Dilated cardiomyopathy (DCM) is a leading cause of cardiovascular morbidity and mortality. The DCMs form a heterogeneous group of disorders with different patterns of inheritance, including autosomal dominant (~23%), X linked (~5%), autosomal recessive, and mitochondrial transmission.1
About 30% of all DCMs are now considered to be inherited and the remaining 70% are sporadic.1
It is becoming increasingly clear, however, that a number of “sporadic” cases of DCM may be accompanied by de novo mutations in genes clearly associated with dominant disorders, complicating the issue of genetic counselling and prevalence of genetic disorders among patients with DCM. The best example is that of laminopathies, a significant contributor to the DCMs with conduction system disease, in which at least 50% of cases are the results of de novo mutations.2
Five genes have so far been associated with X linked forms of cardiomyopathy and skeletal myopathy: tafazzin (also known as G4.5) gene,3
involved in Barth’s syndrome4
; the emerin gene,5
responsible for the X linked variant of Emery-Dreifuss muscular dystrophy6
; lysosome associated membrane protein 2 deficiency,7
involved in Danon’s disease8
; the XK membrane transport protein,9
responsible for McLeod’s syndrome10
; and the dystrophin gene,11
responsible for Duchenne (DMD) and Becker (BMD) muscular dystrophies and for X linked dilated cardiomyopathy (XLDC).12
Table 1 summarises the main features of these conditions.
Table 1 X linked conditions responsible for cardiomyopathy and skeletal myopathy
Dystrophinopathy is the only condition that has been associated with exclusive cardiac involvement (XLDC). This form is secondary to mutations in the dystrophin gene, usually associated with DMD and BMD.11
DMD is the most common form of muscular dystrophy in childhood, occurring in one in 3500 male births.13
DMD is progressive, leading to loss of ambulation by 13 years. Although DMD can be inherited as an X linked condition, about one third of patients have de novo mutations. DMD is caused by a major reduction or absence in dystrophin expression at the sarcolemma.14
Cardiac involvement in DMD develops insidiously during the first decade of life, at a time when skeletal muscle weakness is already significant.14
DCM is the most common type at all ages, occasionally following a mild hypertrophic phase. The clinical pathological aspects of cardiac involvement in DMD were recently reviewed by Finsterer and colleagues.15
Despite the high incidence of cardiac involvement, most patients with DMD remain asymptomatic.16
Respiratory failure caused by diaphragm muscle weakness is the most common cause of death in DMD, which generally occurs when patients reach their 20s.
BMD is a milder allelic form of DMD with an incidence of one in 14 000 live male births, but it is almost as common as DMD among the general population due to patients’ longer survival, usually well into adulthood.17
The clinical severity varies and, while patients at the severe end of the spectrum may be able to walk in their late teens, the majority remain ambulant for life.18
Several studies have indicated that patients with BMD also have a high incidence of clinical cardiac involvement despite their milder skeletal muscle disease.19–21
In fact, some patients with BMD have initially presented with cardiomyopathy that became severe enough to require cardiac transplantation.22
The most common cause of death in BMD is heart failure. In a series of 68 patients with BMD studied from 1976 to 1993 whose diagnosis was confirmed by dystrophin testing, all had preclinical or clinical cardiac involvement by the age of 30.15,19
Female carriers of DMD and BMD, an X linked recessive disorder, have a surprisingly high incidence of cardiac involvement that progresses with age and manifests primarily as cardiomyopathy.15
Cardiac muscle biopsies of DMD and BMD carriers have a mosaic pattern of absent (DMD) or reduced (BMD) dystrophin immunoreactivity mixed with cardiomyocytes with normal dystrophin expression.23
All of the conditions described above are associated with involvement of both skeletal and cardiac muscles. An intriguing example of cardiomyopathy, without any clinical sign of skeletal muscle weakness, is XLDC, an allelic condition to DMD and BMD.
This article reviews the dystrophin gene mutations so far reported in patients with XLDC and summarises the proposed pathogenic mechanisms underlying the condition.