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Practice

PRACTICE

CLINICAL UPDATE

Duchenne muscular dystrophy

1
Hannah Fox Foundation Year 3 , Luke Millington patient co-author, Indu Mahabeer consultant
2
community paediatrician , Henriette van Ruiten consultant in paediatric neurology and neuromuscular
3
diseases
1
Severn Hospice, Shropshire, UK; 2Sandwell & West Birmingham Hospital NHS Trust, Midlands, UK; 3The Great North Children’s Hospital and The
John Walton Muscular Dystrophy Research Centre, Newcastle, UK

What you need to know Box 1: Case study of a delayed diagnosis

• Consider Duchenne muscular dystrophy in boys with delayed motor Patient A presented with speech delay at age 2 and poor fine and gross motor

milestones, positive Gowers’ sign, abnormal gait, muscle pains, calf
hypertrophy, unexplained elevated liver enzymes, learning difficulties,
behavioural problems, or speech and language delay
• Test for creatine kinase levels if you suspect any neuromuscular
condition. Refer children with raised creatine kinase promptly to a
neuromuscular specialist
• Early diagnosis means early access to treatment, improved outcomes,
and better informed family planning
• Early genetic diagnosis is important, as it can enable entry into
appropriate clinical trials
• Where patients have breathlessness, palpitations and arrhythmias,
morning headaches, and repeated chest infections or weight loss,
suspect deterioration and refer for prompt specialist review
copyright.
skills at 2.5 years. He had been referred to several different teams for these
symptoms, including physiotherapy for his poor motor skills and behavioural
psychology. He initially walked at 14 months, but he was always felt to be
poorly coordinated and given a diagnosis of developmental coordination
disorder/dyspraxia. He was able to run but with difficulty and began to struggle
with stair climbing. His inability to stand up after sitting on the floor at school
was attributed to a behavioural problem. It was noted in his first year at school
that he could not run properly and tripped and fell frequently. It took him several
years to be referred to a neuromuscular specialist, who diagnosed him with
DMD aged 8 with a creatine kinase level of over 20 000.
If he had been investigated with a blood test for creatine kinase when his
speech and motor delay had first been noted, an immediate referral to a
neuromuscular specialist could have been triggered. Earlier recognition and
treatment may have meant a better outcome for him and his family.

DMD is rare, with an estimated 2500 affected patients in the

Introduction
Duchenne muscular dystrophy (DMD) is a progressive and
disabling neuromuscular condition that is often diagnosed late.1
In the UK the mean age of diagnosis has remained fairly static
over the past 30 years, currently around 4.3 years of age.2 On
average it takes 1.6 years from first parental concern to diagnosis
of DMD,2 by which time muscle function has already declined
(box 1, case study). Delayed diagnosis of DMD can be
devastating for patients and their families. Outcomes for people
with DMD can be improved with optimum care at the earliest
opportunity, and patients are now living into their fourth
decades.3 4 Early diagnosis also enables parents to make informed
decisions about family planning and can provide access to
innovative treatments and clinical trials. International guidelines
for diagnosis and management of DMD have been established
by the DMD Care Considerations Working Group.5-7
UK.8 Clinicians in primary care may never have seen patients
with this condition, but are key to identifying DMD early and
supporting patients and their families.
What is DMD?
DMD is an X-linked recessive genetic disorder that affects one
in 3600-6000 male live births.9 DMD is caused by mutations in
the dystrophin10 gene, resulting in a severe reduction or absence
of functional dystrophin protein in muscle,11 which is crucial
for maintaining muscle fibre strength and stability. Lack of
functional dystrophin results in degeneration of muscle fibres.12
Becker muscular dystrophy is also caused by dystrophin gene
mutations. Typically it presents later and progresses more
slowly.
When should I suspect DMD?
Warning signs for DMD are listed in box 2. Muscle weakness
typically becomes evident at age 2 to 3. Children develop a
progressive proximal to distal pattern of muscle weakness,
starting with the lower limbs. There might be a delay in the

