Clinical, biochemical and molecular findings of 24 Brazilian patients with glutaric acidemia type 1: 4 novel mutations i
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ORIGINAL ARTICLE
Clinical, biochemical and molecular findings of 24 Brazilian patients with glutaric acidemia type 1: 4 novel mutations in the GCDH gene Angela Sitta 1 & Gilian Guerreiro 2 & Daniella de Moura Coelho 1 & Vitoria Volfart da Rocha 1 & Bianca Gomes dos Reis 1 & Carmen Sousa 3 & Laura Vilarinho 3 & Moacir Wajner 1,4 & Carmen Regla Vargas 1,2,4 Received: 7 August 2020 / Accepted: 11 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Glutaric aciduria type 1 (GA-1) is a rare but treatable inherited disease caused by deficiency of glutaryl-CoA dehydrogenase activity due to GCDH gene mutations. In this study, we report 24 symptomatic GA-1 Brazilian patients, and present their clinical, biochemical, and molecular findings. Patients were diagnosed by high levels of glutaric and/or 3-hydroxyglutaric and glutarylcarnitine. Diagnosis was confirmed by genetic analysis. Most patients had the early-onset severe form of the disease and the main features were neurological deterioration, seizures and dystonia, usually following an episode of metabolic decompensation. Despite the early symptomatology, diagnosis took a long time for most patients. We identified 13 variants in the GCDH gene, four of them were novel: c.91 + 5G > A, c.167T > G, c.257C > T, and c.10A > T. The most common mutation was c.1204C > T (p.R402W). Surprisingly, the second most frequent mutation was the new mutation c.91 + 5G > A (IVS1 ds G-A + 5). Our results allowed a complete characterization of the GA-1 Brazilian patients. Besides, they expand the mutational spectrum of GA-1, with the description of four new mutations. This work reinforces the importance of awareness of GA-1 among doctors in order to allow early diagnosis and treatment in countries like Brazil where the disease has not been included in newborn screening programs. Keywords Glutaric acidemia type 1 . Brazil . GCDH gene . Late diagnosis . Mutations
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11011-020-00632-0) contains supplementary material, which is available to authorized users. * Angela Sitta [email protected] * Carmen Regla Vargas [email protected] 1
Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, 90035-003 Porto Alegre, RS, Brazil
2
Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Ipiranga, 2752, 90610-000 Porto Alegre, RS, Brazil
3
Newborn Screening, Metabolism & Genetics Unit, Human Genetics Department, National Institute of Health Dr Ricardo Jorge, Alexandre Herculano, 321, 4000-055 Porto, Portugal
4
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal de Rio Grande do Sul, Ramiro Barcelos, 2600, Porto Alegre, RS 90035-003, Brazil
Glutaric aciduria type 1 (GA-1, OMIM 231,670) is an autosomal recessive error of metabolism caused by mutations in the glutaryl-CoA dehydrogenase (GCDH) gene mapped to chromosome 19p13.2, leading to severe d
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