Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations

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 cl...

Full description

Saved in:
Bibliographic Details
Published in:Metabolic brain disease 2021-02, Vol.36 (2), p.265-272
Main Authors: Varela, Patrícia, Carvalho, Gerson, Martin, Renan Paulo, Pesquero, João Bosco
Format: Article
Language:English
Subjects:
Accumulation
Biochemistry
Biomedical and Life Sciences
Biomedicine
Brain
Cornea
Enzymatic activity
Fabry's disease
Families & family life
Galactosidase
Globotriaosylceramide
Glycosphingolipids
Mental depression
Mental disorders
Metabolic Diseases
Mutation
Neurology
Neurosciences
Oncology
Original Article
Pathogenicity
Pathogens
Phenotypes
Ribonucleic acid
RNA
Schizophrenia
Signs and symptoms
Tinnitus
Vertigo
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0885-7490
1573-7365
DOI:10.1007/s11011-020-00640-0