Phenotypic Evolution in Fabry Disease: Our Experience in Indian Cohort

Area of Science:

• Genetics and Molecular Biology
• Biochemistry
• Clinical Medicine

Background:

• Fabry disease is a rare genetic disorder caused by mutations in the GLA gene, leading to alpha-galactosidase deficiency.
• Phenotypic variability in Fabry disease complicates diagnosis and management.
• Understanding genotype-phenotype correlations is crucial for personalized treatment strategies.

Purpose of the Study:

• To explore phenotypic evolution in Fabry disease based on demographics, genotype, enzyme activity, and pathogenicity scores.
• To integrate clinical, biochemical, and genomic data for a comprehensive analysis of Fabry disease in Indian patients.
• To identify factors influencing disease onset and progression.

Main Methods:

• Integrated clinical, biochemical, and genomic data from 88 Fabry patients (23 from a new cohort, 65 from published Indian data).
• Assessed alpha-galactosidase enzyme activity and calculated Combined Annotation Dependent Depletion (CADD) scores for mutations.
• Analyzed correlations between mutations, enzyme activity, clinical manifestations (renal, neuropathic, cardiac), and age of onset.

Main Results:

• Affected patients had profoundly reduced alpha-galactosidase activity (0.73% mean normal), while carriers showed 15.64% mean normal activity.
• A heterogeneous mutation spectrum was observed, with 68 distinct mutations identified in the Indian population.
• Highly conserved mutations correlated with renal involvement (p=0.005), while neuropathic pain occurred even with less conserved mutations (p=0.02).
• Age of onset positively associated with enzyme activity (r=0.375, p<0.001), renal disease (r=0.328, p=0.005), and cardiac issues (r=0.278, p=0.026).
• A neonatal case with 0% enzyme activity and a specific GLA mutation (c.613C>G) exemplified severe early-onset disease.

Conclusions:

• Phenotypic variability in Fabry disease is influenced by enzyme activity, mutation conservation, and specific genotypes.
• Delayed diagnosis is common due to rarity and nonspecific symptoms, highlighting the need for integrated diagnostic approaches.
• A combination of whole-exome sequencing (WES) and biochemical assays, coupled with rigorous phenotypic evaluation, is essential for early and accurate Fabry disease diagnosis.