X‐chromosome inactivation in female patients with Fabry disease

Echevarría, Lucía; Bénistan, Karelle; Toussaint, Anne; Dubourg, Odile; Hagege, Albert; Eladari, Dominique; Jabbour, Firas; Beldjord, Chérif; Mazancourt, Philippe de; Germain, Dominique P.

doi:10.1111/cge.12613

Cited by 331 publications

(291 citation statements)

References 60 publications

Supporting

Mentioning

248

Contrasting

Unclassified

Order By: Relevance

“…Moreover, until a few years ago the inactivation of the X chromosome was thought to be random, but today this concept has been revised. It was observed that in some females, the X chromosome inactivation is not random in all tissues but some of them show a skewed inactivation to the wild type X chromosome or the mutated one -phenomenon that, still today, is without an explanation (Echevarria et al, 2015). This results in a great clinical heterogeneity ranging from the absence of the manifestations to a severity comparable to the one of the males affected by Fabry disease (Whybra et al, 2001;MacDermot et al, 2001;Wilcox et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Molecular and clinical studies in five index cases with novel mutations in the GLA gene

Zizzo

Monte²,

Pisani

et al. 2016

Gene

View full text Add to dashboard Cite

Fabry disease is a metabolic and lysosomal storage disorder caused by the functional defect of the α-galactosidase A enzyme; this defect is due to mutations in the GLA gene, that is composed of seven exons and is located on the long arm of the X-chromosome (Xq21-22). The enzymatic deficit is responsible for the accumulation of glycosphingolipids in lysosomes of different cellular types, mainly in those ones of vascular endothelium. It consequently causes a cellular and microvascular dysfunction. In this paper, we described five novel mutations in the GLA gene, related to absent enzymatic activity and typical manifestations of Fabry disease. We identified three mutations (c.846_847delTC, p.E341X and p.C382X) that lead to the introduction of a stop codon in positions 297, 341 and 382. Moreover we found a missense mutation (p.R227P) in the exon 5 of the GLA gene and a single point mutation (c.639+5 GNT) occurring five base pairs beyond the end of the exon 4. These mutations have never been found in our group of healthy control subjects N 2300. The studied patients presented some clinical manifestations, such as cornea verticillata, hypo-anhidrosis, left ventricular hypertrophy, cerebrovascular disorders and renal failure, that, considering the null enzymatic activity, suggest that the new mutations reported here are related to the classic form of Fabry disease. The identification of novel mutations in patients with symptomatology referable to FD increases the molecular knowledge of the GLA gene and it gives clinicians an important support for the proper diagnosis of the disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular and clinical studies in five index cases with novel mutations in the GLA gene

Zizzo

Monte²,

Pisani

et al. 2016

Gene

View full text Add to dashboard Cite

show abstract

“…However, female participants in this study were not tested for X chromosome inactivation and prior studies have shown that female patients who seek medical attention are more severely affected by FD than their counterparts. 29 Otherwise, with exception of history of stroke being an independent predictor of WMHV in the 5th decade of life, the profile of WMH burden determinants appears to reflect the spectrum of accumulating comorbidities typical in the lifetime of FD. Overall, caution should be exercised in interpreting the results of subset analyses, which were exploratory in nature and based on a relatively small number of patients included in per stratum analysis, limiting the power to discover significant associations with the outcome.…”

mentioning

confidence: 89%

Determinants of white matter hyperintensity burden in patients with Fabry disease

