Different renal phenotypes in related adult males with Fabry disease with the same classic genotype

Area of Science:

• Genetics and rare diseases
• Biochemistry
• Clinical medicine

Background:

• Fabry disease, a genetic disorder, typically presents severe phenotypes, particularly renal manifestations, in patients with classical mutations.
• Early diagnosis and understanding of disease variability are crucial for effective management.

Purpose of the Study:

• To investigate the clinical presentation and progression of Fabry disease in three adult male family members with the same genotype.
• To highlight the variability in disease manifestation, especially renal involvement, despite a shared genetic mutation.

Main Methods:

• Dry blood spot screening (DBS) for enzyme activity and DNA analysis for mutation identification.
• Clinical evaluation including laboratory tests (serum creatinine, e-GFR, albuminuria, proteinuria), brain MRI, echocardiogram, and renal biopsy.
• Family history investigation and pedigree analysis.

Main Results:

• Patient 1, with the I354K mutation and absent alpha-galactosidase A (α-Gal A) activity, showed neurological and cardiac symptoms but normal renal function initially. Renal biopsy revealed zebra bodies.
• Patient 2, the brother, died at 49 from sudden death syndrome, exhibiting similar symptoms (neuropathy, cataract, hearing loss, left ventricular hypertrophy) but normal renal parameters prior to death.
• Patient 3, a cousin, experienced early-stage end-stage renal disease (ESRD) requiring transplantation, indicating significant renal burden within the family.

Conclusions:

• Fabry disease exhibits significant phenotypic variability even among individuals with the identical genotype and mutation.
• Renal involvement in Fabry disease can range from normal function to rapid progression to ESRD, underscoring the need for personalized monitoring.
• This family case series emphasizes the importance of comprehensive clinical assessment and genetic analysis for diagnosing and managing Fabry disease.