Duchenne muscular dystrophy (DMD) is the commonest and most severe form of muscular dystrophy. A similar but milder condition known as Becker muscular dystrophy (BMD) is caused by mutations in the same gene. The incidences of DMD and BMD are approximately 1 in 3500 males and 1 in 20 000 males respectively. There is no effective cure for either of these disorders.

Males with DMD usually present between the ages of 3 and 5 years with slowly progressive muscle weakness resulting in an awkward gait, inability to run quickly and difficulty in rising from the floor which can be achieved only by pushing on, or 'climbing up', the legs and thighs (Gowers' sign). Most affected boys have to use a wheelchair by the age of 11 years because of severe proximal muscle weakness in the lower limbs. Subsequent deterioration leads to a lumbar lordosis, joint contractures and cardio-respiratory failure leading to death at a mean age of 18 years.

On examination boys with DMD show an apparent increase in the size of the calf muscles which is actually due to replacement of muscle fibres by fat and connective tissue. This is referred to as pseudohypertrophy and DMD is sometimes known as pseudohypertrophic muscular dystrophy. In addition, approximately one-third of boys with DMD show mild to moderate intellectual impairment with the mean IQ of all cases being 83.

In BMD the clinical picture is very similar but the disease process runs a much less aggressive course. The mean age of onset is 11 years and many patients remain ambulant until well into adult life. Overall life expectancy is only slightly reduced. A few patients with proven mutations in the DMD/BMD gene have been asymptomatic in their fifth or sixth decade.

Both DMD and BMD show X-linked recessive inheritance. Males with DMD rarely, if ever, reproduce. The dystrophin gene has one of the highest known mutation rates in humans - presumably because of its large size.

Deletions of part or all of the gene account for two-thirds of all mutations. These differ in their size and in their position. They arise almost exclusively in maternal meiosis, probably due to unequal crossing over. A small number of affected males with duplications have also been described. Two deletion 'hot spots' exist, one involving the first 20 exons and the other in the centre of the gene around exons 45-53. One of the deletion breakpoint 'hot spots' intron 7 contains a cluster of transposon-like repetitive DNA sequences which could facilitate misalignment in meiosis with a subsequent cross-over leading to deletion and duplication products.

The size of the deletion does not correlate with disease severity. However, deletions which cause DMD usually disturb the translation reading frame. In contrast deletions seen in males with BMD usually do not alter the reading frame so that the amino acid sequence of the protein product of the DMD gene downstream of the deletion is normal. This probably explains why the clinical features in BMD are relatively mild. In clinical practice deletions are usually detected by a multiplex-PCR technique in which several exons are amplified simultaneously. The presence of a deletion is then confirmed by Southern blotting.

Mutations identified in the remaining one-third of affected boys include stop codons, frameshift mutations, altered splicing signals and promoter mutations. Most point mutations in DMD lead to premature translational termination resulting in the production of little if any protein product. In contrast to deletions, point mutations in the DMD gene usually arise in grandpaternal meiosis, most probably due to a copy error in DNA replication.

Until molecular methods were available carrier detection was based on pedigree analysis combined with creatine kinase assay in serum. Creatine kinase is grossly elevated in the serum of boys with DMD and is marginally increased in approximately two-thirds of all carriers. Creatine kinase assay is still used occasionally as an adjunct in carrier detection and family studies, but its lack of sensitivity has led to it being superseded by DNA analysis.

Accurate carrier detection can now be achieved for most female relatives of affected DMD/BMD males by direct mutation/deletion analysis or indirectly by linkage studies using polymorphic intragenic markers. If a microsatellite maps to the site of a deletion, then study of the segregation of the microstellite marker in a family will often provide conclusive evidence of carrier status in relevant female relatives. Care has to be taken when using linkage for carrier detection because there is a high recombination rate of 12% across the DMD gene.