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  • Summary
    • Duchenne Muscular Dystrophy presents in young males between the ages of 2 and 6 years with progressive muscle weakness.
    • It is caused by an X-linked recessive mutation leading to the absence of dystrophin protein.
    • Labs demonstrated markedly elevated CPK leves and diagnosis is made with DNA testing for dystrophin.
    • Treatment involves a multidisciplinary approach to address cardiomyopathy, pulmonary dysfunction, scoliosis, and foot deformities. 
  • Epidemiology
    • Most common hereditary neuromuscular disease
      • first described by Guillaume-Benjamin-Amand Duchenne de Boulogne, a French neurologist who first described the condition in 1861
    • Prevalence 
      • 2-3/10,000
    • Demographics
      • affects young males only
      • age of symptom onset is between 2-6 years of age
  • Etiology
    • Pathophysiology
      • dystrophin
        • expressed in striated and cardiac muscle, brain, and retina
        • large cytoskeletal protein
          • critical component of dystrophin-glycoprotein complex (DGC), important for structural units of muscle
      • dystrophin absence leads to
        • loss of DGC leading to excessive membrane fragility and permeability
        • dysregulation of calcium homeostasis
        • oxidative damage
        • poor muscle fiber regeneration
        • repeated cycles of necrosis and regeneration
          • regenerative capacity diminishes with age
        • progressive replacement of muscle tissue with fibrous and fatty tissue
      • skeletal and cardiac muscle lose elasticity and strength
    • Genetics
      • Xp21.2 dystrophin gene defect due to point deletion and nonsense mutation
      • one third of cases result from spontaneous mutations
      • carrier females typically unaffected, however 2.5-20% of female carriers may still show symptoms
        • Lyon hypothesis
          • normal X chromosome inactivated, X chromosome with mutation is expressed
    • Associated conditions
      • orthopaedic manifestations
        • calf pseudohypertrophy
        • scoliosis
        • equinovarus foot deformity
        • joint contractures
      • nonorthopaedic conditions
        • cardiomyopathy
        • static encephalopathy

  • Physical Exam
    • Symptoms
      • early development
        • typically normal within first few years
        • delayed milestones
        • slower growth velocity
        • may present with mild hypotonia or poor head control
      • progressive weakness affecting proximal muscles first (begins with gluteal muscle weakness)
      • gait abnormalities begin around age 2 to 3 years
        • delayed walking
        • toe walking
        • clumsy, waddling gait
        • difficulty climbing stairs, hopping, or jumping
      • decreased motor skills
      • mild intellectual impairment
      • pharyngeal weakness
        • aspiration, nasal regurgitation of liquids, and nasal quality of voice
      • less common presentations
        • incontinence of urine and stool (late manifestation)
        • malignant hyperthermia
    • Physical exam
      • calf pseudohypertrophy (infiltration of normal muscle with connective tissue)
      • deep tendon reflexes present (unlike spinal muscular atrophy)
      • contractures
        • elbows, hips, knees, ankles
      • lumbar lordosis
        • compensates for gluteal weakness
      • neurogenic scoliosis
      • Gower's sign
        • rises by walking hands up legs to compensate for gluteus maximus and quadriceps weakness
      • Trendelenburg gait
      • fractures
        • frequent falls
  • Evaluation
    • Labs
      • markedly elevated CPK levels (10-200x normal)
        • CPK leaks across defective cell membrane
          • levels peak by age 2 years and decrease with fibrofatty replacement of muscle
        • elevated levels in 80% of asymptomatic carriers
          • peak between 8 and 12 years
    • Muscle biopsy
      • connective tissue infiltration and foci of necrosis
      • muscle fiber necrosis with mononuclear cell infiltrate
      • absent dystrophin with staining
    • DNA testing
      • shows absent or near-absent dystrophin protein
        • typically <5% of normal quantity of dystrophin
    • EMG
      • myopathic
        • decreased amplitude, short duration, polyphasic motor
        • normal conduction velocities
  • Imaging
    • Radiographs
      • usually to characterize fractures due to multiple falls
      • nonspecific features
        • translucent soft tissues (fatty muscle replacement)
        • scoliosis
        • hypoinflated lungs
        • cardiomegaly
    • MRI
      • typical pattern of muscle involvement
