Clinical

aspects of Duchenne muscular

dystrophy

M2M 2015
Muscular Dystrophies Theme
Lecture 3

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DMD is caused by loss of dystrophin

normal

Muscle immunohistochemical
staining for dystrophin

DMD/ mdx

Authors own

Dystrophinopathies
Duchenne muscular dystrophy
Becker muscular dystrophy
Familial cramps + myalgia syndrome
Other

X-linked dilated cardiomyopathy

Isolated elevated CK
ManifesIng carrier females
Isolated quadriceps myopathy

Guillaume-Benjamin
Duchenne de Boulogne
US National Library of Medicine

Onset
DMD: onset <5 years
Incidence 1/5000 boys
Clinical diagnosis typically 2-4 yrs
Wheelchair dependency <13 yrs
BMD: onset > 5yrs
Incidence 1/35 000 male births
Clinical onset variable
Wheelchair dependency >16 yrs

Clinical presentaIons of DMD

Delayed motor milestones
Mean age walking 18m (normal <18 months)
Gait diculIes
Broad-based, waddling gait, proximal weakness
Trouble climbing steps, Gowers manoeuvre
Persistent toe-walking, at feet
FaIgability, frequent falls
Inability to run or to keep up with peers
Calf / thigh cramps, muscle enlargement
Speech delay, learning problems

Physical examinaIon
Waddling gait
Proximal weakness
Enlarged, rubbery muscles

calves +/- quads, gluteal, deltoid, even tongue

early hypertrophy, late pseudohypertrophy
Facial muscles spared
Extra-ocular muscles always spared
Weak neck exors
Lumbar lordosis

Muscle hypertrophy

Muscles look larger but

in fact this apparent
enlargement is due to
increased fat and
brosis rather than an
increase in true muscle
Issue i.e.
pseudohypertrophy

Muscle hypertrophy

http://neuromuscular.wustl.edu/musdist/dmd.html

Gowers sign (1)

Gowers sign (2)

Gowers sign (3)

Gowers sign (4)

Gowers sign (5)

Gowers sign (6)

Gowers sign
Climbing up legs on arising from ground
IndicaIve of proximal weakness in older children (>4

yrs)
Normal in younger children <3 yrs
Non-specic i.e. seen in any muscle disorder causing
proximal weakness
DMD, BMD
Myotonic dystrophy
Congenital myopathies
Muscle disorders of adulthood including steroid myopathy

Muscle atrophy

Authors own

Diagnosis of DMD
Serum creaIne kinase level

Enzyme released by damaged muscle cells into blood

Normal <200 IU/L, DMD >10 000
Thyroid funcIon tests ( blood)
Hypothyroidism can look very much like DMD
GeneIc tesIng (by MLPA) for DMD
PosiIve in 65-70% cases
DeleIons 65%, duplicaIons 5%, point mutaIons 10-15%
Muscle biopsy
High suspicion of DMD, geneIc tests are negaIve
Necessary in about 1/3 of cases

Serum CK (creaIne kinase) levels

Normal (< 200 U/L)

Elevated
(200- 800 U/L)

Markedly elevated
(>1000 U/L)

Congenital myopathies

Congenital myopathies +
muscular dystrophies

Congenital muscular
dystrophies

Endocrine myopathies

Endocrine myopathies

FSH MD

Myotonic dystrophy

Myotonic dystrophy

Duchenne + Becker MD

DermatomyosiIs

DermatomyosiIs

Limb girdle MD

Metabolic myopathies

Metabolic myopathies

Myasthenic syndromes

Idiopathic

SMA

SMA
Pompe disease

Neuropathies

Motor neuropathies

Natural history of DMD

3-6 yrs: honeymoon phase

Mild weakness but overall strength and funcIon may

increase
Increasing disparity between aected child and his peers
8 yrs: diculty climbing stairs, walking

Increasing faIgability, inability to run and jump

Increasingly prominent lumbar lordosis
Progressive contractures Achilles, ITBs, hips
~ 10-13yrs: transiIon to wheelchair use
Respiratory or cardiac failure late teens-early 20s

Duchenne muscular dystrophy

Course

Some variability in course

AmbulaIon lost anywhere between 8-14 years
Gradual decline in upper limb funcIon

Diculty bringing hands to mouth by 16-18years

Death average approx. 25 years
Death is usually from respiratory failure
Cardiac death in about 10%

Cardiomyopathy or arrhythmias

Natural history of Becker MD

Onset amer age 5 yrs

Commonly 5-15 yrs

Occasionally as late as 3rd or 4th decade
Progressive limb-girdle weakness
Calf pain and myalgias common
Able to walk amer 15 yrs
Respiratory failure amer 4th decade
Cardiomyopathy is MORE common than in DMD

Greater strain on heart caused by greater exercise and

acIvity

Duchenne muscular dystrophy

Respiratory decit

Weakness of intercostal muscles > diaphragm

In the early years, vital capacity increases with age

and growth
In the early teens, vital capacity plateaus and then

declines steadily (5-10%/ year)

