scholarly journals Phenotypic Features and Genetic Findings in a Cohort of Italian Pseudoxanthoma Elasticum Patients and Update of the Ophthalmologic Evaluation Score

2021 ◽  
Vol 10 (12) ◽  
pp. 2710
Author(s):  
Federica Boraldi ◽  
Vittoria Murro ◽  
Francesco Demetrio Lofaro ◽  
Dario Pasquale Mucciolo ◽  
Sonia Costa ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Pseudoxanthoma Elasticum ◽  
Posterior Pole ◽  
Optic Disk ◽  
Ectopic Calcification ◽  
Sequence Variants ◽  
Number Of Patients ◽  
Optic Disk Drusen ◽  
Italian Origin ◽  
Rare Sequence

Background: Pseudoxanthoma elasticum (PXE) is a rare ectopic calcification genetic disease mainly caused by ABCC6 rare sequence variants. The clinical phenotype is characterized by typical dermatological, ophthalmological and cardiovascular manifestations, whose frequency and severity are differently reported in the literature. Methods: A retrospective study was performed on 377 PXE patients of Italian origin, clinically evaluated according to the Phenodex Index, who underwent ABCC6 biomolecular analyses. Moreover, 53 PXE patients were further characterized by in-depth ophthalmological examinations. Results: A total of 117 different ABCC6 rare sequence variants were detected as being spread through the whole gene. The severity of the clinical phenotype was dependent on age, but it was not influenced by gender or by the type of sequence variants. In-depth ophthalmological examinations focused on the incidences of coquille d’oeuf, comet lesions, pattern dystrophy-like lesions, optic disk drusen and posterior-pole atrophy. Conclusion: Given the large number of patients analyzed, we were able to better evaluate the occurrence of less frequent alterations (e.g., stroke, myocardial infarction, nephrolithiasis). A more detailed description of ophthalmological abnormalities allowed us to stratify patients and better evaluate disease progression, thus suggesting a further update of the PXE score system.

scholarly journals From Clinical Diagnosis to the Discovery of Multigene Rare Sequence Variants in Pseudoxanthoma elasticum: A Case Report

2021 ◽  
Vol 8 ◽  
Author(s):  
Francesco Demetrio Lofaro ◽  
Dario Pasquale Mucciolo ◽  
Vittoria Murro ◽  
Laura Pavese ◽  
Daniela Quaglino ◽  
...  
Keyword(s):  
Rare Variants ◽  
Wide Spectrum ◽  
Personalised Medicine ◽  
Pseudoxanthoma Elasticum ◽  
Future Perspective ◽  
Sequence Variant ◽  
Sequence Variants ◽  
Generation Sequencing ◽  
Rare Autosomal Recessive Disease ◽  
Rare Sequence

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disease clinically characterised by early cutaneous alterations, and by late clinically relevant ocular, and cardiovascular manifestations. ABCC6 genetic tests are used to confirm clinical PXE diagnosis, but this strategy may be rather challenging when only one ABCC6 pathogenic variant is found. A next-generation sequencing approach focusing on 362 genes related to the calcification process and/or to inherited retinal diseases was performed on a patient with clinical PXE diagnosis (skin papules and laxity, angioid streaks, and atrophy) who was carrier of only one ABCC6 rare sequence variant. Beside ABCC6, several rare sequence variants were detected which can contribute either to the occurrence of calcification (GGCX and SERPINF1 genes) and/or to ophthalmological manifestations (ABCA4, AGBL5, CLUAP1, and KCNV2 genes). This wide-spectrum analysis approach facilitates the identification of rare variants possibly involved in PXE, thus avoiding invasive skin biopsy as well as expensive and time-consuming diagnostic odyssey and allows to broaden and to deepen the knowledge on this complex rare disease and to improve patients' counselling, also with a future perspective of personalised medicine.

scholarly journals Disruption of Abcc6 Transporter in Zebrafish Causes Ocular Calcification and Cardiac Fibrosis

2020 ◽  
Vol 22 (1) ◽  
pp. 278
Author(s):  
Jianjian Sun ◽  
Peilu She ◽  
Xu Liu ◽  
Bangjun Gao ◽  
Daqin Jin ◽  
...  
Keyword(s):  
Vitamin K ◽  
Cardiac Fibrosis ◽  
Clinical Manifestations ◽  
Pseudoxanthoma Elasticum ◽  
Matrix Gla Protein ◽  
Ectopic Calcification ◽  
Transcription Activator ◽  
Multisystem Disorder ◽  
Ectopic Mineralization ◽  
Extensive Calcification

Pseudoxanthoma elasticum (PXE), caused by ABCC6/MRP6 mutation, is a heritable multisystem disorder in humans. The progressive clinical manifestations of PXE are accompanied by ectopic mineralization in various connective tissues. However, the pathomechanisms underlying the PXE multisystem disorder remains obscure, and effective treatment is currently available. In this study, we generated zebrafish abcc6a mutants using the transcription activator-like effector nuclease (TALEN) technique. In young adult zebrafish, abcc6a is expressed in the eyes, heart, intestine, and other tissues. abcc6a mutants exhibit extensive calcification in the ocular sclera and Bruch’s membrane, recapitulating part of the PXE manifestations. Mutations in abcc6a upregulate extracellular matrix (ECM) genes, leading to fibrotic heart with reduced cardiomyocyte number. We found that abcc6a mutation reduced levels of both vitamin K and pyrophosphate (PPi) in the serum and diverse tissues. Vitamin K administration increased the gamma-glutamyl carboxylated form of matrix gla protein (cMGP), alleviating ectopic calcification and fibrosis in vertebrae, eyes, and hearts. Our findings contribute to a comprehensive understanding of PXE pathophysiology from zebrafish models.

