Muscular dystrophies are classified according to which muscles are affected, the mode of inheritance, and the muscle proteins that are deficient or mutated. The major types are: (i) Duchenne and Becker dystrophy; (ii) Myotonic dystrophies; (iii) Limb-girdle dystrophies; (iv) Facioscapulohumeral dystrophy; (v) Congenital dystrophies.
Duchenne and Becker Dystrophy
Duchenne and Becker dystrophy are caused by defects in the dystrophin gene on the X-chromosome and consequently affect males, while female carriers are unaffected or have only mild symptoms. The mutations cause a deficiency of the structural muscle protein dystrophin, and these conditions are therefore classified as dystrophinopathies. Duchenne dystrophy is the most common and severe childhood form of muscular dystrophy, affecting 1 in 3500-5000 male births, and is relentlessly progressive and eventually fatal by the late-20s to early 30s, due to weakness of the respiratory muscles and involvement of the heart.
Muscle weakness usually begins at the age of 4-5yrs, leading to problems with walking, getting up from the floor (Gower’s sign) and falls. Affected boys usually go on to lose the ability to walk and become wheelchair dependent by the age of about 12. The condition can be diagnosed at birth, even before symptoms develop, by finding an elevated creatine kinase level in the blood, making neonatal screening for the disease possible.
There is no curative treatment for Duchenne dystrophy, or for the more benign later-onset Becker dystrophy. However, a course of steroids (prednisone or deflazacort) can slow the progress of weakness and extend the period of walking, but has significant side-effects. A promising novel personalised approach to treatment (developed at the Perron Institute) uses specifically designed antisense oligonucleotides (ASONs) to bypass some dystrophin mutations (e.g. in exon 51of the gene) and two such drugs are currently undergoing clinical trials (Etilpirsen and Golodirsen). Continuous non-invasive ventilatory support is often necessary in the later stages of the disease and, together with the use of a cough-assist device can help to prolong the lifespan. Spinal surgery to correct kyphoscoliosis may also be required in some cases.
Myotonic dystrophies are the most common later-developing types of muscular dystrophy, particularly in individuals of European ancestry and have a prevalence of about 10 per 100,000. Unlike other dystrophies, they are characterised by the symptom of myotonia—i.e. slow release after muscle contraction, for example after gripping the hand—as well as slowly progressive muscle weakness and atrophy, and effects on other parts of the body such as the eyes and the heart, and the endocrine and nervous systems.
There are two main genetic types, DM1 and DM2, which are both inherited in an autosomal dominant manner. DM1 mainly affects the muscles of the face, forearms and lower legs, whereas in DM2 the proximal limb and axial muscles are affected and the clinical course is usually milder, although some patients may experience severe myotonia as well as muscle pain and stiffness. DM1 is caused by mutations in the DMPK gene and DM2 by mutations in the CNBP gene, and the precise diagnosis can be confirmed by molecular genetic testing. The age of onset and degree of weakness may vary considerably between DM1 and DM2. DM1 usually begins in adolescence or early adult life and progresses slowly, but more severe earlier-onset congenital and childhood forms also occur, depending on the type of gene mutation.
Although there is currently no treatment to stop the progression of the muscle weakness, it is important that patients with a myotonic dystrophy should undergo regular medical reviews. This is particularly important in DM1 which may cause other problems that need to be treated, such as cataracts, diabetes, gastrointestinal disorders and most importantly, cardiac arrythmias, which may also occur in patients with DM2. Medications (e.g. mexiletine, phenytoin, procainamide) are available to reduce the myotonia and muscle stiffness, if this is severe and is causing problems with daily activities.
Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic disorders that affect both males and females, and can be inherited either in a dominant or recessive manner. LGMD mainly affects the muscles of the shoulders, upper arms, thighs and pelvic area on both sides of the body. Muscle weakness may develop during childhood, adolescence or adult life and is slowly progressive, with gradual atrophy of the affected muscles which is severe in some cases. In some types of LGMD the respiratory muscles and heart are also affected.
Over 24 LGMD genes have now been identified, eight being associated with an autosomal dominant pattern of inheritance (LGMD1A-H), and 16 with autosomal recessive inheritance (LGMD2A-Q). The most common types are LGMD2A (CAPN3 gene) and LGMD2B (DYSF gene). Precise diagnosis of the defective gene and specific mutation in individual cases and families is now possible with Gene Array technology and Next-Generation sequencing.
As yet, no treatments are available to stop these diseases from progressing, but new genetic therapies are being investigated. It is important that affected individuals should be reviewed regularly by a neurologist as treatments are available to alleviate symptoms of the disease. These include physical and exercise therapy, as well as attention to respiratory function and the heart if these are affected.
Facioscapulohumeral dystrophy (FSHD) affects primarily the muscles of the face, shoulder blades and upper arms, as well as the thighs and lower legs, causing slowly progressive weakness and atrophy, which may be more severe on one side of the body than the other. Typically, there is difficulty closing the eyes completely, whistling, smiling and drinking through a straw. The severity varies considerably in different cases, even in the same family, but in about 20% of cases the weakness becomes severe enough to necessitate the use of a wheelchair. Symptoms usually develop before the age of 20, but can also occur in infancy or later life. People with FSHD may also suffer hearing loss or develop abnormalities of the blood vessels of the eye (retinal vasculopathy), particularly when the disease commences at an early age.
Two types of FSHD have been described, FSHD1 and FSHD2, which are both inherited in an autosomal dominant manner, and have similar clinical features but are caused by different mutations. FSHD1 accounts for about 95% of cases and is caused by abnormal expression of the DUX4 gene in the D4Z4 region of chromosome 4, whereas in FSHD2 there is a mutation in the MCHD1 gene. The specific diagnosis can be confirmed by molecular genetic testing. About 30% of cases of FSHD1 do not have a family history and are thought to be caused by new mutations.
Although there is currently no treatment to arrest or slow the progress of the disease, patients with FSHD should have genetic counselling and regular reviews to detect medical problems that may require treatment, such as retinal eye problems, hearing loss and breathing difficulties. They may also benefit from an exercise program and physical therapy. Some patients may require orthopedic procedures, ankle-foot orthotics or walking aids.