Cardiac involvement in muscular dystrophies: molecular mechanisms

In this review, we draw attention to the multiple mechanisms responsible for the pathogenesis of cardiomyopathies in patients with muscular dystrophies. More than one single mechanism is likely to be involved in the development of skeletal and cardiac muscle pathology even when there is a single protein defect. The best example is dystrophin deficiency, in which increased sarcolemmal permeability following eccentric exercise, reduced force generation, and abnormal signaling are all likely to contribute to the progressive muscle damage observed. In other conditions, such as the sarcoglycanopathies, a protein deficiency both in the striated cardiomyocte and the vascular smooth muscle appears to play a significant role. An entirely different mechanism of disease is likely in defects of nuclear envelope proteins, although the precise pathogenesis of this group of conditions is still not clear. Differences between the organization of skeletal and cardiac muscle protein complex are also only starting to emerge and will very likely be the focus of future research.     

Intellectual function in muscular dystrophies

Summary Intellectual function was studied in 28 boys with Duchenne dystrophy, 12 patients with facioscapulohumeral-type and 10 patients with limb-girdle-type muscular dystrophy. A definite relationship between intelligence level and the type of muscle disease was found. The more severe the genetic damage manifested by the rapidity of progression of muscular dystrophy the more definite the affection of the CNS manifesting as mental deficit. The factors influencing the level and structure of intelligence seem to exert their effect before the manifestation of muscle lesions.     

The treatment of cardiac causes of sudden death, syncope, and seizure

The treatment for pediatric causes for sudden cardiac death can either be general and supportive or, in 2005, can be much more etiology specific. While antiarrhythmic therapy and activity restriction have been for years the mainstay of therapy, newer technologies such as radiofrequency ablation and automatic implantable cardioverter defibrillators (AICDs) are now more commonly applied for certain disease entities. The evolving role for clinical genetic testing to determine the specific etiology of pediatric sudden cardiac death continues to evolve. Further improvements in risk stratification will allow us to determine which patients are at greatest risk, so that aggressive treatment can be delivered to these subgroups. In the future, there may be gene-specific therapies and/or genetic modification.     

Sibling concordance for clinical features of Duchenne and Becker muscular dystrophies

Introduction: The correlation of markers of disease severity among brothers with Duchenne or Becker muscular dystrophy has implications for clinical guidance and clinical trials. Methods: Sibling pairs with Duchenne or Becker muscular dystrophy (n = 60) were compared for ages when they reached clinical milestones of disease progression, including ceased ambulation, scoliosis of ≥ 20°, and development of cardiomyopathy. Results: The median age at which younger brothers reached each milestone, compared with their older brothers ranged from 25 months younger for development of cardiomyopathy to 2 months older for ceased ambulation. For each additional month of ambulation by the older brother, the hazard of ceased ambulation by the younger brother decreased by 4%. Conclusions: The ages when siblings reach clinical milestones of disease vary widely between siblings. However, the time to ceased ambulation for older brothers predicts the time to ceased ambulation for their younger brothers. Muscle Nerve 49 : 814–821, 2014     

Cardiac involvement in limb-girdle muscular dystrophy 2I

Background The C826A mutation in the fukutin-related protein (FKRP) gene is typically associated with autosomal recessive limb-girdle muscular dystrophy 2I (LGMD2I) but oligosymptomatic phenotypes and patients with predominant cardiac involvement are also described. Objective To assess cardiac involvement in patients with LGMD2I. Patients Nine patients from 5 families (2 female, 7 male) homozygous for the 826C > A FKRP mutation were included. Methods Additional to conventional cardiac investigations (electrocardiography and echocardiography) the patients underwent cardiovascular magnetic resonance imaging (CMR). Results/Conclusion Cardiac involvement was detected by CMR in eight of nine patients (reduced left ventricular ejection fraction in 6, enlargement of left ventricular end-diastolic volume in 2 and left ventricular mass in 2) and in four patients by conventional cardiac diagnostic investigations. Two of the nine patients showed no muscle weakness or atrophy but suffered myalgias; both had cardiac manifestation of the disease. CMR is a sensitive method for detecting cardiac abnormalities in patients with LGMD2I and can be used for early detection of mild or subclinical cardiac involvement. Received in revised form: 23 February 2006     

Cardiac transplantation in becker muscular dystrophy

Summary A 23-year-old man with X-linked Becker type muscular dystrophy underwent cardiac transplantation because of dilated cardiomyopathy which was complicated by terminal heart failure. Impairment of muscle function was mild and slowly progressive, whereas the cardiac disease was severe and rapidly progressive. All four chambers of the removed heart were grossly dilated; microscopically, the myocardial fibres were hypertrophic and pale; the nuclei exhibited pleomorphism with variability in nuclear size, shape, and depth of staining.     

