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Debbie and Denny's DMD ppt

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					              Case Study V

           Pediatric Neurology
            March 10th, 2009


 Denver Glass, SPT
 Deborah Landreth, SPT
      Subjective Examination
 Tommy Thomson
 10 y/o male
 Lives at home with parents
 Frequent falls
 Easily fatigues
 Allergies: strawberries,
  peanuts, & latex
 Meds: Prednisone
       Objective Examination
 Physical Examination
  – BP & HR nml
  – RR slightly elevated
  – Muscle loss: legs, pelvis, shoulder, neck, arms
  – Calf muscle enlargement (pseudohypertrophy)
  – Difficulty Ambulating: Tiptoe walking
  – Positive Gower’s Sign
  – Positive Trendelenburg’s Sign
       Examination Continued
 Neurologic Examination
  – All Dermatomes: nml
  – Cranial Nerves: intact
  – UE Reflexes: absent
  – LE Reflexes: Patella absent, Achilles nml
  – Muscle Tone: low
          Muscular Dystrophy1
 Etiology: Genetic inheritance

• Pathophysiology:
      Progressive loss of muscle contractility
      Destruction of myofibrils

• Characteristics:
      Progressive weakness
      Degeneration of skeletal muscles
                Diagnosis
 Confirmed by clinical exam & lab
  procedures
  – Electromyography
  – Muscle biopsy
  – DNA analysis
  – Selected enzyme levels
        Classification Criteria
 9 recognized types
 Rate of progression dependent on type
 Criteria:
  – Mode of inheritance
  – Age of onset
  – Rate of progression
  – Localization of involvement
  – Muscle change
  – Presence of a genetic marker
             Classifications of MD,
                        Campbell table 15.1 c
TYPE            ONSET              INHERITANCE   COURSE
Duchenne        1-4 yrs            X-linked      Rapid
                                                 progressive; loss
                                                 of walking by 9-10
                                                 yrs; death in late
                                                 teens
Becker          5 -10 yrs          X-linked      Slow progressive;
                                                 maintain walking
                                                 past early
                                                 teens;life span
                                                 into 3rd decade
Congenital      Birth              Recessive     Slow, variable;
                                                 short life span
Congenital      Birth              Dominant      Slow; significant
Myotonic                                         intellectual
                                                 impairment
                Classifications of MD,
                         Campbell table 15.1 c

TYPE                  ONSET          INHERITANCE          COURSE
Childhood-onset       1st decade     Dominant/Recessive   Slow progressive;
Facioscapulohumeral                                       loss of walking
                                                          later in life;
                                                          variable life
                                                          expectancy

Emery-Dreifus         Childhood to   X-linked             Slowly
                      early teens                         progressive with
                                                          cardiac
                                                          abnormalities and
                                                          normal life span
Limb-Girdle           Teenage        Recessive            Slowly
                      yrs/early                           progressive;
                      adulthood                           affects shoulder
                                                          girdle and pelvis
                     Impairments
 Primary
  – Weakness
  – Muscle Degeneration
        Due to progressive loss of myofibrils

 Secondary
  –   Contractures
  –   Postural malalignment
  –   Decreased respiratory capacity
  –   Fatigue
  –   Obesity
          Mental Impairments
 IQ averages around 85
   Normal: 90-109


 30% of boys with DMD have IQ under 70
  – Due to loss of dystrophin in brain


 Mental Retardation highest in congenital
  myotonic MD
             Duchenne MD2
 Most common type of MD
 X-linked disorder
 Incidence:
   – 1 in 3500 live male
     births
   – 1 in 50 million female
     births
                          http://www.humanillnesses.com/original/im
 Etiology: absence of    ages/hdc_0001_0002_0_img0183.jpg

  dystrophin
            Duchenne MD3
 Characteristics
  – Progressive wasting of muscle
  – Elevated creatine kinase levels
  – Pseudohypertrophic calf muscles
  – Decreased level of activity
  – Cognitive impairments
Pseudohypertrophic calf muscles




     http://www.mda.org/publications/images/Family-swing.jpg
Muscle groups involved in MD4
   Timeline - Duchenne MD3
Age 2-5:
   Limb-girdle muscles affected
       –   Clumsiness
       –   Falls
       –   Change in gait
       –   Difficulty ascending stairs
Age 6:
     Contractures in gastroc/soleus
     Exaggerated lordosis
     Postive Gower’s sign
     Scoliosis
       – Emergence of pulmonary complications
   Timeline - Duchenne MD
Age 8 - 12:
   Inability to walk


