuscinosis type 7 (NCL7) is a rare form of childhood dementia; it is part of a group of diseases characterized by rapid progressive cognitive decline, blindness associated with retinitis pigmentosa, and seizures. We report the clinical and molecular characteristics of the first Mexican patient with NCL7, highlighting a particularly atypical disease course. The typical presentation form is expected to have reduced life expectancy and an average age of ambulation loss at 12 years. Our 27-year-old patient retains the ability to walk. The patient's unique presentation could, in part, be attributed to her genetic profile: a hypomorphic allele carrying a missense variant (c.1390G>A) and an almost null allele with a frameshift variant (c.1086del), contributing to the preservation of some protein function. Throughout her childhood and early adulthood, our patient experienced a variable response to antiseizure drugs, attributed to a lack of recognition of the disease and the specific efficacy of certain antiseizure medications. Our findings underscore the significance of considering this genetic condition and acknowledging its clinical heterogeneity.

Neuronal Ceroid Lipofuscinosis Type 6 (CLN6) clinical findings and molecular diagnosis: Costa Rica's experience.

BACKGROUND: Commonly known as Batten disease, the neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of rare pediatric lysosomal storage disorders characterized by the intracellular accumulation of autofluorescent material (known as lipofuscin), progressive neurodegeneration, and neurological symptoms. In 2002, a disease-causing NCL mutation in the CLN6 gene was identified (c.214G > T) in the Costa Rican population, but the frequency of this mutation among local Batten disease patients remains incompletely characterized, as do clinical and demographic attributes for this rare patient population. OBJECTIVE: To describe the main sociodemographic and clinical characteristics of patients with a clinical diagnosis for Batten Disease treated at the National Children's Hospital in Costa Rica and to characterize via molecular testing their causative mutations. METHODS: DNA extracted from buccal swabs was used for CLN6 gene sequencing. Participants' sociodemographic and clinical characteristics were also obtained from their medical records. RESULTS: Nine patients with a clinical diagnosis of Batten disease were identified. Genetic sequencing determined the presence of the previously described Costa Rican homozygous mutation in 8 of 9 cases. One patient did not have mutations in the CLN6 gene. In all cases where the Costa Rican CLN6 mutation was present, it was accompanied by a substitution in intron 2. Patients were born in 4 of the 7 Costa Rican provinces, with an average onset of symptoms close to 4 years of age. No parental consanguinity was present in pedigrees. Initial clinical manifestations varied between patients but generally included: gait disturbances, language problems, visual impairment, seizures and psychomotor regression. Cortical and cerebellar atrophy was a constant finding when neuroimaging was performed. Seizure medication was a common element of treatment regimens. CONCLUSIONS: This investigation supports that the previously characterized c.214G > T mutation is the most common causative NCL mutation in the Costa Rican population. This mutation is geographically widespread among Costa Rican NCL patients and yields a clinical presentation similar to that observed for CLN6 NCL patients in other geographies.

Neuronal Ceroid Lipofuscinosis Type 2: A Case Series from Argentina

Abstract Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare autosomal recessive neurodegenerative disorder caused by mutations in the CLN2/TPP1 gene, leading to a deficiency in tripeptidyl peptidase 1 activity. Enzyme replacement therapy with cerliponase alfa (recombinant human TPP1 [rhTPP1]; Brineura®) was approved in the United States and Europe for the treatment of CLN2 disease in 2017. We retrospectively report a cohort of 19 patients with CLN2 assisted in a specialized center in Argentina, including 8 newly diagnosed cases. Speech disorders and white matter changes/ventricular system enlargement were the most frequent clinical and imaging findings at CLN2 disease onset, respectively. Patients treated with cerliponase alfa presented a stable or improved course of the disease in this Latin American real world setting, as described in clinical trials.

"Real world effectiveness of cerliponase alfa in classical and atypical patients. A case series".