Correspondence to H Fox Hannah.fox8@nhs.net

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BMJ 2020;368:l7012 doi: 10.1136/bmj.l7012 (Published 23 January 2020)
development of motor milestones, such as walking, resulting
in the child falling behind their peers developmentally. Other
signs include difficulty with jumping, running, climbing steps,
and rising from the floor. There may be a history of muscle
pain, clumsiness, and frequent falls. Affected boys may display
toe walking or a waddling gait. On examination the child may
have poor head control, hypotonia, calf hypertrophy, or may
demonstrate Gowers’ sign (fig 1), a pattern of difficulty rising
from the floor indicating proximal muscle weakness. A family
history of DMD should raise suspicion.5
Box 2: Warning signs for diagnosis of DMD
Delayed motor developmental milestones
Poor head control
Not walking independently by 18 months
Not running by age 3
Struggling to hop, climb stairs, or get up from the floor in school age
children
Frequent trips or falls
Abnormal gait
Waddling gait
Tiptoe gait
Frequent falls
Unable to get up from the floor without using support from arms to push
up (Gowers’ sign)
Muscle pain or cramps or calf hypertrophy
Episodes of myoglobinuria (cola coloured urine)
Unexplained raised levels of lactate dehydrogenase, alanine
aminotransferase, or aspartate aminotransferase
Learning difficulties and behavioural issues
Speech and language delay
Autistic spectrum disorder
Check creatine kinase levels in children with any clinical suspicion of DMD or
ongoing developmental concerns. If levels are raised, or if you still have
concerns (even if creatine kinase is normal), refer to a paediatric
neuromuscular team for specialist assessment (see also the mnemonic in fig
2)
DMD is also associated with non-motor manifestations. Children
with DMD have a high prevalence of learning and behavioural
problems.13 This can make assessment more difficult, resulting
in further diagnostic delay. Speech delay and failure to thrive
may also coexist.
DMD is always associated with high levels of creatine kinase.
Other enzymes, such as lactate dehydrogenase, alanine
aminotransferase, and aspartate aminotransferase, can also be
raised reflecting muscle damage (not liver damage). DMD
should therefore be considered if a patient has unexplained
raised levels in liver function tests.14 Cases describe delays in
DMD diagnosis as medical professionals focus on liver
dysfunction, even going as far as performing liver biopsies.15
The Royal College of Paediatric and Child Health e-learning
module16 and the MUSCLE mnemonic in fig 2 can help primary
care professionals assess motor skills in children.
How is it diagnosed?
Diagnosis should be made early, ideally by age 2 to 3, when
symptoms start to become evident. A simple, cheap, and readily
available blood test, creatine kinase, has a high sensitivity for
muscular dystrophy and results are quickly available, prompting
referral to neuromuscular specialists for further investigation.
If DMD is suspected, creatine kinase levels should be urgently
checked. A markedly raised creatine kinase level warrants an
urgent referral to a neuromuscular specialist. A mildly raised
creatine kinase level of 1-2 times the normal range should be
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PRACTICE
confirmed through a repeated test and followed up.17 Although
a normal creatine kinase result excludes DMD, not all
neuromuscular conditions are associated with elevated creatine
kinase. Therefore, if you suspect a muscle problem but creatine
kinase levels are within the normal range, a referral to a
neuromuscular specialist may still be warranted. The Muscular
Dystrophy UK website can help identify your local
neuromuscular service.18
The diagnosis of DMD is confirmed by genetic testing.19
Approximately 70% of DMD cases are caused by a single or
multi-exon deletion or duplication detectable by multiplex
ligation dependent probe amplification (MLPA).5 Full
sequencing of the dystrophin gene can detect small genetic
changes, such as point mutations, when DMD is still suspected
but MLPA has failed to identify an abnormality.
How can I explain creatine kinase testing
to parents or carers?
We suggest explaining to parents that a blood test can screen
for certain muscle problems, keeping a broad mind rather than
causing undue concern early in investigation.
What are the risks for female carriers of
the DMD gene mutation?
Being an X-linked condition, DMD predominantly affects boys
and men. Female relatives of patients with DMD should be
copyright.
offered genetic testing for carrier status. A small number of
female carriers can develop muscle symptoms, such as pain,
cramps, or weakness, and learning or behavioural problems.20
Female carriers are also at risk of heart problems,21 and regular
cardiovascular monitoring is recommended.6 Women and girls
