Clinical features of Fabry disease in patients with mutations amenable and non-amenable to migalastat

Alpha-galactosidase A mutations on chromosome Xq22.1 lead to a reduction in cognate enzyme activity, with resultant accumulation of globotriaosylceramide, and the clinical features of Fabry disease (OMIM 301500). Genotype-phenotype relationship is not straightforward. Disease-specific therapy involves intravenous enzyme infusion or more recently oral pharmacological chaperone therapy (for patients with ‘amenable’ mutations, exhibiting relative increase in α-Gal A activity ≥ 1.2-fold above baseline and absolute increase in α-Gal A activity ≥ 3% of wild-type in HEK cells after incubation with 10 uM migalastat). Clinical phenotype was assessed in 200 consented patients with Fabry disease attending the Royal London Free NHS Foundation Trust, with emphasis on features among those with an ‘amenable’ GLA mutation. Additionally, we collated published data on genotype and phenotype recorded in Fabry disease publications describing 147 separate mutations in males and 98 in females, which was used to construct heat maps of clinical features among those with amenable and non-amenable mutations. In the local cohort, a total of 22 distinct amenable mutations were noted in 93 females and 54 males, whilst 28 females and 25 males had a total of 19 non-amenable mutations. The mean age-adjusted severity score of patients with amenable mutations was -0.81 (males -2.27, females 0.64) compared with 5.9 in patients with non-amenable mutations (males 6.5 and females 4.8) p<0.001. Whilst acroparasthesia (88% versus 33% p=0.04) and angiokeratoma (96% versus 26% p=0.002) were more common in patients with non-amenable mutations organ involvement was comparable between the groups (male left ventricular hypertrophy 56% and 59% female left ventricular hypertrophy 25% and 17% male CKD>3 17% and 17% respectively female CKD>3 7% and 4% respectively). Disease burden, as described, in end organ sites of pathology (heart, kidneys) is comparable between those with and without amenable mutations.