Duchenne and Becker muscular dystrophy carriers: Evidence of cardiomyopathy by exercise and cardiac MRI testing
Introduction
Duchenne and Becker muscular dystrophy are progressive neuromuscular diseases caused by mutations in the DMD gene, which encodes dystrophin [1]. Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy, seen in 1/5000 live births [2,3]. Manifestations of DMD in affected boys include profound progressive muscle weakness with loss of ambulation and the development of cardiomyopathy in early adolescence [4,5]. Becker muscular dystrophy (BMD) is less common, presenting in 1/19,000 live births. Dystrophic degeneration of muscle cells, reflected in serum creatine kinase (CK) levels, peak by age 6 years in DMD and 10–15 years in BMD patients [6,7]. BMD subjects generally have less severe disease, although the clinical spectrum of BMD is broad [8,9]. At present, boys with DMD have life expectances on average in their 20's. With improvements in respiratory support, steroid therapy, and respiratory care, cardiomyopathy is now the leading cause of death [[10], [11], [12], [13], [14], [15]].
In 70% of subjects with DMD, an identified DMD gene mutation is causative. In-frame mutations result in the BMD phenotype. The mutation is inherited in an X-linked recessive pattern from a maternal carrier. Fifty percent of the male offspring of female DMD mutation carriers will manifest a DMD phenotype while 50% of female offspring will be carriers. In 30% of DMD boys, the mutation is a de novo occurrence [16,17]. Female carriers should theoretically be spared from phenotypic disease given the presence of a normal DMD gene on their second X-chromosome; however, they have long been reported to demonstrate some manifestations of similar dystrophin-deficient disease. Muscle weakness, abnormal gait, fatigue and cardiac involvement have all been reported [18]. Additionally, there are overtly manifesting young female carriers who present with onset and progression of disease like affected boys that offer evidence of clinical impacts of having one abnormal gene [19]. Many studies describe a non-random X-chromosome inactivation pattern in some manifesting patients, which offers a genetic basis for this varied expression [20].
The mechanism of cardiomyopathy is an absence of functional dystrophin protein (DMD) or deficient levels of dystrophin (BMD). Dystrophin is a large protein, binding actin on the N-terminus and the extra-cellular matrix of the cell at the C-terminus. It functions to stabilize the plasma membrane by transmitting forces from the sarcomeric contraction to the extra-cellular matrix [21,22]. Without dystrophin, myocyte contraction results in membrane damage and fibrofatty replacement, resulting in cardiomyopathy [23,24]. This cardiomyopathy has been increasingly well-described by cardiac magnetic resonance imaging (CMR) for affected boys as a predictable pattern of subepicardial fibrosis [5,[25], [26], [27]] preceding a decrease in left ventricular ejection fraction (LVEF) [[28], [29], [30]]. However, prevalence and characterization of cardiomyopathy in female muscular dystrophy carriers (MDC) has thus far been incomplete. Few have included evaluation by CMR and varied detection methods have resulted in conflicting reports on the prevalence of cardiomyopathy in MDC [[31], [32], [33]]. Lang et al., reported a retrospective study on 22 genetically-confirmed DMD carriers (ages 13.2–60.0 years) utilizing traditional CMR measures, including LVEF and LGE status. They noted that 7/22 patients had LGE and 4/22 (18%) had LV dysfunction (LVEF <55%) [34]. CMR Native T1 mapping is a relatively novel technique to detect myocardial edema and diffuse fibrosis as evidence of occult cardiomyopathy [[35], [36], [37], [38], [39]]. Pre-contrast native T1 mapping for diffuse myocardial fibrosis in DMD boys has been reported to be abnormal and precedes LGE as well as global functional decline.40 T1 mapping has not been reported in DMD carriers.
In addition, studies thus far on the cardiac status of carriers have rested entirely on traditional imaging assessments, with reports of a dilated cardiomyopathy phenotype in a small fraction of patients. Interestingly, exercise stress testing has not been utilized in this population, despite evidence in large scale ischemic and non-ischemic heart failure studies that cardiopulmonary exercise testing (CPET) offers a robust method of prognostication for disease severity in heart failure. Measures of oxygen consumption (peak VO2) and regression slope relating minute ventilation to carbon dioxide output (VE/VCO2 slope) are metrics which are most directly related to outcomes in heart failure [41,42]. We sought to evaluate the prevalence of occult cardiomyopathy in genetically-confirmed MDC subjects using CPET and CMR, including native T1 mapping.
Section snippets
Subjects
Potential MDC subjects were prospectively recruited from a tertiary care muscular dystrophy clinic where their family member was clinically evaluated and from postings at ClinicalTrials.Gov and Parent Project Muscular Dystrophy's website. The study was approved by our institutional review board. Subjects could have no contraindication to CMR or CPET. Control patients were age-matched women from a volunteering cohort responding to an email solicitation sent to the employees at the same hospital.
