Revealing the clinical phenotype of atypical neuronal ceroid lipofuscinosis type 2 disease: Insights from the largest cohort in the world

Abstract

Aim Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by deficient tripeptidyl peptidase 1 (TPP1) enzyme, leading to progressive deterioration of neurological functions commonly occurring in children aged 2–4 years and culminating in early death. Atypical cases associated with earlier or later symptom onset, or even protracted course, have already been reported. Such variable manifestations may constitute an additional challenge to early diagnosis and initiation of appropriate treatment. The present work aimed to analyse clinical data from a cohort of Latin American CLN2 patients with atypical phenotypes. Methods Experts in inborn errors of metabolism from Latin America selected patients from their centres who were deemed by the clinicians to have atypical forms of CLN2, according to the current literature on this topic and their practical experience. Clinical and genetic data from the medical records were retrospectively revised. All cases were presented and analysed by these experts at an Advisory Board Meeting in São Paulo, Brazil, in October 2018. Results Seizures, language abnormalities and behavioural disorders were found as the first manifestations, appearing at the median age of 6 years, an older age than classically described for the late infantile form. Three novel mutations were also identified. Conclusion Our findings reinforce the inclusion of CLN2 in the differential diagnosis of children presenting with seizures, behavioural disorders and language abnormalities. Early diagnosis will allow early initiation of specific therapy.

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

“…The increasing use of Next Generation Sequencing Panels and exome sequencing as tools for the diagnosis of rare diseases may lead to the diagnosis of NCL in patients not previously suspected to have the disease. Due to these advancements in genetic testing, the number of atypical, often milder phenotypes described is rapidly increasing especially in NCL forms where a lysosomal enzyme is affected such as CLN2 disease (8)(9)(10). Electronmicroscopic demonstration of lysosomal storage material in tissues or blood cells can be helpful for detecting an NCL disease.…”

“…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).…”

Tripeptidyl Peptidase 1 (TPP1) Deficiency in a 36-Year-Old Patient with Cerebellar-Extrapyramidal Syndrome and Dilated Cardiomyopathy

“…Lourenco et al summarized that, in patients with atypical CLN2 disease, seizures, language abnormalities, and behavioral disorders were the first symptoms. Moreover, the median age of symptoms onset was 6 years, which is more than described for the classic late infantile form of CLN2 (2-4 years) [15].…”

“…Typically, protracted disease course leads to death in the mid-20s of 30s of life. Other rare atypical forms of CLN2 have also been described [10,[13][14][15].…”

“Atypical” Phenotypes of Neuronal Ceroid Lipofuscinosis: The Argentine Experience in the Genomic Era

“…Massive sequencing methods (NGS) have reduced the time towards the precision diagnosis as early as possible in the evolution of signs and symptoms [23], and gained greater value since ERT for CLN2 disease introduced changes in the CLN2 pathology progression. [3,20,[24][25][26] The general purpose of the present article is to report an observational and retrospective study on "atypical" phenotypes of CLN1, CLN2, and CLN8 diseases in the Cordoba cohort, which show clinical and genomic heterogeneity. A specific aim is to offer an analytical frame of the phenotypic (clinical), proteomic, and genomic characterization for contributing to the study of these "atypical" NCL phenotypes in LA.…”