Hereditary muscular dystrophies and the heart

doi:10.1016/j.nmd.2010.04.008

Neuromuscular Disorders

Volume 20, Issue 8, August 2010, Pages 479-492

https://doi.org/10.1016/j.nmd.2010.04.008 Get rights and content

Summary

Cardiac disease is a common clinical manifestation of neuromuscular disorders, particularly of muscular dystrophies. Heart muscle cells as well as specialized conducting myocardial fibres may be affected by the dystrophic process. The incidence and nature of cardiac involvement vary with different types of muscular dystrophies. Some mainly lead to myocardial disease, resulting in cardiomyopathy and heart failure, while others particularly affect the conduction system, leading to arrhythmias and sudden death. As prognosis of muscular dystrophy patients may be directly related to cardiac status, surveillance and timely management of cardiac complications are important. However, recognition of cardiac involvement requires active investigation and remains challenging since typical signs and symptoms of cardiac dysfunction may not be present and progression is unpredictable.

In this review, we present a comprehensive overview of hereditary muscular dystrophies associated with cardiac disease to provide an efficient strategy for the expertise and management of these diseases.

Introduction

Muscular dystrophies form a heterogeneous group of inherited disorders that are clinically characterized by progressive skeletal muscle wasting and weakness. Clinical diagnosis is based on distribution and severity of muscular involvement, mode of inheritance and concomitant symptoms. Genetic testing can confirm the diagnosis if the gene defect is known (see Table 1).

Cardiac disease is a common clinical manifestation of neuromuscular disorders, particularly of muscular dystrophies. Cardiac involvement is not necessarily related to the degree of skeletal myopathy and may even be the presenting or predominant symptom. Cardiac death can result from progressive heart failure, due to ventricular dysfunction, or from sudden death, presumably caused by heart block or malignant arrhythmias. As quality of life and survival of muscular dystrophy patients have improved as a result of advances in medical management, heart failure and arrhythmias contribute to a larger extent to mortality.

This review serves as a comprehensive overview of the extensive literature on hereditary muscular dystrophies associated with cardiac disease. Molecular pathology, clinical aspects, cardiac findings and the mechanism and risk of cardiac death of these disorders are summarized to provide insight into the appropriate clinical approach and therapeutic options.

Section snippets

Search strategy and selection criteria

A literature search was performed to find individual studies and reviews published on cardiac involvement in muscular dystrophies. Muscular dystrophies and myopathies of interest were identified using PubMed and OMIM database. Subsequently, a more extensive PubMed search was performed using the specific type of muscular dystrophy in combination with any of the following keywords: etiology, diagnosis, heart disease, cardiomyopathy, arrhythmias, (sudden) death, prognosis, treatment. Furthermore,

Dystrophinopathies

Dystrophinopathies refer to the disorders Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and X-linked dilated cardiomyopathy (XLCM). The incidence of DMD is estimated at 1 in 3500 male newborns with a prevalence of 6 in 100,000 males [2]. DMD is characterized by weakness of leg, pelvic and shoulder girdle muscles starting in early childhood. The introduction of home nocturnal ventilation has raised the mean age of death from 19 to at least 25 years [3].

BMD is a milder variant

Emery–Dreifuss muscular dystrophy

Emery–Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows, Achilles tendons (toe walking) and posterior cervical muscles (rigid spine), and muscle weakness in a humero-peroneal distribution. Joint contractures occur in early childhood, often before there is any significant weakness.

