Neuromuscular

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DYSTROPHINOPATHIES

Clinical syndromes
  Becker
  Cardiomyopathy
  Cramps
  Duchenne
  Female carrier
  Mental retardation
  Microdeletion
  Outliers
Dystrophin gene
  Mutations
  Genotype vs Phenotype
Dystrophin protein
  Related glycoproteins
Treatments
Pathology
  Duchenne
  Becker

Dystrophin: External link

From: A Kornberg

Duchenne muscular dystrophy
Standing from supine position

From Bramwell: Diseases of the Spinal Cord



Dystrophinopathies: Clinical

  Dystrophin ; Chromosome Xp21.2-p21.1; Recessive

Becker
Cardiomyopathy
Cramps
Duchenne
  Laboratory
Female carrier
Mental retardation
Microdeletion
Outliers

From NLM
Guillaume-Benjamin
  Duchenne de Boulogne


De la Paralysie Musculaire Pseudo-hypertrophique...
1868
  • Clinical syndromes: General
  • Duchenne muscular dystrophy
    • Epidemiology
      • Incidence: 1:3,600–9,300 live male births
      • Newborn screening 36: CK levels at 12 days to 1 month = 1,800 to 5,400
    • Genotype: Dystrophin
      • 96% with frameshift mutation
      • 30% with new mutation
      • 10% to 20% of new mutations are gonadal mosaic
    • Clinical
      • Weakness
        • Onset age: 2 to 5 yrs
        • Distribution
          • Proximal > Distal
          • Symmetric
          • Legs & Arms
          • Most involved muscles: Adductor magnus in legs
          • Relatively spared muscles: Gracilis & Sartorius
        • Course
          • Reduced motor function by 2 to 3 years
          • Steady decline in strength: After 6 to 11 years
        • Gowers sign
          • Standing up with the aid of hands pushing on knees
          • External link: YouTube
        • Loss of Ambulation
      • Muscle hypertrophy
        • Especially calf
        • May be generalized
        • Increases with age
        • Most commonly due to: Muscle replacement by fat & connective tissue
        • Some relatively spared muscles may have true hypertrophy
      • Musculoskeletal
        • Contractures
          • Especially ankles; Also hips & knees
          • Treatment
            • Non-surgical
              • Night splints on ankles: More effective than passive stretch 3
            • Surgical
              • Contracture release of ankles, knees or hips
              • Early ambulation after surgery
        • Scoliosis
          • Onset: Most after loss of ambulation
          • Partial relation to ambulation & growth status
            • May be reduced if walking & standing are prolonged to ≥ 16 to 18 years
          • Treatment: Surgical insertion of spinal rod
            • Evaluation: X-ray; Sitting scoliosis series
            • Timing of surgery: Usually before primary curve is 25%
            • Vital capacity: Ahould be ≥ 40% of predicted
      • Other clinical features
        • Cardiomyopathy: Dilated; Especially > 15 years
        • Mental retardation: Mean IQ ~ 88
        • Night blindness
          • Altered response to flashes of light in dark adapted state
          • ERG: b-wave, Reduced amplitude
          • Dp260: Isoform of dystrophin in retina
        • Gastrointestinal: Rare
          • Type: Pseudo-obstruction; Gastric dilatation
          • Upper GI tract
          • Late in disease course
      • Death
        • Most common between 15 - 25 years
        • Due to respiratory or cardiac failure
        • Life prolonged by ~ 6 years to 25 years with respiratory support 8
        • Life shortened by 2 years with cardiomyopathy
    • Laboratory
      • Serum
        • CK: Very high
          • Highest: Ambulant patients; Up to 100x upper limit of normal
          • Lower
            • Increasing age: Less correlation between age & CK in Becker MD
            • Lowest: Late stage disease; Severe muscle atrophy
            • Birth: Increases over weeks after birth
        • Troponin I: Elevated above normal but not to levels in cardiac ischemia
        • Liver enzymes 18
          • High AST, ALT & LDH
          • Up to 23x upper limit of normal
          • Levels linearly correlate with CK level
          • Normal: Alkaline phosphatase, γ-glutamyl transferase
      • Muscle biopsy
