(DMD)Duchenne muscular dystrophy-dr mohamed abunada

(DMD)Duchenne muscle dystrophy, presentation and managment

1. Duchenne Muscular Dystrophy Duchenne Muscular Dystrophy
(DMD)(DMD)
Dr. Mohamed AbunadaDr. Mohamed Abunada
Pediatric Neurology Pediatric Neurology
DepartmentDepartment
Dr. Al rantisi specialized Dr. Al rantisi specialized
children Hospitalchildren Hospital

2. Muscular DystrophyMuscular Dystrophy
First described in the 1830’s muscular First described in the 1830’s muscular
dystrophy is a group of more than 30 dystrophy is a group of more than 30
diseases that affect the skeletal diseases that affect the skeletal
muscles muscles
These muscles will experience progressive These muscles will experience progressive
weakening and eventually degeneration weakening and eventually degeneration
Muscular dystrophy can affect the heart, Muscular dystrophy can affect the heart,
lungs, eyes, spine, brain, endocrine lungs, eyes, spine, brain, endocrine
system, and gastrointestinal system as system, and gastrointestinal system as
well as other organs. well as other organs.

3. Major ClassificationsMajor Classifications
The dystrophies are a group of genetic The dystrophies are a group of genetic
myopathies. myopathies.
The usual cause is a defect in a structural proteinThe usual cause is a defect in a structural protein
For most dystrophies, the abnormal gene and For most dystrophies, the abnormal gene and
gene product are established.gene product are established.
There are eight major classifications of muscular There are eight major classifications of muscular
dystrophy. Each classification differs by the dystrophy. Each classification differs by the
“extent and distribution of muscle weakness, age “extent and distribution of muscle weakness, age
of onset, rate of progression, severity of of onset, rate of progression, severity of
symptoms, and family history (including any symptoms, and family history (including any
pattern of inheritance)” . pattern of inheritance)” .

5. ClassificationsClassifications
1. Duchenne MD*1. Duchenne MD*
2. Becker MD2. Becker MD
3. Facioscapulohumeral MD *3. Facioscapulohumeral MD *
4. Myotonic MD*4. Myotonic MD*
5. Emery-Dreifuss MD5. Emery-Dreifuss MD
6. Limb-girdle MD6. Limb-girdle MD
7. Congenital MD7. Congenital MD
8. Oculopharyngeal MD 8. Oculopharyngeal MD
*most common forms*most common forms

6. Becker MDBecker MD
Cause is insufficient production of dystrophin, Cause is insufficient production of dystrophin,
a protein that helps keep muscle cells intact. a protein that helps keep muscle cells intact.
Similar to Duchenne MD with a later onset and Similar to Duchenne MD with a later onset and
slower progressionslower progression
The rate of progressive, symmetric muscle The rate of progressive, symmetric muscle
atrophyatrophy and weakness varies greatly among and weakness varies greatly among
affected individuals affected individuals

7. Emery-Dreifuss MDEmery-Dreifuss MD
Cause is mutations in the genes that Cause is mutations in the genes that
produce emerin, lamin A or lamin C, produce emerin, lamin A or lamin C,
proteins in the membrane that proteins in the membrane that
surrounds the nucleus of each muscle surrounds the nucleus of each muscle
cell.cell.
Onset is usually by 10 years of age.Onset is usually by 10 years of age.
This disease causes slow but This disease causes slow but
progressive wasting of the upper arm progressive wasting of the upper arm
and lower leg muscles and symmetric and lower leg muscles and symmetric
weakness weakness

8. Congenital MD Congenital MD
Cause is genetic mutations affecting some of Cause is genetic mutations affecting some of
the proteins necessary for muscles and the proteins necessary for muscles and
sometimes for the eyes and or brain. (MEB sometimes for the eyes and or brain. (MEB
Syndrome, Walker Warburg Syndrome)Syndrome, Walker Warburg Syndrome)
Present at birth or evident by age 2 Present at birth or evident by age 2
Varies with type; many are slowly progressive; Varies with type; many are slowly progressive;
some shorten life span some shorten life span
The majority of patients are unable to sit or The majority of patients are unable to sit or
stand without support, and some affected stand without support, and some affected
children may never learn to walk children may never learn to walk

