Genotype–Phenotype Correlation in a New Fabry-Disease-Causing Mutation

Abstract

Background: Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by α-galactosidase A deficiency leading to intracellular glycosphingolipid accumulation. FD manifestation is multisystem, and can differ depending on disease-related genetic variants. Currently, more than 700 different FD-causing mutations have been identified in the human GLA gene. We identified a novel mutation in a Lithuanian family with classical manifestations of Fabry disease, revealing severe effects to the cardiovascular systems of heterozygous women. Case presentation: A 49-year-old woman underwent echocardiography due to progressive dyspnea that lasted seven years, reduced physical activity, and periodic cardiac arrhythmia. Echocardiography revealed left ventricular hypertrophy with normal diastolic function. The patient had experienced acroparesthesia in her upper limbs and abdominal pain since childhood, and in the last decade had experienced mild proteinuria without renal failure. Her renal biopsy was typical for Fabry disease. The patient’s brain magnetic resonance imaging (MRI) (T2 flair) showed white matter hyperintensities lesions. DNA sequencing of the proband, her mother and one of her sons showed a novel GLA gene exon 2 mutation, c.270C>G (p.Cys90Trp). All three patients had decreased α-galactosidase A activity and specific FD manifestations. Conclusions: A novel GLA mutation, c.270C>G (p.Cys90Trp), was found in a Lithuanian family with a classical form of Fabry disease in heterozygous women with predominant cardiac involvement. However, the exact manifestation of this mutation is still unclear as it is newly reported and further research must be done.

The Cardiovascular Phenotype in Fabry Disease: New Findings in the Research Field

“…This database is continuously updated based on new findings from the literature. Recently, a novel GLA mutation, c.270C>G (p.Cys90Trp), was identified in a Lithuanian family with a classical form of Fabry disease in heterozygous women with predominant cardiac phenotype [ 22 ]. Furthermore, a novel severe mutation, a gross deletion of 3′ region of the GLA gene including coding parts of exon 7, has been highlighted in a 55 years old woman with the diagnoses of hypertrophic cardiomyopathy (HCM), high blood pressure and dyslipidaemia [ 23 ].…”

Fabry disease pain: patient and preclinical parallels

“…54 Most mutations are missense, but nonsense mutations, insertions and deletions (INDELS), or mutations causing improper gene splicing also occur leading to variable degrees of enzyme activity. 3,17,29,226 The genetic prevalence of Fabry disease is considerably higher than current estimates of the clinical prevalence. This discrepancy likely occurs because not all genetic mutants result in severe disease, and other genetic and environmental factors can play a role in modulating the disease severity as evidenced by the diverse phenotypes observed for the same mutation.…”

Fabry Nephropathy in a Young Female Patient Presenting with Only Urinary Mulberry Bodies Treated with Chaperone Therapy

“…More than 700 FD-causing mutations have been identified in genes encoding human α-GAL A. The range of phenotypes for α-GAL A mutations can vary widely, depending on the individual genotype in patients with FD [ 9 ]. The most commonly identified pathogenic mutations in Japanese FD are M296I, R227X, R112H, R112C, and R301Q [ 2 ].…”