        • Endomysial fibrosis
        • Variable fiber size: Small fibers rounded
        • Muscle fiber necrosis & regeneration
        • Myopathic grouping
        • Hypercontracted (opaque) muscle fbers
        • Muscle fiber internal archetecture: Normal or immature
        • Dystrophin: Absent staining
        • Other membrane proteins
          • Sarcoglycans: Reduced
          • Aquaporin 4: Reduced; Varied levels
      • Diagnostic & Lab testing
        • Muscle dystrophin
          • Histochemical staining: Dystrophin protein absent in muscle
          • Weatern blot: Dystrophin protein absent
        • Genetic: Deletion, Duplication, Small mutation, Point mutation 10
          • Southern blot: Detects large deletions
          • Sequencing of gene: Required to detect point & other small mutations
        • MRI
        • External link
    • Treatments
      • Prednisone 28
        • Doses
          • Weekly dosing 6
            • Total dose: 5 to 10 mg/kg/week starting dose
              • Dosing schedule: 2.5 to 5 mg/kg/day on Friday & Saturday evenings
            • Side effects: Fewer than daily prednisone
              • Weight gain: Some patients; Less than daily prednisone
              • Cushingoid features: Mild
              • Irritability: On day of dose
              • Growth
                • Not prominently impaired
                • More growth (1" per year) than with daily prednisone
          • Daily dosing
            • Dose: 0.75 mg/kg/day starting dose
            • Less optimal benefit:risk ratio than weekly regimen
        • Effects of treatment
          • Walking: Prolonged by 2 to 5 years
          • Strength: Increased
          • Falling: Reduced
          • Pulmonary function: Improved
          • Most beneficial
            • While patient still ambulatory
            • ? When started at early age (3 to 5 years)
          • Scoliosis: May prolong walking long enough to reduce likelihood or severity
      • Deflazacort
        • Dose: 0.9 to 1.2 mg/kg/day starting dose
        • Side effects
          • Weight gain: Frequent; Less than daily prednisone
          • Vertebral fractures: High frequency; Up to 100% by 9 years
          • Short stature 27
      • Antisense oligonucleotides
        • Exon 51 skip (Eteplirsen)
          • Genetic effect: Change out-of-frame to in-frame deletion
          • Dystrophin effect: Mild increase
          • Frameshift deletions with possible benefit
            • General: Must include exons 50-51 or 51-52
            • Specific deletions: Exon 50; 52; 43-50; 45-50; 47-50; 48-50; 49-50
            • External link: Skipping tool
          • Clinical effects
            • Slower decline in respiratory & arm function
            • May not benefit cardiac function
      • Trials 33
        • Other ASO: Exons 45; 53 (Vyondys)
        • Gene replacement
          • Minidystropphin
          • Microdystrophin 34
            • Dystrophin expression: Present in muscle fibers
            • Clinical: Functional improvement
            • Serum CK: Reduced
        • Utrophin: Up regulation
        • Nonsense mutation read through: Gentamycin; Ataluren
        • Myostatin or ActRIIB inhibition
      • ? Oxandrolone: 0.1 mg/kg/day
      • Cardiac
    • Exon skippable mutations & Frequencies
      • Exons: 8 (4%), 44 (8%), 45 (13%), 50 (5%), 51 (15%), 52 (3%), 53 (9%), 55 (2%)
      • Exon 8 & 44 skippable mutations: Longer ambulation, especially 3 to 7 & 45 deletions
      • Exon 44 skippable mutations: More revertant fibers in muscle
      • Exon 51 skippable mutations: Shorter ambulation
    • External link: Duchenne biography




DMD: Hypertrophic
leg muscle



Gowers sign


Dystrophic muscle (Erb)
Dystrophic
muscle (Erb)



DMD MRI: Adductor magnus involvement

  • Outliers
  • Cramp & myalgia syndromes
  • Dystrophinopathies: Cardiomyopathy 5

    Dystrophin gene 1

    Dystrophin protein 1

    Dystrophin: Genotypes & Phenotype Correlations

    Mutation types & size
      Point
        Missense
        Splice
          Pseudoexons
      Deletions
        Chromosome
      Duplications
    Reading frame
    Dystrophin, Other
    Modifiers & Other genes