of reproductive age who are carriers should be offered early
counselling for family planning, including discussion about
possible pre-implantation or prenatal genetic testing. Non-carrier
mothers of sons with DMD still have a slightly higher risk of
having another affected child compared with the general
population and therefore should be offered counselling.
What are the key elements of successful
management?
Primary care
Every person diagnosed with DMD should be referred to a
neuromuscular specialist for regular follow-up. However,
primary care clinicians have an important role in their overall
care7 (box 3). Nearly half of people with muscle wasting
conditions and their carers surveyed in 2013 by Muscular
Dystrophy UK22 felt their general practitioner did not understand
their condition well enough. A strong relationship with a named
general practitioner is essential to offer support and stability to
affected families.
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BMJ 2020;368:l7012 doi: 10.1136/bmj.l7012 (Published 23 January 2020)
Box 3: The role of primary care clinicians in management of
DMD7
Respiratory
• Ensure appropriate vaccination, such as the pneumococcal vaccine
and yearly influenza vaccine. Avoid live vaccines for patients on steroids
• Chest infections can precipitate respiratory failure; prompt antibiotic
treatment should be given if there are concerns about infection
• Look out for symptoms of nocturnal hypoventilation (table 1), which
should prompt referral to a respiratory specialist
Endocrine
• For patients on corticosteroids, reinforce the risk of adrenal insufficiency
and of not stopping steroids suddenly. If unable to take steroids orally,
or if unwell, consider giving a stress dose of steroids (intravenous or
intramuscular hydrocortisone). Patients should have a steroid information
card
• Monitor side effects of corticosteroids, such as delayed puberty,
hypertension, diabetes mellitus, skin changes, infections
Gastrointestinal
• Monitor weight and nutrition; refer to dietitians if appropriate
• Consider gastroprotection for symptomatic patients on corticosteroids
Cardiac
• Encourage cardiovascular health and fitness, screen for cardiovascular
risk factors such as hypertension (especially for patients on
corticosteroids)
General
• Liaise with specialists regarding referral to appropriate therapy services
• Monitor for red flags which might indicate clinical deterioration and refer
appropriately (table 1)
• Provide access to psychosocial care for patients and their families
• Signpost families to advocacy groups and sources of support
Care of patients with DMD involves optimising quality of life
and proactively anticipating and treating complications as they
arise. Recommendations for DMD based on international
consensus were published in 2010 and updated in 2018.5-7 A
family guide to help patients and carers to understand the
condition and required management is also available.23
Corticosteroids are the mainstay of treatment. Moderate quality
evidence shows that corticosteroids (0.75 mg/kg/day of
prednisolone or 0.9 mg/kg/day of deflazacort on daily or
intermittent regimes) improve muscle function and help prolong
ambulation, delay the development of respiratory complications,
postpone or avoid orthopaedic complications, and might delay
cardiac complications.24-28 Corticosteroid treatment is associated
with notable side effects, however, including weight gain,
cushingoid appearance, behavioural changes, delayed puberty,
reduced growth, increased risk of fractures (including vertebral
fractures), cataracts, and hirsutism.25 27 An adjusted lower dose
may be required for patients who develop unacceptable side
effects on the recommended dose.
Multidisciplinary teams
Optimal care in DMD is best achieved by a multidisciplinary
team, normally led by a neuromuscular specialist. Disease
progression should be monitored every six months using
standardised muscle function assessments, such as the North
Star Ambulatory Assessment.5 29 A team of physiotherapists,
orthotists, orthopaedic surgeons, and occupational therapists
monitor muscle function, aiming to minimise contractures and
deformities. Community paediatricians, community
physiotherapists, speech and language therapists, and dietitians
are also involved in the overall clinical care of patients.5 29
Annual cardiac surveillance is essential from diagnosis onwards
to screen for early signs of cardiac failure and promptly initiate
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and monitor cardiac treatment. Additional specialists, such as
respiratory physicians, are involved as disease progresses.
Psychological support, sometimes supplemented by mental
health professionals, is integral to holistic care of patients and
their families.
Emerging treatments
Management of DMD has changed substantially over the past