Respiratory failure typically occurs in the late teens or

early 20s

Sleep-disordered breathing
Muscle weakness causes restricIve lung disease

In all neuromuscular disorders, respiratory muscle funcIon is worst

in sleep
Decreased respiratory muscle tone and central drive
This sleep-disordered breathing (SDB) is worst in REM sleep
May manifest with sleepiness, headache etc
FaIgability, poor exercise tolerance, poor school performance
Symptoms relate to CO2 retenIon, not to hypoxia
Does not cause shortness of breath or cough
Progresses to nocturnal and then also dayIme hypovenIlaIon
Early recogniIon enables appropriate treatment

Typical forms of lung disease

Obstruc(ve lung disease

Increased resistance to airow due to parIal or complete obstrucIon at any
level (trachea, bronchi, terminal or respiratory bronchioles)
Lung funcIon tests show decreased maximal airow rates during forced
expiraIon, usually measured by forced expiratory volume in 1 sec (FEV1)
Restric(ve lung disease
Reduced expansion of lung parenchyma and decreased total lung capacity.
Lung funcIon tests show a reduced total lung capacity (TLC), and an
expiratory ow rate that is normal or reduced proporIonately to TLC.
RestricIve defects occur in two general condiIons
(1) chest wall disorders e.g. neuromuscular diseases, severe obesity,
kyphoscoliosis
(2) chronic inters((al and inltra(ve diseases, e.g. pneumoconioses and
intersIIal brosis

Advanced Duchenne muscular dystrophy

Respiratory decit

Progresses to nocturnal and then also dayIme

hypovenIlaIon

Hypoxia occurs late in the disease course

Development of atelectasis, pneumoniIs

Pump failure- poor inaIon and emptying of lungs

Loss of respiratory reserve correlates with severity of

kyphoscoliosis

Scoliosis is caused by weakness of paraspinal muscles

Diaphragm relaIvely spared Ill late in disease

Cardiac involvement in DMD and BMD

Dilated cardiomyopathy > hypertrophic > conducIon defects
Cardiomyopathy

Decreased lem ventricular contracIlity , occasional cardiac failure

Commonly asymptomaIc/ subclinical
1/3 teenage yrs, by 18 yrs, all >18 yrs
Symptoms omen minimal unIl late owing to musculoskeletal
limitaIons
Myocardial brosis, sinus tachycardia, ectopic rhythms

90% abnormal ECG

Cardiac death in 10% of cases
Cardiomyopathy more common in Becker MD

 2011 UpToDate

Dilated cardiomyopathy most

common in DMD
(NB: Images differ slightly from those in presentation)

Orthopaedic involvement in DMD

Early toe-walking common

Achilles tendon and ilioIbial band (ITB) contractures

Progressive contractures: hips, knees, elbows, wrists

More problemaIc amer wheelchair-bound, immobile

Scoliosis
Increases rapidly amer non-ambulant

Leitao et al. Sao Paulo Medical Journal 113: 995 999, 1995

Scoliosis repair
stabilises but
does not
improve
respiratory
funcIon
http://www.uofmhealth.org/News/884surgical+approach+to+treat+scoliosis+

CNS involvement
Non-progressive (staIc) cogniIve impairment

Aects verbal > performance IQ

Mean IQ shimed 1SD, approx. 80 (normal: 100)
No good correlaIon with locaIon of deleIons
Two major types
Reduced verbal IQ
Reduced total IQ < 80
Occasional auIsm

DistribuIon of IQ scores in boys with DMD

36
32

33
30
27

PMD Cases
TOTAL -106

24
TOTAL No. OF CASES

Normal IQ distribuIon

21

20

MEAN IQ = 86.1

18
15
12
8

9
6

10

12

11

3
0
<50

50-59

60-69

70-79

80-89

90-99 100-109 110-119 120+

IQ RANGE

Cohen et al. Dev Med.Child Neurol 1968; 10:754-765.

CogniIve issues in DMD

Degree of cogniIve involvement is variable

1/3 signicant learning diculIes

SelecIve impairment of verbal working memory skills
leads to increased risk of learning diculty
Greater diculty remembering stories, diculty
manipulaIng verbal informaIon that requires
immediate memory storage, diculty with
comprehension
Prole similar in subjects with DMD regardless of
whether high or low intelligence

CogniIve problems in DMD may be

mulIfactorial
Altered dystrophin expression in brain

StaIc intellectual decits

Eect of chronic illness
School absences
Psychosocial eects
Anxiety
Depression
Behavioural problems (increased by steroids)
Eect upon family
Parental expectaIons
Parental mood problems

DMD: Summary: clinical ndings

Boys appear relaIvely normal for rst few years of life
Then: rapid loss of muscle strength and funcIon
MulIple systems involved

Musculoskeletal
Respiratory
Cardiac
CNS
Orthopaedic
Management must address all aected systems