Age 20-30
   Death, secondary to cardiac and respiratory
    complications
Timeline – Duchenne MD




 www.parentprojectmd.org.np/.../DMD_boys_sm.jpg
              NCMRR
   Model of Disease and Disability
 Pathophysiology:
      Progressive loss of muscle contractility
      Destruction of myofibrils
 Impairment:
      Muscle weakness
      Contractures
      Decreased ROM

 Functional Limitation
      Difficulty with walking
      Difficulty with standing
      Difficulty with transfers
              NCMRR
   Model of Disease and Disability
 Disability
      ADL’s/Self Care
      Mobility
 Societal Limitation
      Environmental access: stairs, power wheelchair
       access, Huts
      Societal attitudes: Confined to wheelchair, social
       stigma
            Pathophysiology4,5
 X-linked recessive disorder

 Mutated dystrophin gene
  Xp21

 Xp21 codes for muscle
  membrane protein
  dystrophin

 Dystrophin is located in the
  sarcolemma

 Links the muscle surface
  membrane to actin
             Pathophysiology4,5
 Sarcolemma susceptible to
  damage during contraction,
  especially eccentric

 Influx of Ca2+

 Cell destruction occurs due to
  the activation of calpain, a
  calcium-activated proteinase

 Muscle cells are replaced by
  fatty and connective tissues,
  and contractures develop
         Research Timeline5
 1860 – 1900 French physician Guillaume
  Duchenne de Boulogne described what
  would later be called ‘Duchenne Muscular
  Dystrophy’

 1930 – 1960 X-chromosome-linked
  inheritance pattern for DMD confirmed
         Research Timeline5
 1984 – 1988 Gene responsible for DMD is
  identified by Louis Kunkel’s team

 Protein made from DMD gene is described,
  named dystrophin and localized to muscle-
  fiber membrane
         Research Timeline5
 1989 – 1994 Corticosteroid prednisone
  confirmed to slow the progression of DMD in
  several clinical trials

 Transferring functional dystrophin genes into
  DMD-affected tissues (gene therapy)
  explored in cells and mice
         Research Timeline5
 1995 – 2000 Stem cells to treat DMD comes
  under consideration

 Mice with DMD found to benefit from high
  levels of utrophin (a protein similar to
  dystrophin)
         Research Timeline5
 2000-2005 Corticosteroids found to
  stimulate utrophin production

 Compound called PTC124 found to allow
  cells to ignore molecular stop signs and
  produce normal dystrophin protein
  molecules
         Research Timeline5
 2005 – 2009 PTC124 found to restore
  dystrophin in about half of boys with DMD in
  28-day trial

 Stem cells carrying an exon-skipping
  compound cause significant recovery of
  muscle form and function in dystrophin-
  deficient mice
                Interventions1
 Major goals
  – Prevent joint contractures
  – Prevent spinal deformities
  – Prolong ambulation
  – Overall health and function
                  Interventions1
   Contracture prevention
   Strength training
   Corticosteroids
   Aquatic Therapy
   HEP
   Breathing exercises
    – Slow the loss of vital capacity
 E Stim
    – Slow the progression of muscle weakness
               Contractures3
 Primary consideration in treatment
 Why so important?
  – Limit joint function
  – Contribute to mm weakness
  – Muscle force is related to its length
  – Contractures are often permanent
  – Lead to ambulation loss
              Contractures3,1
 Treatment
  – Positioning
  – Passive/Active Stretching
      Slowly & Avoid Pain
      Gastroc/soleus
      TFL
  – Night splints
      Slow progression of
       ankle contractures
  – Daytime AFO’s
      Decreasing trend
                             www.mda.org/publications/Quest/q85heelcord.html
               Contractures1
 Surgical management
  – Achilles Tendon
    lengthening
  – Fasciotomies of TFL
    and ITB
  – Posterior tibialis
    transfer into the 3rd
    cuneiform




                            www.mda.org/publications/Quest/q85heelcord.html
 Study: Effects of stretching Achilles
    Tendon & night splints, Hyde6
 Group A: Passive stretching and night
  splints
  – Achilles Tendon
  – Hip Flexors
  – Knee Flexors
  – ITB
  – 10 x a day
 Study: Effects of stretching Achilles
    Tendon & night splints, Hyde6
 Group B: Passive stretching only (10 x a
  day)

 Result: Group A benefited by an annual
  delay of 23% in the development of
  contractures

