4/3/2014 Duchenne Muscular Dystrophy In the classroom Physically Educationally Emotionally Sue Nicklin, PT First Off – Translation Tips! • The ‘r’ sound is tricky, in Australia you don’t pronounce it when it is written and do pronounce it when it’s not • The Australian accent replaces most of your short vowels with long ones • Pronunciation is generally on a different syllable • When my intonation rises at the end of a sentence, don’t worry I’m not asking you a question Duchenne Muscular Dystrophy • Most prevalent and disabling of the inherited neuromuscular disorders. • Clinical features become evident between 2-5 years of age • Progressive weakness that begins with microscopic changes in muscle • Boys lose the ability to walk at about 10 years of age and die of respiratory insufficiency or as a result of cardiomyopathy by late teens to mid-twenties (average 17.7 in 1960) without steroid use and mid to late twenties with steroids (average 27 now) 1
4/3/2014 Genetics of DMD • X- Linked recessive inheritance therefore generally only affects boys. Girls are carriers and can have carrier symptoms. Rarely girls have 2 disrupted X chromosomes and have full DMD • Incidence of about 1 in 3600 boys • 1/3 familial, 1/3 new mutation, 1/3 new maternal mutation Cause of DMD • The ‘disrupted’ gene is responsible for the production of dystrophin • Dystrophin is a protein found on the inner side of the muscle cell membrane, responsible for maintaining the structure of the cell’s membrane. Most of the other proteins involved in muscle cell integrity require the dystrophin superstructure. • Without dystrophin, muscle cells break down and die during normal muscle contractions, leading to progressive muscle weakness 2
4/3/2014 Looking Deeper • Normally our muscles regenerate themselves throughout our life. But by the time these boys are 6 or 7 they’ve broken down so much without regenerating that they have no integrity left • In dystrophin-deficient muscle, the blood vessels do not dilate creating a deficit in blood flow, therefore the supply of nutrients to the muscle is also reduced. This prevents regeneration of damaged muscle Muscle Weakness • Membrane damage continues to occur with the result of damaged muscle being replaced by scarring and fat. This contributes to muscle contractures and lost elasticity of the muscles. It makes the muscles look bigger but significantly weaker • Affects larger muscles first therefore impacts on standing, walking, running, getting up from the floor or chairs initially • Progresses to smaller less heavily used muscles DMD – Muscle Facts • Affects all muscle: Striated, Cardiac and Smooth • The more you use the muscle the faster it will degenerate and die • The worst type of contraction for the muscle is Eccentric, followed by Isometric followed by Concentric • Muscle cell lifespan is being preserved by use of Steroids • The muscle is still muscle – if you train them they will get stronger temporarily but this will speed the degeneration. You CAN train the muscle, the question is SHOULD you! 3
4/3/2014 DMD – Not just about the legs • Dystrophin is found in the brain and although it’s specific action is unclear, the impact of it’s loss is very clear! • Smooth Muscle implications – Constipation for a variety of reasons • Cardiac implications – At times heart failure is rapidly progressive DMD - Not even just about the child • In 2/3 of cases, Mom is a carrier • This also means half the children are affected, the boy with DMD and half the sisters are carriers • DMD is a relentless, progressive terminal disease – all members of the close and distant family are affected Stressors on the family • Financial strain • Lack of sleep • Families face loss and grief many times – Their ‘normal’ child – Their hopes and expectations for the future – Their lifestyle – Ultimately, the child himself 4
4/3/2014 Why do we care so much about Carriers? In each carrier statistically half of their cells have DMD • Half the muscle cells are dystrophin deficient (which is mostly surmountable but will often express as quick fatigue in a parent often relied upon for heavy lifting) • Half the brain is dystrophin deficient (also surmountable but may show OCD and rigid thinking patterns) • Half the heart is dystrophin deficient – cardiomyopathy common Early Diagnosis of DMD • DMD is generally first suspected by Pediatric PTs, OTs and SLPs not by doctors • The kids present as ‘clumsy kids’, ‘low tone kids’, ‘toe walkers’, “SI kids” or with ‘language delays’ • Standard PT treatment of these disorders involves strengthening, core muscle stability exercises and games to improve their co-ordination • All of these treatments will hurt a child with DMD because the muscle contractions emphasized are eccentric control and therefore increasing speed of muscle deterioration • Stretching programs are helpful Early Diagnosis • Early diagnosis allows parents to make informed decisions about subsequent children • Early diagnosis is important to be able to adjust expectations and therapy programs allowing emphasis on energy conservation and stretching rather than strengthening • It reduces parental anxiety that they have “done something wrong” and gives them access to a huge support system 5
4/3/2014 There is now something we can do! • Steroids and other symptomatic drugs are improving strength, improving lung capacity, reducing heart disease and improving life expectancy. Although they can’t be started at birth, early start of steroids and other therapies are changing the outlook for these children and their families • Research is progressing rapidly leading to clinical trials and novel drugs addressing DMD from the symptomatic through to the genetic level Early Warning Signs • Weakness pattern rather than coordination difficulties • Any loss of gross motor skills • Anterior neck weakness (head lag in young children who are walking) • Combined motor and speech delay esp if cognition is normal (but not exclusively) • Infants who avoid mid position – don’t squat to play, don’t stoop to get dropped toys • Modified Gowers – any infant needing to pull to stand by putting a hand on their knee Now what do I do? Beg for Testing • CK testing (sometimes called CPK) – Creatine phosphokinase. • In children, even a reading that is double accepted level should be referred to a Pediatric Neurologist • Normal CK doesn’t mean normal child • Normal range is up to 250 units (of enzyme activity) per liter(of blood) • Mildly elevated (About 500 u/l) – CMT, SMA • DMD will be in the tens of thousands, with Becker about 500 - thousands 6
4/3/2014 So the CK was 20 000. Now What? • Sequencing the gene – gives genetic confirmation of DMD without muscle biopsy • Biopsy is now a very last resort • Sequencing tells us – why the gene is faulty, how likely there is Cardiac involvement, and the potential for intellectual impairment. Also required for clinical trials • PPMD assists with sequencing costs – www.skipahead.com The Duchenne timeline Progression Facts • Predictive function – Loss of standing from floor - >50% lose ambulation in next year – Earlier loss of ambulation – predicts earlier loss of self feeding and NIV (Non Invasive Ventilation) • Typical 1 year changes – 2 pound loss of knee extension strength – 3-7 second increase in time to climb stairs – 7 point increase in Northstar – 44m decline in 6 Minute Walk test – Forced Vital Capacity 5% decline 7
4/3/2014 Implications Throughout Progression • Poor bone density even before steroid use – fracture rate is high (esp. Spinal and Femurs) – Current Gold Standard requires Operative Internal Fixation because atrophy from casting and NWB is often irretrievable • If the child is on a steroid regime, stress (like a fracture or surgery) can trigger Adrenal Crisis • So many kids with Neuromuscular Diseases also carry the RYR1 gene that it is now ‘presumed’ that they have it. The RYR1 gene can trigger a fatal response to inhaled anesthetics (Malignant Hyperthermia) Treatment for Early DMD • Speech Therapy – generally the most applicable in the early age. Language, Literacy and Phonics training are generally the most relevant services early • Preventative Treatments – stretching programs for families, night splints to retain ROM, teaching energy conservation techniques to family, childcare and schools • Support Services – grief counselling, genetic counselling, sibling services Steroids – The Good • Shown to alter the rate of decline in muscle function • If administered early (about 4) may allow walking for an extra 3 years • Improved lung function • Reduced requirement for surgical spinal intervention and when required is later 8
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