Search

Background: Moyamoya angiopathy (MMA) is a rare cerebrovascular condition leading to stroke. Mutations in 15 genes have been identified in Mendelian forms of MMA, but they explain only a very small proportion of cases. Our aim was to investigate the genetic basis of MMA in consanguineous patients having unaffected parents in order to identify genes involved in autosomal recessive MMA., Methods: Exome sequencing (ES) was performed in 6 consecutive consanguineous probands having MMA of unknown etiology. Functional consequences of variants were assessed using western blot and protein 3D structure analyses., Results: Causative homozygous variants of NOS3, the gene encoding the endothelial nitric oxide synthase (eNOS), and GUCY1A3, the gene encoding the alpha1 subunit of the soluble guanylate cyclase (sGC) which is the major nitric oxide (NO) receptor in the vascular wall, were identified in 3 of the 6 probands. One NOS3 variant (c.1502 + 1G > C) involves a splice donor site causing a premature termination codon and leads to a total lack of eNOS in endothelial progenitor cells of the affected proband. The other NOS3 variant (c.1942 T > C) is a missense variant located into the flavodoxine reductase domain; it is predicted to be destabilizing and shown to be associated with a reduction of eNOS expression. The GUCY1A3 missense variant (c.1778G > A), located in the catalytic domain of the sGC, is predicted to disrupt the tridimensional structure of this domain and to lead to a loss of function of the enzyme. Both NOS3 mutated probands suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. The GUCY1A3 mutated proband presented an adult-onset MMA associated with an early-onset arterial hypertension and a stenosis of the superior mesenteric artery. None of the 3 probands had achalasia., Conclusions: We show for the first time that biallelic loss of function variants in NOS3 is responsible for MMA and that mutations in NOS3 and GUCY1A3 are causing fifty per cent of MMA in consanguineous patients. These data pinpoint the essential role of the NO pathway in MMA pathophysiology., (© 2023. The Author(s).)

Importance: Li-Fraumeni syndrome is a cancer predisposition syndrome that is associated with a high, lifelong risk of a broad spectrum of cancers that is caused by pathogenic TP53 germline variants. A definition that reflects the broad phenotypic spectrum that has evolved since the gene discovery is lacking, and mechanisms leading to phenotypic differences remain largely unknown., Objective: To define the phenotypic spectrum of Li-Fraumeni syndrome and conduct phenotype-genotype associations across the phenotypic spectrum., Design, Setting, and Participants: We analyzed and classified the germline variant data set of the International Agency for Research on Cancer TP53 database that contains data on a cohort of 3034 persons from 1282 families reported in the scientific literature since 1990. We defined the term Li-Fraumeni spectrum to encompass (1) phenotypic Li-Fraumeni syndrome, defined by the absence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting clinical Li-Fraumeni syndrome criteria; (2) Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting Li-Fraumeni syndrome testing criteria; (3) attenuated Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family with cancer who does not meet Li-Fraumeni syndrome testing criteria; and (4) incidental Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family without a history of cancer. Data analysis occurred from November 2020 to March 2021., Main Outcomes and Measures: Differences in variant distribution and cancer characteristics in patients with a germline TP53 variant who met vs did not meet Li-Fraumeni syndrome testing criteria., Results: Tumor spectra showed significant differences, with more early adrenal (n = 166, 6.5% vs n = 0), brain (n = 360, 14.17% vs n = 57, 7.46%), connective tissue (n = 303, 11.92% vs n = 56, 7.33%), and bone tumors (n = 279, 10.98% vs n = 3, 0.39%) in patients who met Li-Fraumeni syndrome genetic testing criteria (n = 2139). Carriers who did not meet Li-Fraumeni syndrome genetic testing criteria (n = 678) had more breast (n = 292, 38.22% vs n = 700, 27.55%) and other cancers, 45% of them occurring after age 45 years. Hotspot variants were present in both groups. Several variants were exclusively found in patients with Li-Fraumeni syndrome, while others where exclusively found in patients with attenuated Li-Fraumeni syndrome. In patients who met Li-Fraumeni syndrome genetic testing criteria, most TP53 variants were classified as pathogenic/likely pathogenic (1757 of 2139, 82.2%), whereas 40.4% (404 of 678) of TP53 variants identified in patients who did not meet the Li-Fraumeni syndrome genetic testing criteria were classified as variants of uncertain significance, conflicting results, likely benign, benign, or unknown., Conclusions and Relevance: The findings of this cohort study suggest that this new classification, Li-Fraumeni spectrum, is a step toward understanding the factors that lead to phenotypic differences and may serve as a model for other cancer predisposition syndromes.

