Genotype⁻Phenotype Correlation in a New Fabry-Disease-Causing Mutation.

Area of Science:

• Genetics
• Biochemistry
• Rare Diseases

Background:

• Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency.
• Accumulation of glycosphingolipids due to enzyme deficiency leads to multisystemic manifestations.
• Over 700 mutations in the GLA gene have been identified, contributing to varied disease phenotypes.

Observation:

• A novel GLA gene mutation, c.270C>G (p.Cys90Trp), was identified in a Lithuanian family with classical Fabry disease.
• The proband, a 49-year-old woman, presented with progressive dyspnea, left ventricular hypertrophy, and white matter hyperintensities on MRI.
• Affected family members, including heterozygous women, exhibited decreased alpha-galactosidase A activity and FD-specific symptoms, with predominant cardiac involvement.

Findings:

• The novel GLA mutation c.270C>G (p.Cys90Trp) is associated with classical Fabry disease.
• Heterozygous women carrying this mutation showed significant cardiovascular manifestations.
• Reduced alpha-galactosidase A activity was confirmed in all affected individuals.

Implications:

• This discovery expands the spectrum of known GLA mutations and their associated phenotypes in Fabry disease.
• The findings underscore the importance of genetic screening for early diagnosis and management of Fabry disease, particularly in families with cardiac involvement.
• Further research is warranted to fully elucidate the clinical manifestations and long-term effects of the c.270C>G mutation.