The clinical utility of total concentration of urinary globotriaosylsphingosine plus its analogues in the diagnosis of Fabry disease

Alharbi, Fahad J.; Baig, Shanat; Rambhatla, Srinivasa Bhargav; Vijapurapu, Ravi; Auray‐Blais, Christiane; Boutin, Michel; Steeds, Richard P.; Wheeldon, Nigel; Dawson, Charlotte; Geberhiwot, Tarekegn

doi:10.1016/j.cca.2019.10.005

Cited by 14 publications

(13 citation statements)

References 22 publications

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“…38 Like urinary Gb 3 concentration, total urinary concentration of lyso-Gb 3 and its structural analogs represent a specific diagnostic biomarker, and is elevated in both classical and non-classical FD patients. 39 3.2.3 | Does lyso-Gb3 have a prognostic value in therapeutic drugs monitoring in FD patients?…”

Section: Gastro-intestinal Abdominal Pain Diarrhoeamentioning

confidence: 99%

Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease

et al. 2021

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Fabry disease (FD) is an X-linked genetic disease due to pathogenic variants in GLA.The phenotype varies depending on the GLA variant, alpha-galactosidase residual activity, patient's age and gender and, for females, X chromosome inactivation. Over 1000 variants have been identified, many through screening protocols more susceptible to disclose non-pathogenic variants or variants of unknown significance (VUS).This, together with the non-specificity of some FD symptoms, challenges physicians attempting to interpret GLA variants. The traditional way to interpreting pathogenicity is based on a combined approach using allele frequencies, genomic databases, global and disease-specific clinical databases, and in silico tools proposed by the American College of Medical Genetics and Genomics. Here, a panel of FD specialists convened to study how expertise may compare with the traditional approach. Several GLA VUS, highly controversial in the literature (p.Ser126Gly, p.Ala143Thr, p.Asp313Tyr), were re-analyzed through reviews of patients' charts. The same was done for pathogenic GLA variants with some specificities. Our data suggest that input of geneticists and physicians with wide expertise in disease phenotypes, prevalence, inheritance, biomarkers, alleles frequencies, disease-specific databases, and literature greatly contribute to a more accurate interpretation of the pathogenicity of variants, bringing a significant additional value over the traditional approach.

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Section: Gastro-intestinal Abdominal Pain Diarrhoeamentioning

confidence: 99%

Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease

et al. 2021

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“…Recently, it was proposed that the sum of urinary lyso-Gb3 levels plus that of its analogues may have diagnostic utility, as it has a sensitivity and specificity of 100% for the diagnosis of both classic and non-classic forms. It can be a good diagnostic marker, complementary to the measurement of a-gal A activity and the concentration of plasma lyso-Gb3 [92]. However, it should be noted that lyso-Gb3 and analogues profiled in urine have a high interindividual variability [89], so more studies with a larger number of patients are required to validate its clinical utility.…”

Section: Accumulation Biomarkersmentioning

confidence: 99%

Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

Carnicer-Cáceres

Arranz-Amo

Cea-Arestin

et al. 2021

JCM

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Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in which several mediators could be implicated, inducing multiorgan lesions, mainly in the kidney, heart and nervous system, resulting in clinical manifestations of the disease. Enzyme replacement therapy was shown to delay disease progression, mainly if initiated early. However, a diagnosis in the early stages represents a clinical challenge, especially in patients with a non-classic phenotype, which prompts the search for biomarkers that help detect and predict the evolution of the disease. We have reviewed the mediators involved in different pathogenic mechanisms that were studied as potential biomarkers and can be easily incorporated into clinical practice. Some accumulation biomarkers seem to be useful to detect non-classic forms of the disease and could even improve diagnosis of female patients. The combination of such biomarkers with some response biomarkers, may be useful for early detection of organ injury. The incorporation of some biomarkers into clinical practice may increase the capacity of detection compared to that currently obtained with the established diagnostic markers and provide more information on the progression and prognosis of the disease.

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“…Lyso-Gb3 is involved in cardiac and renal dysfunction [31,32], for example by promoting the release of pro-inflammatory cytokines [1]. Hence, lyso-Gb3 may serve as a biomarker to distinguish FD phenotypes from subjects without FD [33,34], monitor disease progression [30], and may be used as a factor indicating prognosis and disease burden [35,36]. Lyso-Gb3 was found higher in men with FD when compared to women and in patients with classical FD phenotype than in those with nonclassical phenotype [37].…”

Section: Discussionmentioning

confidence: 99%

Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure

et al. 2020

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Background. Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the a-galactosidase A (a-GalA) gene. We investigated the impact of individual amino acid exchanges in the a-GalA 3D-structure on the clinical phenotype of FD patients. Patients and methods. We enrolled 80 adult FD patients with a-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the a-GalA 3Dstructure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment. Results. Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. a-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women). Conclusions. The type of amino acid exchange location in the a-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.

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The clinical utility of total concentration of urinary globotriaosylsphingosine plus its analogues in the diagnosis of Fabry disease

Cited by 14 publications

References 22 publications

Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease

Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease

Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure

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