Recent
advances in paediatric muscular dystrophies
Kate Bushby - UK
Summary: The inherited muscle diseases of childhood remain a
significant cause of disability. Enormous progress in determining the underlying
genetic causes of these disorders has led to much greater precision in
diagnosis and better guidance about prognosis for individual conditions. This
has been particularly striking in recent years in the elucidation of the
genetic basis for muscular dystrophies presenting in the first year of life
(the congenital muscular dystrophies) or later in childhood (Duchenne and
Becker muscular dystrophies, Emery–Dreifuss muscular dystrophy and the
limbgirdle muscular dystrophies). Improved understanding of pathogenesis and
disease progression means that management interventions can be more logically
planned, allowing a considerable impact on well-being and longevity. Support
for respiratory impairment and cardiac and nutritional problems can be
logically planned and applied in a disease-specific manner. The potential of
gene-based therapies for these conditions, or specific pharmacological
modification of the phenotype, remains a major goal of basic research.
About Duchenne Muscular Dystrophy:
Duchenne and Becker muscular dystrophy The
discovery in 1987 of the dystrophin gene as the cause of Duchenne and Becker
muscular dystrophies (DMD and BMD) was a major milestone in the
characterisation of all other inherited muscle diseases. Molecular diagnosis
via DNA analysis in DMD and BMD is now standard practice, at least for the
deletion and duplication mutations that account for the disease in
approximately 60–70% of cases. It remains disheartening that, while diagnosis
of DMD is now routine at the molecular level, the age at diagnosis remains over
4.5 years.14 Early diagnosis is important to
allow family counselling and begin appropriate management. Continuing education
of primary care and community staff coming into contact with preschool children
is needed to promote the early diagnosis of this condition: for example, by
having a low threshold for testing serum CK levels in young boys who are not
walking by the age of 18 months, or who fail to learn to run or jump normally.
After years of uncertainty and debate about the medical treatment of DMD, a
consensus is beginning to emerge that several key points of management are
likely to improve prognosis in this condition. Two large-scale systematic
reviews of the use of corticosteroids to improve muscle strength in DMD
conclude that daily corticosteroid treatment does improve muscle strength, and
is likely to (1) prolong ambulation, (2) delay or reduce the need for spinal
surgery, (3) promote the maintenance of respiratory function, and (4) have
(possibly) a cardioprotective effect.15,16 These
effects seem to be the same with the use of either prednisolone or deflazacort.
However, it is also clear that longterm use of steroids is associated with a
risk of clinically significant side-effects. Prednisolone appears to have a
higher association with weight gain than deflazacort, which has a higher
incidence of (usually asymptomatic) cataracts. Both treatments may be
associated with an increase in osteoporosis that may result in vertebral
fractures. So while steroid treatment is probably effective in increasing
muscle strength in most boys with DMD, the treatment needs to be carefully
monitored and the dose titrated if necessary. Further studies are required to
explore the use of alternative steroid regimes. A greater understanding of the
underlying disease course in DMD and the availability of treatments to modify
the complications of cardiomyopathy and progressive respiratory failure have
also altered the natural history of this condition. Surveillance for cardiac
impairment and treatment of progressive abnormalities with ACE inhibition and b
blockade, even in the absence of symptoms, has now been recommended.
Cardiomyopathy in DMD occurs in almost all patients, but is usually
asymptomatic because of the low levels of activity. For patients with the
milder allelic condition BMD, and for a small proportion of carriers of DMD and
BMD, cardiac complications are also important and may be out of proportion to
the skeletal muscle disease. Cardiac surveillance is crucial to allow intervention
before an untreatable cardiomyopathy supervenes. Finally,
proper respiratory care (including monitoring for the inexorable decline in
respiratory function seen in DMD, and intervention with nocturnal ventilation
where indicated) has dramatically altered lifespan in DMD, which should no
longer be regarded necessarily as a disorder which is uniformly lethal in
childhood. This change in life expectancy
has important social implications for the affected young person and his family.
Practice points for management of DMD:
·
Detection of
early symptoms of DMD should be an important part of pre-school
surveillance.
·
Corticosteroids do
improve strength in DMD but need to be used with attention to the possible
side-effects.
·
Proper management of
respiratory deterioration in DMD is associated with improved life expectancy
·
Cardiac surveillance is
essential to detect and allow treatment of frequently asymptomatic but
progressive cardiomyopathy.