ÃÛÌÒAPP
In the Northern Region, Professors Straub and Lochmuller lead the multidisciplinary service for patients with inherited neuromuscular disorders.
New patients and adults are seen at the Centre for Life, paediatrics at the Royal Victoria Infirmary, and there are outreach clinics held within the Northern Region. The Service also sees patients from across the country with possible diagnoses of rare neuromuscular disorders.
The most common forms of muscular dystrophy are:
- Duchenne muscular dystrophy (DMD)
- Becker’s muscular dystrophy (BMD)
The dystrophin gene is found on the X chromosome and can have many different mutations which will cause problems with the production of the dystrophin protein within muscle. Dystrophin protein is needed for the mechanical stability of skeletal, cardiac and smooth muscle cells. The gene is also transcribed within brain tissue, hence the presentation with some mild learning difficulties in approximately 30% boys with DMD.
DMD
This is an X-linked recessive condition. It is the most common and severe form of the muscular dystrophies. Most female carriers will be unaffected, although a few may have mild muscle weakness.
It is characterized by progressive muscle weakness from the age of 3-5 yrs. Boys with DMD may present with delay in walking. Boys with DMD never achieve a ‘normal run’, and very few learn to jump with both feet together.
There is classic proximal muscle wasting and calf swelling, due to loss of muscle and its replacement by fat and connective tissue. This results in early loss of ambulation between age 7 yr and 13 yrs and worsening respiratory failure, arrthymias and cardiomyopathy, with death in their late teens/early 20’s from cardiorespiratory failure.
Diagnosis should be considered in those boys with developmental delay, especially walking difficulties combined with speech delay. For example they may have tiptoe walking or an unsteady gait. They often have difficulty getting up from the floor, and have to ‘climb up’ their legs using their hands to get to standing (Gower’s manoeuvre). They may also have difficulty climbing the stairs, needing to get both feet onto the step before tackling the next one.
BMD
This form of muscular dystrophy is clinically similar, but usually milder than DMD. It is caused by different forms of mutation within the dystrophin gene that result in reduced levels of the dystrophin protein. The mean age of onset is age 11 yrs with muscle weakness, with loss of ability to walk, presenting much later at age 40-50yrs. Often cramps with exercise are the only indication early on, but some boys are also late to walk and are unable to run quickly. Later in their teens and 20’s, muscle weakness increases causing delay in fast walking, running and climbing stairs. It may be difficult for them to lift heavy objects above waist height. Cognitive impairment is not a major feature.
Manifesting female carriers
A small percentage of female carriers may have symptoms of myalgia/cramps (5%) and mild/moderate muscle weakness on testing (15%), although most of these are unaware of any weakness prior to testing. Blood tests would show a raised creatine (CK) level.
There is unequivocal evidence that approximately 10% of female carriers of dystrophin mutations (DMD or BMD) develop overt cardiac failure even without having skeletal muscle involvement. All carriers should therefore have an echo and ECG at diagnosis or from age 16 yrs, and 5 yearly thereafter. If a carrier has muscle weakness or cardiac symptoms, then more frequent investigation is required.
Steroids and DMD
There is a discussion on the use of steroids in Duchenne muscular dystrophy here.
Diagnosis and investigations
- Family history: especially relevant are any other affected males within the maternal family.
- Developmental history: examination: gait, run, proximal muscle weakness, calf hypertrophy.
- Creatine kinase (CK): CK is an enzyme found in muscle and is raised in the muscular dystrophies: usually to level of several thousand. Children with DMD invariably have serum levels >10 times normal.
- DNA analysis for deletion/duplication mutations and also linkage studies if no mutation found.
- Muscle biopsy if no mutation identified, but there is strong clinical and family picture. The biopsy allows a quantitative picture of how the muscle is affected. Since an increasing number of mutations are being identified, muscle biopsy is less frequently needed.
- Echocardiogram/ECG/respiratory studies: those with DMD should have echo & ECG every two years from diagnosis until age 10 yrs and then annually thereafter, and also before any surgery.
Those with BMD should have echo and ECG every 5 years.
Both those with DMD and BMD are at increased risk of cardiac complications perioperatively and it is important that anaesthetists be aware.
Prenatal diagnosis
- Available to carriers of a known dystrophin mutation by chorionic villous sampling (CVS) at 11 weeks gestation.
- Available to mothers of de novo Duchenne mutations, because of the risk of germ line mosaicism (i.e. the mutation may not be within the genomic DNA present in all the cells of the body, but may be a germ line mutation occurring within some ova).
- Available in families where linkage studies suggest a ‘high risk X chromosome’.
- Pre-implantation genetic diagnosis (PGD) may be possible. See also Preconception counselling for a known genetic disorder
Predictive testing
Of newborn males. Women at risk of being carriers, but who do not wish to have prenatal testing and who give birth to a son may wish to have him tested before considering further pregnancies. CK is high in cord blood and within the first week, but can sometimes be equivocal. A value in the normal range excludes DMD, but if equivocal, needs to be repeated at 6 weeks of age; otherwise testing is best done at 6 weeks. Need to bear in mind that vaccinations given i.m. will raise the CK level.
For a mother of an affected boy with a known mutation that is not present in the mother’s genomic DNA there is a suggested 1 in 5 (20%) risk to a future son who inherits the same X chromosome as his affected brother. This gives an overall 5% risk to future pregnancies.
In families of an affected boy with a known mutation that is not present in his mother’s genomic DNA, any sisters of the affected boy should be offered mutation-based carrier testing. If they inherit the same maternal X as their brother, they will have a 20% risk of being carriers as a result of maternal germ line mosaicism.
If the mutation in an affected individual is unknown, assessment of carrier status in female relatives is more complex.