10. Limb-Girdle Muscular DystrophiesLimb-Girdle Muscular Dystrophies
Autosomally determined face-sparing, Autosomally determined face-sparing,
proximally predominant, progressive muscular proximally predominant, progressive muscular
dystrophiesdystrophies
10% autosomal dominant(6 subtypes, LGMD1A-F)10% autosomal dominant(6 subtypes, LGMD1A-F)
90% autosomal recessive(11 subtypes, LGMD2A-K)90% autosomal recessive(11 subtypes, LGMD2A-K)
Age at onset varies greatly (usually 1Age at onset varies greatly (usually 1
stst
– 3 – 3
rdrd

decade)decade)
Defective proteins coded by mutant genes may Defective proteins coded by mutant genes may
be detected by immunohistochemistry or be detected by immunohistochemistry or
immunoblottingimmunoblotting

11. Limb-girdle dystrophiesLimb-girdle dystrophies
Causes:Causes:
SarcoglycanopathiesSarcoglycanopathies
Calpain deficiencyCalpain deficiency
Caveolin deficiencyCaveolin deficiency
Dysferlin deficiency etc.Dysferlin deficiency etc.
α, β, γ, δ sarcoglycansα, β, γ, δ sarcoglycans

12. SarcoglycanopathiesSarcoglycanopathies
Clinical presentation:Clinical presentation:
Age of onset and severity is heterogeneous, usually Age of onset and severity is heterogeneous, usually
starts between 2 and 20 yearsstarts between 2 and 20 years
Clinically often indistinguishable from Duchenne-Clinically often indistinguishable from Duchenne-
dystrophydystrophy
No cardiac involvementNo cardiac involvement
Diagnosis:Diagnosis:
Normal dystrophin immunostaining, abnormal Normal dystrophin immunostaining, abnormal
immunostaining with sarcoglycansimmunostaining with sarcoglycans
Genetic examination, where availableGenetic examination, where available

13. Myotonic MD Myotonic MD
Cause is a repeated section of DNA on either Cause is a repeated section of DNA on either
chromosome 19 or chromosome 3.chromosome 19 or chromosome 3.
Onset of the congenital form appears at birth. More Onset of the congenital form appears at birth. More
common forms may begin in teen or adult years. common forms may begin in teen or adult years.
Affects the central nervous system and other body Affects the central nervous system and other body
systems, including the heart, adrenal glands and systems, including the heart, adrenal glands and
thyroid, eyes, and gastrointestinal tract thyroid, eyes, and gastrointestinal tract
Symptoms first seen in muscles in the hands and feetSymptoms first seen in muscles in the hands and feet
Distinctive symptoms include muscle tensing, cramps, Distinctive symptoms include muscle tensing, cramps,
or inability to relax muscles.or inability to relax muscles.

14. Duchenne Muscular Dystrophy(DMD) Duchenne Muscular Dystrophy(DMD)
DMD affects mostly DMD affects mostly malesmales at a rate of at a rate of 1 in 3,500 1 in 3,500
birthsbirths..
There are over 200 types of mutations that can cause There are over 200 types of mutations that can cause
any one of the forms of muscular dystrophy.any one of the forms of muscular dystrophy.
DMD is the DMD is the most severemost severe and and common typecommon type of of
muscular dystrophy.muscular dystrophy.
DMD is characterized by the wasting away of muscles.DMD is characterized by the wasting away of muscles.
Diagnosis in Diagnosis in boysboys usually occurs usually occurs between 16 months between 16 months
and 8 years.and 8 years.
Parents are usually the first to notice problem.Parents are usually the first to notice problem.
Death from DMD usually occurs by age of 20.Death from DMD usually occurs by age of 20.

