Clinical and Genetic Heterogeneity in a Large Family with Pseudoxanthoma Elasticum: MTHFR and SERPINE1 Variants as Possible Disease Modifiers in Developing Ischemic Stroke

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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.

Introduction

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive connective tissue disorder caused by pathogenic variants in the ABCC6 gene (MIM *603234), causing dystrophic mineralization and fragmentation of the elastic fibres. Estimated prevalence varies widely (between 1 per 25,000 and 1 per 100,000) without geographic or ethnic predilection.1, 2 PXE is a systemic disorder with a large clinical variability, (MIM #264800), characterized by three major features: skin lesions, eye and vascular manifestations. Skin lesions are usually the first and most prominent clinical sign of PXE, in the form of yellowish soft papules, often forming plaques with a cobblestone appearance, usually seen on the lateral aspect of the neck or the flexural creases.3 Eye involvement is present in 89–96% of cases and might cause severe visual impairment due to macular hemorrhage and disciform scarring of the macula. Characteristic ophthalmologic findings include peaud'orange or mottled hyper-pigmentation of the retina, angioid streaks, peripapillary atrophy and subretinal neovascularization.3,4 Vascular manifestations are determined from the medial calcification that make the arterial blood vessels fragile5 leading to hemorrhagic and ischemic events, such as gastrointestinal bleeding, intermittent claudication and rarely myocardial infarcts and stroke. Cerebral involvement is mainly due to small vessels disease and affected patients show a 3.6-fold increase of stroke risk compared to the general population.6 Herein, we report the clinical and molecular findings of a large PXE family in which two different pathogenic variants in ABCC6 determined variable genotypes that may only partially explain the intrafamilial phenotypic heterogeneity. We also discuss how classic thrombophilic gene variants could represent disease modifier factors for developing ischemic stroke in PXE.

Section snippets

Ethics statement

Clinical investigations were conducted in accordance with the ethical standards laid down in the 1964

Declaration of Helsinki and its later amendments. Molecular testing was achieved in the genetic laboratory at the Department of Molecular and Translational Medicine of the University of Brescia in compliance with the

Italian legislation on genetic diagnostic tests. Written informed consent for genetic testing, participation to the study, and publication of clinical data was obtained from all

Case Index

A 43-year-old woman (Fig. 1, IV:8) was admitted for sudden onset of perioral paresthesia one month before. Personal history revealed high blood pressure (HBP) and hypercholesterolemia both well-controlled by ramipril (dosage 5 mg/die) and statins (atorvastatin 20 mg/die). Family history was remarkable for pseudoxanthoma elasticum as her pedigree showed (Fig. 1). At the time of our first observation, the proband had normal vital signs, including blood pressure, while typical PXE skin lesions at

Mutational screening of the ABCC6 gene

The family, native of Southern Italy, consisted of 33 members (Fig. 1), whom four were clinically and genetically diagnosed with PXE. They were three siblings (IV:8, IV:9, IV:10) and their father (III:3). Four ancestors on paternal lineage were suspected of having the disease (I:2, II:2, II:4 and III:2). Ten asymptomatic individuals underwent genetic analysis for study segregation, i.e. the descendants of the three affected siblings (V:1–V:6), the proband's mother (III:4) and three cousins

Clinical assessment of the family members

Main demographic and clinical data of PXE patients are summarized in Table 1. PXE affected members, with age range of 40–75 years, were three siblings (IV:8, IV:9, IV:10, 2 females and 1 male, respectively) and their father (III:3). The first disturbance for all patients were skin lesions noticed at mean age of 34.5 ± 2.0 years (range 32–37 years). The mean age at diagnosis was 40.75 ± 2.62 (range 37–43 years). Similar skin lesions were reported also in I:2, II:2 and II:4. Ophthalmologic

Discussion

To date, a large number of PXE patients have been published and about 400 different PXE-associated pathogenic variants in ABCC6 are deposited in the LOVD and HGMD Professional. However, no genotype–phenotype correlations have emerged so far, it should be noted that there is huge phenotypic variability, both intra- and inter-familial, and the involvement of any given organ system can predominate in certain families.10, 11 Cardiovascular involvement is one of the major complications of PXE,

Acknowledgment

The authors have no acknowledgement.

Declaration of Competing Interest

None.

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