Men with p.D322E or p.I232T mutations developed prominent and similar cardiovascular disease at similar ages (>30 years), despite markedly different α-GalA activities (1.4% vs 14.9% of wild-type).
Observational (n=41)
How do different α-galactosidase A gene mutations (p.D322E vs p.I232T) affect the clinical and cardiovascular phenotype in families with Fabry disease?
Different missense mutations in Fabry disease can lead to similar prominent cardiovascular disease (LVH) at similar ages despite markedly different residual α-GalA activities.
BACKGROUND: (α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). METHODS AND RESULTS: Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. CONCLUSIONS: missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.
Aðalsteinsdóttir et al. (Tue,) conducted a observational in Fabry Disease and Hypertrophic Cardiomyopathy (n=41). α-galactosidase A gene mutations (p.D322E or p.I232T) was evaluated on Clinical manifestations and left ventricular hypertrophy. Men with p.D322E or p.I232T mutations developed prominent and similar cardiovascular disease at similar ages (>30 years), despite markedly different α-GalA activities (1.4% vs 14.9% of wild-type).