 Important: Contractures in Achilles Tendon
  are the most significant precipitating cause
  of loss of ambulation
  Muscle Training with MD, Ansved
               20027
 Beneficial or Harmful?
 Lack of well designed studies
  – Mix of MD types
  – Different stages
  – Short term v. Long Term effects
  Muscle Training with MD, Ansved
               20027
Outcomes:

Slowly Progressive myopathic disorders:
High resistance strength training at
  submaximal levels is beneficial
  Muscle Training with MD, Ansved
               20027
Outcomes:

Rapidly progressive myopathic disorders:
 High resistance strength training is highly
  controversial.
 Mechanical stress of the mm fibers should be
  avoided
 Low resistance training may be beneficial,
  metabolic & contractile properties are optimized
             Strength        Training1


 Emphasis of exercise program changes after cessation of
  walking
 Upper Extremity for transfers
   – Shoulder depressors
   – Triceps
 Coordinate ADL’s
  into therapy
   – Grooming
   – Dressing
   – Feeding
            Corticosteroids8,9
 Only effective pharmacologic treatment
 Prednisone and Deflazacort (not available in
  U.S)
 Daily treatments
  – Improve muscle strength & function
  – Slow progression of weakness
  – Prolong ambulation
  – Delay respiratory & cardiac dysfunction
              Corticosteroids8,9
 Side Effects
  –   Weight gain
  –   Growth suppression
  –   Vertebral Fractures
  –   Irritability
 Optimal Management: Monitor
  –   Diet
  –   Blood Pressure
  –   Osteoporosis
  –   Cataracts
                    Goals
 LTG 1: Pt to amb 50’ x 3 independently in order
  to maintain household mobility in 4 weeks
 STG 1: Pt to amb 75’ x 3 in pool with min
  assist in 2 weeks.
 LTG 2: Pt caregiver to demonstrate proper
  ROM and HEP execution in order to prolong
  ambulation in 2 weeks
 STG 2: Pt caregiver to observe ROM during PT
  treatment in 1 week.
         Functional Assessments
 PEDI
 Clinical Protocol for Functional Testing in
  DMD, MH Brooks.
  A. Pulmonary
  B. Functional grades
        Arms & Shoulders
        Hips & Legs
  C. Time to perform functions (i.e. standing from
     lying supine or climbing 4 stairs)
               Home Assessment1
 Power wheelchair
 Van with a lift or ramp to
  transport a power wheelchair

 Track system for transfers
 Bed modification
   – Pt is unable to change positions
   – Airflow mattress
   – Hospital bed
 Bathroom modification
   – Urinal
   – Shower
   – Tub lift



                                        www.abledata.com/abledata.cfm?pageid=19327
             DMD video
 http://www.youtube.com/watch?v=TrPQAKoj
  O3s&feature=related
     APTA Practice Patterns10
 Musculoskeletal
  – 4C: Impaired Muscle
    Performance


 Neuromuscular
  – 5A: Primary Prevention/Risk
    Reduction for Loss of
    Balance and Falling
  – 5B: Impaired Motor Learning
    Development
     APTA Practice Patterns10
 Cardiovascular/Pulmonary
  – 6B: Impaired Aerobic
    Capacity/Endurance
    Associated with
    Deconditioning
  – 6E: Impaired Ventilation and
    Respiration/Gas Exchange
    Associated with Ventilatory
    Pump Dysfunction or
    Failure
             Future Research
 nNOS Study
 Gene Therapy
  – Myoblast Transfer
  – Stem Cells
  – PTC
 Utrophin

                        http://www.kumc.edu/stemcell/images/background.jpg
   Study: Wai, published March
             2009 11

 Identified location of genetic material
  responsible for the production of nNOS
 nNOS
  – Assists dystrophin
  – Produces nitric oxide
      Multiple muscle functions:
        –   Contraction
        –   Regeneration
        –   Atrophy
        –   Glucose Uptake
        –   Blood Perfusion
   Study: Wai, published March
             2009 11

 nNOS location:
  – Typically: cytosolic surface of sarcolemma
  – In the absence of dystrophin: delocalized
      Effects:
        –   Impaired vasodilation
        –   Focal ischemia
        –   Necrosis
        –   Overall mm damage


  All contribute to fatigues in pts with DMD
   Study: Wai, published March
             2009 11

 Created synthetic genes with dystrophin
 Performed gene therapy on mice lacking
  dystrophin
 Mice genetically corrected
 Missing nNOS restored
 Mice no longer experienced
  mm fatigue and damage
 Myoblast transplantation: Study by
           Partridge T.12
 First gene therapy to be suggested for DMD

