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Duchenne muscular dystrophy (DMD) is complicated by an early and progressive left ventricular (LV) dysfunction. Despite the reduction of ejection fraction (EF) usually manifests in the second decade, subtle alterations in LV mechanics can be detected earlier. Longitudinal and circumferential LV deformation, evaluated by speckle tracking echocardiography (STE), are considered sensitive markers of early dysfunction. We retrospectively examined clinical and echocardiographic data of 32 DMD children with preserved LV function. According to the median age, patients were then divided into younger and older than 9 years, and compared to 24 age-matched healthy subjects. Six-minute-walk test (6MWT), North Star Ambulatory Assessment (NSAA), and a comprehensive cardiac evaluation were performed. Although EF was within the normal range, DMD patients had significantly lower values than healthy controls, and the same occurred for the remaining conventional systolic and diastolic indices. Global longitudinal strain (GLS) was reduced in all patients (older and younger, both p < 0.001). Global circumferential strain (GCS) was reduced only in older patients (< 0.001). Both GLS and GCS worsened with age in DMD patients (GLS p = 0.005; GCS p = 0.024). GLS was significantly worse in the apical segments and in the postero-lateral wall. GCS in the antero-septal, anterior and antero-lateral segments was significantly reduced in older patients, with a prevalent involvement of the sole septal wall in the younger boys. 6MWT appeared to be correlated inversely to GLS and directly to EF. A longitudinal evaluation should be scheduled in DMD boys to assess the global cardiac performance over time and to evaluate the impact of therapies.

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as “writer” of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann–Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein–Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.

Stage A and B heart failure (HF) include asymptomatic patients without and with structural cardiac disorder, respectively. Asymptomatic left ventricular (LV) dysfunction represents an early stage of HF that should be recognized to prevent overt HF development. Echocardiography plays a pivotal role in assessment of cardiac structure and function and represents the ideal imaging technique for screening in the general population, thanks to its availability, feasibility, and low cost. Traditional echocardiography, with LV systolic and diastolic function and cardiac remodeling assessment, is usually performed. Development of new technologies may offer additional information and insights in detection of early LV dysfunction.

S100 proteins are demonstrated to exert a protective role in the gastrointestinal tract. In the present study, we investigated whether S100B protein, that is typically expressed by enteroglial cells, is detectable in feces and could be a useful noninvasive indicator of gut chronic inflammation.This clinical prospective study included n=48 patients suffering Crohn's disease (CD) or ulcerative colitis (UC) and non IBD-controls. The clinical disease activity was evaluated using Harvey-Bradshaw or Mayo Score Index while the diagnosis of IBD was defined based on standard endoscopic and histological criteria. S100B and calprotectin were extracted and analyzed using commercial enzyme-linked immunosorbent assay (ELISA) kits.Unlike calprotectin, S100B was significantly decreased in both CD and UC compared to non IBD-patients. The strongest quantitative alterations of S100B were detected concomitantly with signs of active or quiescent disease, including high/normal expression of fecal calprotectin, mucosal damage/cryptitis, mucin depletion and inflammatory infiltrate, as defined by endoscopic evaluation and histological analysis. At the onset of disease and under no Infliximab-based therapy, the lowest was detected suggesting that S100B in feces could have a potential diagnostic value for IBD.Testing for S100B and calprotectin could be a useful screening tool to better predict IBD activity.

Contains fulltext : 81709.pdf (Publisher’s version ) (Closed access) The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi-Hunermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.

Defective activity of dosage-sensitive transcription factors (TFs) has been established to change gene expression and cause a phenotypic effect during brain development. ARX is a bifunctional transcription factor capable of activating or repressing gene transcription, whose mutations have been found in a wide spectrum of neurodevelopmental disorders ranging from severe cortical malformations to mild Intellectual Disability (ID). Here, we report that ARX is a dosage-sensitive X-linked gene whose protein acts as a concentration-dependent TF in the regulation of direct and indirect disease targets. Our results demonstrate that not only a reduction but also an extra dosage of ARX may disturb the tuneable bifunctional activity and produce brain disorders.

15q13.3 microduplication syndrome, genomic rearrangment, gentotype-phenotype correlation