Background: Adult patients with cystic fibrosis (CF) experience daily physical symptoms and disabilities that can be challenging to address for health care teams., Methods: We sought to identify the most frequent topics that CF adults need to discuss with health care teams using a custom questionnaire including 62 items., Results: Fifty patients were included, 70% men, mean age 27.6 years, with a mean body mass index of 21.8 kg/m 2 . Mean FEV 1 % was 64% of predicted value. Forty-two percent of patients selected at least one topic. The most frequently selected topics were fatigue (20%), professional or scholar worries (18%), procreation (16%), physical activities (16%) and evolution of CF disease (16%). Women were more frequently concerned about fatigue, procreation and profession/school., Conclusions: Using a custom questionnaire, we identified that CF adults express various unmet needs that extend beyond usual respiratory and nutritional concerns or treatment adherence. The interest of this questionnaire by health care team for improving therapeutic management of CF patients remains to be validated., Trial Registration: The study was registered on ClinicalTrials.gov (NCT02924818) on 5th October 2016., (© 2021. The Author(s).)

Background: Allergy, the most frequent immune disorder affecting 30% of the world's population, is the consequence of immunoglobin E (IgE) sensitization to allergens. Among the genetic factors suspected to be involved in allergy, the HLA class-II genomic region is a strong candidate., Objective: To assess the association between HLA class-II alleles and specific IgE (sIgE) sensitization to a large number of respiratory allergen molecules., Methods: The analysis relied on 927 participants of the EGEA cohort, including 497 asthmatics. The study focuses on 26 aeroallergens recognized by sIgE in at least 5% of the study population (determined with the MEDALL chip with sIgE ≥ 0.3 ISU) and 23 imputed HLA class-II alleles. For each sIgE sensitization and HLA class-II allele, we fitted a logistic regression model accounting for familial dependence and adjusted for gender, age, and genetic principal components. p-values were corrected for multiple comparisons (False Discovery Rate)., Results: Most of the 19 statistically significant associations observed regard pollen allergens (mugwort Art v 1, olive tree Ole e 1, timothy grass Phl p 2, Phl p 5 and plantain Pla l 1), three were mold allergen (Alternaria Alt a 1), and a single one regards house dust mite allergen (Der p 7). No association was observed with pet allergens. The strongest associations were found with mugwort Art v 1 (OR = 5.42 (95%CI, 3.30; 8.88), 4.14 (2.65; 6.47), 3.16 (1.88; 5.31) with DQB1*05:01, DQA1*01:01 and DRB1*01:01, respectively)., Conclusion: Our results support the important role of HLA class-II alleles as immune response genes predisposing their carriers for sensitization to various major pollen allergens., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Concerns exist that the positive association of physical activity with better lung function, which has been suggested in previous longitudinal studies in smokers, is due to reverse causation. To investigate this, we applied structural equation modeling (SEM), an exploratory approach, and marginal structural modeling (MSM), an approach from the causal inference framework that corrects for reverse causation and time-dependent confounding and estimates causal effects, on data from participants in the European Community Respiratory Health Survey (ECRHS, a multicentre European cohort study initiated in 1991-1993 with ECRHS I, and with two follow-ups: ECRHS II in 1999-2003, and ECRHS III in 2010-2014). 753 subjects who reported current smoking at ECRHS II, with repeated data on lung function at ECRHS I, II and III, physical activity at ECRHS II and III, and potential confounders at ECRHS I and II, were included in the analyses. SEM showed positive associations between physical activity and lung function in both directions. MSM suggested a protective causal effect of physical activity on lung function (overall difference in mean β (95% CI), comparing active versus non-active individuals: 58 mL (21-95) for forced expiratory volume in one second and 83 mL (36-130) for forced vital capacity). Our results suggest bi-directional causation and support a true protective effect of physical activity on lung function in smokers, after accounting for reverse causation and time-dependent confounding., Competing Interests: The authors have declared that no competing interests exist.

