Duchenne muscular dystrophy

Question 1

Define

Answer 1

Muscular dystrophies: a group of inherited disorders with progressive muscle degeneration

Question 2

Duchenne aetiology

Answer 2

X-linked recessive (Xp21 gene mutation)

1/3 have de novo mutations

Results from a deletion of the gene for dystrophin(connects cytoskeleton of a muscle fibre to the surrounding extracellular matrix through the cell membrane)

A lack of dystrophin leads to myofibre necrosis
* There is an influx of calcium ions, a breakdown of the calcium calmodulin complex and an excess of free radicals
* This leads to the myofibre necrosis

Presents around 1-3yo  diagnosis at 5yo

Question 3

Presentation Duchenne

Answer 3

Onset of symptoms at 1-6 years

Waddling gait

Toe-walking

Difficulty running, climbing stairs (mounting stairs one step at a time) or getting up from a seating or lying position

By 10 years, braces are required for walking

By 12 years, most children are wheelchair bound

20% associated with learning disability

May be some language delay

Gower’s sign positive

Pseudohypertrophy of the calves (due to the replacement of muscle by fat and fibrous tissue)

In school, boys tend to be clumsier and slower than peers

Primary dilated cardiomyopathy

DDx for delayed walking:

Generalized developmental delay - Down’s syndrome, Fragile X syndrome

Neuromusc cause - cerebral palsy, DMD

MSK - DDH

Normal late walker - most cases

Question 4

Duchenne investigation

Answer 4

• Examination
• Basic observations
• Bloods- RAISED plasma CK levels present from birth
• EMG- establishes myopathic nature, exclude neurogenic causes of muscle weakness
• Muscle biopsy- immunostaining for dystrophin
• Lung function- decreased vital capacity due to reduced muscle strength  hypoventilation, atelectasis
• Genetic testing - genetic testing rather than a muscle biopsy is now used to make a diagnosis

Question 5

Duchenne management

Answer 5

MDT care

• Glucocorticoids- improve muscle strength over 6 months to 2 years
• Atluren- drug allows the bypass of the nonsense mutation and production of a small amount of dystrophin
• Early aggressive management of cardiomyopathy
• If LV EJF drops, cardioprotective drugs (e.g. carvedilol) and LV assist devices may be considered
• Respiratory care and assisted respiration may be required at a later stage
• CPAP (weakness of intercostal muscles  nocturnal hypoxia  daytime headache, irritability, etc.)
• Immunisation: usual, pneumococcal and influenza
• Prophylactic antibiotics for children with low vital capacity

Orthopaedic
* Tendoachilles lengthening and scoliosis surgery may be required
* Scapular fixation

Occupation/ Physiotherapy- moderate physical exercise, mobility aids, night splints, braces, spinal support, physiotherapy helps prevent contractures

Education- Mainstream with support or special school for children with physical disabilities and/or learning disabilities

Genetic counselling - esp if thinking of having another child

Psychological- support and counselling for parent and child, respite care

NOTE: antenatal diagnosis is possible

Question 6

Complications/ Prognosis

Answer 6

Complications
* Weakness of intercostal muscles may lead to nocturnal hypoxia
* This presents with daytime headache, irritability and loss of appetite
* Respiratory failure
* Loss of mobility
* Osteoporosis and vertebral compression fractures associated with glucocorticoids
* Weight loss/ malnutrition
* Sexual dysfunction
* Cardiac failure
* Hypersomnolence and morning headaches

Prognosis

Often not walking by 10-14 years

Life expectancy: 20-30 years

Often die from respiratory failure or associated cardiomyopathy

Scoliosis is a common complication

Question 7

Becker’s muscular dystrophy

Answer 7

Slowly progressive X-linked recessive degenerative muscle disorder, characterised by muscle weakness and wasting of variable distribution and severity

Aetiology
* Allelic with Duchenne muscular dystrophy
* Exon deletions exist in the dystrophin gene Xp21 in 70% of cases
* Dystrophin levels are between 30-80% normal
* Abnormal translation of the dystrophin gene produces abnormal but partially functional dystrophin

Presentation
* Similar features to Duchenne muscular dystrophy
* Disease progresses MORE SLOWLY
* Symptoms appear around 10 years and are milder than those in Duchenne
* Learn to walk a little later than usual
* Muscle cramps after exercise
* Struggle with sports at school
* As they age, they struggle with lifting objects, etc
* Symmetrical pelvic and shoulder girdle weakness
* Average age of onset: 11 years

Can walk into their 40s and 50s but then require a wheelchair

Life expectancy: middle to old age

Question 8

Myotonic disorders - dystrophy

Answer 8

Myotonic Disorders

Myotonic Dystrophy: Autosomal dominant multisystem disorder characterised by progressive muscle wasting, muscle weakness and myotonia

Myotonia is abnormally sustained muscle contraction

Aetiology
* Most common adult-onset (20s to 30s) muscular dystrophy
* Genetic Defect
* Expansion of CTG nucleotide triplet at the 3 ‘UTR of the DMPK gene on Chromosome 19
* Genetic Anticipation
* The disease has an earlier onset or increased severity in the offspring than in parents as a result of further triplet expansion in successive generations
* There are disturbances in muscle fibre maturation with incomplete differentiation as a result

Infants: small undifferentiated muscle fibres

Children: Type I fibre atrophy, central nuclei, sarcoplasmic masses, ring fibres

PRESENTATION
* Oligohydramnios, reduced foetal movements
* Hypotonia
* Feeding difficulties
* Respiratory difficulties
* Thin ribs
* Talipes
* It is useful to examine the mother for myotonia
* This may manifest as slow release of handshake or difficulty releasing the tightly clasped fist
* Progressive muscle loss and weakness (smaller muscles > larger muscles; reverse of Duchenne’s)
* Older children can present with a myotonic facial appearance, learning difficulties and myotonia

Adults develop cataracts, and males develop baldness, testicular atrophy and T2DM

Mild myotonic dystrophy:

Cataracts, slight muscle weakness in adulthood

Classic myotonic dystrophy:

Myotonia, muscle wasting, frontal balding, hypogonadism, cardiomyopathy, cardiac arrhythmias, DM, respiratory impairment, adverse reaction to anaesthesia

Myopathic facies: Bilateral ptosis, wasting of frontalis and temporalis muscle, weakness of sternomastoids, lack of facial expression

Investigations

Examination

Bloods: Raised CPK

Muscle biopsy

EMG- characteristic ‘diver boomer’ spontaneous electrical discharge by 3 years old

DNA mutation analysis

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MANAGEMENT

MDT Care

Physiotherapy- strength and flexibility training

SALT- difficulty swallowing and dysarthria due to muscle weakness

Occupational therapy- specially designed utensils for hand weakness, wrist braces

Medical: quinine, procainamide, support respiratory and GI problems, monitor for deformities

Surgical- cataract operations

Orthopaedic- ankle-foot arthroses for foot-drop

Genetic counselling- antenatal diagnosis

Psychological support- parent and child

Complications

Joint contractures

Foot deformities

Early-onset dementia

Prognosis

Death occurs due to cardiac conduction defects

Prognosis depends on number of CTG repeats

Extent of learning disability and early appropriate MDT involvement

The older the child is when muscle weakness first noticed, the slower the progression and less serious the consequences

Most do NOT survive past 50 years