 Injections of genetically normal myoblast to
  repair diseased –damaged muscle fibers

 Provides some functional benefit but was
  limited to small area around the injection site
 Myoblast transplantation: Study by
           Partridge T.12
 Most work has recently been directed towards
  selecting more ‘stem cell-like’ myogenic cells
  which might be more effective at reconstituting
  large regions of muscle

 Stem cells are easier to collect from donors and
  are not restricted to graft site region (good and
  bad)

 Stem cells have many orders of magnitude adrift
  of what would be needed for therapeutic
  purposes… need more sensitive markers!
 PTC124: Letters from Nature13
 Nonsense mutations promote premature
  translational termination and cause
  anywhere from %5 - %70 of the individual
  cases of most inherited diseases

 PTC124 promoted dystrophin production in
  primary muscle cells from humans and mdx
  mice expressing dystrophin nonsense
  alleles
  PTC124: Letters from Nature13
 Oral bioavailabity and pharmacological
  properties indicate potential for treatment

 So far test have been done on mdx mice
  and DMD muscle biopsies

 Further research needs to be done but this
  looks promising!
 Utrophin: Study by Courdier-Fruh14
 Utrophin : a dystrophin-related protein

 Elevated levels improve stability and protect
  myofibrils

 Glucocorticoids: 6a-methylprednisolone-21 sodium
  succinate (PDN)

 Methods: Tested in mice and human muscle
  biopsies

 The study’s results showed PDN caused ~%35
  increase utrophin in 5 – 7 days
 Utrophin: Study by Courdier-Fruh14
 What are the set backs?

 PDN is a steroid, which can cause osteoporosis

 PDN at high concentrations directly inhibits calpain

 But PDN might influence protein breakdown
  indirectly by normalizing the Ca2+ homeostasis

 Conclusion: further research is needed
                                References
   1 Campbell   K. Physical Therapy for Children 3rd Edition. Missouri: Saunders;2006.

   2Ciafaloni
             E, Moxley, R. Treatment Options for Duchenne Muscular Dystrophy. Current
    Treatment Options in Neurology. 2008; 10: 86-93.

   3Lovering,   R M, Porter, N C, & Bloch, R J. The Muscular Dystrophies: From Genes to
    Therapies. Physical Therapy [serial online]; 85, 12: 1372-1384. , Available at:
    http://find.galegroup.com/itx/start.do?prodId=HRCA. Accessed March 03, 2009.

   4Goodman C, Fuller K, Boissonault W. Pathology: Implications for the Physical
    Therapist 2nd Edition. Pennsylvania: Saunders; 2003

   5Duchenne Muscular Dystrophy (DMD). The Muscular Dystrophy Association Website.
    Available at: http://www.mda.org/disease/DMD.html . Accessed March 04, 2009.

   6 Hyde, S, Floytrup, I, Glent S, et al. A randomized comparative study of two methods
    for controlling Tendo Achilles contracture in Duchenne muscular dystrophy.
    Neuromuscular Disorders. June 2000;10:257-263.

   7 AnsvedT. Muscle training in muscular dystrophies. Scandinavian Physiological Society.
    March 2001;171:359-366.

   8 WongBL W, Christopher, C. Corticosteroids in Duchenne muscular dystrophy: a
    Reappraisal. Journal of Child Neurology. March 2002;17, 3:183-190.
                                 References
   9 MLB, A M, E G, et al. Bone mineral density and bone metabolism in Duchenne
    muscular dystrophy. Osteoporosis International: A Journal Established As Result Of
    Cooperation Between The European Foundation For Osteoporosis And The National
    Osteoporosis Foundation Of The USA. September 29, 2003;14:761-767.

   10Bohmert   J, Moffat M, Zadai C. Guide to Physical Therapist Practice Revised 2nd
    Edition. Virginia: APTA; 2003

   11 Lai,
          Y, Thomas, G, Yongping, Y, et al. Dystrophins carrying spectrin-like repeats 16
    and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse
    model of muscular dystrophy. Journal of Clinical Investigation. March 2009;119:624-35.

   12 Partridge   T. Myoblast transplantation. Neuromuscular Disorders. 2002;12:S3-S6.

   13Welch E, et al. PTC124 targets genetic disorders caused by nonsense mutations.
    Nature. 2007; 447:87-91.

   14 Courdier-Fruh I, Lee B, Briguet A, Meier T. Glucocorticoids-mediated regulation of
    utrophin levels in human muscle fibers. Neuromuscular Disorders.2002;12:95-104.

				
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