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Query: UMLS:C0018801 (heart failure)
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Two Japanese brothers with Becker muscular dystrophy were shown by polymerase chain reaction (PCR) and cDNA sequence analysis to produce a dystrophin gene transcript lacking a single exon: that is, number 13. Despite having the same deletion mutation, the brothers showed clearly different clinical phenotypes: the younger brother developed cardiac failure at the age of nine, while the elder brother was asymptomatic. As alternative splicing was not responsible for this clinical difference, the amount of dystrophin transcript was examined by using reverse transcription semi-nested and parallel PCR. The results showed that the amount of the dystrophin transcript in the younger brother was 20% of that of the elder brother. This finding suggested that lesser amount of dystrophin transcript in the younger brother was responsible for the early onset of cardiac failure. This would represent a novel molecular mechanism for dystrophinopathy.
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PMID:Early cardiac failure in a child with Becker muscular dystrophy is due to an abnormally low amount of dystrophin transcript lacking exon 13. 944 58

Duchenne/Becker muscular dystrophies (DMD/BMD) are the most common inherited muscular disease and caused by mutations in the dystrophin gene. A half to two-thirds of DMD and BMD patients carry deletions (usually of several kilobases of genomic DNA). The clinical progression in DMD and BMD patients with deletions can be predicted in 92% of cases based on whether the deletion maintains or disrupts the translational reading frame (frame-shift hypothesis). However, some exceptional cases have been reported in which some posttranscriptional modifications were suggested, such as alternative splicing and reinitiation of translation. Splicing mutation is one kind of mutations of dystrophin gene, and usually induced by a small mutation of exon-intron boundary sequence. However, intraexonal small mutation also induces exon skipping, due to disruption of an exon recognition sequence, which is an intraexonal sequence and necessary for splicing of the upstream intron. Carrier diagnosis is one of the important clinical application of genetic diagnosis. In the case of DMD/BMD with deletions of the dystrophin gene, carrier diagnosis is difficult because of the existence of normal X chromosome. In these cases a linkage analysis is useful, and in some cases non-carriers can be directly diagnosed on the basis of microsattelite polymorphism detected in deleted region of patient. For the molecular diagnosis of DMD/BMD it is important to analyze not only at the genomic DNA level, but also at the mRNA, protein, and clinical levels. And the relationship between the molecular abnormality and clinical phenotype should be examined, especially extramuscular symptoms such as heart failure and mental retardation.
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PMID:[Genetic diagnosis of Duchenne/Becker muscular dystrophy; clinical application and problems]. 954 79

Dilated cardiomyopathy (DCM) is a heart muscle disorder characterized by cardiac dilatation and impaired systolic function. In an increasing number of all DCM cases a specific etiology can be identified and in the remaining patients DCM is termed idiopathic. There is a wide variation of the clinical presentation in DCM. The majority of patients manifests classical disease, i.e. heart failure due to left (and right) ventricular systolic dysfunction. However, some cases may come to clinical attention because of supraventricular arrhythmias such as sinus node dysfunction, AV-block or atrial fibrillation. Although a multitude of etiologies may be responsible for DCM (e.g. viral, immunological, toxic), the disease is inherited as a single gene disorder in at least 20 to 35% of cases. Most genetic forms of DCM are caused by autosomal dominant gene defects. Six dominant disease loci on chromosomes 1p1-q1, 1q32, 3p22-p25, 6q23, 9q13 und 10q21-q23 have been identified but the corresponding disease genes are not yet known. X-linked DCM without skeletal muscle disease is a rare variety of adult DCM which can be caused by specific mutations in the dystrophin gene on chromosome Xp21.
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PMID:[Genetics of dilated cardiomyopathy]. 959 29