15. DMD Gene and DystrophinDMD Gene and Dystrophin
FunctionFunction
The DMD gene encodes for the protein The DMD gene encodes for the protein
dystrophin, found in muscle cells and dystrophin, found in muscle cells and
some neurons.some neurons.
Dystrophin provides strength to muscle cells by Dystrophin provides strength to muscle cells by
linking the internal cytoskeleton to the surface linking the internal cytoskeleton to the surface
membrane.membrane.
Without this structural support, the cell membrane Without this structural support, the cell membrane
becomes permeable.becomes permeable.
 Under normal wear and tear stem cells within the Under normal wear and tear stem cells within the
muscle regenerate new muscle cells and repair muscle regenerate new muscle cells and repair
the damage.the damage.
In DMD the damage to muscle cells is so extreme In DMD the damage to muscle cells is so extreme
that the supply of stem cells are exhausted and that the supply of stem cells are exhausted and
repair can no longer occur.repair can no longer occur.

16. Clinical FeaturesClinical Features
Genotype of DMDGenotype of DMD
Females carry the DMD Females carry the DMD
gene on the X gene on the X
chromosome.chromosome.
Females are carriers and have a Females are carriers and have a
50% chance of transmitting the 50% chance of transmitting the
disease in each pregnancy.disease in each pregnancy.
Sons who inherit the mutation Sons who inherit the mutation
will have the disease.will have the disease.
Daughters that inherit the Daughters that inherit the
mutation will be carriers.mutation will be carriers.
The DMD gene is located on The DMD gene is located on
the Xp 21 band of the X the Xp 21 band of the X
chromosome.chromosome.

17. Genotype of DMDGenotype of DMD
(Cont.)(Cont.)
During the translocation process, a mutation During the translocation process, a mutation
occurs.occurs.
Mutations leading to the Mutations leading to the absence of dystrophinabsence of dystrophin
Very Large Deletions (lead to absence of dystrophin)Very Large Deletions (lead to absence of dystrophin)
Mutations causing Mutations causing reading errorsreading errors (causes a (causes a
degraded, low functioning DMD protein degraded, low functioning DMD protein
molecule)molecule)
DeletionDeletion
DuplicationDuplication
Point MutationsPoint Mutations

19. Clinical FeaturesClinical Features
Phenotype of DMDPhenotype of DMD
Delays in early childhood stages involving Delays in early childhood stages involving
muscle use, in 42% of patients.muscle use, in 42% of patients.
Delays in standing aloneDelays in standing alone
Delays in sitting without aidDelays in sitting without aid
Delays in walking (12 to 24 months)Delays in walking (12 to 24 months)
Toe walking or flat footednees. Toe walking or flat footednees.
Child has a hard time climbing.Child has a hard time climbing.
Learning difficulties in 5% of patients.Learning difficulties in 5% of patients.
Speech problems in 3% of patients.Speech problems in 3% of patients.
Leg and calf pain.Leg and calf pain.
Mental development is impaired. IQ’s usually Mental development is impaired. IQ’s usually
below 75 points.below 75 points.
Memory problemsMemory problems
Carrying out daily functionsCarrying out daily functions

20. Clinical Features Clinical Features (Cont.)(Cont.)
Increase in bone fracturesIncrease in bone fractures due to the decrease due to the decrease
in bone density.in bone density.
Wheelchair bound by 12Wheelchair bound by 12 years of age. years of age.
Cardiomyopathy at 14 to 18 yearsCardiomyopathy at 14 to 18 years..
Few patients live beyond 30 years of age.Few patients live beyond 30 years of age.
RespiratoryRespiratory problems and problems and cardiomyopathy cardiomyopathy leading to leading to
congestive heart failure are the usual cause of death.congestive heart failure are the usual cause of death.

21. Hypertrophic
leg muscle
DMD
Enlarged calves
BMD
Toe walking
BMD

24. Approach to Diagnosis of Childhood Muscular Approach to Diagnosis of Childhood Muscular
DystrophyDystrophy
N o D e l e t i o n
D e t e c t e d
D i a g n o s i s o f D y s t r o p h i n o p a t h y ( D M D o r B M D )
D e l e t i o n N o t
I n f o r m a t i v e
f o r S e v e r i t y
D e l e t i o n I n f o r m a t i v e
f o r S e v e r i t y .
P o s i t i v e F a m i l y H i s t o r y
D e l e t i o n
D e t e c t e d
D N A A n a l y s i s
f o r D y s t r o p h i n
G e n e A b n o r m a l i t y
M a l e
A b n o r m a l
D y s t r o p h i n
M e r o s i n a n d
A d h a l i n A n a l y s i s
N o r m a l
D y s t r o p h i n
M u s c l e B i o p s y
F e m a l e
E l e v a t e d
M u s c u l a r D y s t r o p h y
U n l i k e l y
N o r m a l
C K
M u s c u l a r W e a k n e s s

