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A comparison of central nervous system involvement in patients with classical Fabry disease or the later-onset subtype with the IVS4+919G>A mutation.

ABSTRACT: Patients with the later-onset IVS4+919G>A (IVS4) Fabry mutation are known to have positive central nervous system involvement compared with age- and sex-matched controls. This study compares central nervous system manifestations in patients with the IVS4 mutation or classical Fabry mutations.This was a retrospective analysis of magnetic resonance imaging (MRI) data from Taiwanese patients enrolled in the Fabry Outcome Survey (sponsored by Shire; data extracted March 2015).Twenty-five IVS4 (19 males) and 12 (four males) classical Fabry patients underwent MRI at a median (range) age of 60.7 (45.0-70.4) and 43.0 (18.0-61.4) years, respectively. All patients received agalsidase alfa enzyme replacement therapy; two (16.7%) classical Fabry patients underwent MRI before treatment start. The pulvinar sign occurred in eight (32.0%; seven males) IVS4 and six (50.0%; three males) classical Fabry patients. Infarction occurred in eight (32.0%) IVS4 and four (33.3%) classical Fabry patients. Fazekas scores of 0, 1, 2, and 3 were found for 15 (60.0%), seven (28.0%), two (8.0%), and one (4.0%) of the IVS4 patients and for six (50.0%), four (33.3%), two (16.7%), and 0 classical Fabry patients, respectively. Abnormal height bifurcation of the basilar artery was observed in 40.0% of IVS4 and 58.3% of classical Fabry patients; abnormal laterality was observed in 4.0% of IVS4 and 16.7% of classical Fabry patients. Median (range) basilar artery diameter was 2.7 (1.4-4.0) mm in IVS4 and 3.2 (2.3-4.7) mm in classical Fabry patients (P?=?0.0293); vascular stenosis was noted in 8.3% of IVS4 patients but in no classical Fabry patients.A similar range of MRI findings was found for both IVS4 and classical Fabry patients. Notably, basilar artery diameter was larger in classical Fabry patients than IVS4 patients.

SUBMITTER: Lee HJ

PROVIDER: S-EPMC5294737 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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A comparison of central nervous system involvement in patients with classical Fabry disease or the later-onset subtype with the IVS4+919G>A mutation.

Lee Han-Jui HJ Hsu Ting-Rong TR Hung Sheng-Che SC Yu Wen-Chung WC Chu Tzu-Hung TH Yang Chia-Feng CF Bizjajeva Svetlana S Tiu Chui-Mei CM Niu Dau-Ming DM

BMC neurology 20170206 1

<h4>Background</h4>Patients with the later-onset IVS4+919G>A (IVS4) Fabry mutation are known to have positive central nervous system involvement compared with age- and sex-matched controls. This study compares central nervous system manifestations in patients with the IVS4 mutation or classical Fabry mutations.<h4>Methods</h4>This was a retrospective analysis of magnetic resonance imaging (MRI) data from Taiwanese patients enrolled in the Fabry Outcome Survey (sponsored by Shire; data extracted ...[more]

PMID: 28166746

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Project description:The classic phenotype of Fabry disease, X-linked alpha -galactosidase A (alpha -Gal A) deficiency, has an estimated incidence of approximately 1 in 50,000 males. The recent recognition of later-onset variants suggested that this treatable lysosomal disease is more frequent. To determine the disease incidence, we undertook newborn screening by assaying the alpha-Gal A activity in blood spots from 37,104 consecutive Italian male neonates. Enzyme-deficient infants were retested, and "doubly screened-positive" infants and their relatives were diagnostically confirmed by enzyme and mutation analyses. Twelve (0.03%) neonates had deficient alpha-Gal A activities and specific mutations, including four novel missense mutations (M51I, E66G, A73V, and R118C), three missense mutations (F113L, A143T, and N215S) identified previously in later-onset patients, and one splicing defect (IVS5(+1G-->T)) reported in a patient with the classic phenotype. Molecular modeling and in vitro overexpression of the missense mutations demonstrated structures and residual activities, which were rescued/enhanced by an alpha-Gal A-specific pharmacologic chaperone, consistent with mutations that cause the later-onset phenotype. Family studies revealed undiagnosed Fabry disease in affected individuals. In this population, the incidence of alpha-Gal A deficiency was 1 in approximately 3,100, with an 11 : 1 ratio of patients with the later-onset : classic phenotypes. If only known disease-causing mutations were included, the incidence would be 1 in approximately 4,600, with a 7 : 1 ratio of patients with the later-onset : classic phenotypes. These results suggest that the later-onset phenotype of Fabry disease is underdiagnosed among males with cardiac, cerebrovascular, and/or renal disease. Recognition of these patients would permit family screening and earlier therapeutic intervention. However, the higher incidence of the later-onset phenotype in patients raises ethical issues related to when screening should be performed--in the neonatal period or at early maturity, perhaps in conjunction with screening for other treatable adult-onset disorders.

Dataset Information

A comparison of central nervous system involvement in patients with classical Fabry disease or the later-onset subtype with the IVS4+919G>A mutation.

Publications

A comparison of central nervous system involvement in patients with classical Fabry disease or the later-onset subtype with the IVS4+919G>A mutation.

Similar Datasets

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