five years as new potential therapeutic approaches have been
developed30 (box 4). This rapid development of new therapies
means that many clinical trials are currently running
(www.clinical trials.gov, dmdhub.org). The treatment landscape
for children with DMD is now more promising. Early diagnosis
and timely access to potential disease modifying therapies offers
new hope for this group of patients.
Box 4: Emerging treatments for DMD
Ataluren (also called Translarna), has now been approved by the National
Institute for Health and Care Excellence (NICE) as a treatment for ambulatory
patients with DMD in the UK under a management access agreement. Ataluren
is a mutation-specific therapy, suitable for approximately 10-15% of the DMD
population. Other therapeutic approaches currently being evaluated in clinical
trials include mutation-specific strategies to correct the underlying genetic
cause of the disease (such as exon skipping), gene therapy, and
non-mutation-dependent strategies including repurposing of existing drugs
(tamoxifen, idebenone) and therapies to improve overall muscle function
(givinostat, anti-myostatin). Innovative steroids (vamorolone) and NF-kB
inhibitors (edasalonexent) are being investigated as potential alternatives to
corticosteroids, aiming to maintain their efficacy while reducing or avoiding
the side effects associated with traditional corticosteroids.
copyright.
DMD in adulthood
Life expectancy for people with DMD has increased, and most
live adult lives. Some are able to live independently, study at
university, and enter employment. Transition of care from
paediatric to adult services is challenging because of a lack of
adult neuromuscular services in some areas and poor
coordination between professionals involved. Support from
general practitioners is crucial during this period.
Advance care planning is important since the clinical trajectory
of DMD can be unpredictable, progressing from periods of
stability to a sudden medical crisis. Patients and carers can
benefit from timely access to respite and palliative services and
these options should be discussed early in the disease. Evidence
shows a shared reluctance to discuss end-of-life care options
among health professionals, young patients, and their carers.31
What are the key complications and their
recommended management?5 6
Cardiac
Absence of dystrophin in the heart muscle is associated with
the development of a dilated cardiomyopathy in most patients.
This presents with signs of heart failure or arrhythmias, though
patients may not develop symptoms until the cardiomyopathy
is well advanced, on account of their immobility. All patients
need annual cardiac surveillance by specialists, which may
involve ultrasound echocardiograms, cardiac magnetic resonance
imaging, and 24 hour holter monitoring. Many patients take
cardioprotective medications, such as ACE inhibitors and
β-blockers.32 33
Respiratory
Patients with DMD develop respiratory failure and are at risk
of sudden respiratory complications. Serial monitoring of lung
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BMJ 2020;368:l7012 doi: 10.1136/bmj.l7012 (Published 23 January 2020)
function and sleep studies are important in detecting respiratory
impairment, more likely to occur in the later non-ambulant
phase. Survival can be prolonged by lung volume recruitment,
assisted coughing, nocturnal assisted ventilation, and continuous
non-invasive ventilation.4 34-36
Endocrine and metabolic
Long term use of corticosteroids increases the risk of
osteoporosis. Patients with DMD commonly develop
pathological low trauma vertebral or long bone fractures.37 38
These can be asymptomatic. Annual dual energy x ray
absorptiometry scans and lateral spine radiographs are
recommended for surveillance every 1-2 years in patients treated
with corticosteroids. Vitamin D supplementation and adequate
calcium intake are recommended. Intravenous bisphosphonate
is considered first line in patients with vertebral and long bone
fractures because of DMD associated osteoporosis.6 Input from
an endocrinologist may also be required to manage side effects
associated with corticosteroid use, such as delayed puberty,
glucose intolerance, and obesity.
Gastrointestinal
Consultation with a dietitian is important to encourage a
balanced diet and help prevent obesity (commonly caused by
corticosteroid treatment and limited mobility) or undernutrition
(common in later stages of the disease). Speech and language
therapy teams may help patients manage dysphagia.
Gastroenterologists can manage gastric motility problems and
may consider placement of a gastrostomy tube for
undernutrition, dysphagia, and aspiration at a later stage.
Gastroprotective therapy should be given in the presence of
gastrointestinal symptoms.
Orthopaedic
Musculoskeletal problems require a multidisciplinary approach,
