Orphanet J Rare Dis. 2026 Jul 25;21(1):375. doi: 10.1186/s13023-026-04506-z.
ABSTRACT
BACKGROUND: Fabry disease (FD) is an X-linked sphingolipidosis caused by enzyme α-Galactosidase A (α-Gal A) deficiency due to pathogenic variants in GLA gene. Progressive glycosphingolipid accumulation leads to subsequent myocyte injury, which frequently induces concentric remodeling and manifests as left ventricular hypertrophy (LVH). This study aims to describe the prevalence of FD in patients with LVH diagnosis in a Mexican population.
METHODS: Consecutive and unrelated patients with echocardiographic evidence of left ventricular hypertrophy (LVH) without known cause were screened for FD in a Mexican cardiology referral center. Globotriaosylsphingosine (lyso-Gb3) levels and α-Gal A activity were measured using the dry blood spot method in all male individuals. Patients with positive dried blood spot testing and female patients were confirmed by single-gene sequencing.
RESULTS: 205 patients with LVH (48.5 ± 18.7 years) were included. Of these, 53% were male, 60% were in NYHA functional class I, and 43% were asymptomatic. Dyspnea was the most frequently reported symptom, occurring in 26% of cases. Among study participants, three women were diagnosed with FD (1.5%). GLA gene sequencing revealed two pathogenic variants, NM_000169.3(GLA):c.559 A > G (p.Met187Val) and NM_000169.3(GLA):c.679 C > T (p.Arg227Ter), and a variant of unknown significance (VUS) reclassificated to a likely pathogenic variant NM_000169.3(GLA):c.122 C > G (p.Thr41Ser). Cascade screening identified three additional women with FD.
CONCLUSION: These results emphasize the need for genetic screening for FD in female individuals with LVH. Further studies are needed to understand genotype-phenotype correlations in females with genetic variants in the GLA gene, particularly those with VUS and novel variants, as they pose challenges for diagnosis and treatment.
PMID:42919303 | DOI:10.1186/s13023-026-04506-z