25. InvestigationsInvestigations
Serum CPK LevelSerum CPK Level

26. management of DMD and BMD management of DMD and BMD
SYMPTOM MANAGEMENTSYMPTOM MANAGEMENT — In addition to — In addition to
muscle weakness, muscle weakness, cardiaccardiac, , pulmonarypulmonary, and , and
orthopedicorthopedic complications are frequently complications are frequently
associated with DMD and BMD. associated with DMD and BMD.
The anticipation and early detection of organ The anticipation and early detection of organ
involvement is important for optimal therapy.involvement is important for optimal therapy.
Furthermore, patients should be evaluated by Furthermore, patients should be evaluated by
pulmonarypulmonary and and cardiac specialistscardiac specialists prior to any prior to any
surgery . surgery .

27. American Thoracic Society guidelines American Thoracic Society guidelines
recommend thatrecommend that
allall patients with DMD should receive the patients with DMD should receive the
pneumococcal vaccinepneumococcal vaccine and an and an annual annual
influenza vaccination.influenza vaccination. The pneumococcal The pneumococcal
vaccine can provide immunity for 5 to 10 vaccine can provide immunity for 5 to 10
years. years.
Nocturnal mouth intermittent positive pressure Nocturnal mouth intermittent positive pressure
Ventilation can be used to treat symptomatic Ventilation can be used to treat symptomatic
nocturnal hypoventilation, and respiratory nocturnal hypoventilation, and respiratory
assistance may be used during periods of assistance may be used during periods of
respiratory infection respiratory infection

28. Cardiac diseaseCardiac disease
angiotensin converting enzyme angiotensin converting enzyme (ACE)(ACE) inhibitors inhibitors
and and beta blockersbeta blockers, to treat asymptomatic left , to treat asymptomatic left
ventricular dysfunction and overt heart failure.ventricular dysfunction and overt heart failure.
Echocardiography Echocardiography should be obtained around should be obtained around
age 10 years in boys with DMD and BMD and age 10 years in boys with DMD and BMD and
then repeated then repeated annuallyannually or or biannuallybiannually..

Cardiac evaluation of female carriers should Cardiac evaluation of female carriers should
begin after teenage years. begin after teenage years.

29. Orthopedic interventionsOrthopedic interventions
Therapeutic interventions in DMD/BMD are Therapeutic interventions in DMD/BMD are
specifically aimed at specifically aimed at
1.maintaining function, 1.maintaining function,
2.preventing contractures. 2.preventing contractures.
The mainstays of physical therapy are passive The mainstays of physical therapy are passive
stretching exercises to prevent contractures of stretching exercises to prevent contractures of
the iliotibial band, the Achilles tendons, and the iliotibial band, the Achilles tendons, and
flexors of the hip. flexors of the hip.

31. orthopedic interventionsorthopedic interventions
Multiple additional interventions may be used based upon Multiple additional interventions may be used based upon
the patient's requirements and severity of disease: the patient's requirements and severity of disease:
Lightweight plastic ankle-foot orthosesLightweight plastic ankle-foot orthoses should be applied if should be applied if
the foot remains in plantar flexion during sleep. the foot remains in plantar flexion during sleep.
Standing and/or walking may be maintained by using Standing and/or walking may be maintained by using long-long-
leg braces. leg braces.
SurgerySurgery may be performed to may be performed to release contractures of the hip release contractures of the hip
flexors, iliotibial bands, and Achilles tendons. flexors, iliotibial bands, and Achilles tendons.
Standing and ambulation may prevent scoliosis. Standing and ambulation may prevent scoliosis.
Spine surgerySpine surgery to stabilize or correct scoliosis may improve to stabilize or correct scoliosis may improve
patient comfort, particularly for those confined to a patient comfort, particularly for those confined to a
wheelchair, and may benefit pulmonary function . wheelchair, and may benefit pulmonary function .
Orthopedic evaluationsOrthopedic evaluations should monitor for scoliosis and should monitor for scoliosis and
other complications and surgical interventions should be other complications and surgical interventions should be
utilized as needed. utilized as needed.
Chest and spine radiographyChest and spine radiography should be ordered on an as- should be ordered on an as-
needed basis. needed basis.