We report the case of a neonate with a new, previously undescribed, glucose-6-phosphate dehydrogenase (G6PD) gene mutation, which was revealed by severe cholestasis, hyperbilirubinemia, and transient liver dysfunction. The severity of the clinical phenotype with ongoing chronic hemolytic anemia suggests that this mutation belongs to class 1 G6PD deficiency. The hemizygous mutation «c.675G>c; p.Trp225Cys» was detected by genomic sequencing. Since severe G6PD deficiency can be revealed by cholestasis, it is important to check G6PD enzyme activity when faced with a case of liver dysfunction in the neonatal period., (Copyright © 2019. Published by Elsevier Masson SAS.)

Introduction: Medulloblastoma is the most common malignant cerebral tumor during childhood, arising in the posterior fossa. Children treated for medulloblastoma often experience working memory (WM) deficits, affecting their quality of life and school performance. The aim of the present study undertaken to describe the cerebellar involvement in WM deficits observed in these children., Material and Methods: 23 healthy children and 11 children treated for medulloblastoma were included into study. All subjects performed a detailed neuropsychological examination, an anatomical and functional MRI. Stimuli were presented to the participants with alternating sensory modality and nature of communication in a block design during functional magnetic resonance imaging acquisitions. Non-parametric tests were used for analyzing neuropsychological and behavioral data. SPM8 and SUIT (Spatially Unbiased Atlas Template) were used for anatomical and functional MRI data analyses., Results: Patients had cerebellar resections mainly located in the left posterior lobe. Patients had significantly reduced intelligence quotient, central executive and visuospatial WM. In healthy children group, fMRI showed activations for non-verbal and visuospatial WM in the left posterior cerebellar lobe., Conclusion: This study provides further evidence that left posterior cerebellar lobe plays a critical role in WM. Indeed, lesions of left posterior cerebellar lobe were associated with WM impairment in children treated for cerebellar medulloblastoma. Additionally, fMRI using WM tasks showed activation in the left posterior cerebellar lobe in healthy children. Taken together, these findings may help for improving treatment and rehabilitation of children referred for cerebellar tumor., (Copyright © 2019. Published by Elsevier Masson SAS.)

Neonatal severe protein C deficiency is a serious disease. There is no uniform approach for long-term preventive treatment of thrombotic events. We report the case of neonatal severe protein C deficiency treated with warfarin oral suspension. An international normalized ratio (INR) from 2.5 to 3.5 was expected. The INR was measured by home monitoring using the Coaguchek XS ® (Roche Diagnostics, Mannheim, Germany) monitor. During 2years of warfarin treatment, there were only two minor episodes of purpuric access and no bleeding was reported. This case suggests that the early introduction of warfarin oral suspension, home-care monitoring, and parental education programs may be a beneficial treatment option for children with protein C deficiency., (Copyright © 2017. Published by Elsevier SAS.)

Some patients with microvillus inclusion disease due to myosin 5B (MYO5B) mutations may develop cholestasis characterized by a progressive familial intrahepatic cholestasis-like phenotype with normal serum gamma-glutamyl transferase activity. So far MYO5B deficiency has not been reported in patients with such a cholestasis phenotype in the absence of intestinal disease. Using a new-generation sequencing approach, we identified MYO5B mutations in five patients with progressive familial intrahepatic cholestasis-like phenotype with normal serum gamma-glutamyl transferase activity without intestinal disease., Conclusion: These data show that MYO5B deficiency may lead to isolated cholestasis and that MYO5B should be considered as an additional progressive familial intrahepatic cholestasis gene. (Hepatology 2017;65:164-173)., (© 2016 by the American Association for the Study of Liver Diseases.)