Neuronal ceroid lipofuscinosis in the South American-Caribbean region: An epidemiological overview

Abstract

Neuronal ceroid lipofuscinoses (NCLs) comprise 13 hereditary neurodegenerative pathologies of very low frequency that affect individuals of all ages around the world. All NCLs share a set of symptoms that are similar to other diseases. The exhaustive collection of data from diverse sources (clinical, genetic, neurology, ophthalmology, etc.) would allow being able in the future to define this group with greater precision for a more efficient diagnostic and therapeutic approach. Despite the large amount of information worldwide, a detailed study of the characteristics of the NCLs in South America and the Caribbean region (SA&C) has not yet been done. Here, we aim to present and analyse the multidisciplinary evidence from all the SA&C with qualitative weighting and biostatistical evaluation of the casuistry. Seventy-one publications from seven countries were reviewed, and data from 261 individuals (including 44 individuals from the Cordoba cohort) were collected. Each NCL disease, as well as phenotypical and genetic data were described and discussed in the whole group. The CLN2, CLN6, and CLN3 disorders are the most frequent in the region. Eighty-seven percent of the individuals were 10 years old or less at the onset of symptoms. Seizures were the most common symptom, both at onset (51%) and throughout the disease course, followed by language (16%), motor (15%), and visual impairments (11%). Although symptoms were similar in all NCLs, some chronological differences could be observed. Sixty DNA variants were described, ranging from single nucleotide variants to large chromosomal deletions. The diagnostic odyssey was probably substantially decreased after medical education activities promoted by the pharmaceutical industry and parent organizations in some SA&C countries. There is a statistical deviation in the data probably due to the approval of the enzyme replacement therapy for CLN2 disease, which has led to a greater interest among the medical community for the early description of this pathology. As a general conclusion, it became clear in this work that the combined bibliographical/retrospective evaluation approach allowed a general overview of the multidisciplinary components and the epidemiological tendencies of NCLs in the SA&C region.

A needle in a haystack? The impact of a targeted epilepsy gene panel in the identification of a treatable but rapidly progressive metabolic epilepsy: CLN2 disease

“…Interestingly, p.Arg208* was observed exclusively in the subset of Brazilian patients, while p.Asp276Val was observed in all patients from the Argentinean subset and in some patients from the Brazilian subset. In accordance with our results, a previous study 2 with South American and Caribbean NCL patients found the most frequent variants to be p.Asp276Val, followed by p.Pro295_Gly296insGluAsnPro and p.Arg208*, in a cohort with a high number of Argentinian and Brazilian patients.…”

“…The 2 most frequently reported variants in this global sample were c.509–1 G > C (27%) and c.622 C > T [p.(Arg208*)] (23%), while the allelic frequency of p.Asp276Val was only found in 2%. Thus, when comparing our results in combination with the South American and Caribbean study 2 to the global report, 20 p.Asp276Val seems to be a regional-specific variant of interest for CLN2 diagnosis in Latin America.…”

“…1 Currently, 14 NCL types have been identified: CLN1, CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, CLN8, CLN9, CLN10, CLN11, CLN12, CLN13, and CLN14; however, to date, neuronal ceroid lipofuscinosis type 2 (CLN2) is the only NCL with an approved targeted therapy. 2 Neuronal ceroid lipofuscinosis type 2 is caused by biallelic pathogenic variants of the TPP1 gene, leading to a deficiency of the lysosomal tripeptidyl-peptidase 1 (TPP1) enzyme. Children with classic CLN2 disease commonly have their first seizures between the ages of 2 and 4 years, in most cases preceded by delayed language development and followed by Objective To evaluate the results of the Latin America Epilepsy and Genetics Program, an epilepsy gene panel, as a comprehensive tool for the investigation of CLN2 among other genetic causes of epilepsy.…”

“…1 Currently, 14 NCL types have been identified: CLN1 , CLN2 , CLN3 , CLN4 , CLN5 , CLN6 , CLN7 , CLN8 , CLN9 , CLN10 , CLN11 , CLN12 , CLN13 , and CLN14 ; however, to date, neuronal ceroid lipofuscinosis type 2 (CLN2) is the only NCL with an approved targeted therapy. 2…”

Ceroid lipofuscinosis type 5: novel pathogenic variants and unexpected phenotypic findings

“…However, given the rarity of this variant in population databases and the higher frequency in this series, we believe that this variant has a founder effect in Brazil, and haplotype analysis could not determine that it is definitely of Amerindian origin. An epidemiological study including 261 patients from South America/Caribbean found three cases of CLN5, reinforcing the rarity of this disease 4…”