X-linked recessive EDMD (EDMD1) has a prevalence of 1 in 100,000 males. It can result from various mutations in the STA gene [43]. The protein product (emerin) is a component of the

Limb-girdle muscular dystrophy

Limb-girdle muscular dystrophies (LGMD) are a clinically and genetically heterogeneous group of muscular dystrophies in which the pelvic and shoulder girdle musculature is predominantly involved [72]. Currently, 7 autosomal dominant (LGMD1A to LGMD1G) and 13 autosomal-recessive forms (LGMD2A to LGMD2 M) are recognized [1]. The disease course of autosomal dominant LGMD usually is relatively mild [73]. Age of onset ranges from childhood to the fourth decade. The clinical picture of

Myotonic dystrophy

Myotonic dystrophy is characterized by autosomal dominant inheritance, progressive muscle weakness and wasting, myotonia and multisystem complications. There are two distinct forms recognized: myotonic dystrophy type 1 and myotonic dystrophy type 2.

Congenital muscular dystrophy

Congenital muscular dystrophy (MDC) describes a number of inherited disorders in which muscle weakness is present at birth or within the first 6 months of life. MDC has either a slowly progressive or non-progressive course. Morbidity and mortality rates depend on the type of congenital muscular dystrophy. Some children die in infancy, whereas others can live into adulthood with only minimal disability. Nearly all forms are inherited in an autosomal-recessive manner. Structural brain defects,

Facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy with normal life span and a prevalence of 1 in 20,000. Shoulder girdle weakness is usually the presenting clinical symptom. It is often asymmetrical with relative sparing of the deltoid muscles. Facial muscle involvement, often mild and asymmetrical, is frequently present in the majority of cases at the time of diagnosis. Involvement of abdominal, foot extensor and pelvic muscles occur at a later stage of the

Myofibrillar myopathies

Myofibrillar myopathies (MFM) refer to a group of genetically distinct disorders that are frequently associated with peripheral neuropathy and involvement of the heart muscle. Clinically, MFM presents in adult life with slowly progressive weakness of distal and proximal muscles. Diagnosis is mainly based on muscle histology, showing morphologic changes resulting from disintegration of the sarcomeric Z-disk and myofibrils, followed by accumulation of myofibrillar degradation products and ectopic

Other muscular dystrophies

In distal myopathies, cardiomyopathy is not a consistent feature. Mild-moderate cardiomyopathy was present in 1 of the 3 affected members with late-onset autosomal dominant distal myopathy, which has recently been identified as a ZASPopathy [154].

A few rare X-linked myopathies are associated with cardiomyopathy. X-linked vacuolar cardiomyopathy and myopathy (Danon disease) is caused by mutations in the gene encoding lysosome-associated membrane protein-2 (LAMP-2) at Xq24 [155]. Muscle biopsies

General aspects

Muscular dystrophies are associated with progressive physical disabilities and medical complications. Although curative treatment is not yet available, quality of life and survival of muscular dystrophy patients have improved as a result of advances in medical management based on multi-disciplinary care [165]. In general, current symptomatic treatment is designed to maintain and support muscle strength, promote mobility, prevent contractures and maintain optimal physical and emotional health.

Conclusion

Surveillance and timely management of cardiac complications are important since long-term prognosis may be directly related to cardiac status. With increased quality of life and prolonged survival of muscular dystrophy patients, heart failure and arrhythmias contribute to a larger extent to premature death. Recognition of cardiac involvement requires active investigation, since the typical signs and symptoms of cardiac dysfunction may not be present, possibly secondary to the patient’s muscular

