Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.

Background-The influence of age on the main epidemiological, clinical, echocardiographic, microbiological, and prognostic features of patients with infective endocarditis remains unknown. We present the series with the largest numbers and range of ages of subjects to date that analyzes the influence of age on the main characteristics of patients with isolated left-sided infective endocarditis. Furthermore, this series is the first one in which patients have been distributed according to age quartile. Methods and Results-A total of 600 episodes of left-sided endocarditis consecutively diagnosed in 3 tertiary centers were stratified into age-specific quartiles and 107 variables compared between the different groups. With increasing age, the percentage of women, previous heart disease, predisposing disease (diabetes mellitus and cancer), and infection by enterococci and Streptococcus bovis also increased. Valvular insufficiency and perforation and Staphylococcus aureus infection were more common in younger patients. The therapeutic approach differed depending on patient age because of the growing proportion of older patients who only received medical treatment. Clinical course and hospital prognosis were worse in the older patients because of increased surgical mortality among them. Conclusions-Increasing age is associated with less valvular impairment (insufficiency and perforation), a more favorable microbiological profile, and increased surgical mortality among adults with left-sided infective endocarditis. (Circulation. 2010;121:892-897.)

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ObjectiveBicuspid aortic valve (BAV) is the most common congenital heart disease. This study aimed to determine the prevalence rate of BAV in first-degree relatives (FDR) and the inheritance pattern according to different morphotypes and aortic dilation.MethodsBAV probands were consecutively studied at eight tertiary referral centres. After sequential screening, FDR were included in the study. The BAV morphotype, aortic dilation and aortic phenotype were assessed by transthoracic echocardiography.ResultsSeven hundred and twenty-four FDR of 256 BAV probands agreed to undergo family screening. The prevalence of BAV was 6.4% in FDR (9.2% in men, 3.5% in women, p=0.002). Aortic dilation was diagnosed in 9.6% of FRD with tricuspid aortic valves (TAV), with a root phenotype in 2.7% and tubular in 6.9% and more frequently in the presence of arterial hypertension (OR 4.48; CI 95% 2.51 to 7.99; p=0.0001) and valvular regurgitation (OR 5.87, CI 95% 1.37 to 25.16; p=0.025). The heritability (h2 ) of BAV was highly significant (0.47; p=0.002); however, no concordance was observed among valve morphotypes. Aortic dilation heritability was not significant.ConclusionsThe BAV prevalence rate in FDR was low (6.4%) but aortic dilation was observed in 9.6% of FDR with TAV. The heritability of BAV was high without concordance in valve morphotypes, and aortic dilation heritability was not observed. Patients with BAV should be made aware of its familial pattern.

From an epidemiologic point of view, right-sided infective endocarditis (RSIE) affects different types of patients: intravenous drug users (IDUs), cardiac device carriers (pacemakers and implantable automatic defibrillators), and the “3 noes” endocarditis group: no left-sided, no IDUs, no cardiac devices. Our objective is to describe and compare the clinical profile and outcome of these groups of patients.Every episode of infective endocarditis (IE) consecutively diagnosed in 3 tertiary centers from 1996 to 2012 was included in an ongoing multipurpose database. We assessed 85 epidemiologic, clinical, echocardiographic, and outcome variables in patients with isolated RSIE. A bivariated comparative analysis between the 3 groups was conducted.Among 866 IE episodes, 121 were classified as isolated RSIE (14%): 36 IDUs (30%), 65 cardiac device carriers (54%), and 20 “3 noes” group (16%). IDUs were mainly young men (36 ± 7 years) without previous heart disease, few comorbidities, and frequent previous endocarditis episodes (28%). Human immunodeficiency virus infection was frequent (69%). Cardiac device carriers were older (66 ± 15 years) and had less comorbidities (34%). Removal of the infected device was performed in 91% of the patients without any death. The “3 noes” endocarditis group was composed mainly by middle-age men (56 ± 18 years), health care related infections (50%), and had many comorbidities (75%). Whereas Staphylococcus aureus were the most frequent cause in IDUs (72% vs 34% in device carriers and 34% in the “3 noes” group, P = 0.001), coagulase negative Staphylococci predominated in the device carriers (58% vs 11% in drug users and 35% in the “3 noes”, P < 0.001). Significant differences in mortality were found (17% in drug users, 3% in device carriers, and 30% in the “3 noes” group; P < 0.001).These results suggest that RSIE should be separated into 3 groups (IDUs, cardiac device carriers, and the “3 noes”) and considered as independent entities as there are relevant epidemiologic, clinical, microbiological, echocardiographic, and prognostic differences among them.

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PNH is a heterogeneous disorder involving the peripheral nerves in patients with a high propensity for developing autoimmunity. Associated muscle diseases are frequent in the form of myositis, myasthenia gravis, or nonspecific myopathic pathologic findings. VGKC-Abs were uncommon in this series.

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