DMD Long Flashcards
Genetics of DMD?
Steadily progressive XLR
- Xp21.2 gene, dystrophin gene (one base pair deletion)
- Dystrophin deficient muscle is susceptible to muscle injury and degeneration of fibres is a feature
- Dystrophin is found in skeletal muscle, smooth muscle and central nervous system
- Most severe are frameshift mutations that code for premature stop codons - 96% have a frameshift mutation, 10-20% of new mutations are gonadal mosaic
- Mutations in the gene that result in the production of abnormal dystrophin result in Beckers
- Phenotypes: DMD, BMD, DMD Cardiomyopathy only (usually female carriers)
Life expectancy of someone with DMD?
~40 years –> how are family/patient coping with prognosis?
Important Qs for DMD history?
1) Initial diagnosis (usually 3-5yo) - what Symptoms (late walking, clumsiness, assoc cognitive impairment?), Time between onset of symptoms and diagnosis, Investigations
2) Stages of deterioration (usually 6yo onward)
3) Current function
4) Number of hospitalisations
6) Treatment: any steroids? surgical procedures? PT/OT/breathing exercises, plan for future treatments, alternative therapies
7) Complications and their management: Functional impairment/aids/modifications, transport needs, scoliosis, joint contractures, resp/cardio/gastro involvement, constipation, urinary function, obesity, learning skills/modifications for school, steroid complications
8) Social: ?Difficulties at school – 1SD lower IQ, ?Poor job prospects, Limitations on lifestyle, ?Poor body image/self esteem, Peer reactions, ?Depression, impact On family, ?Benefits and support groups, ?Car/wheelchair, Families understanding of the disease (Contingency plans, Genetic counselling - maternal cardiac screening?)
9) Family Hx of DMD?
Examination steps in DMD exam?
1) General: Posture, Small interscapular muscle bulk, Small proximal limb musculature, Lordosis/scoliosis, Small thighs, Prominent calves/pseudohypertrophy, Describe the wheelchair, Respiratory involvement - ↑ RR, Mood, intellect, Steroid side effects (cushingoid, striae, obesity, inc BP)
2) Neuro: Test for power against gravity, Then against resistance, Knee jerk often lost, Contractures – ankles/hips/knees
3) Gait: Foot drop –> weak tib ant, Inversion due to strong tib post and weak peroneals, Walking on toes –> tight tendoachilles, Higher stepping gait than normal, Knee locking gait due to weak quads, Trendelenburg gait, Overall the gait is waddling, Gowers
4) Cardiac: Signs of CCF – dilated cardiomyopathy (Starts at ~10yrs and in all patients by 18 years)
5) Respiratory: ↓ lung volume/expansion, Signs of OSA
Ix in DMD?
1) CK grossly elevated: usually <5000 Becker, 5000 Duchennes
2) Muscle biopsy: Useful if genetic tests are inconclusive, degenerative changes and extensive fibrosis, infiltration with macrophages, ↑ fibre size variability
3) Western Blot: See absence of dystrophin
4) EMG: Decreased size of the motor unit potential (can also be seen in myopathy) + Spontaneous fibrillations
5) Dystrophin mutation testing: Detection in muscle, Immunohistochemistry + Electrophoresis
6) MLPA DNA PCR/Hi res chromosomal microarray: 60-70% can be detected and they are most commonly deletions of one or more exons
7) Prenatal diagnosis is available by CVS or amniocentesis by direct testing for abnormalities in the dystrophin gene
Psychosocial Mx in DMD?
Management is by a multidisciplinary team
* Role of the general paediatrician is to keep in close contact with the team, to make any changes and to deal with problems that arise between clinic visits such as managing intercurrent illness
o Education of the patient and family members
o Expectation of a grief reaction from parents and feelings of guilt, anger, depression
o Ensuring supports: From professionals and non professionals, Muscular dystrophy association, Society for crippled children
o Informing about financial assistance - Care, transport costs, accommodation, home modification
o Managing treatment difficulties: Seeking second opinions, Alternative therapies, Non-compliance
o Managing how to inform the patient and family: Making sure it is done adequately + identifying denial
Allied Health Therapies used in DMD?