including physiotherapy, occupational therapy, rehabilitation
specialists, orthoses, or surgery.39 Patients need monitoring for
the development of joint contractures and scoliosis. Widespread
treatment with corticosteroids has reduced the risk of developing
severe scoliosis and therefore reduced the number of patients
requiring surgical correction.40
Emergencies
Adrenal crisis—a potentially life threatening complication of
chronic corticosteroid treatment. It is important that families
are aware of the risk, and know never to stop corticosteroids
suddenly or omit doses. They should also know when to give
a “stress” dose.
Fat embolism—a life threatening complication of fractures that
can present with shortness of breath, tachycardia, or altered
consciousness, and requires emergency care.
Anaesthetic risk—anaesthetic risk is increased for patients with
DMD who need surgery. Depolarising muscle relaxants and
inhaled anaesthetics should be avoided as they can lead to life
threatening hyperkalaemia and rhabdomyolysis.
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PRACTICE
“One step at a time”—a patient’s perspective by co-author Luke
Millington
My parents first suspected there was something wrong when they saw me
struggling with steps and stairs. It wasn’t until I was about 5 or 6 that I became
aware that there was something different, but I never realised the implications
of my diagnosis of Duchenne muscular dystrophy.
I began using a wheelchair when I fractured my femur, having fallen down
steps at the age of 13. So steps seem to be a significant part of my journey,
and as I am now 20 and becoming more independent with so many paths to
follow, I have adopted the rule of one step at a time.
At the moment I am focusing on learning to drive, as I now have an adapted
vehicle; then I want to explore work, volunteering, or getting a girlfriend and
possibly independent living. These could be in any order but all are options
and on my bucket list. I don’t really think much about the future and the things
I will lose—this would drag me down. I know I am luckier than some of my
peers with Duchenne as I don’t seem to have lost much function in the past
four years. I don’t think this is entirely due to my being on a drug trial. I think
my attitude has been important: my optimism, drive, and personality. I
appreciate having been on a trial and now receiving medication on the
extended access programme. Being on the trial made me feel listened to,
supported, and offered me hope.
How patients were involved in the creation of this article
We asked Luke, a patient with DMD, to review this article and to contribute
his story. He has put his own thoughts down for the patient’s perspective
(bmj.com). We also asked the family of another child with DMD to share their
experience of delayed diagnosis (box 1).
How this article was created
This article was created with the aim of producing a guide to help the
non-specialist diagnose DMD early and manage patients’ ongoing care. A
search of ‘‘Duchenne muscular dystrophy’’ from the Cochrane Collaboration
copyright.
in February 2019 yielded seven Cochrane reviews, of which five were included
as they were relevant to the scope of this article. Diagnosis and management
is written with reference to the international consensus DMD guidelines written
by the DMD Care Considerations Working Group, updated in 2018.5-7 Evidence
was also sought by signposting from experts in the care of DMD and from a
personal archive of references.
Education into practice
What might prompt you to request a blood test for creatine kinase?
Who is your local neuromuscular specialist for referrals?
What are the major challenges in looking after adult patients with DMD,
and how can you ensure smooth transition of care from paediatric to adult
services?
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BMJ 2020;368:l7012 doi: 10.1136/bmj.l7012 (Published 23 January 2020)
Additional educational resources for health professionals
Royal College of Paediatrics and Child Health https://www.rcpch.ac.uk/
resources/recognising-neuromuscular-disorders-elearning
A free e-learning module that suggests a practical approach for the
non-specialist to recognise children with neuromuscular disorders early.
Accessible through RCPCH Compass (self-registration required, free to
access)
Muscular Dystrophy UK www.musculardystrophyuk.org
A free website from with an information for health professionals section,
including a list of referral centres: https://www.musculardystrophyuk.org/
get-the-right-care-and-support/people-and-places-to-help-you/
professionals-and-organisations/muscle-centres/
Royal College of General Practitioners http://elearning.rcgp.org.uk/course/
info.php?popup=0&id=183
A RCGP e-learning module focusing on management of DMD in primary
care. Free to those who are members of the RCGP. Worth one accredited
