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CC BY 4.0 · Arq Neuropsiquiatr 2024; 82(05): s00441786854
DOI: 10.1055/s-0044-1786854
Original Article

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

Uma agulha no palheiro? Impacto de um painel genético de epilepsia direcionado para a identificação de uma epilepsia metabólica tratável, mas de progressão rápida: CLN2
Charles Marques Lourenço 
1   Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto SP, Brazil.
,
Juliana Maria Ferraz Sallum 
2   Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Oftalmologia e Ciências Visuais, São Paulo SP, Brazil.
,
Alessandra Marques Pereira 
3   Hospital Moinhos de Vento, Porto Alegre RS, Brazil.
,
Paula Natale Girotto 
4   Santa Casa de São Paulo, Faculdade de Ciências Médicas, São Paulo SP, Brazil.
,
Fernando Kok 
5   Mendelics Análise Genômica, São Paulo SP, Brazil.
,
Daniel Reda Fenga Vilela 
6   BioMarin Brasil Farmacêutica Ltda., São Paulo SP, Brazil.
,
Erika Barron 
6   BioMarin Brasil Farmacêutica Ltda., São Paulo SP, Brazil.
,
André Pessoa 
7   Hospital Albert Sabin, Fortaleza CE, Brazil.
8   Universidade Estadual do Ceará, Fortaleza CE, Brazil.
,
Bibiana Mello de Oliveira 
9   Universidade Federal do Rio Grande do Sul, Porto Alegre RS, Brazil.
› Author Affiliations Support The authors declare that the present study was sponsored by BioMarin Pharmacetical Inc. (Novato, CA, United States).
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Abstract

Background Neuronal ceroid lipofuscinoses (NCL) are a group of autosomal recessive, inherited, lysosomal, and neurodegenerative diseases that causes progressive dementia, seizures, movement disorders, language delay/regression, progressive visual failure, and early death. Neuronal ceroid lipofuscinosis type 2 (CLN2), caused by biallelic pathogenic variants of the TPP1 gene, is the only NCL with an approved targeted therapy. The laboratory diagnosis of CLN2 is established through highly specific tests, leading to diagnostic delays and eventually hampering the provision of specific treatment for patients with CLN2. Epilepsy is a common and clinically-identifiable feature among NCLs, and seizure onset is the main driver for families to seek medical care.

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.

Methods A total of 1,284 patients with epilepsy without a specific cause who had at least 1 symptom associated with CLN2 were screened for variants in 160 genes associated with epilepsy or metabolic disorders presenting with epilepsy through an epilepsy gene panel.

Results Variants of the TPP1 gene were identified in 25 individuals (1.9%), 21 of them with 2 variants. The 2 most frequently reported variants were p.Arg208* and p.Asp276Val, and 2 novel variants were detected in the present study: p.Leu308Pro and c.89 + 3G > C Intron 2.

Conclusion The results suggest that these genetic panels can be very useful tools to confirm or exclude CLN2 diagnosis and, if confirmed, provide disease-specific treatment for the patients.

Resumo

Antecedentes As lipofuscinoses ceroides neuronais (neuronal ceroid lipofuscinoses, NCLs, em inglês) são um grupo de doenças autossômicas recessivas, hereditárias, lisossomais e neurodegenerativas que causam demência progressiva, crises epiléticas, distúrbios de movimento, atraso/regressão da linguagem, deficiência visual progressiva e morte precoce. A lipofuscinose ceroide neuronal tipo 2 (neuronal ceroid lipofuscinosis type 2, CLN2, em inglês), causada por variantes patogênicas bialélicas do gene TPP1, é a única com terapia-alvo aprovada. O diagnóstico laboratorial é realizado por testes específicos, o que leva a atrasos diagnósticos e, consequentemente, prejudica a disponibilização de tratamento. A epilepsia é uma característica comum e clinicamente identificável entre as NCLs, e o início das convulsões é o principal motivo para as famílias buscarem atendimento médico.

Objetivo Avaliar os resultados do Programa de Epilepsia e Genética da América Latina, um painel genético, como uma ferramenta abrangente para a investigação de CLN2 entre outras causas genéticas de epilepsia.

Métodos Um total de 1.284 pacientes com epilepsia sem uma causa específica e que tinham pelo menos 1 sintoma associado à CLN2 foram rastreados em busca de variantes em 160 genes associados à epilepsia ou a distúrbios metabólicos que apresentam epilepsia, por meio de um painel genético.

Resultados Variantes do gene TPP1 foram identificadas em 25 indivíduos (1,9%), sendo que ; 21 apresentavam duas variantes. As duas variantes mais frequentes foram p.Arg208* e p.Asp276Val, e duas variantes novas foram detectadas neste: p.Leu308Pro e c.89 + 3G > C Intron 2.

Conclusão Os resultados sugerem que os painéis genéticos de epilepsia podem ser uma ferramenta útil para confirmar ou excluir o diagnóstico de CLN2 e, se confirmado, fornecer tratamento específico para os pacientes.

Keywords

Neuronal Ceroid Lipofuscinoses - Neurodegenerative Diseases - Epilepsy - Diagnosis

Palavras-chave

Lipofuscinoses Ceroides Neuronais - Doenças Neurodegenerativas - Epilepsia - Diagnóstico

Editor-in-Chief

Hélio A. G. Teive.


Associate Editor

Lécio Figueira Pinto.


Authors' Contributions

All authors equally contributed through online discussions and by reviewing all draft versions of the texts and tables. All authors approved the submitted version of the manuscript. DRFV provided scientific inputs to the manuscript under no influence of the commercial strategy of BioMarin Brasil Farmacêutica LTDA.


Supplementary Material



Publication History

Received: 30 January 2024

Accepted: 30 March 2024

Article published online:
19 May 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)

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Bibliographical Record
Charles Marques Lourenço, Juliana Maria Ferraz Sallum, Alessandra Marques Pereira, Paula Natale Girotto, Fernando Kok, Daniel Reda Fenga Vilela, Erika Barron, André Pessoa, Bibiana Mello de Oliveira. 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. Arq Neuropsiquiatr 2024; 82: s00441786854.
DOI: 10.1055/s-0044-1786854
 

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