Dilated cardiomyopathy is one of the leading causes of heart failure and a primary cause for heart transplantation in patients below the age of 40 years. Despite major advances in diagnostic procedures such as examination of myocardial biopsies, the etiology remains unknown in many patients. Chronic inflammation or myocarditis and chronic alcohol abuse are considered two main etiologic factors in dilated cardiomyopathy. A third causal factor, namely genetic transmission of the disease, is at least as common as myocardial inflammation or toxic damage. Several prospective studies of relatives of patients with dilated cardiomyopathy proved that about 25-30% of all cases are of familial etiology. The most common mode of inheritance is autosomal dominant. Less frequently is the disease inherited as an X-chromosomal trait. Autosomal recessive and mitochondrial transmission is rare. The penetrance is highly variable and age dependent. Many relatives of patients with DCM show only minor cardiac abnormalities and it is unknown whether they progress to full cardiomyopathy in later life. Examination of families has identified so far eight disease genes, namely the dystrophin, tafazzin, cardiac actin, desmin, lamin A/C, delta- sarcoglycan, cardiac beta-myosin heavy chain, and cardiac troponin T gene. Certain mutations in lamin A/C cause conduction system disease and dilated cardiomyopathy, whereas other mutations cause in addition skeletal muscle myopathy. Dystrophin mutations are the cause of the rare X-linked dilated cardiomyopathy without skeletal muscle involvement and a progressive course in young men. Other mutations in the dystrophin gene, mainly deletions, are the cause of the muscular dystrophy Becker and Duchenne which also present with dilated cardiomyopathy. Mutations of the desmin, delta-sarcoglycan, the cardiac actin and beta-myosin heavy chain as well as the troponin T gene are known to cause autosomal dominant-dilated cardiomyopathy without other abnormalities. The infantile X-linked DCM is caused by mutations of the tafazzin gene. The onset of the disease is typically within the first year of life and death occurs usually in childhood. Most patients may in addition be characterized by skeletal myopathy, short stature, neutropenia and abnormal mitochondria, also referred to as Barth syndrome. Knowledge of the DCM disease genes led to the new hypothesis that dilated cardiomyopathy is a disease of the myocardial force generation or force transmission. Many more disease loci are known but the responsible disease genes are not yet identified. Better understanding of the expression and function of disease genes may eventually result in new diagnostic and therapeutic tools in order to improve the prognosis of this severe disorder.
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PMID:[Genetics of dilated cardiomyopathy]. 1151 75

Duchenne muscular dystrophy (DMD) is the most common disabling and lethal genetic muscle disorder, afflicting 1 of every 3500 males. Patients with DMD experience progressive muscle degeneration and weakness and succumb to respiratory or cardiac failure by their early twenties. No treatment is currently available for DMD. Mutations in the dystrophin gene result in lack of a functional dystrophin protein in striated muscle, which induces instability in the muscle cell membrane leading to persistent muscle injury after contraction. We have previously created novel minidystrophin genes and demonstrated that adeno-associated virus (AAV)-mediated intramuscular delivery of the minigenes effectively ameliorated mdx dystrophic histopathology and led to normal cell membrane integrity for more than 1 year. In this paper, we investigated whether AAV-minidystrophin could also improve mdx muscle contractile function. Two-month-old adult male mdx mice, with established muscular dystrophy, were given a single-dose injection of an AAV-minidystrophin vector in the tibialis anterior (TA) muscle of one leg, with the untreated contralateral leg used as a control. The treated TA muscle showed both (1) a significant increase in isometric force generation and (2) a significant increase in resistance to lengthening activation-induced muscle force decrements. We conclude that AAV-minidystrophin gene treatment is effective in improving mdx muscle contractile function.
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PMID:Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice. 1221 66

Dystrophinopathies are due to mutations in the dystrophin gene on chromosome Xp21.1 and comprise the allelic entities Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and X-linked dilative cardiomyopathy (XLDCM). In all three entities, the heart is affected to various degrees, depending on the stage of the disease and the type of the mutation (cardiac involvement, CI). The pathoanatomic evidence of CI in dystrophinopathies is the replacement of myocardium by connective tissue or fat. In DMD/BMD, the left ventricular posterobasal and lateral walls are most extensively affected, sparing the right ventricle and the atrium. Degree and dynamics of CI vary among the three entities. In DMD/BMD, CI usually remains subclinical in the early stages of the disease. Typical initial manifestations of CI in DMD/BMD are sinus tachycardia, tall R1 in V1, prominent Q in I, aVL, V6 or in II, III, and aVF, increased QT dispersion and possibly autonomic dysfunction. Initially, echocardiography is normal or shows regional wall motion abnormalities in areas of fibrosis. With spreading of fibrosis, left ventricular dysfunction and ventricular arrhythmias additionally occur. In the final stages of the disease, systolic function may lead to heart failure and sudden death. Subclinical or clinical CI is present in about 90% of the DMD/BMD patients but is the cause of death in only 20% of the DMD and 50% of the BMD patients. XLDCM is a rapidly progressive, almost exclusively myocardial disorder, starting in teenage males as heart failure due to dilative cardiomyopathy (CMP), leading to death from intractable heart failure within 1-2 years after diagnosis. Therapy of arrhythmias and CMP in all three disorders follows the established cardiological recommendations. Due to its protective effect, ACE inhibitors are recommended already at the early stages of the disease. Beta-blockers may be an additional option if indicated.
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PMID:The heart in human dystrophinopathies. 1258 17

Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration resulting from the loss of the cytoskeletal protein dystrophin. Most patients develop significant cardiomyopathy, with heart failure being the second leading cause of death in DMD. Compared with the extensive studies on skeletal muscle defects and potential therapy in DMD, very little attention has been directed at the increasing incidence of heart failure in DMD. Here we show that a single systemic injection of recombinant adeno-associated virus (rAAV2/6) harboring micro-dystrophin leads to extensive cardiac transduction, with micro-dystrophin correctly localized at the periphery of the cardiac myocytes and functionally associated with the sarcolemmal membrane. Significantly, micro-dystrophin gene transfer corrected the baseline end-diastolic volume defect in the mdx mouse heart and prevented cardiac pump failure induced by dobutamine stress testing in vivo, although several parameters of systolic function were not corrected. These results demonstrate that systemic gene delivery of micro-dystrophin can restore ventricular distensibility and protect the mdx myocardium from pump dysfunction during adrenergic stimulation in vivo.
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PMID:Systemic administration of micro-dystrophin restores cardiac geometry and prevents dobutamine-induced cardiac pump failure. 1744 Apr 45

Duchenne muscular dystrophy (DMD), the most prevalent lethal genetic disorder in children, is caused by mutations in the 2.2-MB dystrophin gene. Absence of dystrophin and the dystrophin-glycoprotein complex (DGC) from the sarcolemma leads to severe muscle wasting and eventual respiratory and/or cardiac failure. There is presently no effective therapy for DMD. Several lines of evidence have suggested that methods to increase expression of utrophin, a dystrophin paralog, show promise as a treatment for DMD. Adeno-associated viral (AAV) vectors are a promising vehicle for gene transfer to muscle, but microutrophin transgenes small enough to be carried by AAV have not been tested for function. In this study, we intravenously administered recombinant AAV (rAAV2/6) harboring a murine codon-optimized microutrophin (DeltaR4-R21/DeltaCT) transgene to adult dystrophin(-/-)/utrophin(-/-) (mdx:utrn(-/-)) double-knockout mice. Five-month-old mice demonstrated localization of microutrophin to the sarcolemma in all the muscles tested. These muscles displayed restoration of the DGC, increased myofiber size, and a considerable improvement in physiological performance when compared with untreated mdx:utrn(-/-) mice. Overall, microutrophin delivery alleviated most of the pathophysiological abnormalities associated with muscular dystrophy in the mdx:utrn(-/-) mouse model. This approach may hold promise as a treatment option for DMD because it avoids the potential immune responses that are associated with the delivery of exogenous dystrophin.
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PMID:Microutrophin delivery through rAAV6 increases lifespan and improves muscle function in dystrophic dystrophin/utrophin-deficient mice. 1866 59

Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. It is characterized by progressive muscle wasting and weakness of variable distribution and severity. Heart is involved leading to heart failure. Conduction abnormalities are unusual. We report a case of complete atrio-ventricular block in a DMD patient.
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PMID:Complete atrioventricular block in Duchenne muscular dystrophy. 1881 87

We describe a young adult male presenting with cardiac failure necessitating cardiac transplantation 7 months after presentation. Skeletal muscle biopsy showed mosaic immunostaining for dystrophin. DNA studies showed somatic mosaicism for a nonsense mutation in the dystrophin gene (Arg2905X). The frequency of normal versus mutant genes were determined in blood/DNA (50:50), muscle/DNA (80:20) and muscle/mRNA (90:10). These data are consistent with genetic normalization processes that may biochemically rescue skeletal muscle in male somatic mosaic patients mitigating muscle symptoms (gradual loss of dystrophin-negative skeletal muscle tissue replaced by dystrophin-positive stem cells). To our knowledge, this is only the second reported case of a clinically ascertained patient showing somatic mosaicism for Duchenne muscular dystrophy (DMD). We hypothesize that many somatic mosaic males for DMD exist, yet they are not detected clinically due to genetic normalization. Somatic mosaicism for DMD should be considered in acute heart failure with dilated cardiomyopathy, as genetic normalization in heart is unlikely to occur.
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PMID:Somatic mosaicism for Duchenne dystrophy: evidence for genetic normalization mitigating muscle symptoms. 1953 Jan 90


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