Pediatric optic disk drusen: a retrospective study of 63 children

2021 ◽  
Vol 25 (4) ◽  
pp. e49
Author(s):  
Barrett N. Thompson ◽  
Garrett C. Nix ◽  
Lauren C. Ditta ◽  
Mary E. Hoehn ◽  
Natalie C. Kerr
Keyword(s):  
Retrospective Study ◽  
Optic Disk ◽  
Optic Disk Drusen

Atypical presentation of pseudoxanthoma elasticum with abdominal cutis laxa: Evidence for a spectrum of ectopic calcification disorders?

2011 ◽  
Vol 155 (11) ◽  
pp. 2855-2859 ◽  
Author(s):  
Olivier M. Vanakker ◽  
Bart P. Leroy ◽  
Leon J. Schurgers ◽  
Cees Vermeer ◽  
Paul J. Coucke ◽  
...  
Keyword(s):  
Pseudoxanthoma Elasticum ◽  
Cutis Laxa ◽  
Ectopic Calcification ◽  
Atypical Presentation

scholarly journals Pathogenic Effect of GDAP1 Gene Mutations in a Yeast Model

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 310 ◽  
Author(s):  
Weronika Rzepnikowska ◽  
Joanna Kaminska ◽  
Dagmara Kabzińska ◽  
Andrzej Kochański
Keyword(s):  
Gene Mutations ◽  
Causative Mutation ◽  
Mitochondrial Morphology ◽  
Clinical Genetics ◽  
Sequence Variant ◽  
Sequence Variants ◽  
Pathogenic Variants ◽  
Pathogenic Effect ◽  
And Function ◽  
Rare Sequence

The question of whether a newly identified sequence variant is truly a causative mutation is a central problem of modern clinical genetics. In the current era of massive sequencing, there is an urgent need to develop new tools for assessing the pathogenic effect of new sequence variants. In Charcot-Marie-Tooth disorders (CMT) with their extreme genetic heterogeneity and relatively homogenous clinical presentation, addressing the pathogenic effect of rare sequence variants within 80 CMT genes is extremely challenging. The presence of multiple rare sequence variants within a single CMT-affected patient makes selection for the strongest one, the truly causative mutation, a challenging issue. In the present study we propose a new yeast-based model to evaluate the pathogenic effect of rare sequence variants found within the one of the CMT-associated genes, GDAP1. In our approach, the wild-type and pathogenic variants of human GDAP1 gene were expressed in yeast. Then, a growth rate and mitochondrial morphology and function of GDAP1-expressing strains were studied. Also, the mutant GDAP1 proteins localization and functionality were assessed in yeast. We have shown, that GDAP1 was not only stably expressed but also functional in yeast cell, as it influenced morphology and function of mitochondria and altered the growth of a mutant yeast strain. What is more, the various GDAP1 pathogenic sequence variants caused the specific for them effect in the tests we performed. Thus, the proposed model is suitable for validating the pathogenic effect of known GDAP1 mutations and may be used for testing of unknown sequence variants found in CMT patients.

scholarly journals Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea

2020 ◽  
Author(s):  
Angela Delaney ◽  
Adam B Burkholder ◽  
Christopher A Lavender ◽  
Lacey Plummer ◽  
Veronica Mericq ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Sequence Variants ◽  
Hypothalamic Amenorrhea ◽  
Individual Susceptibility ◽  
The Face ◽  
Stress Variability ◽  
And Function ◽  
And Control ◽  
Previous Identification ◽  
Rare Sequence

Abstract Context Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. Objective We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. Design We compared patients with HA to control women. Setting The study was conducted at secondary referral centers. Patients and Other Participants Women with HA (n = 106) and control women (ClinSeq study; n = 468). Interventions We performed exome sequencing in all patients and controls. Main Outcome Measure(s) The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. Results RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). Conclusions Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.

scholarly journals Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Lazar Velicki ◽  
Djordje G. Jakovljevic ◽  
Andrej Preveden ◽  
Miodrag Golubovic ◽  
Marija Bjelobrk ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Clinical Phenotype ◽  
Genetic Disorder ◽  
Positive Family History ◽  
Mitral Annulus ◽  
Genetic Determinants ◽  
Myosin Binding Protein ◽  
Number Of Patients ◽  
History Of ◽  
The Difference

Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations. Methods As a part of the international multidisciplinary SILICOFCM project (www.silicofcm.eu) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography. Results The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p = 0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p = 0.085). Laboratory analyses revealed normal levels of creatinine (85.5 ± 18.3 vs. 81.3 ± 16.4 µmol/l; p = 0.487) and blood urea nitrogen (10.2 ± 15.6 vs. 6.9 ± 3.9 mmol/l; p = 0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p = 0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p = 0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p = 0.001). The difference in diastolic function, i.e. E/e′ ratio between the two groups was also noted (MYBPC3 8.8 ± 3.3, MYH7 13.9 ± 6.9, p = 0.079). Conclusions Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.

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