Lymphocyte capping in muscular dystrophies

Since reports of lymphocyte capping in muscular dystrophies of various authors revealed controversial results, we investigated 47 patients and carriers with Duchenne or Becker-Kiener muscular dystrophy according to different methods. There was no significant reduction of cap formation compared to 64 healthy controls, both groups showing a mean of about 75% caps. Reduced numbers of caps, however, could be demonstrated in three otherwise healthy probands aged 70 years or more, two patients under interferon treatment, four patients under high dose methotrexate therapy as well as one patient with untreated chronic myeloic leukemia. Thus lymphocyte capping in our experience is far from being a valid method for carrier detection or prenatal diagnosis of muscular dystrophies.     

Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy

Background

One of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited.

A scapular onset muscular dystrophy without facial involvement: Possible allelism with facioscapulohumeral muscular dystrophy

A dominantly inherited muscular dystrophy with onset in the shoulder girdle and later progression to the lower limbs is described. The disorder was clinically distinguishable from known facioscapulohumeral, scapulohumeral and limb girdle syndromes. A 38 kb allele detected by probe p13E-11 (D4F104S1) segregated with the disease. Linkage analysis gave a maximum lod score of z = 1.61 at θ = 0.01 with the 4q35 marker D4S184 (affected only analysis z = 1.20 at θ = 0.01) suggesting probable allelism with facioscapulohumeral muscular dystrophy.     

Evaluation of the cardiomyopathy in becker muscular dystrophy

To evaluate the features and the course of cardiomyopathy in Becker muscular dystrophy, 68 patients–identified by clinical assessment and by reduced dystrophin labeling and/or DNA analysis–were followed in the years 1976–1993, for periods ranging from 3 to 18 years (mean 8). Patients periodically underwent clinical, electrocardiographic, echocardiographic, nuclear, and radiological assessments. Preclinical cardiac involvement was found in 67.4% of patients under 16 years of age, decreasing to 30% in patients older than 40. Clinically evident cardiomyopathy was found in 15% of patients under 16 years of age, increasing to 73% in patients older than 40. A real, dilated cardiomyopathy is the most frequent type of myocardial involvement after the age of 20. Results show that the severity of cardiac involvement can be unrelated to the severity of skeletal muscle damage and confirm that cardiac dysfunction is a primary feature of Becker muscular dystrophy.© 1995 John Wiley &Sons, Inc.     

Hypotheses and recent findings concerning aetiology and pathogenesis of the muscular dystrophies

Summary The survey reports recent findings and current hypotheses on the aetiology and pathogenesis of the muscular dystrophies. Briefly presented are (1) biochemical anomalies of structure and metabolism, (2) membrane defects, (3) the neural hypothesis, (4) the vascular hypothesis, and (5) the connective tissue hypothesis. At present, research interest is focused primarily on membrane structure and biochemistry, on neural muscle trophism, and on the genetic aspects of abnormalities in molecular biology.Whether the progressive muscular dystrophies are primary disorders of voluntary muscle or whether the primary alteration is located outside of the muscle still remains unknown.

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Zusammenfassung Die Übersicht informiert über die wesentlichen derzeit vertretenen Hypothesen und über neue Befunde zur Ursache und Pathogenese der progressiven Muskeldystrophien. Kurz dargestellt werden 1. die biochemischen Anomalien der Struktur und des Stoffwechsels, 2. Membrandefekte, 3. die neurale Hypothese, 4. die vasculäre Hypothese und 5. die Bindegewebshypothese. Im Vordergrund des augenblicklichen Interesses stehen die Struktur und Biochemie der Membranen, die nervale Muskeltrophik und genetisch-molekularbiologische Aspekte.Die Frage, ob die progressiven Muskeldystrophien primäre Erkrankungen der Muskulatur sind oder ob die primären Veränderungen extramuskulär lokalisiert sind, ist aufgrund der derzeitigen Kenntnisse nicht klar zu beantworten.

     

The role of the dystrophin-glycoprotein complex in the molecular pathogenesis of muscular dystrophies

The dystrophin-glycoprotein complex is considered to be a major trans-sarcolemmal structure which provides a linkage between the subsarcolemmal actin cytoskeleton and the extracellular matrix component laminin. Recently, deficiency of the dystrophin-associated proteins has been shown to play an important role in the molecular pathogenesis of several forms of muscular dystrophy. These include Duchenne muscular dystrophy (DMD), symptomatic DMD carriers, Becker muscular dystrophy and severe childhood autosomal recessive muscular dystrophy with DMD-like phenotype prevalent in North Africa. In Fukuyama-type congenital muscular dystrophy (FCMD), the finding of abnormal expression of the dystrophin-associated proteins may provide a clue to its molecular pathogenesis. These recent findings indicate that the linkage between the subsarcolemmal cytoskeleton and extracellular matrix via the dystrophin-glycoprotein complex is critical for maintaining the integrity of muscle cell function.     

