GLA Gene Mutation in Hypertrophic Cardiomyopathy with a New Variant Description: Is it Fabry's Disease?

Abstract

Background Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the alpha galactosidase A gene (GLA) that lead to the enzymatic deficiency of alpha galactosidase (α-Gal A), resulting in the accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), causing multiple organ dysfunctions. Objective To perform GLA gene screening in a group of patients with echocardiographic diagnosis of hypertrophic cardiomyopathy (HCM). Methods a cross-sectional study was conducted with HCM patients from a university hospital. Patients with coronary artery disease and valvulopathies were excluded. Mutation analysis of the GLA gene was performed. In male subjects, the analysis was performed after evidence of low α-Gal A activity. Results 60 patients with echocardiographic diagnosis of HCM were included. Age ranged from 12 to 85 years and 60% were women. Mean myocardial fibrosis percentage on MRI was 10.7 ± 13.1% and mean ventricular thickness was18.7 ± 6.7 mm. Four patients had the following GLA gene mutations: c.967C>A (p.Pro323Thr), not yet described in the literature; c.937G>T (p.Asp313Tyr); and c.352C>T (p.Arg118Cys). All patients had normal levels of lyso-Gb3 and non-ischemic myocardial fibrosis on magnetic resonance imaging; one patient had proteinuria and one patient had ventricular tachycardia. Conclusion in this study, the frequency of mutation in the GLA gene in patients with HCM was 6.7%. A novel mutation in exon 6 of the GLA gene, c.967C>A (p.Pro323Thr), was identified. Patients with HCM may have GLA mutations and FD should be ruled out. Plasma (lyso-Gb3) levels do not seem to be sufficient to attain a diagnosis and organ biopsy should be considered.

Is the alpha‐galactosidase A variant p.Asp313Tyr (p.D313Y) pathogenic for Fabry disease? A systematic review

“…We identified 15 studies 5,10,[15][16][17][18][19][20][21][22][23][24][25][26][27] comprising a total of 85 individuals (23 males, 62 females, mean age 41.6 ± 18.6, median 44, age range 6-78 years old) who were genetically screened because they were suspected with FD or were family members of FD patients or family members of carriers of an FD related variant. One male with two variants in the GLA gene (the pathogenic variant p.Gly411Asp (c.1232G>A) and the p.Asp313Tyr) had enzyme activity <5%, elevated lysoGb 3 and presented with the classical FD phenotype, was excluded from the analysis.…”

Description of a New GLA Gene Variant in a Patient with Hypertrophic Cardiomyopathy. Is it Fabry Disease?

“…This mutation has not been previously described, showing the originality of this work. 8 Two other variants were described in this group of patients: c.937G>T (p.Asp313Tyr) and c.352C>T (p.Arg118Cys). Interestingly, three of the four patients who had mutations in the GLA gene were females, a phenomenon also found in the article published by Csányi B et al, 7 when they described the Ile239Met variant.7 This finding is little expected in patients with FD due to inactivation of the X chromosome in heterozygous women, resulting in milder symptoms.…”

“…In the current issue of the Brazilian Archives of Cardiology, Chaves-Markman et al. 8 found mutations in the GLA gene in 6.7% of a cohort of 60 HCM patients and reported a new variant, c.967C>A (p.Pro323Thr), a missense mutation. This mutation has not been previously described, showing the originality of this work.…”

Sphingolipid lysosomal storage diseases: from bench to bedside

“… Farber Disease Acid Ceramidase ASAH1 Cer Type I: Early-onset premature death at age 2-3 years • Hepatosplenomegaly • Joint contractures • Voice hoarseness • Inflammation of subcutaneous nodules, along with other neurological manifestations [ 46 , 78 – 81 ] Type II: intermediate • Decreased neurological inflammation-related symptoms • Longer lifespan Type III: mild Type IV: Neonatal-visceral • Organomegaly and visceral manifestations Type V: Neurological-Progressive • Progressive neurodegeneration and seizures Type VI • Combined Farber and Sandhoff diseases and associated symptoms Fabry Disease α-GAL GLA Gb3, lyso-Gb3 Males : During childhood or adolescence • Corneal dystrophy • Acroparesthesia • Angiokeratomas, and hypohidrosis, followed by progressive multi-system involvement leading to kidney failure, cerebrovascular disease, and hypertrophic cardiomyopathy in affected males • Females range from having no symptoms to severe ones. [ 82 – 89 ] Females : Heterozygous Mild late-onset disease (adult-onset) or severe disease. Homozygous Similar onset as males Krabbe Disease GALC GALC psychosine Infantile: 3-6 months.…”