The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes.

Hypertrophic Cardiomyopathy and Primary Restrictive Cardiomyopathy: Similarities, Differences and Phenocopies.

Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These "sarcomeric cardiomyopathies" also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with HCM and primary RCM may coexist in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology has been recently described and supports the hypothesis that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy.

Co-inheritance of mutations associated with arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically distinct disorders of the myocardium. Here we describe for the first time co-inheritance of mutations in genes associated with ACM or HCM in two families with recurrence of both cardiomyopathies. Among the double heterozygotes for mutations in desmoplakin (DSP) and myosin binding protein C (MYBPC3) genes identified in Family A, two were diagnosed with ACM and two with HCM.

Mutations in NEBL encoding the cardiac Z-disk protein nebulette are associated with various cardiomyopathies.

Introduction: Transgenic mice overexpressing mutated NEBL, encoding the cardiac-specific Z-disk protein nebulette, develop severe cardiac phenotypes. Since cardiomyopathies are commonly familial and because mutations in a single gene may result in variable phenotypes, we tested the hypothesis that NEBL mutations are associated with cardiomyopathy.

Material And Methods: We analyzed 389 patients, including cohorts of patients with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and left ventricular non-compaction cardiomyopathy (LVNC).

Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy.

Objective: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset.

A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life.

Background: Mutations in the cardiac myosin binding protein C (MYBPC3) gene account for a significant proportion of patients affected with hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the penetrance and the impact of a frequent founder MYBPC3 mutation on HCM clinical expression and prognosis.

Methods And Results: Mutation screening of MYBPC3 gene was performed in 97 HCM probands.

No evidence of cardiomyopathy in spinal and bulbar muscular atrophy.

Objectives: Spinal and bulbar muscular atrophy (SBMA) is a lower motor neuron disease caused by a CAG repeat expansion within the androgen receptor (AR) gene. Toxic nuclear accumulation of mutant AR has been observed in tissues other than nervous system including cardiac muscle. Moreover, CAG polymorphism length within AR has been associated with an increased risk of heart disease.

Pilot trial of clenbuterol in spinal and bulbar muscular atrophy.

Objective: To test the efficacy and tolerability of clenbuterol in patients with spinal and bulbar muscular atrophy (SBMA).

Methods: Twenty patients with a diagnosis of SBMA were given oral clenbuterol (0.04 mg/d) for 12 months.

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy.

Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan (α-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients.

Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice.

Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease (1/500) and the most common cause of sudden cardiac death in young people. Pathogenic mutation detection of HCM is having a growing impact on the medical management of patients and their families. However, the remarkable genetic and allelic heterogeneity makes molecular analysis by conventional methods very time-consuming, expensive and difficult to realise in a routine diagnostic molecular laboratory.

Consensus statement on standard of care for congenital muscular dystrophies.

Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse.

Cardiac findings in congenital muscular dystrophies.

Cardiac involvement (CI) in congenital muscular dystrophies (CMDs) has been only rarely investigated so far. By means of a systematic literature search we reviewed the literature about CI in CMD and found that CI is apparently absent in Ullrich CMD or CMD with integrin deficiency and only mild in Bethlem CMD. CI in merosin deficiency includes dilated cardiomyopathy and systolic dysfunction.

Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy.

Aims: Hypertrophic cardiomyopathy (HCM) is an important cause of heart failure-related disability over a wide range of ages. Profiles of severe progressive heart failure symptoms and death, or heart transplantation deserve more complete definition within large patient cohorts.

Methods And Results: Clinical and morphological features of heart failure were assessed in 293 consecutive HCM patients over a median follow-up of 6 (inter-quartile range 2-11) years.

Risk of arrhythmias in myotonic dystrophy: trial design of the RAMYD study.

