Fabry disease due to D313Y and novel GLA mutations

Abstract

ObjectivesOur aim is to report four novel α-gal A gene (GLA) mutations resulting in Fabry disease (FD) and provide evidence of pathogenicity of the D313Y mutation regarding which contradictory data have been presented in the literature.Setting and participantsTwenty-five family members of nine unrelated patients with definite FD diagnosis, 10 clinically suspected cases and 18 members of their families were included in this polycentric cohort study.Primary and secondary outcome measuresGenotyping and measurement of lyso-Gb3 was performed in all individuals. The α-Gal A activity was measured in all men as well as plasma and urine Gb3 concentration in selected cases. Optical and electron microscopy was performed in kidney biopsies of selected patients. All the above were evaluated in parallel with the clinical data of the patients.ResultsFourteen new cases of FD were recognised, four of which were carrying already described GLA mutations. Four novel GLA mutations, namely c.835C>T, c.280T>A, c.924A>C and c.511G>A, resulting in a classic FD phenotype were identified. Moreover, FD was definitely diagnosed in five patients carrying the D313Y mutation. Eight D313Y carriers were presenting signs of FD despite not fulfilling the criteria of the disease, two had no FD signs and two others were apparently healthy.ConclusionsFour novel GLA pathogenic mutations are reported and evidence of pathogenicity of the D313Y mutation is provided. It seems that the D313Y mutation is related to a later-onset milder phenotype than the typical phenotype with normal lysoGb3 concentration. Our study underlines the significance of family member genotyping and newborn screening to avoid misdiagnoses and crucial delays in diagnosis and treatment of the disease.

Genotype-Phenotype Variations of Renal Complications in Fabry Disease Q279X Mutation

“…Q279X) in exon 6 of the GLA gene was identified in four members (30 + 24, range 1-60 years) of a greek family. [15] The proband´s clinical description (a 31.year-old-man) is very similar to that observed in our patient 2, but not in patient 1, because he is currently under ERT with beneficial result in regard with kidney function, proteinuria and pain. There is no description about dialysis and its complications.…”

Is the alpha‐galactosidase A variant p.Asp313Tyr (p.D313Y) pathogenic for Fabry disease? A systematic review

“…One of the 19 hemizygotes with available Gb 3 /lysoGb 3 measurements (5%) and 7 of the 55 heterozygotes (13%) had elevated lysoGb 3 in plasma or Gb 3 in urine (no available data in 4 hemizygotes and 7 heterozygotes: 11/85). The hemizygote had normal lysoGb 3 at initial presentation but elevated plasma and urine Gb 3 3 years later when he developed end‐stage renal disease 10 . Three heterozygotes with elevated urine Gb 3 , had normal lyso‐Gb 3 in plasma.…”

“… g One male had normal lysoGb 3 at initial presentation and elevated plasma and urine Gb 3 3 years later 10 …”

Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1‐year Phase 1/2 clinical trial

“…Fabry disease (FD) (OMIM #301500) is an X‐linked genetic disorder caused by a deficiency in the activity of the lysosomal enzyme alpha‐galactosidase A (α‐Gal A) (EC 3.2.1.22), resulting from more than 900 mutations in the GLA gene . Classically affected male patients typically have no or very low residual enzyme activity and demonstrate accumulation of globotriaosylceramide (Gb3) within tissues and organs, where it is thought to contribute to serious progressive pathology in the kidneys, cardiovascular system, and nervous system .…”