Dystrophin is largest gene in body – prone to duplications/deletions. Large errors can be picked up quickly on testing. Point mutations (30%) takes more sequencing work.
Duchenne MD is X-linked but girls can get symptoms. Life expectancy was 18-20 yrs but now with steroids and non-invasive ventilation, 40 plus.
Different natural history trajectories identified – makes trials hard, as not comparable…
Becker muscular dystrophy is similar but less severe. Other muscular dystrophies include myotonic dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophies, and congenital muscular dystrophies. Spinal muscular atrophy related. Management of all similar.
Diagnosis
Often delayed. Classically delayed motor milestones, frequent falls, abnormal gait, muscle pain; but sometimes speech and language delay, learning difficulty more prominent. Urine/bowel issues. Later difficulty with jumping, running, climbing steps, and rising from the floor.
Leg flexors tend to stay strong cf extensors – leads to lordosis and contractures, and classic posture where weight forward to avoid jack knifing.
Calf hypertrophy classic. Tone and reflexes reduced (cf cerebral palsy).
Gower’s sign – using hands/arms to get up from floor and to standing position
Creatine kinase levels are elevated. Diagnosis is confirmed by genetic testing.
If CK normal, then EMG and muscle biopsy required.
Treatment
Lung function should be monitored.
Steroids are recommended from diagnosis. Preserves ambulation, respiratory function (delays the need for mechanical ventilation); avoids/delays scoliosis surgery; delays onset of cardiomyopathy; increased survival.
ACE inhibitors recommended to delay onset of cardiomyopathy.
Gene therapy difficult because of size of gene and problem of packing into vector!
Lots of trials. Givinostat approved by FDA – old drug for JIA! – conditional license in UK, early access programme in UK. Vamorolone is steroid, potent but less side effects eg bone/growth – now recommended by NICE (January 2025).
FDA has approved first gene therapy treatment – but have been fatalities and effect over time unclear.
Ataluren – oral – but EMA have withdrawn license due to poor efficacy.
Family Support
[Zoya Al-Haswani – Heartlands Hospital]