First Off Translation Tips! The r sound is tricky, in Australia - - PDF document

4/3/2014 1

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

• f

a sentence, don’t worry I’m not asking you a question

Duchenne Muscular Dystrophy

• Most

prevalent and disabling

• f

the inherited neuromuscular disorders.

• Clinical features become evident between 2-5 years
• f 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)

4/3/2014 2

Genetics of DMD

• X- Linked recessive inheritance therefore

generally

• nly

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
• f 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

• ther 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

4/3/2014 3

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

• f

damaged muscle

Muscle Weakness

• Membrane damage continues to occur with the

result

• f

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

• r 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!

4/3/2014 4

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

4/3/2014 5

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

4/3/2014 6

There is now something we can do!

• Steroids

and

• ther

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

4/3/2014 7

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

4/3/2014 8

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

4/3/2014 9

Steroids – The Bad

• Weight gain
• Behavior changes: Quick mood changes

and a shorter fuse

• Suppression of the immune system and risk
• f Adrenal Crisis
• Other effects – Osteoporosis, Slowing of

growth, Cataracts

Which Steroid? What Dose? Schedule?

• Continuing studies in this area
• Trying to maximize benefit while minimizing side

effects

• No definitive results yet but it is argued that

deflazocort reduces weight gain and behavioral issues while prolonging ambulation when compared to Prednisone

• Trialing on/off scheduling

Exercise?

• If you don’t exercise enough the muscle cells

atrophy becoming weaker (accelerating the disease)

• If you exercise too much the muscle cells die

(accelerating the disease)

• Some forms of exercise are much worse than
• thers – Eccentric exercise is worst
• Recommendation

is for normal developmental exercise rather than therapeutic exercise

4/3/2014 10

Aquatic Therapy

Excellent at any stage

Treatment for Transitional DMD

• Generally 8 – 14 year olds as they transition

to a chair

• Energy conservation still very important but

emphasis shifts to UE – typing rather than writing, predictive text, ‘Dragon’, dictation

• Teacher education – for both the DMD

cognitive profile and energy saving classroom and assessment tools

• Equipment for home as more pressure is

placed on parents to lift and support

Wheelchairs

• Earlier is better
• Transitioning to the wheelchair is often one
• f the more traumatic moments in DMD

progression but mostly for the parents. The kids are often happy to be able to keep up with their friends again

• Most important to get a power chair that has

tilt (55°) and lateral support as these help to reduce scoliosis

• High/Low function allows gravity assisted sit

to stand and prolongs independent mobility

4/3/2014 11 New Challenges Treatment for Late Stage DMD

• Wheelchair prescription becomes very important.

Alterations in joystick controllers as UE muscles deteriorate

• Equipment needs become paramount in schools

and homes and later to workplaces

• Technology to allow unrestricted access to the

curriculum

• Respiratory care
• Feeding/Chewing Difficulties
• Cognitive profile, increased fatigue, increased work

load and poor sleep will all add up, requiring a higher level of assistance in later grades

Cognition

• Non progressive
• High Comorbidity with Autism and ADHD
• Intellectual impairment in 30% of cases
• Cognitive profile fairly consistent in other 70%
• f cases  Verbal IQ less than Performance

IQ.

4/3/2014 12

Relative Strengths

• Vocabulary and naming skills.
• Ability to categorize
• Rote learning (visual & verbal)
• Memory for specific detail (esp. visual)
• Good general knowledge

Relative Weaknesses

• Verbal intelligence
• Attention focusing and regulation
• Phonological Awareness deficits
• Language delays (receptive &

expressive)

• Difficulties with Social & Emotional

interactions

Sensory Processing Disorders

• Many

boys display sensory processing disorders esp. in the areas

• f

touch, vestibular and food preferences, even before they need to change food due to difficulties with chewing

• Sensory Profile useful to determine areas of

deficit

• Can respond to treatment

4/3/2014 13

Other behavioral Implications

• Boys have problems with mental flexibility. They

may be rigid in their thinking and have a “one track mind”.

• May appear shy (or rude) as they interpret new

(esp unexpected) information or people slowly.

• As such, they may have trouble with transitions,

changes in expectations, or become easily frustrated if things don’t go their way.

Managing Behaviors

• Encourage boys to be well organised and prepared for

tasks

• Thoroughly

prepare boys for new situations by explaining what is likely to happen and what is expected

• f them i.e. going into assembly, going on a school trip,

starting a new class, meeting family members, going

• shopping. Explain what will happen at these events and

what you want them to do.

• Give

boys clear boundaries and expectations for behavior and give them lots of praise when things are going well

Education - Academics

• Delayed acquisition of skills for reading and writing.
• Delayed expressive language in younger children.

– Eg. “Describe a picture”, or “make a sentence about….”

• Difficulties understanding, processing and retaining classroom

language.

• Literacy problems: Difficulties identifying, manipulating, and blending

sounds in words.

• No studies in the literature are described on DMD and mathematics.

Particular problems have been observed in automatisation of computational tables, holding numbers in your head, doing mental calculations and understanding mathematical language. 6x7= ?? 4x3= ??

4/3/2014 14

Research for a ‘Cure’ – Modifying Genes

• 1. Modifying gene itself

– Read Through of Premature Nonsense mutation – Phase III (Confirmatory) trials (Ataluren) – Exon Skipping specific deletions – Phase IIb trials (Eteplirsen). Currently only Exon 51 trials

• Stable Pulmonary Function and 6MW tests (over 2yrs)
• 2. Gene transfer

– Viral - AAV – Non-viral - plasmid

• 3. Cell transfer

– Local - myoblasts – Systemic - mesoangioblasts

Research for a Cure – Restoring Muscle

• 1. Upregulation of compensatory genes

– Utrophin

• Increased transcription
• Increased translation

 7 Integrin

• Increased translation
• 2. Protein delivery

– Biglycan

Thoughts about the ‘Cure’

• Currently most promising ‘cure’ is about repairing

‘out of frame’ deletions to make them ‘in frame’. Essentially changing Duchenne to Beckers MD

• These treatments will slow down the progression of

DMD but will not freeze it or cure the damage already done

• These treatments are close but will be very specific

to genetic mutation (Only 15% of boys with DMD will benefit from skipping 51, only 10-12% have a Nonsense mutation) and will be very expensive

4/3/2014 15

Final Thoughts

• It is important to remember that the social and emotional

well being

• f

a student with Duchenne Muscular Dystrophy is of far greater concern than striving for the best physical or academic outcome although as the age ‘limit’ increases progressively more of these kids require college and employment strategies

• It is important to remember that rehabilitation is not an
• ption
• Efforts should be directed towards offering choices and

involving the boys in all the decisions which affect their lives

• There is real hope for new treatments with continuing

research