Abstract
Fabry disease (FD) is a rare X-linked glycosphingolipidosis caused by mutations in GLA, a gene responsible for encoding α-galactosidase A, an enzyme required for degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body. FD patients present a broad spectrum of clinical phenotype and many symptoms are shared with other diseases, making diagnosis challenging. Here we describe a novel GLA variant located in the 5′ splice site of the intron 3, in four members of a family with neuropsychiatric symptoms. Analysis of the RNA showed the variant promotes alteration of the wild type donor site, affecting splicing and producing two aberrant transcripts. The functional characterization showed absence of enzymatic activity in cells expressing both transcripts, confirming their pathogenicity. The family presents mild signs of FD, as angiokeratoma, cornea verticillata, acroparesthesia, tinnitus, vertigo, as well as accumulation of plasma lyso-Gb3 and urinary Gb3. Interestingly, the man and two women present psychiatric symptoms, as depression or schizophrenia. Although psychiatric illnesses, especially depression, are frequently reported in patients with FD and studies have shown that the hippocampus is an affected brain structure in these patients, it is not clear whether the Gb3 accumulation in the brain is responsible for these symptoms or they are secondary. Therefore, new studies are needed to understand whether the accumulation of Gb3 could produce neuronal alterations leading to psychiatric symptoms.
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Acknowledgments
This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2014/27198-8) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
Funding
This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2014/27198–8) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
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PhD. Patricia Varela: conceptualized and designed the study, designed the data collection experiments, drafted the initial manuscript, carried out the analyses, reviewed and revised the manuscript and approved the final manuscript as submitted.
MD. Gerson Carvalho: providing the samples analyzed in this work, analyzed the clinical symptoms of patients, reviewed and revised the manuscript, and approved the final manuscript as submitted.
PhD. Renan Paulo Martin: carried out the initial analyses, reviewed and revised the manuscript and approved the final manuscript as submitted.
PhD. Joao Bosco Pesquero: conceptualized and designed the study, drafted the initial manuscript, carried out the initial analyses, reviewed and revised the manuscript and approved the final manuscript as submitted. Corresponding author and guarantor for the article.
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The Research Ethics Committee of the Federal University of São Paulo, Brazil approved this protocol (0585/07 and 0354/18). All procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013. All subjects involved in this study were older than 16 year at the time of the study. All four patients gave written informed consent agreeing to participate in the study and for the publication of their clinical cases. The consent was in accordance with the Declaration of Helsinki.
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Varela, P., Carvalho, G., Martin, R.P. et al. Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations. Metab Brain Dis 36, 265–272 (2021). https://doi.org/10.1007/s11011-020-00640-0
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DOI: https://doi.org/10.1007/s11011-020-00640-0