Genotypic and phenotypic divergence: lessons from a family of Fabry’s disease

Abstract

Fabry’s disease is an uncommon X-linked disease in which the activity of α-galactosidase A (AGalA), a lysosomal enzyme, is deficient. Clinical manifestation results from occlusive microvascular lesions affecting the heart, kidneys, peripheral nerves and brain. A Chinese kindred with 5 members in two generations were found to be affected by Fabry’s disease. Diagnosis was established by genetic analysis and/or measurement of serum AGalA activity. The index patient was a 24-year-old pregnant woman who was heterozygous for Fabry’s disease seeking genetic counseling. The patient was reassured after a chorionic villus sample showed only wild type AGalA gene in a male fetus. The baby was delivered full term and postnatal serum AGalA was assessed to be normal. Her mother was investigated for asymptomatic proteinuria and a renal biopsy revealed podocytes packed with myelin bodies. Their serum AGalA activities were subnormal. The two maternal uncles of the patient had clinically manifest Fabry’s disease. One of them suffered end stage renal disease when 35 years old and the other had cardiomyopathy since he was 33 years of age. They had low serum AGalA activity. Direct sequencing of the AGalA gene of the uncles identified a missense mutation in exon 1 predicting a leucine to praline substitution (L14P). The patient’s 22-year-old younger sister had a normal serum AGalA activity. Analysis, however, showed that both the patient and her sister harbored the defective gene and were heterozygous for Fabry’s disease. Fabry’s disease is rare and the diagnosis may be easily missed or delayed. Clinical manifestations can very among affected members of the same kindred. Normal serum AGalA activity in a female does not exclude heterozygous Fabry’s disease. Genetic analysis is mandatory for female members of kindred of Fabry’s disease seeking genetic counseling.