Elsevier

Neuromuscular Disorders

Volume 18, Issue 8, August 2008, Pages 650-655
Neuromuscular Disorders

Cardiac assessment of limb–girdle muscular dystrophy 2I patients: An echography, Holter ECG and magnetic resonance imaging study

https://doi.org/10.1016/j.nmd.2008.06.365Get rights and content

Abstract

Mutations in the FKRP gene may be associated with cardiac involvement. The aim of our study was to assess myocardial involvement in patients with LGMD2I, using physical examination, echocardiography, resting and 24-h ambulatory electrocardiogram and cardiac magnetic resonance imaging, with particular attention to the detection of myocardial morphologic abnormalities. Patients were compared to matched controls. Twenty-three patients were enrolled (men 10 – women 13; 32.3 ± 9.5 years). Twenty-two had the C826A gene mutation (homozygous 12, heterozygous 10). Nine patients had severe muscle alterations, 10 had milder muscle involvement and 4 had isolated exertional myoglobinuria. When compared to controls, LGMD2I patients had reduced left ventricular ejection fraction (50.8 ± 13.9 versus 66.6 ± 3.8%, p < 0.0001). Sixty percent of patients had reduced left ventricular ejection fraction, including 8% with severe reduced left ventricular ejection fraction <30%. None had significant arrhythmia. Gene mutation and the severity of the muscle disease were not predictive of cardiac involvement. Cardiac magnetic resonance imaging displayed a high prevalence of myocardial functional abnormalities, fatty replacement and fibrosis, among the 13 patients investigated. Reduced contractility and cardiac magnetic resonance imaging morphological abnormalities are highly prevalent in LGMD2I patients suggesting that all patients should be referred for cardiac evaluation.

Introduction

Mutations in the Fukutin-related protein gene (FKRP) result in several phenotypes including congenital muscular dystrophy 1C [1], limb–girdle muscular dystrophy 2I (LGMD 2I) [2] and more recently muscle–eye–brain disease and Walker–Warburg syndrome [3]. FKRP gene encodes a putative Golgi resident glycosyltransferase that is involved in α-dystroglycan (α-DG) glycosylation [4]. The pathogenesis of FKRP mutations appears to be linked to a downregulation of α-DG and phenotypic severity is correlated to depletion of α-DG and secondary reduction in laminin-α2 [4], [5], [6].

In LGMD 2I patients, the most common mutation is the C826A mutation (L276I). In homozygous C826A mutation, patients generally exhibit milder and late-onset muscular dystrophy, whereas the heterozygous C826A mutation is associated with more severe and early-onset type of muscular dystrophy phenotypically related to Duchenne muscular dystrophy [7].

Indeed, left ventricular hypokinesis, dilated cardiomyopathy and heart failure have been reported in LGMD 2I [8], [9], [10], [11], [12], [13]. Its prevalence was ranged from 10 to 50% in the literature, using electrocardiogram (ECG) and conventional echocardiography. Recently, Gaul et al. demonstrated that myocardial involvement is more frequent when LGMD 2I patients were investigated using cardiac magnetic resonance imaging (CMR) in addition to conventional tools. They found left ventricular (LV) abnormalities (systolic dysfunction, dilatation, or hypertrophy) in eight of nine LGMD 2I patients with CMR, versus only in 4 patients with ECG and echocardiography. However, morphologic myocardial abnormalities such as fibrosis (late contrast enhancement) or fatty infiltration were not investigated, whereas those abnormalities are frequent and are correlated to the clinical outcome of patients with hypertrophic, dilated and right ventricular arrhythmogenic cardiomyopathies. In addition, cardiac complications, particularly rhythm and conductive disturbances, may have been underestimated in previous studies which did not include Holter ECG monitoring.

The aim of this study was to assess the prevalence of cardiac involvement in LGMD 2I patients using conventional cardiac investigations, including systematic 24 h Holter ECG monitoring, and CMR, with particular attention to the detection of myocardial morphologic abnormalities.

Section snippets

Patients and investigations

Twenty-three patients with genetically proven LGMD 2I attending the Muscle Institute of Pitié Salpétrière Hospital and the department of Cardiology in Cochin Hospital, both in Paris, France, were included after informed consent. Patients were assigned to a severity group according to standard muscular assessments performed during routine follow up. Functional stage followed the scheme of Walton [14]. Patients were classified as severe (Duchenne-like) or milder muscular disease (Becker-like or

Results

Twenty-three patients (13 men, 10 women, mean age 32.3 ± 9.5 years) from 18 families were included (Table 1). Twelve patients were homozygous for the C826A mutation; 10 were heterozygous for the C826A mutation; one was homozygous for the Y182C mutation. Nine patients had severe early-onset muscular disease (Duchenne-like), 10 had milder phenotype and were still able to walk without any support and 4 had isolated exertional myoglobinuria. Demographic characteristics did not differ between severe

Discussion

The main findings of our study are (1) a high prevalence of cardiac involvement in LGMD 2I patients (mean age 32.3 ± 9.5 years), resulting in reduced LVEF in 14/23 patients (60%) including 2/23 patients (8.6%) with severe LV dysfunction, (2) frequent LV and RV fatty infiltration and fibrosis that is accurately detected by CMR (3) the absence of severe arrhythmia, (4) the absence of significant difference between patients with severe or mild muscular disease or between homozygous and heterozygous

Limitations

Like all previous studies on this subset of patients, our study population is small. This may account for the absence of significant difference in cardiac involvement between patients with severe versus mild muscular phenotype. However, standard echographic monitoring showed significant cardiomyopathy in 60% of patients and severe cardiomyopathy was found in all subgroups of patients. Therefore, close follow-up seems warranted.

CMR was not performed in all patients, and no patient was

Conclusion

Reduced contractility is highly prevalent in LGMD 2I patients regardless of gene mutation and the severity of the muscular disease suggesting that all patients should be referred for cardiac evaluation. CMR allows early detection of patients with LV and/or RV fatty replacement and/or fibrosis. Moreover these abnormalities are associated to LV dysfunction. The prognosis of these morphological abnormalities remains to be studied prospectively.

Acknowledgement

The authors do thank Dr. Mamursztejn for his help during the study.

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