Authors
E.A.C. Beenakker, M.D.
Clinical features
Initial complaints in most boys with DMD are an abnormal gait with toe walking, frequent falls and difficulties with climbing stairs. There is often a history of delayed achievement of motor milestones. The mean age at diagnosis is between 4 and 5 years (Mohamed K et al. 2000; Crisp et al, 1982; Felisari et al., 2000), when proximal weakness is sufficiently severe to produce a waddling gait and problems with rising from the floor.
On physical examination one may find mild proximal weakness in the lower limbs with a Gowers sign, shortened ankle tendons and tendon reflexes that are still present. There is compensatory lumbar hyperlordosis which disappears when the child is sitting. The calf muscles are large and feel quite firm or even rubbery due to replacement of muscle fibres by fibrofatty tissue. Besides muscle weakness mental impairment is present in DMD (Cohen et al., 1968). Approximately 33% of the patients has an intelligence quotient - score below 75 (Bresolin et al., 1994).Natural course and prognosis
Due to the progressive nature of the muscle disease, there is a linear decline in muscle strength making the children wheelchair bound at a mean age of 9.5 years (Van Essen et al., 1997). Scoliosis is a frequent complication which may require surgical intervention. Nocturnal hypoventilation may be the first sign of respiratory insufficiency. If present, the child awakens frequently, is afraid of sleep and has headaches in the early morning. Signs of cardiomyopathy are already present in 25% of patients under 6 years, up to 59% in those between ages 6 and 10, without giving any symptoms (Nigro et al., 1988). Eventually, DMD patients die from respiratory insufficiency due to intercurrent infection or aspiration, or from cardiac arrhythmia. Patients who do not receive artificial ventilation from an early stage die at a mean age of 19 years, those who are ventilated at a mean age of 25 years (Van Essen et al., 1992).
Epidemiology
The estimated birth prevalence of DMD is 1 in 4200 live born males (Van Essen et al., 1992).
Pathophysiology / etiology
DMD is caused by mutations of the dystrophin gene which is located on the short arm of the X-chromosome (Xp21) (Monaco et al., 1988). The protein product, called dystrophin, is situated at the sarcolemma in muscle fibres (Zubryzycka-Gaarn et al., 1988; Bonilla et al., 1988), and is part of the dystrophin-glycoprotein-complex (DGC) (Campbell and Kahl, 1989). The DGC provides a structural link between the actin cytoskeleton and the extracellular matrix, thereby stabilising the sarcolemma during cycles of muscle contraction and relaxation (Petrof et al., 1993). However, the precise mechanism by which dystrophin deficiency causes the destruction of muscle fibres is still unknown.
Differential diagnosis
The diagnosis of DMD is based on clinical signs and symptoms and confirmed by raised serum concentration of creatine kinase (CK) (Zatz et al., 1991), absence of dystrophin in muscle biopsy (Bakker et al., 1997), and the finding of a mutation in the dystrophin gene.
The muscle biopsy shows abnormalities typical of muscular dystrophy such as necrosis and attempted regeneration of individual muscle fibres, increased variability of muscle fibre diameter with both hypertrophic and small fibres, and central nuclei. In an end-stage biopsy, almost the entire muscle is replaced by fibrofatty tissue.
To confirm the clinical diagnosis immunohistochemical analysis of the muscle biopsy is usually performed.
If this shows complete absence or severe reduction of dystrophin with only an occasional fibre (less than 5%) staining positively (Bakker et al., 1997), further genetic analysis is performed.
DMD must be differntiated from Becker muscular dystrophy (BMD), which is caused by mutations in the same gene but has a milder phenotype.
Ancillary investigations
In all DMD patients serum CK is raised from birth onwards and exceeds at least 10 times the normal upper limit (Zatz et al., 1991). After 5 years of age the concentration slowly declines.
Genetics
Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder with an estimated birth prevalence of about 1:4200 live born males. Mutations in the dystrophin gene can cause DMD or Becker muscular dystrophy (BMD). This is explained by the reading frame hypothesis (Monaco et al., 1988), which states that mutations that disrupt the reading frame (frame-shift) eventually leads to dystrophin deficiency and usually cause DMD. In BMD patients however mutations maintain the reading frame (in-frame mutations) and generally result in abnormal but partly functional dystrophin. The reading frame rule holds true for over 92% of all DMD and BMD cases.
In DMD and BMD, 65% of the pathogenic changes are large partial deletions (Koenig et al., 1987; den Dunnen et al., 1989) usually deleting multiple exons and 5% are partial duplications (den Dunnen et al., 1989; Hu et al., 1990) of one or more exons. Deletions and duplications can be detected by Multiplex Ligation dependent amplification (MLPA) analysis (Schouten et al., 2002).
These one or more exon deletions/duplications are clustered in two hot-spot regions of the gene, one proximal region comprising exons 2-20 and one more distal region comprising exons 45-53 in the gene (den Dunnen et al., 1989).
Part of the remaining 35% of pathogenic changes are most likely explained by small duplications/deletions or point mutations that cannot be detected by means of MLPA. These small changes can be detected, however, by one of many different pre-screening methods or direct sequencing. One of the most sensitive methods is Melting Curve analysis (MCA) which has a detection rate of almost 100%.
Therapy
There is no cure for DMD. Treatment goals are to maintain function, prevent contractures, and provide psychological support to the child and its family. Main efforts should be directed towards keeping these children standing and walking as long as possible. Passive stretching exercises, use of splints to maintain the feet in an neutral position during the night, and use of long-leg braces for walking are important in this respect. Scoliosis can not be prevented and, if progressive, surgical correction is the only effective way to straighten the spine.
Steroids do have a beneficial effect on muscle force and muscle function, but their use is not yet generally accepted because of uncertainties about both the positive and negative effects on the long run.
Other treatments aiming at the correction of the gene defect itself are not yet available for clinical use.
