Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young

Brabander, Isabel De; Yperzeele, Laetitia; Groote, Chantal Ceuterick‐de; Brouns, Raf; Baker, Robert J.; Belachew, Shibeshih; Delbecq, J.; Keulenaer, Gilles W. De; Dethy, Sophie; Eyskens, François; Fumal, Arnaud; Hemelsoet, Dimitri; Hughes, D.A.; Jeangette, Sandrine; Nuytten, Dirk; Redondo, P.; Sadzot, Bernard; Sindic, Christian; Sheorajpanday, Rishi; Thijs, Vincent; Broeckhoven, Christine Van; Deyn, Peter Paul De

doi:10.1016/j.clineuro.2012.11.003

Cited by 34 publications

(41 citation statements)

References 27 publications

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“…Vice versa, all subjects in whom a diagnosis of FD was excluded had normal lysoGb3 values. This confirms previous data that lysoGb3 is normal in individuals with a neutral GLA variant, such as p.A143T, p.E66Q, p.S126G and p.R118C variants 14 29 34 38 39 47. Negative biopsies in individuals with two of these variants (p.A143T and p.E66Q) support these findings 14 38 47…”

Section: Discussionsupporting

confidence: 91%

Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease

et al. 2015

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LysoGb3 is a reliable diagnostic tool to discern classical FD from subjects without FD. This study suggests that the same applies to patients with a non-classical phenotype. LysoGb3 values of female patients overlap with controls. Consequently, in uncertain cases, increased lysoGb3 values are very suggestive for FD, but normal values cannot exclude FD. Confirmation in larger cohorts and data on the specificity of small lysoGb3 increases are necessary.

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Section: Discussionsupporting

confidence: 91%

Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease

et al. 2015

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“…We investigated whether plasma lysoGb3 could serve as such a marker (7). All p.A143T mutation carriers reported here and elsewhere had normal plasma lysoGb3 levels (13), supporting the notion that these mutations are polymorphisms. We showed that all male p.P60L carriers had plasma lysoGb3 values only just above the reference range.…”

Section: Discussionsupporting

confidence: 71%

“…Family 1 illustrates the necessity to perform a biopsy on an affected organ, excluding FD in this case. Brabander et al described 10 p.A143T carriers of whom 2 had a stroke and 3 had LVH without classical FD signs . Despite similar biochemical and histological results, they concluded that p.A143T is associated with late onset FD.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance

et al. 2014

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Fabry disease' (FD) phenotype is heterogeneous: alpha-galactosidase A gene mutations (GLA) can lead to classical or non-classical FD, or no FD. The aim of this study is to describe pitfalls in diagnosing non-classical FD and assess the diagnostic value of plasma globotriaosylsphingosine. This is a case series study. Family 1 (p.A143T) presented with hypertrophic cardiomyopathy (HCM), absent classical FD signs, high residual alpha-galactosidase A activity (AGAL-A) and normal plasma globotriaosylsphingosine. Co-segregating sarcomeric mutations were found. Cardiac biopsy excluded FD. In family 2 (p.P60L), FD was suspected after kidney biopsy in a female with chloroquine use. Males had residual AGAL-A, no classical FD signs and minimally increased plasma globotriaosylsphingosine, indicating that p.P60L is most likely non-pathogenic. Non-specific complications and histology can be explained by chloroquine and alternative causes. Males of two unrelated families (p.R112H) show AGAL-A <5%, but slightly elevated plasma globotriaosylsphingosine (1.2-2.0 classical males >50 nmol/l). Histological evidence suggests a variable penetrance of this mutation. Patients with GLA mutations and non-specific findings such as HCM may have non-classical FD or no FD. Other (genetic) causes of FD-like findings should be excluded, including medication inducing FD-like storage. Plasma globotriaosylsphingosine may serve as a diagnostic tool, but histology of an affected organ is often mandatory.

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“…Two studies were subsequently added by the authors because of their interest for the research question: Whybra et al, 11 not selected with the search, and Sher et al ,12 initially excluded based on the publication date <1980. These studies included 21 cohort studies,13–31 2 high-risk group screening studies32 33 and 2 registry studies 34 35. Details on selection and inclusion are presented in figure 1.…”

Section: Resultsmentioning

confidence: 99%

“…The high-risk group screening studies revealed that CV was absent in all adult individuals (n=29, 12 men) who were identified with a GLA variant 32 33…”

Section: Resultsmentioning

confidence: 99%