1) Physiotherapy: Passive range of movement exercises daily for prevention of contractures, Strength exercises against gravity or resistance, Can’t be done once they are very weak, Chest physio I
2) Occupational therapy: Prescribing equipment, Home visits and visits to the school, Aids for activities of daily living, Aids for posture, Assess the need for lifting machines, ramps for the house, modifications to the home
3) Equipment: Wheelchairs (Usually manual from age 9, electric from age 11)
Also: Orthopedic surgeries (elongation tendoachilles if still walking, tenotomies/tibilais posterior transfer, scoliosis Mx), Steroids
Surgical Mx in DMD?
1) Elongation of tendoachilles if still walking (Weakness is more of a problem than contractures)
2) Tenotomies or tibialis posterior transfer,
3) Management of scoliosis
- Occurs at 13-15yo
- If Cobb angle >30, Thoracolumbar curvature
- Most apparent when in the wheelchair during the pubertal growth spurt
- Bracing does not work in these children
- things to consider before surgery include: Fitness for surgery, VC >50%, Substantial growth capacity remaining, Progressive curve
4) Surgical issues: Post op they need early mobilization to prevent decompensation, Cannot use neuromuscular depolarizing agents
When to use steroids in DMD and how much?
- The recent advance has been using steroids while they are still walking to preserve some motor function - Prednisone delays disease progression, prolongs the ability to walk, maintains function, delays or prevents the formation of scoliosis, preservation of respiratory function (unknown MOA)
- Schedules vary between centres: Can be ten days on ten days off @0.75mg/kg/day, Can be alternate daily
Should not be used under 5 and the timing and dose needs to be monitored to avoid unwanted side effects
SEs of steroids?
Weight gain
Hypertension
Osteoporosis
Hyperglycaemia
Easy bruising
Behavioural problems
New alternative is Deflazacort – better for weight gain/behavior but ↑↑↑ risk of cataracts
Complications of DMD?
1) Restrictive lung disease: Due to weakness of the diaphragm, chest wall and abdominal muscles. Main cause of death around 22 years
- Recurrent chest infections should be treated aggressively
- Cor pulmonale can be a complication due to hypoxia due to ventilation failure and ventilation/ perfusion inequality secondary to scoliosis
- Monitoring: 6 monthly respiratory function tests (↓FVC – restrictive pattern, Max insp pressure= diaphragm function, Max exp pressure= chest wall and abdominal muscles and the ability to cough)
- Hypercapnoea and hypoventilation – think OSA! - Restless at night, Somnolent by day, Morning headaches, Anorexia, General malaise
- Management: FVC <30%, Bi level vent support (nocturnal BIPAP) –> Can be continued to 24 hour ventilation (May need to consider a tracheostomy)
2) Dilated cardiomyopathy (no conduction issues(: Can be responsive to ACE/beta-blocker therapy (usually perindopril), Require an annual echo + ECG over 10 yo (2yearly from diagnosis), Test carriers every 5 years
3) Contractures – splints to prevent
4) Obesity 2o immobility
5) Constipation
6) Can result in overflow incontinence - Managed with diet and aperients
7) Urinary incontinence: Anticholinergics, Treat coexisting constipation
8) Depression and anxiety
9) Reduced IQ: Often attend normal school, Usually have IQ 1 standard deviation below siblings because dystrophin is expressed in the brain, Outlook for work is poor
10) Sleep: Difficulty due to nocturnal hypoventilation but also due to inability to turn –> Need pressure mattress
11) Bone health: Osteoporosis and fractures –> Due to immobility and prolonged steroid use. Need vitamin D and bisphosphonates
12) Psychosocial: Vocation, Sex education, Genetic counselling (Can detect carriers and prenatal testing is an option, One third of DMD mutations are new mutations, should involve a geneticist)
Mx of Restrictive Lung Disease in DMD?
1) Recurrent chest infections should be treated aggressively
2) Monitoring: 6 monthly respiratory function tests (↓FVC – restrictive pattern, Max insp pressure= diaphragm function, Max exp pressure= chest wall and abdominal muscles and the ability to cough)
3) Hypercapnoea and hypoventilation – think OSA! - Restless at night, Somnolent by day, Morning headaches, Anorexia, General malaise
4) Management: FVC <30%, Bi level vent support (nocturnal BIPAP) –> Can be continued to 24 hour ventilation (May need to consider a tracheostomy)
5) PT involvement
