The material covered in this review was obtained entirely from personal knowledge, the reference sources listed, and PubMed literature searches.
SeminarThe muscular dystrophies
Section snippets
Clinically defined types of muscular dystrophy
On the basis of distribution of predominant muscle weakness, six major forms can be delineated (figure 1), with the addition of congenital dystrophy, in which muscle weakness is more generalised (panel 1).
Distal muscular dystrophy
In this muscular dystrophy, weakness is mainly distal. The disorder can be divided into two main groups: late onset (over 40 years of age) with autosomal dominant inheritance, including Welander's disease; and early onset (less than 30 years of age) with autosomal recessive inheritance. However, apart from one recessive form (Miyoshi type), which is associated with deficiency of the sarcolemmal-associated protein dysferlin, the underlying cause of these dystrophies is unknown.28 Since
Facioscapulohumeral muscular dystrophy
This dystrophy derives its name from the muscle groups that are mainly affected first: facial and shoulder girdle. Later, foot extensors and pelvic-girdle muscles become involved. The heart is not implicated in most cases, though arrhythmias and conduction defects have been described.29 Mental impairment is not a feature, but retinal vascular disease and hearing loss can arise. This autosomal dominant disorder is associated with subtelomeric deletion of chromosome 4q, with loss of 3·3 kb
Oculopharyngeal muscular dystrophy
This disorder has mainly been studied in French Canada, where the disease can be traced back to immigrants from France in 1634. However, although most frequent in Canada, the disorder also occurs in other parts of North America and Europe. Onset is around the third decade of life, affecting the extraocular muscles (though frank diplopia is rare), and upper facial muscles with ptosis, and there is weakness of the neck and proximal upper (and even lower) limb musculature. Dysphagia is a serious
Limb-girdle muscular dystrophy
In this disorder, weakness affects mainly the proximal limb-girdle musculature. So far, 15 genetically different types have been identified, which show great clinical and genetic heterogeneity. Autosomal dominant forms are very rare and generally less severe than recessive types; they have been reviewed in detail elsewhere.32 Several of these disorders are associated with clinically significant cardiac involvement (types 1B, 1D, 2C, 2E, and 2F), and affected individuals should therefore be
Serum creatine kinase
Measurement of serum concentration of creatine kinase is a simple and inexpensive diagnostic test for severe forms of dystrophy known to be associated with high concentrations. In Duchenne muscular dystrophy, serum creatine kinase values are raised from birth, and testing in neonates for early diagnosis could reduce the possibility of further affected boys in a family.33 There is still a worrying delay in diagnosis of the disorder in early childhood.34
Electromyography
This method is important for establishment
Epidemiology
Because X-linked Duchenne muscular dystrophy has been clearly defined for many years, its incidence has been fairly well established. On the basis of some 40 studies including several million male births, incidence at birth of Duchenne muscular dystrophy is around 300 × 10−6, and its prevalence in the population (in terms of the total male population) is around 60×10−6.38
Epidemiological figures for other dystrophies have, in the past, not been very reliable, but as these disorders become better
Broadening the definition of muscular dystrophy
Recognition of the molecular basis of certain dystrophies has led to further research, which has shown a broadening of the associated phenotype. Most importantly, an association with cardiomyopathy has been recorded for many forms of dystrophy, which in some cases is associated with conduction defects. In several disorders–most notably some cases of Becker and Emery-Dreifuss muscular dystrophy–the associated cardiomyopathy might be the presenting and main feature, rather than muscle weakness.
Intrafamilial and interfamilial variation
The accepted idea of one gene=one protein=one disease is, in many monogenic disorders, now proving to be an oversimplification. In the β-thalassaemias for example, the associated phenotypes indicate not only the heterogeneity of mutations in the β-globin gene but also the effects of modifier genes and environmental factors.40 This problem is now clearly evident in the dystrophies. For example, different mutations of the LMNA gene can present not only as Emery-Dreifuss muscular dystrophy but
Pathophysiology
Although much research is focused on future availability of some form of gene therapy, discovery of an effective drug treatment is also possible. However, this finding would depend on a clear understanding of the pathophysiology of these disorders. When dystrophin was discovered to be the protein defect in Duchenne muscular dystrophy, researchers naturally assumed that, since this protein is associated with the sarcolemma, deficiency of dystrophin would result in breakdown of muscle membrane.
Genetic counselling and prenatal diagnosis
Prevention by counselling and prenatal diagnosis is now possible for almost all muscular dystrophies. However, for prevention to be reliable a precise diagnosis is essential. Diagnosis is based mainly on careful clinical examination to establish the main type of dystrophy, followed by relevant laboratory investigations, which in many cases–and certainly when prenatal diagnosis is to be considered–should include identification of the specific mutation. These laboratory investigations are often
Management and treatment
Management of individuals with dystrophy depends very much on the type of dystrophy and its severity. Because of the severity and high frequency of Duchenne muscular dystrophy, most concern has centred on management of this disorder.
Search strategy and selection criteria
References (77)
- et al.
ENMC sponsored workshop on congenital muscular dystrophy held in Naarden, The Netherlands, Oct 27-28, 2000
Neuromuscul Disord
(2002) - et al.
Prenatal diagnosis in congenital muscular dystrophy
Lancet
(1995) - et al.
Cardiac abnormalities and skeletal muscle weakness in carriers of Duchenne and Becker muscular dystrophies and controls
Neuromuscul Disord
(2001) - et al.
Dystrophin: the protein product of the Duchenne muscular dystrophy locus
Cell
(1987) - et al.
An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus
Genomics
(1988) - et al.
Workshop report: neonatal screening for muscular dystrophy
Neuromuscul Disord
(1993) - et al.
Failure of early diagnosis in symptomatic Duchenne muscular dystrophy
Lancet
(1999) - et al.
Strategy for mutation analysis in the autosomal recessive limb-girdle muscular dystrophies
Neuromuscul Disord
(2001) Population frequencies of inherited neuromuscular diseases - a world survey
Neuromuscul Disord
(1991)- et al.
Neuromuscular disorders in childhood: a descriptive epidemiological study from western Sweden
Neuromuscul Disord
(2000)