Muscular Dystrophy

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Muscular Dystrophy
Craig M. McDonald, MD, Associate
Professor.Departments of PMR and Pediatrics.UC
Davis School of Medicine.cmmcdonald_at_ucdavis.edu
Director RRTC in Neuromuscular Diseases, UCDMC
Neuromuscular Disease Clinic, and UCDMC
Pediatric Rehabilitation Program.
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Duchenne/BeckerMuscular Dystrophy
1. Natural History2. Clinical Findings
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Natural History of Duchenne Muscular Dystrophy
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Duchenne Muscular Dystrophy (Pseudohypertrophic
MD) Outlier Duchenne Muscular
Dystrophy Becker Muscular Dystrophy
(Severe) Becker Muscular Dystrophy (Mild)
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X-linked Recessive InheritanceXp21.2 loci
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Immunofluorescence Stain Dystrophin
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DMD/BMD Gene
XP 21 locus 2.4 million base pairs Exons 1 -
79 Hotspots Exons 3 - 19
Exons 42 - 60
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Dystrophin
427 Kd protein
Cytoplasmic side of skeletal/cardiac
sarcolemmal membrane 2 of total
sarcolemmal protein lt 3 quantity
Duchenne phenotype 3 20 quantity
Outlier phenotype 20 80 quantity
Becker phenotype or 90 100
abnormal structure
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Muscular DystrophyBasic Concepts
Dystrophy muscle wasting
In a dystrophic myopathy there is loss of
functional muscle tissue over time with
resulting weakness.
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Normal Dystrophin-Glycoprotein Complex
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DMD Patients / Mdx Mouse
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Nature of the Injury Proposed Mechanisms

• Mechanical weakening of the
• sarcolemma
• Abnormal calcium influx
• Aberrant cell signaling
• Oxidative stress
• Recurrent muscle ischemia

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Mechanically Weakened Sarcolemma Hypothesis

• Normal diaphragm

• mdx diaphragm

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Mechanically Weakened Sarcolemma Hypothesis

• Passive stretch, isometric and eccentric
  contractions used to produce varying levels of
  sarcolemmal stress (ECCgtISOgtPAAS)
• For any given level of stress, mdx more prone to
  sarcolemmal disruption (from Petrof et al, PNAS
  1993)

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Mechanically Weakened Sarcolemma Hypothesis

• Greater pathology in the mdx diaphragm
  reflection of greater wear tear due to
  continuous workload
• (from Stedman et al, Nature 1991)

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Simplified View of Pathophysiology in DMD

• Muscle membrane susceptible to mechanical injury
• Injury to sarcolemmal membrane
• Calcium influx / oxidative stress
• Degeneration of fibers
• Cycles of degeneration and regeneration
• Irreversible necrosis / loss of fiber
• Replacement of fiber by fat and connective tissue

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Muscular Dystrophy Muscle Biopsy Findings

• Histology
• Normal fibers
• Hypertrophy of fibers
• Degeneration of fibers
• Atrophy of fibers
• Regeneration of fibers
• Connective tissue/fatty
• infiltration

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Muscle Biopsy 3-yr-old, Normal
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Muscle Biopsy 3-yr-old, DMD
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Muscle Biopsy 9-yr-old, DMD
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Triceps Biopsy 19-yr-old, DMD (Postmortem)
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Biceps Muscle (Gross Pathology) 19-yr-old, DMD
(Postmortem)
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Gastrocnemius Muscle 19-yr-old, DMD (Postmortem)
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Pattern of Weakness in DMD

• Neck flexor weakness (earliest muscle group to
  show weakness)
• Proximal weakness greater than distal (UE/LE)
• Lower extremity weakness predates years
• Hip extensors weaker than flexors
• Knee extensors weaker than flexors
• Ankle dorsiflexors weaker than plantarflexors

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Quantitative Strength Testing in DMD
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Classic Early Findings in DMD (Preschool and
Early School Age)

• Neck flexor weakness
• Toe walking
• Lordotic posturing
• Calf pseudo-hypertrophy
• Gowers sign
• Posterior axillary depression sign

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Diagnostic Workup in DMD / BMD

• Clinical presentation
• Elevated CK
• EMG rarely used
• DMD / BMD gene deletion studies PCR (blood)
• Muscle biopsy (histology)
• Quantitative dystrophin analysis (Western blot)

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CK vs. Age (3 to 17 years)
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CK values may be 10-fold higher in younger
patients with DMD (e.g. 25,000 vs. 2,500 in a 3
year old vs. 12 year old)
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Gait Adaptations in DMD
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Postural Adaptations in DMD

• Lordosis shoulder retraction
• Knee extension
• Equinus posturing

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Progressive Increase in Toe Walking / Equinus
Posturing
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Progressive Increase in Toe Walking / Equinus
Posturing
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Progressive Increase in Lumbar Lordosis
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Progressive Increase in Lumbar Lordosis
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Tredelenberg Gait / Gluteus Medius Lurch
(compensates for hip abductor weakness)
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Increasing Postural Challenges Due to Hip
Extensor and Knee Extensor Weakness
Increased difficulty maintaining balance.
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Transition to Wheelchair

