Expanding the clinical and genetic spectrum of ALPK3 variants: phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants

Introduction Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined.Methods and Results We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults.Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-1 6.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6x10(-5); U.S. cohort, P = 2.2x10(-13)).Conclusion Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.Genetics of disease, diagnosis and treatmen

Biallelic loss of human CTNNA2, encoding ?N-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration

PubMedID: 30013181Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding ?N-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The ?N-catenin paralog, ?E-catenin, acts as a switch regulating the balance between ß-catenin and Arp2/3 actin filament activities 1 . Loss of ?N-catenin did not affect ß-catenin signaling, but recombinant ?N-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of ?N-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons. © 2018, The Author(s).R01NS048453, P01HD070494, R01NS041537, P30NS047101, R01NS052455 Qatar National Research Fund: 6-1463-351 Howard Hughes Medical Institute Brain and Behavior Research Foundation R00HD082337 National Alliance for Research on Schizophrenia and Depression Simons Foundation Autism Research InitiativeWe thank the patients and their families for participation. We thank A. Wynshaw-Boris for generous scientific and editorial input. The research was supported by NIH R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101, Qatar National Research Fund number 6-1463-351, the Simons Foundation Autism Research Initiative, and the Howard Hughes Medical Institute (to J.G.G). A.E.S. is a recipient of an A.P. Giannini Fellowship and an NIH Pathway to Independence Award, R00HD082337. S.T.B. is supported by a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. We thank the Broad Institute and Yale Center for Mendelian Disorders (UMIHG008900 to D. MacArthur and H. Rehm, and UMIHG006504 to R. Lifton and M.G.), and the Gregory M. Kiez and Mehmet Kutman Foundation (to M.G). We acknowledge M. Gerstein, S. Mane, A. B. Ekici, and S. Uebe for sequencing support and analysis, the Yale Biomedical High Performance Computing Center for data analysis and storage, the Yale Program on Neurogenetics, and the Yale Center for Human Genetics and Genomics. Exome data have been deposited into the database of Genotypes and Phenotypes (phs000288)

Human COQ4 deficiency: Delineating the clinical, metabolic and neuroimaging phenotypes.

Background Human coenzyme Q4 (COQ4) is essential for coenzyme Q(10) (CoQ(10)) biosynthesis. Pathogenic variants in COQ4 cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency. Methods Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed. Results We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ(10) and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. Conclusion Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ(10) supplementation, alternative treatment strategies are warranted

Trapidil, an inhibitor for phosphodiesterase and platelet-derived-growth factor, ameliorates corrosive esophageal burn in rats

WOS: 000232286600004PubMed: 16210831Corrosive esophageal burn is a common health problem in the pediatric age group and causes serious esophageal injuries. The medical treatment In acute phase of corrosive esophageal injury is of particular importance for prevention of esophageal stricture. We therefore aimed to investigate the possible beneficial effect of trapidil (triazolopyrimidine), an inhibitor for phosphodiesterase and platelet-derived-growth-factor, during acute phase of esophageal corrosive injury. Wistar albino rats were randomly allocated to untreated, treated, and sham-operated groups (n = 10 for each group). Corrosive esophageal burn was generated with 10% NaOH solution. The rats were left untreated (untreated group) or treated with trapidil as a single dose of 40 mg/kg intraperitoneally after one hour of the injury (treated group). Abdominal esophageal segment was isolated and tied in sham-control group. The studied esophageal segment was removed from each animal after 24 hours. Malondialdehyde (MDA) and nitric oxide (NO) levels were measured in the esophageal tissues. The ulcer depth was graded by histopathologic examination. MDA and NO levels were significantly higher in the untreated group than in the treated group. Namely, trapidil treatment significantly decreased MDA and NO levels in the injured tissues, the levels of which are similar to those in the tissues of control animals. The grades of ulcer depth were significantly improved in the treated group. These results indicate that the reactive oxygen radicals increase in the early phase of corrosive esophagitis and cause tissue damage. We suggest that trapidil treatment may be useful in acute phase of corrosive esophageal injury

Contemporary Presentation and Management of Valvular Heart Disease The EURObservational Research Programme Valvular Heart Disease II Survey

International audienceBackground: Valvular heart disease (VHD) is an important cause of mortality and morbidity and has been subject to important changes in management. The VHD II survey was designed by the EURObservational Research Programme of the European Society of Cardiology to analyze actual management of VHD and to compare practice with guidelines. Methods: Patients with severe native VHD or previous valvular intervention were enrolled prospectively across 28 countries over a 3-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients, corresponding to Class I recommendations specified in the 2012 European Society of Cardiology and in the 2014 American Heart Association/American College of Cardiology VHD guidelines. Results: A total of 7247 patients (4483 hospitalized, 2764 outpatients) were included in 222 centers. Median age was 71 years (interquartile range, 62-80 years); 1917 patients (26.5%) were >= 80 years; and 3416 were female (47.1%). Severe native VHD was present in 5219 patients (72.0%): aortic stenosis in 2152 (41.2% of native VHD), aortic regurgitation in 279 (5.3%), mitral stenosis in 234 (4.5%), mitral regurgitation in 1114 (21.3%; primary in 746 and secondary in 368), multiple left-sided VHD in 1297 (24.9%), and right-sided VHD in 143 (2.7%). Two thousand twenty-eight patients (28.0%) had undergone previous valvular intervention. Intervention was performed in 37.0% and scheduled in 26.8% of patients with native VHD. The decision for intervention was concordant with Class I recommendations in symptomatic patients with severe single left-sided native VHD in 79.4% (95% CI, 77.1-81.6) for aortic stenosis, 77.6% (95% CI, 69.9-84.0) for aortic regurgitation, 68.5% (95% CI, 60.8-75.4) for mitral stenosis, and 71.0% (95% CI, 66.4-75.3) for primary mitral regurgitation. Valvular interventions were performed in 2150 patients during the survey; of them, 47.8% of patients with single left-sided native VHD were in New York Heart Association class III or IV. Transcatheter procedures were performed in 38.7% of patients with aortic stenosis and 16.7% of those with mitral regurgitation. Conclusions: Despite good concordance between Class I recommendations and practice in patients with aortic VHD, the suboptimal number in mitral VHD and late referral for valvular interventions suggest the need to improve further guideline implementation