32. NutritionNutrition
Exposure to Exposure to sunshinesunshine and a and a balanced diet that balanced diet that
is rich in vitamin D and calciumis rich in vitamin D and calcium is important to is important to
improve bone density and reduce the risk of improve bone density and reduce the risk of
fractures. fractures.
Vitamin D supplementationVitamin D supplementation if the serum if the serum
concentration of vitamin D is less than 20 concentration of vitamin D is less than 20
ng/mL is recommended. ng/mL is recommended.
Weight should be monitoredWeight should be monitored and controlled to and controlled to
avoid obesity. It is recommended that patients avoid obesity. It is recommended that patients
receive receive routine evaluation by a nutritionistroutine evaluation by a nutritionist. .

33. TREATMENTTREATMENT
CorticosteroidsCorticosteroids are the mainstay of treatment are the mainstay of treatment
for for DMDDMD and are offered as treatment for and are offered as treatment for
boys who are boys who are over the age of five years. over the age of five years.
PrednisonePrednisone —is beneficial in the treatment —is beneficial in the treatment
of DMD and is associated with a significant of DMD and is associated with a significant
increase in strengthincrease in strength, , muscle functionmuscle function, and , and
pulmonary function.pulmonary function.
Little is known of the effect of prednisone in Little is known of the effect of prednisone in
patients with BMD. patients with BMD.

34. Practice Parameter: Practice Parameter:
Corticosteroid Treatment Of Corticosteroid Treatment Of
Duchenne Muscular DystrophyDuchenne Muscular Dystrophy
An Evidence-Based Report of the American Academy of An Evidence-Based Report of the American Academy of
Neurology and the Child Neurology SocietyNeurology and the Child Neurology Society
Richard T. Moxley III, MD, Stephen Ashwal MD, Shree Richard T. Moxley III, MD, Stephen Ashwal MD, Shree
Pandya, MS, PT, Anne Connolly, MD, Julaine Florence, Pandya, MS, PT, Anne Connolly, MD, Julaine Florence,
MHS, PT, Katherine Mathews, MD, Lisa Baumbach, MD, MHS, PT, Katherine Mathews, MD, Lisa Baumbach, MD,
Craig McDonald, MD, Michael Sussman, MD, Craig McDonald, MD, Michael Sussman, MD,
Christine Wade, PhD, PTChristine Wade, PhD, PT
Published in Published in NeurologyNeurology 2005;64:13-20 2005;64:13-20

35. RecommendationsRecommendations
PrednisonePrednisone has been demonstrated to have a has been demonstrated to have a
beneficial effect on muscle strength and function in beneficial effect on muscle strength and function in
boys boys between 5 to 15 years of age between 5 to 15 years of age with DMD and should with DMD and should
be offered (at a dose of 0.75 mg/kg/d) as treatmentbe offered (at a dose of 0.75 mg/kg/d) as treatment..
Maintaining Maintaining a dosage of 0.75 mg/kg/da dosage of 0.75 mg/kg/d is optimal; but, if is optimal; but, if
side effects require a decrease in prednisone, tapering side effects require a decrease in prednisone, tapering
to dosages as low as 0.3 mg/kg/d gives significant to dosages as low as 0.3 mg/kg/d gives significant
improvement.improvement.
Benefits and side effects of corticosteroid therapy Benefits and side effects of corticosteroid therapy
need to be monitored. Timed function tests, need to be monitored. Timed function tests,
pulmonary function tests, and age at loss of pulmonary function tests, and age at loss of
independent ambulation are useful to assess benefits. independent ambulation are useful to assess benefits.
 An offer of treatment with corticosteroids should An offer of treatment with corticosteroids should
include a balanced discussion of potential risks. include a balanced discussion of potential risks.

