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Fabry disease (FD) is an inherited neurologic disorder caused by deficiency of the enzyme alpha-galactosidase A. Dr. Palaiodimou et al. performed a systematic review and meta-analysis of 40 studies reporting D313Y as a single occurring variant in the galactosidase alpha (GLA) gene in different populations with or without clinical manifestations of FD. They concluded that D313Y variation seems to correlate with an atypical, mild late-onset phenotype with predominantly neurologic FD manifestations. They recommended monitoring for neurologic involvement to identify D313Y-positive patients with latent or early-FD pathology, who may qualify for enzyme-replacement therapy or chaperone treatment. In response, Dr. Lackova et al. cite their recent study which found D313Y variants in 4 of 127 consecutive patients with Parkinson disease, with an allele frequency 5 times that reported in the general population, and similar to that found in another study of 180 consecutively screened patients with multiple sclerosis, 6 of whom had the variant. They call for further epidemiologic, clinical, and basic research studies to better understand the role of this variant in patients with different neurologic disorders, especially because other authors have stated it has no pathogenic significance. Responding to these comments, the authors note that whereas parkinsonism is not considered a typical FD manifestation, misdiagnosis of multiple sclerosis in patients with an ultimate FD diagnosis has been previously reported. The authors also report that on updating their analysis with the findings shared by Dr. Lackova et al. the pooled proportion of D313Y variation among patients with neurologic disorders increased to 0.8% with significant subgroup differences compared with patient cohorts with cardiac or renal manifestations (whereas originally no significant differences were observed). Overall, this exchange highlights our evolving understanding of the potential association of the D313Y variation with central and peripheral neurologic manifestations.
Fabry disease (FD) is an inherited neurologic disorder caused by deficiency of the enzyme alpha-galactosidase A. Dr. Palaiodimou et al. performed a systematic review and meta-analysis of 40 studies reporting D313Y as a single occurring variant in the galactosidase alpha (GLA) gene in different populations with or without clinical manifestations of FD. They concluded that D313Y variation seems to correlate with an atypical, mild late-onset phenotype with predominantly neurologic FD manifestations. They recommended monitoring for neurologic involvement to identify D313Y-positive patients with latent or early-FD pathology, who may qualify for enzyme-replacement therapy or chaperone treatment. In response, Dr. Lackova et al. cite their recent study which found D313Y variants in 4 of 127 consecutive patients with Parkinson disease, with an allele frequency 5 times that reported in the general population, and similar to that found in another study of 180 consecutively screened patients with multiple sclerosis, 6 of whom had the variant. They call for further epidemiologic, clinical, and basic research studies to better understand the role of this variant in patients with different neurologic disorders, especially because other authors have stated it has no pathogenic significance. Responding to these comments, the authors note that whereas parkinsonism is not considered a typical FD manifestation, misdiagnosis of multiple sclerosis in patients with an ultimate FD diagnosis has been previously reported. The authors also report that on updating their analysis with the findings shared by Dr. Lackova et al. the pooled proportion of D313Y variation among patients with neurologic disorders increased to 0.8% with significant subgroup differences compared with patient cohorts with cardiac or renal manifestations (whereas originally no significant differences were observed). Overall, this exchange highlights our evolving understanding of the potential association of the D313Y variation with central and peripheral neurologic manifestations.
Footnotes
Author disclosures are available upon request (journal{at}neurology.org).
- Received March 31, 2023.
- Accepted in final form March 31, 2023.
- © 2023 American Academy of Neurology
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