INTRODUCTION: Late infantile neuronal ceroid lipofuscinosis is an autosomal recessive disease caused by mutations in the CLN2/TPP1 gene, with secondary enzyme deficiency. In classical phenotypes, initial symptoms include seizures and delayed language development between 2 and 4 years of age. This article describes the presentation of CLN2 disease in a cohort of Colombian patients, as well as the impact of treatment on the course and progression of the disease. METHODS: Case series report of 8 patients with a confirmed diagnosis of neuronal ceroid lipofuscinosis treated with cerliponase alfa who remained on clinical and paraclinical follow-up for up to 24 months before and after treatment. RESULTS: An atypical phenotype, associated with initial symptoms and late diagnosis, was present in 5/8 patients. The most frequent symptoms were seizures and developmental delay, with age of onset at 24 months (classical phenotype) and 48 months (atypical phenotype). A novel mutation (c.1438G > A) was found in two siblings. All of the patients received cerliponase alfa, and there were no serious adverse events. No decline in the clinical status greater than 2 points on Hamburg, Weill Cornell and CNL2 clinical assessment scale was observed during follow-up after treatment initiation. CONCLUSION: This is the first case series reported for neuronal ceroid lipofuscinosis patients in Colombia. In contrast with other reports, the majority of cases reported here displayed an atypical phenotype. Our study highlights the importance of early diagnosis and timely initiation of therapy, which is a feasible therapy, well tolerated by patients and accepted by caregivers in this country, generating a positive impact in the quality of life of CLN2 patients and on disease outcome.

Position of Experts Regarding Follow-Up of Patients with Neuronal Ceroid Lipofuscinosis-2 Disease in Latin America

Abstract Given the lack of standardized guidance for follow-up of patients with neuronal ceroid lipofucsinosis-2 disease in Latin-American countries and the heterogeneity of the region, an expert panel was created with the participation of 11 pediatric neurologists from Colombia, Argentina, Brazil and Chile. The aim of the expert panel was to describe a framework for standardized follow-up in patients with neuronal ceroid lipofucsinosis-2 disease, on or off therapy, that could benefit patients and treating physicians alike. Experts made recommendations in the following areas: seizures, abnormal movements and ataxia, sleep disorders and pain, cognitive function, visual function, hearing and speech, cardiac function, quality of life, and motor function. Recommendations include the most appropriate tools for use in the Latin-American context and health care systems, and provide feasible follow-up guidance, applicable in public and private healthcare facilities. They take into consideration the availability of clinical assessment resources, tools (scales, questionnaires, paraclinical tests) and access to these tools in Latin-American countries, as well as other regional and local needs defined by the participating experts.

Physiotherapy for Children with CLN2 Disease

Abstract CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, genetic, paediatric-onset, neurodegenerative lysosomal storage disorder characterised by seizures, ataxia, rapid loss of motor function and language ability, dementia, visual loss and early death. Physiotherapy plays an important role in the management of CLN2 disease, aiming to maintain the best possible functioning and autonomy of the child, support the child's participation in everyday life, limit secondary complications and maintain or improve quality of life. This article discusses the physiotherapeutic treatment of children diagnosed with CLN2 disease. Based on the author's clinical experience, frequent muscular impairments associated with CLN2 disease, their impact on affected children's sensorimotor abilities and autonomy, and physiotherapy interventions are described. Common muscular deficits included abnormal muscle tone leading to poor trunk control, difficulty standing upright, often accompanied by equinus contractures and movement disorders such as myoclonus. The use of orthotic and adaptive medical devices that support an erect posture in locomotion and positioning appear to be particularly beneficial for prolonging sensorimotor control, communication and food intake. In conclusion, early initiation of physiotherapy is recommended and should include the provision of adaptive walking, standing, sitting and positioning aids.

An Adapted Clinical Measurement Tool for the Key Symptoms of CLN2 Disease

Abstract Neuronal ceroid lipofuscinosis type-2 (CLN2) disease is a rare, autosomalrecessive,pediatric-onset,neurodegenerative lysosomal storage disease caused by mutations in the TPP1 gene. Cerliponase alfa (Brineura®), a recombinant form of human tripeptidyl peptidase-1, was recently developed as a treatment for CLN2 disease. In clinical trials, the primary end point to evaluate treatment effect was the aggregate score for the motor and language (ML) domains of the CLN2 Clinical Rating Scale, an adaptation of the Hamburg scale's component items that include anchor point definitions to allow consistent ratings in multinational, multisite, clinical efficacy studies. Psychometric analyses demonstrated that the ML score of the CLN2 Clinical Rating Scale and individual item scores are well defined and possess adequate measurement properties (reliability, validity, and responsiveness) to demonstrate a clinical benefit over time. Additionally, analyses comparing the CLN2 Clinical Rating Scale ML ratings to the Hamburg scale's ML ratings demonstrated adequate similarity.