37. Potential side effects of corticosteroid therapy need to
be assessed:
•Weight gain
•Cushingoid appearance
•Cataracts
•Short stature
•Acne
•Excessive hair growth
•Gastrointestinal symptoms
•Behavioral changes
If excessive weight gain occurs (>20% over estimated
normal weight for height over a 12 month period), based
on available data, it is recommended that the dosage of
prednisone be decreased (to 0.5 mg/kg/d with a further
decrease after 3-4 months to 0.3 mg/kg/d if excessive
weight gain continues).

38. Future Research
Double blind, randomized, controlled studies are Double blind, randomized, controlled studies are
needed to compare daily treatment with prednisone to needed to compare daily treatment with prednisone to
other treatment regimens, such as: other treatment regimens, such as:
a)a) higher dose alternate day treatment (5 mg/kg every higher dose alternate day treatment (5 mg/kg every
other day) other day)
b)b) intermittent treatment (0.75 mg/kg/d for 10 days – intermittent treatment (0.75 mg/kg/d for 10 days –
stop for 10 days – repeat cycle)stop for 10 days – repeat cycle)
c)c) high dose pulses on weekends (5mg/kg on Friday high dose pulses on weekends (5mg/kg on Friday
and Saturday) and and Saturday) and
d)d) deflazacort (0.9 mg/kg/d). deflazacort (0.9 mg/kg/d).
The goal of these studies is to establish more clearly The goal of these studies is to establish more clearly
the optimal dose, optimal age to initiate treatment, and the optimal dose, optimal age to initiate treatment, and
optimal dose schedule to improve function with the optimal dose schedule to improve function with the
least possible side effects.least possible side effects.

39. NOVEL THERAPIESNOVEL THERAPIES
Gene therapyGene therapy
Experimental gene therapies are currently under Experimental gene therapies are currently under
evaluation (whether by transplanted myoblast evaluation (whether by transplanted myoblast
or direct genetic manipulation) .or direct genetic manipulation) .

40. CreatineCreatine
Creatine monohydrate has been studied for its Creatine monohydrate has been studied for its
potential to increase muscle strength in NMD and potential to increase muscle strength in NMD and
muscular dystrophies muscular dystrophies
Creatine treatment was associated with improved grip Creatine treatment was associated with improved grip
strength of the dominant hand and increased fat free strength of the dominant hand and increased fat free
mass compared with placebo. mass compared with placebo.
In light of the limited data and apparently modest In light of the limited data and apparently modest
benefit attributed to creatine in the studies, benefit attributed to creatine in the studies,
demonstration of clinically important improvement in demonstration of clinically important improvement in
larger trials is needed before recommending this larger trials is needed before recommending this
treatment for patients with DMD. treatment for patients with DMD.

41. Stem cell therapyStem cell therapy
The use of stem cells in the treatment of The use of stem cells in the treatment of
DMD and BMD is under investigation but DMD and BMD is under investigation but
remains experimental remains experimental

42. PROGNOSIS (DMD)PROGNOSIS (DMD)
some improvement between three and six some improvement between three and six
years of age.years of age.
followed by gradual deterioration, leading followed by gradual deterioration, leading
to wheelchair bounding by age of 12 yearsto wheelchair bounding by age of 12 years
Most patients with DMD die in their late Most patients with DMD die in their late
teens or twenties from respiratory teens or twenties from respiratory
insufficiency (most commonly) or insufficiency (most commonly) or
arrhythmia secondary to cardiomyopathy. arrhythmia secondary to cardiomyopathy.

43. PROGNOSIS (BMD)PROGNOSIS (BMD)
patients with BMD typically remain patients with BMD typically remain
ambulatory beyond the age of 16 years and ambulatory beyond the age of 16 years and
into adult life.into adult life.
they survive beyond the age of 30 years. they survive beyond the age of 30 years.
The most common cause of death is heart The most common cause of death is heart
failure from dilated cardiomyopathy, which failure from dilated cardiomyopathy, which
also causes considerable morbidity in these also causes considerable morbidity in these
patients despite their milder skeletal muscle patients despite their milder skeletal muscle
involvement involvement

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