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.
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The data of this study are not publicly available due to privacy or ethical restrictions.
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Acknowledgements
We gratefully acknowledge the financial support of Fundo de Incentivo à Pesquisa e Eventos (FIPE/HCPA) (Porto Alegre, Brazil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Brasília, Brazil), and Pró-Reitoria de Pesquisa/ UFRGS (PROPESP/UFRGS) (Porto Alegre, Brazil). We would like also to thank all staff, but especially the doctors of the Medical Genetics Service of the Clinical Hospital of Porto Alegre, as well as the physicians from the other hospitals of Brazil.
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A.S, L.V. e C.R.V. conceived and planned the study. A.S. wrote the manuscript with the support from G.G., L.V., C.S., M.W. and C.R.V. A.S, D.M.C, V.V.R. and B.G.R performed the organic acids and acylcarnitines analysis and performed the compilation of patients’ data. C.S. performed the molecular analysis. All authors discussed the results and contributed to the final manuscript.
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The study was approved by the Ethics Committee of Clinical Hospital of Porto Alegre (2015 − 0616).
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Sitta, A., Guerreiro, G., de Moura Coelho, D. et al. Clinical, biochemical and molecular findings of 24 Brazilian patients with glutaric acidemia type 1: 4 novel mutations in the GCDH gene. Metab Brain Dis 36, 205–212 (2021). https://doi.org/10.1007/s11011-020-00632-0
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DOI: https://doi.org/10.1007/s11011-020-00632-0