Clinical and Genetic Heterogeneity in a Large Family with Pseudoxanthoma Elasticum: MTHFR and SERPINE1 Variants as Possible Disease Modifiers in Developing Ischemic Stroke. Bruno, G., Ritelli, M., Di Pietro, A., Cipriano, L., Colombi, M., Lus, G., & Puoti, G. Journal of Stroke and Cerebrovascular Diseases, 30(6):105744, April, 2021.
Clinical and Genetic Heterogeneity in a Large Family with Pseudoxanthoma Elasticum: MTHFR and SERPINE1 Variants as Possible Disease Modifiers in Developing Ischemic Stroke [link]Paper  doi  abstract   bibtex   
Background and objectives Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by pathogenic variants in the ABCC6 gene. The phenotypic spectrum of PXE is highly variable and includes principally three major features: skin lesions, eye and vascular manifestations, while brain manifestations are less common. To date about 400 different PXE associated variants in ABCC6 gene are described without any evident genotype–phenotype correlation. Herein, we report the clinical and molecular findings of a large PXE family with clinical and genetic intra-familial variability with significant cerebrovascular involvement. Methods The analysis of the ABCC6 gene was performed in the proband and her familiars for the definition of genetic background. Then, in order to determine why some affected individuals had more prominent brain involvement, we investigated classic thrombophilic gene variants. Results Molecular findings disclosed two different ABCC6 mutations, i.e., the recurrent p.(Arg518Gln) and the novel p.(Val1285Met) missense substitution responsible of a pseudo-dominant inheritance. The study of thrombophilic gene variants revealed the presence of 4G/4G SERPINE1 genotype in the proband and in her father, which both developed ischemic stroke. The proband carried also the C677T variant the MTHFR gene. Conclusion We argue, for the first time, that the 4G/4G SERPINE1 genotype could represent an additional risk factor in PXE for developing ischemic stroke, which adds up to the already known predisposing conditions. Therapeutic implications are discussed, we also advise that PXE patients should be adequately screened for cerebral vasculopathy, even more if familial history is suggestive of brain complications.
@article{bruno_clinical_2021,
	title = {Clinical and {Genetic} {Heterogeneity} in a {Large} {Family} with {Pseudoxanthoma} {Elasticum}: {MTHFR} and {SERPINE1} {Variants} as {Possible} {Disease} {Modifiers} in {Developing} {Ischemic} {Stroke}},
	volume = {30},
	issn = {1052-3057},
	shorttitle = {Clinical and {Genetic} {Heterogeneity} in a {Large} {Family} with {Pseudoxanthoma} {Elasticum}},
	url = {https://www.sciencedirect.com/science/article/pii/S1052305721001476},
	doi = {10.1016/j.jstrokecerebrovasdis.2021.105744},
	abstract = {Background and objectives
Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by pathogenic variants in the ABCC6 gene. The phenotypic spectrum of PXE is highly variable and includes principally three major features: skin lesions, eye and vascular manifestations, while brain manifestations are less common. To date about 400 different PXE associated variants in ABCC6 gene are described without any evident genotype–phenotype correlation. Herein, we report the clinical and molecular findings of a large PXE family with clinical and genetic intra-familial variability with significant cerebrovascular involvement.
Methods
The analysis of the ABCC6 gene was performed in the proband and her familiars for the definition of genetic background. Then, in order to determine why some affected individuals had more prominent brain involvement, we investigated classic thrombophilic gene variants.
Results
Molecular findings disclosed two different ABCC6 mutations, i.e., the recurrent p.(Arg518Gln) and the novel p.(Val1285Met) missense substitution responsible of a pseudo-dominant inheritance. The study of thrombophilic gene variants revealed the presence of 4G/4G SERPINE1 genotype in the proband and in her father, which both developed ischemic stroke. The proband carried also the C677T variant the MTHFR gene.
Conclusion
We argue, for the first time, that the 4G/4G SERPINE1 genotype could represent an additional risk factor in PXE for developing ischemic stroke, which adds up to the already known predisposing conditions. Therapeutic implications are discussed, we also advise that PXE patients should be adequately screened for cerebral vasculopathy, even more if familial history is suggestive of brain complications.},
	language = {en},
	number = {6},
	urldate = {2021-04-06},
	journal = {Journal of Stroke and Cerebrovascular Diseases},
	author = {Bruno, Giorgia and Ritelli, Marco and Di Pietro, Andrea and Cipriano, Lorenzo and Colombi, Marina and Lus, Giacomo and Puoti, Gianfranco},
	month = apr,
	year = {2021},
	keywords = {4G/5G, Alamut, MTHFR C677T, PAI-1, Pseudoxanthoma elasticum, SERPINE1, SOPHiA DDM, Stroke, Thrombophilia},
	pages = {105744},
}

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