Коррекция двигательных и поведенческих функций в лечении и реабилитации больных шизотипическим расстройством

На основании особенностей невербального поведения больных шизотипическим расстройством разработаны поведенческие методы, применение которых в их комплексной терапии позволяет добиться более полной редукции психопатологической симптоматики.Behavioral methods were worked out basing of the peculiarities of non−verbal behavior of the patients with schizotypical disorders. The use of the methods in complex therapy allows to achieve more complete reduction in psychopathological signs

Altered Chromosomal Positioning, Compaction, and Gene Expression with a Lamin A/C Gene Mutation

Lamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression.To investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction.These data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered

Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy.

OBJECTIVES: We sought to further define the role of sarcomere mutations in dilated cardiomyopathy (DCM) and associated clinical phenotypes. BACKGROUND: Mutations in several contractile proteins contribute to DCM, but definitive evidence for the roles of most sarcomere genes remains limited by the lack of robust genetic support. METHODS: Direct sequencing of 6 sarcomere genes was performed on 334 probands with DCM. A novel D230N missense mutation in the gene encoding alpha-tropomyosin (TPM1) was identified. Functional assessment was performed by the use of an in vitro reconstituted sarcomere complex to evaluate ATPase regulation and Ca(2+) affinity as correlates of contractility. RESULTS: TPM1 D230N segregated with DCM in 2 large unrelated families. This mutation altered an evolutionarily conserved residue and was absent in >1,000 control chromosomes. In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca(2+) sensitivity, maximum activation, and Ca(2+) affinity compared with wild-type TPM1. Clinical manifestations ranged from decompensated heart failure or sudden death in those presenting early in life to asymptomatic left ventricular dysfunction in those diagnosed during adulthood. Notably, several affected infants had remarkable improvement. CONCLUSIONS: Genetic segregation in 2 unrelated families and functional analyses conclusively establish a pathogenic role for TPM1 mutations in DCM. In vitro results demonstrate contrasting effects of DCM and hypertrophic cardiomyopathy mutations in TPM1, suggesting that specific functional consequences shape cardiac remodeling. Along with previous reports, our data support a distinctive, age-dependent phenotype with sarcomere-associated DCM where presentation early in life is associated with severe, sometimes lethal, disease. These observations have implications for the management of familial DCM

Familial Dilated Cardiomyopathy Caused by an Alpha-Tropomyosin Mutation: The Distinctive Natural History of Sarcomeric DCM

OBJECTIVES: We sought to further define the role of sarcomere mutations in dilated cardiomyopathy (DCM) and associated clinical phenotypes. BACKGROUND: Mutations in several contractile proteins contribute to DCM, but definitive evidence for the roles of most sarcomere genes remains limited by the lack of robust genetic support. METHODS: Direct sequencing of 6 sarcomere genes was performed on 334 probands with DCM. A novel D230N missense mutation in the gene encoding alpha-tropomyosin (TPM1) was identified. Functional assessment was performed by the use of an in vitro reconstituted sarcomere complex to evaluate ATPase regulation and Ca(2+) affinity as correlates of contractility. RESULTS: TPM1 D230N segregated with DCM in 2 large unrelated families. This mutation altered an evolutionarily conserved residue and was absent in >1,000 control chromosomes. In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca(2+) sensitivity, maximum activation, and Ca(2+) affinity compared with wild-type TPM1. Clinical manifestations ranged from decompensated heart failure or sudden death in those presenting early in life to asymptomatic left ventricular dysfunction in those diagnosed during adulthood. Notably, several affected infants had remarkable improvement. CONCLUSIONS: Genetic segregation in 2 unrelated families and functional analyses conclusively establish a pathogenic role for TPM1 mutations in DCM. In vitro results demonstrate contrasting effects of DCM and hypertrophic cardiomyopathy mutations in TPM1, suggesting that specific functional consequences shape cardiac remodeling. Along with previous reports, our data support a distinctive, age-dependent phenotype with sarcomere-associated DCM where presentation early in life is associated with severe, sometimes lethal, disease. These observations have implications for the management of familial DCM

Desmoplakin cardiomyopathy, a fibrotic and inflammatory form of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathy

Background: Mutations in desmoplakin (DSP), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of DSP cardiomyopathy have been limited to small case series. Methods: Clinical and genetic data were collected on 107 patients with pathogenic DSP mutations and 81 patients with pathogenic plakophilin 2 (PKP2) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed. Results: DSP and PKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with DSP (55% versus 0% for PKP2, P<0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with DSP versus 40% for PKP2 (P<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for DSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for DSP cases (P<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for PKP2 cases (P<0.001) but was poorly associated for DSP cases (P=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (91%) groups (P=non-significant). Conclusions: DSP cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used