Elevated Lyso-Gb3 Suggests the R118C GLA Mutation Is a Pathological Fabry Variant

Area of Science:

• Genetics
• Biochemistry
• Medical Science

Background:

• Fabry disease (FD) is an X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency.
• Accumulation of globotriaosylsphingosine (lyso-Gb3) is implicated in FD pathogenesis.
• The clinical significance of the R118C alpha-galactosidase (GLA) gene variant is debated.

Purpose of the Study:

• To investigate the clinical significance of the R118C GLA gene variant in a family.
• To correlate enzyme levels and lyso-Gb3 accumulation with clinical presentation.

Main Methods:

• Clinical assessment of three family members with the R118C variant.
• Measurement of residual alpha-galactosidase A enzyme activity.
• Quantification of plasma globotriaosylsphingosine (lyso-Gb3) levels.

Main Results:

• All three family members exhibited clinical signs consistent with Fabry disease.
• Low residual enzyme levels were observed in affected individuals.
• One heterozygote presented with elevated lyso-Gb3 levels.

Conclusions:

• The R118C GLA variant is associated with clinical manifestations of Fabry disease.
• Elevated lyso-Gb3 serves as a reliable biomarker for pathogenic GLA variants.
• While potentially milder, the R118C variant necessitates careful patient monitoring and risk factor management.