continued professional development point
Child Muscle Weakness https://childmuscleweakness.org/
A website targeted at health professionals to help identify children with
neuromuscular disorders from “signs” and “clinical evaluation”
Lancet Neurology https://www.thelancet.com/journals/laneur/article/
PIIS1474-4422(18)30024-3/fulltext
Detailed management guidelines for the diagnosis, investigation, and
management of DMD.5-7 These are also available free through the Treat
MND network: http://www.treat-nmd.eu/care/dmd/diagnosis-management-
DMD/
Paediatric Musculoskeletal Matters International http://www.pmmonline.
org/doctor.
A website to help health professionals better investigate and manage
children with musculoskeletal problems
Information resources for patients and families
Muscular Dystrophy UK www.musculardystrophyuk.org
A free-to-access website providing information and support to muscular
dystrophy patients and their carers, including updates on research
breakthroughs and charity campaigns. MDUK produces a useful Alert
card to be shown to health professionals in an emergency: http://www.
musculardystrophyuk.org/wp-content/uploads/2016/11/INF2-DMD-alert-
card-web-new.pdf
Duchenne UK www.duchenneuk.org
A free-to-access website providing information and support to patients
with DMD and their carers
Action Duchenne https://www.actionduchenne.org
A free-to-access website containing information and sources of support
for patients and their families
DMD Hub https://dmdhub.org
A free-to-access website providing information on clinical trials in DMD
Duchenne Family Support Group https://www.dfsg.org.uk
A national charity run by families for families affected by DMD that provides
a support network for parents, their families, and professionals
Patient consent obtained.
Contributorship statement HF wrote the first draft and takes full responsibility
for the work as guarantor. All authors were involved in further drafts and approvals
of the final manuscript.
We acknowledge the expert advice received from Professor Tracey Willis, consultant
paediatric neurologist with a specialty interest in neuromuscular disorders, visiting
professor, Chester University, based at The Robert Jones and Agnes Hunt
Orthopaedic Hospital NHS Foundation Trust and Birmingham Children's Hospital.
We acknowledge the expert advice received from Dr Michela Guglieri, senior
lecturer at Newcastle University and consultant neurologist with a specialty interest
in paediatric and adult neuromuscular disorders, based at the John Walton Muscular
Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS
Foundation Trust, Newcastle upon Tyne, UK.
We also acknowledge the contribution of Claire Bassie, advanced nurse practitioner
in neuromuscular care, based at the Robert Jones Agnes Hunt Orthopaedic Hospital
NHS Foundation Trust.
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Competing interests The BMJ has judged that there are no disqualifying financial
ties to commercial companies. The authors declare the following other interests:
none.
Further details of The BMJ policy on financial interests are here: https://www.bmj.
com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-
competing-interests
Provenance and peer review: commissioned, based on an idea from the authors.
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16 Royal College of Paediatric and Child Health. Recognising neuromuscular disorders -
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17 National Task Force for Early Identification of Childhood Neuromuscular Disorders.
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Table

Table 1| Red flags that may indicate clinical deterioration in DMD

Red flag May indicate Suggested action

Palpitations or arrhythmias
Morning headaches. Not feeling bright or alert in the
morning. Lack of appetite. Excessive daytime tiredness
Repeated chest infections, breathlessness
Unintended weight loss
Spinal curvatures or joint contractures
Conduction defects or cardiomyopathy
Nocturnal hypoventilation
Deteriorating respiratory function
Dysphagia. Poor oral intake
Spinal curvatures or joint contractures
Urgent cardiology or neuromuscular review
Urgent respiratory or neuromuscular review
Respiratory review
Review by neuromuscular and speech and language teams.
Possible gastrostomy requirement
Neuromuscular or orthopaedic review

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Figures

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Fig 1 Diagram to show Gowers’ sign, a pattern of walking arms up the thighs to stand up from a squatting position, indicative
of proximal muscle weakness

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Fig 2 MUSCLE mnemonic, which demonstrates key features of DMD and the importance of early testing of creatine kinase2

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