• Average age to wheelchair
• 10 years (range 7-13)

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Predicting Transition to Wheelchair in DMD

• Time to walk 30 feet
• lt 6 seconds ? gt 2 years to chair
• 6-12 seconds ? 1-2 years to chair
• gt 12 seconds ? lt 1 year to chair

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Lower Extremity Bracing in DMD
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KAFO / Polypropylene Long Leg Braces
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Lightweight Polypropylene KAFO Used in DMD
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Ankle Plantarflexion Contractures
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Contractures in DMD
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Knee Flexion Contractures in DMD
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Hip Flexion Contractures in DMD
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Static Positioning of Limbs Leads to Contractures
in DMD
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Elbow Flexion Contractures in DMD
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Static Positioning Leads to Contractures in DMD
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Severe Equinovarus Contractures in DMD
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Early Orthopedic Surgery to Prolong Ambulation
in DMD

• Heel cord lengthening (judicious)
• /- Posterior tibialis lengthening
• Iliotibial band release
• Immediate mobilization to standing
• on OP day 1 POD 1

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Lower Extremity OrthopedicSurgery in DMD

• Early prophylactic surgery may prolong brace free
  ambulation
• Late surgery at time of transitional walking
  allows ambulation in KAFOs for 1 to 3 years

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• Hip flexor
• lengthening
• IT band release
• TAL

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Scoliosis in DMD
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Problems Associated with SevereSpinal Deformity
Poor sitting balance Difficulty w/ upright
seating and positioning Pain Difficulty in
parent / attendant care Exacerbation of
underlying restrictive pulmonary disease
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Severe Scoliosis in End-Stage DMD
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Scoliosis may be mild and non-progressive in
10-15 of DMD cases.
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TLSO bracing is not effective in DMD.
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Spinal fusion is the only effective treatment of
scoliosis in DMD.
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Luque segmental instrumentation
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Unit rod instrumentation
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Surgical Indications for Spine Fusion in DMD

• Scoliosis gt 20-25 degrees
• FVC gt 40 preferred
• FVC lt 30 absolute contraindication
• Absence of severe cardiomyopathy

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Curve Type, Pulmonary Status and Progression

• Kyphoscoliosis with rotation progress
• Collapsing hyperlordosis progress
• Peak FVC lt 2.0 liters tend to progress
• Absence of kyphosis or lordosis and peak FVC gt
  2.5 liters tend not to progress

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Typical mild curve in outlier DMD note the
absence of lordosis or kyphosis.
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Restrictive Lung Disease in DMD
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Respiratory Muscle Weakness and Fatigue

• Restrictive lung disease
• Expiratory muscle weakness produces ineffective
  cough, problems clearing secretions, increased
  infections
• Inspiratory weakness hypoventilation /
  hypercarbia
• ? Respiratory failure

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Early Course of Restrictive Lung Disease in DMD

• Decreased static airway pressures during the late
  first decade
• Increase in FVC to age 10 to 12, at which time a
  plateau is reached
• Linear decline in FVC with age during the second
  decade

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PFTs used for Prognostication in DMD

• Peak FVC 2.7 liters FVC 4 / yr
• Peak FVC lt 1.7 liters FVC 10 /yr

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Signs of Impending Respiratory Failure in DMD

• FVC lt 20-25 predicted
• MIP lt 25-30 cm H2O
• PaCO2 gt 55

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Non- Invasive Ventilation with BIPAP
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Cardiomyopathy in DMD

• Clinically significant cardiomyopathy rare before
  age 10
• Fibrosis posterior wall left ventricle
• Myocardium exhibits abnormal contractility
• Purkinje abnormalities lead to tachyarrythmias

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Cardiomyopathy in DMD

• Regular monitoring with
• ECG
• Echo
• Holter monitor

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Cardiomyopathy in DMD

• Treatment with
• Digitalis
• Afterload reduction
• Anti-arrythmics

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Weight Management in Neuromuscular Disease

• Obesity (sedentary)
• Cacchexia (end-stage)

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Weight Gain in DMD
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Cachexia in Late-Stage DMD
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Current Treatments in DMD

• Corticosteroids
• Prednisone (daily vs. pulsed)
• Deflazacort
• Beta-2 Agonists
• Albuterol SR
• Anabolic steroids
• Oxandrolone

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Theoretical Treatments in DMD and Other NMDs

• Myoblast transfer
• Gene therapy
• Direct injection of plasmid DNA
• Viral transmission vector
• Human stem cell therapy

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Acknowledgment

• This work was supported by the National
  Institute on Disability and Rehabilitation
  Research Grant HB133B980008 and NIH Grant R01
  HD35714.