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Subclinical cardiac involvement present as electrocardiographic abnormalities in various neuromuscular diseases
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Cardiac involvement is commonly present in various neuromuscular diseases which may develop life-threatening consequences. The early manifestation is often asymptomatic which however has been insufficiently studied.
We aim to characterize electrocardiographic (ECG) changes in neuromuscular diseases without cardiac symptoms.
Adults having genetically and/or pathologically confirmed type 1 myotonic dystrophy (DM1), Becker muscular dystrophy (BMD), limb girdle muscular dystrophies (LGMDs) and mitochondrial diseases (MtDs) but without history of heart diseases and cardiovascular symptoms were enrolled. The 12-lead ECG characteristics and other test results at diagnosis were retrieved and analyzed.
196 patients with neuromuscular diseases (44 DM1, 25 BMD, 82 LGMDs, 45 MtDs) were consecutively enrolled. ECG abnormalities were identified in 107 (54.6%) patients with a prevalence of 59.1% in DM1, 76.0% in BMD, 40.2% in LGMDs and 64.4% in MtDs. Conduction block was more commonly present in DM1 than the other groups (P < 0.01), which had a longest PR interval and QRS duration of 186.1 ± 38.3 ms and 104.2 [90.0–108.0]ms, respectively. QT prolongation was most frequently seen in DM1 (P < 0.001). Left ventricular hypertrophy features were found in BMD, LGMDs and MtDs (P < 0.05) without intergroup difference, while a significantly higher right ventricular amplitude is observed in BMD than in other groups (P < 0.001).
Subclinical cardiac involvement is commonly present as ECG abnormalities in multiple adult neuromuscular diseases before associated symptoms occur and show diversity in different groups.
Childhood muscular dystrophies
2023, Handbook of Clinical Neurology
Infancy- and childhood-onset muscular dystrophies are associated with a characteristic distribution and progression of motor dysfunction. The underlying causes of progressive childhood muscular dystrophies are heterogeneous involving diverse genetic pathways and genes that encode proteins of the plasma membrane, extracellular matrix, sarcomere, and nuclear membrane components. The prototypical clinicopathological features in an affected child may be adequate to fully distinguish it from other likely diagnoses based on four common features: (1) weakness and wasting of pelvic-femoral and scapular muscles with involvement of heart muscle; (2) elevation of serum muscle enzymes in particular serum creatine kinase; (3) necrosis and regeneration of myofibers; and (4) molecular neurogenetic assessment particularly utilizing next-generation sequencing of the genome of the likeliest candidates genes in an index case or family proband. A number of different animal models of therapeutic strategies have been developed for gene transfer therapy, but so far these techniques have not yet entered clinical practice. Treatment remains for the most part symptomatic with the goal of ameliorating locomotor and cardiorespiratory manifestations of the disease.
Muscular dystrophy
2022, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders, Second Edition
Muscular dystrophies are a heterogeneous group of inherited progressive disorders of muscle characterized pathologically by destruction of muscle and its replacement by fatty and fibrous tissue. The most common muscular dystrophies are Duchenne muscular dystrophy, myotonic dystrophy types 1 and 2, and facioscapulohumeral dystrophy. Muscle weakness is a major manifestation and often has an early onset, but initial symptoms may also be reported in early or even late adulthood. Genes with mutations causing muscular dystrophies typically play major roles in muscle development and maintenance of muscle function, including the reinforcement and repair of the plasma membrane. The considerable mechanical forces involved in contractility and the energy demands for metabolism and regeneration significantly affect the physiology of muscle fibers. Recent scientific advances have improved our diagnostic abilities and enabled experimental studies of gene therapy and conventional pharmacological treatments that should eventually lead to effective treatment of these hereditary disorders.
259th ENMC international workshop: Anaesthesia and neuromuscular disorders 11 December, 2020 and 28–29 May, 2021
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Neuromuscular disorders are a diverse group of disorders with variable cardiac involvement necessitating specialized cardiac evaluation. Duchenne muscular dystrophy is most severely affected, and cardiac disease is now the leading cause of death. Advanced imaging technology including echocardiography and cardiac magnetic resonance imaging can lead to early identification of affected myocardium and direct pharmacotherapies to slow the progression of cardiomyopathy. Becker muscular dystrophy is also associated with cardiomyopathy, usually with a later onset and slower course. Carriers of dystrophin mutations can also develop cardiomyopathy and require screening. Several subtypes of limb-girdle muscular dystrophy have similar risks of cardiac disease as Duchenne muscular dystrophy. Some neuromuscular disorders including myotonic dystrophies and Emery-Dreifuss muscular dystrophy are primarily associated with conduction defects and can require pacemaker implantation. And other disorders such as Friedreich ataxia and Pompe disease can be associated with hypertrophic cardiomyopathy. New therapies and interventional strategies can be used to improve the quality and duration of life in neuromuscular patients with cardiac involvement. Based on this diversity, a multidisciplinary approach including a cardiologist is essential to optimize care for the patient with a neuromuscular disorder.
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The dystrophinopathies fall along a spectrum of muscular dystrophy phenotypes, with variable involvement of skeletal and cardiac muscle, inherited in an X-linked recessive pattern. The diagnosis of dystrophinopathy should be suspected in any patient with a highly elevated serum creatine kinase level beyond the context of rhabdomyolysis secondary to exertional, toxic, or metabolic myopathy. Genetic testing for dystrophinopathy is highly sensitive and specific, and identifying a proband will often lead to implications for several relatives at risk for cardiomyopathy, weakness, or anesthetic reactions. Management of the dystrophinopathies is focused primarily on supportive care, although steroid therapy has changed the natural history of Duchenne muscular dystrophy is now standard of care internationally. An exciting and ongoing area of investigation of the dystrophinopathies is focused on the potential for altering or replacing dystrophin gene expression, with one approved therapy in the United States and another in Europe available for subsets of patients depending on their genotype, as well as other phenotype modulators under investigation as a way of improving muscle health and slowing the rate of muscle degeneration.