et al. 2016

View full text Add to dashboard Cite

Objective: Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD).Methods: Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p , 0.05 for all analyses.Results: Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 6 14.9 (range 9.6-72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2. Cerebrovascular disease, including stroke, is a significant source of morbidity in patients with Fabry disease (FD), an X-linked lysosomal storage disorder characterized by reduced activity of the enzyme a-galactosidase A.1 Burden of MRI-detectable white matter hyperintensity (WMH) has been linked to risk of stroke, 2 poor poststroke outcome, 3 and functional disability in aging adults 4 ; however, there are no systematic studies of WMH in patients with FD. Previously, nonquantitative studies have documented WMH lesions in adults with FD, 5,6 pediatric patients, 7 and the Fabry Outcome Survey registry participants. 8 A comparison of CT and MRI findings in patients with FD suggested the potential utility of a rating scale in this population. 9 The recently published Stroke in Young Fabry Patients (SIFAP1) study 10 showed detailed neuroimaging MRI characteristics including WMH assessed using a validated ordinal scale 11,12 ; however, it failed to identify any FD-specific MRI characteristics.

show abstract

“…In FD heterozygotes, the α-GalA activities are often borderline normal or normal due to random X-chromosomal inactivation [3]. Our findings suggest that this biomarker may improve initial diagnose of clinically relevant FD, particularly in female patients.…”

Section: Discussionmentioning

confidence: 72%

“…These studies are limited since the sample size is relatively small and larger studies are needed to confirm our findings. In addition, the degree of random X-chromosomal inactivation is the most prominent epigenetic factor that determines if a Type 1 Classic or Type 2 Later-Onset heterozygote will be symptomatic [3]. It would be useful to correlate the degree of "Lyonization" with the LysoGb3 levels.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Plasma lyso-Gb3: a useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes

Nowak¹,

Mechtler²,

Desnick³

et al. 2017

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the -galactosidase A gene (GLA) that result in absent or markedly reduce -galactosidase A (-GalA) enzymatic activity. As a result, the major glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) accumulate in plasma, urine and tissue lysosomes. In females, the diagnosis can be complicated by the fact that 40-50% of GLA-mutation confirmed heterozygotes have normal or only slightly decreased leukocyte -GalA activities. Recently, LysoGb3 has been appreciated as a novel FD biomarker, especially for therapeutic monitoring. METHODS: Among our GLA-mutation proven FD patients, we screened 18 heterozygotes whose leukocyte -GalA activity was determined at initial diagnosis. For these females, we measured their serum LysoGb3 levels using highly-sensitive electrospray ionization liquid chromatography tandem mass spectrometry. RESULTS: We identified three unrelated females in whom the accumulating LysoGb3 was increased, whereas their leukocyte -GalA activities were in the normal range. CONCLUSION: LysoGb3 serves as an useful biomarker to improve the diagnosis of FD heterozygotes and for therapeutic evaluation and monitoring. Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the α-galactosidase A gene (GLA) that result in absent or markedly reduce α-galactosidase A (α-GalA) enzymatic activity. As a result, the major glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) accumulate in plasma, urine and tissue lysosomes. In females, the diagnosis can be complicated by the fact that 40-50% of GLA-mutation confirmed heterozygotes have normal or only slightly decreased leukocyte α-GalA activities. Recently, LysoGb3 has been appreciated as a novel FD biomarker, especially for therapeutic monitoring. Methods: Among our GLA-mutation proven FD patients, we screened 18 heterozygotes whose leukocyte α-GalA activity was determined at initial diagnosis. For these females, we measured their serum LysoGb3 levels using highly-sensitive electrospray ionization liquid chromatography tandem mass spectrometry. Results: We identified three unrelated females in whom the accumulating LysoGb3 was increased, whereas their leukocyte α-GalA activities were in the normal range. Conclusion: LysoGb3 serves as an useful biomarker to improve the diagnosis of FD heterozygotes and for therapeutic evaluation and monitoring.

show abstract

X‐chromosome inactivation in female patients with Fabry disease

Cited by 331 publications

References 60 publications

Molecular and clinical studies in five index cases with novel mutations in the GLA gene

Molecular and clinical studies in five index cases with novel mutations in the GLA gene

Determinants of white matter hyperintensity burden in patients with Fabry disease

Plasma lyso-Gb3: a useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes

Contact Info

Product

Resources

About