Subject characteristics
Of the 77 carriers of a DMD mutation, the average age was 41.3 ± 8.5 years and did not differ from the non-carrier (40.6 ± 10.3 years) or control groups (42.9 ± 7.2 years). There were 117 Caucasian, 6 Asian, 1 Hispanic and 1 Middle Eastern subjects in the study. Of MDC subjects, 49% self-identified as having a “musculoskeletal disorder” along with 50% of non-carrier mothers (Table 1). Despite this, only 4 MDC and 1 non-carrier mom reported that exercise was limited by musculoskeletal complaints
Discussion
This study highlights the importance of genetic testing for mothers of boys with DMD/BMD as our data support that heterozygote DMD mutation conveys a risk for cardiac disease manifestations with 48% of MDC showing subepicardial LGE patterns. The decline in LVEF appears to trail the LGE findings, which is similar to affected males. The use of CMR allows early detection of fibrofatty replacement of myocardium, a pathognomonic finding of dystrophin-associated cardiomyopathy that occurs prior to
Conclusion
Based upon our work, we would advocate for genetic testing of all potential carriers of DMD mutations and for CMR in the cardiac evaluation of proven carriers of dystrophin mutations. Additional longitudinal studies are required to determine the predictive quality of cardiac fibrosis in this unique population. Of particular interest in our longitudinal assessments will be the false-positive subjects with RecVE but without fibrosis in our baseline CMR, in particular given evidence of diffuse
Funding
Parent Project Muscular Dystrophy, Hackensack, New Jersey.
The Heart Center, Nationwide Children's Hospital, Columbus Ohio.
Disclosures
Dr. Mah is an Advisory Board Member for Catabasis. Dr. Mendell is a consultant for AveXis, Inc. Sarepta Therapeutics, Exonics Therapeutics, and Myonexus Therapeutics. He has no investments in products that are under study. Dr. Al-Zaidy is a paid consultant for AveXis, Inc. Dr. Camino was employed at Nationwide Children's Hospital during collection of this data but now is an employee of Parent Project Muscular Dystrophy. Dr. Hor is a consultant for Medtronics and Catabasis as well as an Advisory
Acknowledgements
We would like to thank the many Nationwide Children's Hospital team members that supported the successful recruitment and execution of the longitudinal trial. Special thanks to Kathleen R. Church from the Center for Gene Therapy; Taylor Perdue, Ross Edwards, Heather Hermiller, Amy Tipton, Paula Woods, Angela Montgomery and Teresa Alley from Cardiac Imaging; Carine E. Leslie BS, Jennifer Cotto MS from the Center for Biobehavioral Health; Vidu Garg MD from The Heart Center and Ann Salvator, MS
References (58)
- et al.
Dystrophin and mutations: one gene, several proteins, multiple phenotypes
Lancet Neurol.
(2003) - et al.
Skeletal, cardiac, and smooth muscle failure in Duchenne muscular dystrophy
Pediatr. Neurol.
(1996) - et al.
The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy
Int. J. Cardiol.
(1990) - et al.
Serum creatine-kinase (CK) and pyruvate-kinase (PK) activities in Duchenne (DMD) as compared with Becker (BMD) muscular dystrophy
J. Neurol. Sci.
(1991) The muscular dystrophies
Lancet.
(2002)- et al.
Evolution of life expectancy of patients with Duchenne muscular dystrophy at AFM Yolaine de Kepper Centre between 1981 and 2011
Ann Phys Rehabil Med.
(2013) - et al.
All-cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy
J. Am. Coll. Cardiol.
(2013) - et al.
Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation
Neuromuscul. Disord.
(2002) - et al.
Characteristics and outcomes of cardiomyopathy in children with Duchenne or Becker muscular dystrophy: a comparative study from the Pediatric Cardiomyopathy Registry
Am. Heart J.
(2008) - et al.
Variability in clinical, genetic and protein abnormalities in manifesting carriers of Duchenne and Becker muscular dystrophy
Neuromuscul. Disord.
(1993)
Genetic and early clinical manifestations of females heterozygous for Duchenne/Becker muscular dystrophy
Pediatr. Neurol.
Clinical and genetic characterization of manifesting carriers of DMD mutations
Neuromuscul. Disord.
Duchenne muscular dystrophy: deficiency of dystrophin at the muscle cell surface
Cell
Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management
Lancet Neurol.
Dystrophin genotype-cardiac phenotype correlations in Duchenne and Becker muscular dystrophies using cardiac magnetic resonance imaging
Am. J. Cardiol.
Prevalence and distribution of late gadolinium enhancement in a large population of patients with Duchenne muscular dystrophy: effect of age and left ventricular systolic function
J. Cardiovasc. Magn. Reson.
Myocardial delayed enhancement by magnetic resonance imaging in patients with muscular dystrophy
J. Am. Coll. Cardiol.
Female dystrophinopathy: review of current literature
Neuromuscul. Disord.
Society for Cardiovascular Magnetic Resonance I and Cardiovascular Magnetic Resonance Working Group of the European Society of C. Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement
J Cardiovasc Magn Reson.
Increased myocardial native T1 and extracellular volume in patients with Duchenne muscular dystrophy
J. Cardiovasc. Magn. Reson.
Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping
J. Am. Coll. Cardiol.
Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing
J. Cardiovasc. Magn. Reson.
Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support
J. Biomed. Inform.
Cardiac abnormalities and skeletal muscle weakness in carriers of Duchenne and Becker muscular dystrophies and controls
Neuromuscul. Disord.
Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy
Neuromuscul. Disord.
Report of MDA muscle disease symposium on newborn screening for Duchenne muscular dystrophy
Muscle Nerve
Duchenne muscular dystrophy: a 30-year population-based incidence study
Clin Pediatr (Phila)
A mathematical analysis of creatine kinase activity in the course of Duchenne muscular dystrophy
Muscle Nerve
Evidence-based path to newborn screening for Duchenne muscular dystrophy
Ann Neurol.
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