Immunodetection analysis of muscular dystrophies in Mexico

Introduction: The muscular dystrophies (MDs) result from perturbations in the myofibers. These alterations are induced in part by mechanical stress due to membrane cell fragility, disturbances in mechanotransduction pathways, muscle cell physiology, and metabolism. Methods: We analyzed 290 biopsies of patients with a clinical diagnosis of muscular dystrophy. Using immunofluorescence staining, we searched for primary and secondary deficiencies of 12 different proteins, including membrane, costamere, cytoskeletal, and nuclear proteins. In addition, we analyzed calpain‐3 by immunoblot. Results: We identified 212 patients with varying degrees of protein deficiencies, including dystrophin, sarcoglycans, dysferlin, caveolin‐3, calpain‐3, emerin, and merosin. Moreover, 78 biopsies showed normal expression of all investigated muscle proteins. The frequency rates of protein deficiencies were as follows: 52.36% dystrophinopathies; 18.40% dysferlinopathies; 14.15% sarcoglycanopathies; 11.32% calpainopathies; 1.89% merosinopathies; 1.42% caveolinopathies; and 0.47% emerinopathies. Deficiencies in lamin A/C and telethonin were not detected. Conclusion: We have described the frequency of common muscular dystrophies in Mexico. Muscle Nerve, 2012     

Congenital muscular dystrophies and the extracellular matrix

During the past decade, considerable progress in the field of congenital muscular dystrophies (CMDs) had led to the identification of a growing number of causative genes. This genetic progress has uncovered crucial pathophysiological concepts and has been instrumental in redefining clinical phenotypes. Important new pathogenic mechanisms include the disorders of O-mannosyl-linked glycosylation of alpha-dystroglycan as well as the involvement of a collagen type VI in the pathogenesis of congenital disorders of muscle. Thus, an emerging theme among gene products involved in the pathogenesis of congenital muscular dystrophy is their intimate connection to the extracellular matrix. In this review, we focus on the clinical phenotypes that we are correlating with the novel genetic and biochemical findings encountered within CMD. This correlation will frequently lead to a considerably expanded clinical spectrum associated with a given CMD gene.     

Cardiac involvement in patients with lamin A/C gene mutations: a cohort observation

Introduction: LMNA gene mutations are associated with cardiac and skeletal muscle alterations. Methods: A cohort of 21 mutated individuals was assessed with clinical and instrumental investigations over the years. Results: The median observation period was 6 years. Cardiac compromise was detected in 16 patients. Bradyarrhythmias were the most frequent manifestations, followed by supraventricular arrhythmias. Two individuals suffered from nonsustained and 1 from sustained ventricular tachyarrhythmias. Dilated cardiomyopathy was detected in 3 patients. Evaluation of the frequencies of the clinical expressions showed a high probability of suffering from analogue heart compromise in study subjects bearing the same LMNA gene mutation. Conclusions: Cardiac involvement represents a very common phenotypic expression of LMNA gene mutation. Subjects sharing common genetic background seem to suffer from analogue pattern of cardiac manifestation. Muscle Nerve 46: 187–192, 2012     

The childhood limb-girdle muscular dystrophies

The heterogeneous childhood limb-girdle muscular dystrophies have originally been defined as a group of autosomal recessive and dominant diseases with progressive weakness and wasting of shoulder and pelvic-girdle muscles. Over the last 12 years, the underlying genetic defects for many of the diseases have been identified and insight into pathomechanisms of disease has been gained. At the same time, improved diagnostic techniques have allowed to extend the phenotypic spectrum for many of these devastating conditions, which showed that clinical symptoms and pathological findings are not restricted to skeletal muscles. Childhood limb-girdle muscular dystrophies are systemic diseases that often affect the musculoskeletal, respiratory, and cardiovascular system and that can go along with central nervous system involvement and gastrointestinal symptoms. The systemic nature of the diseases requires adequate management strategies that improve symptoms, longevity, and quality of life of the patients. As we are entering an era of translational research the need for precise molecular diagnoses, a thorough understanding of the natural history of the diseases and guidelines for standardized assessments of the patients become even more relevant. In this review, the best characterized childhood limb-girdle muscular dystrophies are discussed and their management aspects highlighted.     

Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies

Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next‐generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57 : 6–15, 2018