Progressive Respiratory Insufficiency in the Absence of Cardiac Disease in Late-Stage Duchenne Muscular Dystrophy

Discussion

This case is interesting for 2 aspects. First, the patient was free of any cardiac symptoms, and clinical and instrumental cardiologic investigations were not indicative of cardiac disease, neither during previous years nor at the last follow-up at age 25 years. In the majority of cases, cardiac involvement starts early and remains subclinical during the first years after onset. In DMD patients < 6 years the ECG is already abnormal in 78% of the cases.¹ In the final stages of the disease, 90% or more of the patients have at least ECG abnormalities.⁴ Frequently, cardiac involvement progresses during the course to dilated cardiomyopathy or ventricular arrhythmias.

Absence of cardiac involvement in the advanced stages of the disease is rare and may be explained by several assumptions. Possibly this patient was still too young to have developed cardiac involvement until age 25 years and would develop cardiac disease during the following years. Such an assumption is not improbable, since cardiac involvement in other patients has been shown to be progressive during the disease course⁵ or to occur only late in life.⁶ Possibly, there are dystrophin mutations, which are not associated with cardiac involvement. There is an ongoing debate about the genotype-phenotype correlation of cardiac involvement in DMD.⁷ Some studies indicated that certain mutations favor the development of cardiac involvement,^8,9 whereas others did not confirm this assumption.^7,10 From a study of 4 patients with Becker muscular dystrophy it was speculated that dystrophin deletions around exon 1 impair dystrophin expression selectively in cardiac muscle, sparing the skeletal muscle,⁹ and in a study of 320 dystrophinopathic patients, mutations proximal to exon 45 of the dystrophin gene were associated with a higher degree of cardiac involvement than mutations distal to exon 45.⁷ In another study a higher incidence of cardiomyopathy was found in DMD patients carrying deletions at the N-terminal portion of dystrophin.⁸ Whether a deletion of exons 13–43 is generally associated with absence or delayed occurrence of cardiac involvement remains speculative.

Absence of cardiac involvement may be also attributed to the presence of pure intronic rearrangement, in addition to the deletion, leading to aberrant pseudo-exon inclusion.¹¹ It is also possible that cardiac involvement was subclinical and could not be detected by the methods applied. The patient might have had subclinical arrhythmias not detectable on long-term ECG recordings. Absence of cardiac involvement may be also attributed to absence of sleep-disordered breathing. Sleep-disordered breathing may cause pulmonary hypertension, systemic arterial hypertension, myocardial thickening,¹² reduced vagal modulation of the heart rate¹³ or ventricular arrhythmias, and sudden cardiac death.¹⁴

Moreover, the patient presented with a history of continuously progressive respiratory insufficiency due to weakness of the respiratory muscles, resulting in a vital capacity of 17% at age 25 years (see Fig. 2). Interestingly, pulse oximetry at age 25 years revealed normal oxygen saturation, particularly during the night, despite dysfunction of the respiratory muscles. Normal oxygen saturation despite muscular respiratory dysfunction could be explained by the immobility of the patient and the disappearance of muscle cells due to the dystrophic process, conditions that both require less oxygen than normal. The discrepancy between the marked decline of respiratory function and absence of cardiac involvement is not unusual, since cardiac involvement does not seem to be related to respiratory dysfunction,¹⁰ and could be explained by the type of deletion present in this case. Weakness of the respiratory muscles in the absence of cardiac disease has been previously reported in DMD patients.¹⁰ Because of normal oxygen saturation during day and night, there was yet no indication to recommend noninvasive ventilation, despite the fact that respiratory problems are much more frequently the cause of death in DMD than cardiac involvement.

In conclusion, this case shows that single patients with DMD may not develop cardiac involvement until age 25 years, neither clinically nor subclinically. Possibly, dystrophin deletions of exons 13–43 are prone to absence or late development of cardiac involvement. Contrary to cardiac involvement, weakness of the respiratory muscles may continuously progress and may limit life expectancy and outcome in these patients.