Objective: Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy in adults. DM1 is a multisystem disorder also affecting the heart with an increased incidence of sudden death, which has been explained with the common impairment of the conduction system often requiring pacemaker implantation; however, the occurrence of sudden death despite pacemaker implantation and the observation of major ventricular arrhythmias generated the hypothesis that ventricular arrhythmias may play a causal role as well. The aim of the study was to assess the 2-year cumulative incidence and the value of noninvasive and invasive findings as predictive factors for sudden death, resuscitated cardiac arrest, ventricular fibrillation, sustained ventricular tachycardia and severe sinus dysfunction or high-degree atrioventricular block.

Risk of arrhythmia in type I myotonic dystrophy: the role of clinical and genetic variables.

Objective: To examine the association between the presence of arrhythmia in type 1 myotonic dystrophy (DM1) and clinical-genetic variables, evaluating their role as predictors of the risk of arrhythmia.

Methods: 245 patients with genetically proven DM1 underwent clinical and non-invasive cardiological evaluation. Severity of muscular involvement was assessed according to the 5 point Muscular Disability Rating Score (MDRS).

Cardiovascular magnetic resonance signs of ischemia in hypertrophic cardiomyopathy.

Background: Recurrent myocardial ischemia has been recognized as playing an important role in the pathophysiology of hypertrophic cardiomyopathy (HCM) and cardiovascular magnetic resonance (CMR), with or without gadolinium, is a promising method of evaluating fibrosis, edema and hypoperfusion. The aim of this study is to evaluate the interrelationship between late enhancement (LE) and other signs of ischemia, such as edema and perfusion defects, and to relate them to clinical data in order to describe the stage of the disease.

Methods: Forty-four patients were evaluated by CMR cine images, T2-weighted sequences for edema and LE sequences.

Evidence that pharmacological strategies lack efficacy for the prevention of sudden death in hypertrophic cardiomyopathy.

Objective: To determine the efficacy of pharmacological treatment in the prevention of sudden cardiac death in hypertrophic cardiomyopathy (HCM).

Design: Clinical outcome was assessed retrospectively in 293 patients with HCM, including 173 who were taking cardioactive medications.

Setting: Department of Cardiology, University of Padua, Padua, Italy; a tertiary HCM Centre.

MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy.

In order to characterize, at the clinical, molecular and imaging level, myopathies due to MYH7 gene mutations, MYH7 gene analysis was conducted by RT-PCR/SSCP/sequencing in two patients diagnosed with myosin storage myopathy and 17 patients diagnosed with scapulo-peroneal myopathy of unknown etiology. MYH7 gene studies revealed the 5533C>T mutation (Arg1845Trp) in both myosin storage myopathy and in 2 of the 17 scapulo-peroneal patients studied. 5533C>T segregation analysis in the mutation carrier families identified 11 additional patients.

Generalized lysosome-associated membrane protein-2 defect explains multisystem clinical involvement and allows leukocyte diagnostic screening in Danon disease.

Danon disease, an X-linked dominant disorder, results from mutations in the lysosome-associated membrane protein-2 (LAMP2) gene and presents with hypertrophic cardiomyopathy, skeletal myopathy, and mental retardation. To investigate the effects of LAMP2 gene mutations on protein expression in different tissues, we screened LAMP2 gene mutations and LAMP-2 protein deficiency in the skeletal muscle of nine unrelated patients with hypertrophic cardiomyopathy and vacuolar myopathy. We identified three novel families (including one affected mother) with unreported LAMP2 gene null mutations and LAMP-2 protein deficiency in skeletal and myocardial muscle, leukocytes, and fibroblasts.

Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I.

Background: Limb-girdle muscular dystrophy type 2I is caused by mutations in the fukutin-related protein gene (FKRP). FKRP encodes a putative glycosyltransferase protein that is involved in alpha-dystroglycan glycosylation.

Objectives: To identify patients with limb-girdle muscular dystrophy type 2I and to derive genotype-phenotype correlations.

LGMD2E patients risk developing dilated cardiomyopathy.

Sarcoglycan gene mutations cause various limb-girdle muscular dystrophies. The sarcoglycans are expressed both in skeletal and cardiac muscle but, surprisingly, so far only a few sarcoglycanopathy patients have had documented cardiomyopathy. We studied six patients with beta-sarcoglycanopathy.