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ReviewHereditary muscular dystrophies and the heart

Summary

Introduction

Section snippets

Search strategy and selection criteria

Dystrophinopathies

Emery–Dreifuss muscular dystrophy

Limb-girdle muscular dystrophy

Myotonic dystrophy

Congenital muscular dystrophy

Facioscapulohumeral muscular dystrophy

Myofibrillar myopathies

Other muscular dystrophies

General aspects

Conclusion

Neuromuscul Disord

Neuromuscul Disord

Lancet

Genomics

J Am Coll Cardiol

Int J Cardiol

Am Heart J

Neuromuscul Disord

Am J Cardiol

J Am Coll Cardiol

Am Heart J

Am Heart J

Neuromuscul Disord

Am Heart J

Neuromuscul Disord

Lancet

Neuromuscul Disord

Neuromuscul Disord

Neuromuscul Disord

J Heart Lung Transplant

Neuromuscul Disord

Am J Hum Genet

Neuromuscul Disord

J Am Coll Cardiol

Am J Hum Genet

Am J Hum Genet

J Biol Chem

J Neurol Sci

Neuromuscul Disord

Neuromuscul Disord

Neurotherapeutics

Neuromuscul Disord

Neuromuscul Disord

Clinical studies in benign (Becker type) X-linked muscular dystrophy

Clin Genet

Becker-type muscular dystrophy

Muscle Nerve

The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. I. Natural history

J Neurol

Evolution of cardiac abnormalities in Becker muscular dystrophy over a 13-year period

J Neurol

X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus

Circulation

Dystrophin protects the sarcolemma from stresses developed during muscle contraction

Proc Natl Acad Sci USA

Mechanisms of Muscle Degeneration, Regeneration, and Repair in the Muscular Dystrophies

Annu Rev Physiol

Cardiac involvement in progressive muscular dystrophy of the Duchenne type

Jpn Heart J

Cardiac conduction abnormalities in children with Duchenne’s progressive muscular dystrophy: electrocardiographic features and morphologic correlates

Circulation

Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy

Pediatrics

Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states

Nat Med

ACE inhibitor bulks up muscle

Nat Med

Subclinical cardiomyopathy in Becker muscular dystrophy

Br Heart J

Evaluation of the cardiomyopathy in Becker muscular dystrophy

Muscle Nerve

Myocardial involvement is very frequent among patients affected with subclinical Becker’s muscular dystrophy

Circulation

Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy

Circulation

Review
Hereditary muscular dystrophies and the heart