        • upper limb
          • preferential involvement of tricepsbicepsteres majorsupraspinatusinfraspinatus, subscapularis
          • deltoid usually spared
        • lower limb
          • early involvement of gastrocnemius
          • followed by gluteus maximus/medius, adductor magnus
          • followed by iliopsoas, quadriceps, rectus femoris, biceps femoris, peroneus longus, soleus
          • relative sparing of sartoriusgracilissemitendinosussemimembranosus, and tibialis posterior muscles, even in advanced stages
    • Echocardiogram
      • dilated cardiomyopathy
        • present in all patients by late teens/early 20s
  • Differential 
      • Similarity and Distinguishing features of differential diagnosis
      • Similar traits to Duchenne's
      • Distinguishing traits from Duchenne's
      • Becker's
      • Calf pseudohypertrophy
      • Markedly elevated CPK
      • X-linked transmission
      • Becker's has slower progression of weakness with diagnosis made later (~8 yrs) and longer life expectancy
      • Prone to cardiomyopathy
      • Dystrophin decreased instead of absent due to in-frame mutation
      • Spinal muscular atrophy
      • Proximal weakness
      • Onset of weakness is earlier in childhood
      • Absent deep tendon reflexes and fasciculations
      • CPK levels are normal
      • Pseudohypertrophy is absent
      • Emery-Dreifuss dystrophy
      • Similar clinical picture
      • No calf pseudohypertrophy
      • CPK levels near normal
      • Elbow and ankle contractures develop early
      • Limb girdle dystrophy
      • Progressive motor weakness
      • No calf pseudohypertrophy
      • CPK levels are only mildly elevated
      • Guillain-Barre syndrome
      • Acute onset of weakness
      • Absent deep tendon reflexes
      • CPK levels are normal
      • CSF fluid analysis is diagnostic
  • Treatment
    • Nonoperative
      • corticosteroid therapy
        • indications
          • 5 to 7-year-old children with progressive disease
        • goals
          • to maintain ambulatory capacity as long as possible
        • outcomes
          • significant positive effect on disease progression
            • acutely improves strength, slows progressive weakening, prevents scoliosis formation, and prolongs ambulation
              • prednisone/deflazacort decreases rate of scoliosis requiring fusion from 92% to 20%
            • delays loss of ambulation and upper extremity function
            • delays deterioration of pulmonary function
            • reduces incidence and progression of cardiomyopathy
            • overall improved mortality
        • side effects
          • osteonecrosis
          • osteoporosis/osteopenia
          • excessive weight gain/cushingoid features
          • adrenal suppression
          • GI symptoms
          • mood lability
          • headaches
          • short stature
          • cataracts
        • medications
          • prednisone
          • deflazacort
            • oxazoline derivative of prednisone
            • advantages
              • better side effect profile
                • lesser effect on glucose metabolism, even in those with a family history of diabetes
                • lower risk of osteoporosis/osteopenia
            • disadvantages
              • expensive compared to prednisone
                • average cumulative 20-year cost per patient ($175K for prednisone; $2.3M for deflazacort)
      • oligonucleotide splicing modulators
        • gene therapy agents
          • eteplirsen (exon 51), golodirsen (exon 53), viltolarsen (exon 53), casimerson (exon 45)
          • FDA approved between 2016 and 2020
        • mechanism
          • mutation specific exon skipping
          • bypass out-of-frame mutation, converting to in-frame deletion and restoring open reading frame
            • essentially converts DMD to BMD
            • theoretically a more functional protein and less harmful mutation
        • indications
          • must identify specific site of mutation prior to initiating therapy
            • most mutations cluster in "hot spot" exons 45-53, accounting for up to 50% of DMD patients
        • advantages
          • increased survival
          • prolonged ambulatory time
        • disadvantages
          • expensive as dosing varies by patient age, weight, and insurance coverage
            • $300K/year for patient of typical weight
            • up to $1M/year for 40 kg patient
          • most patients receiving routine treatments discontinue therapy after ~7 months
            • tend to be older and with more advanced disease than patients enrolled in clinical trials
            • possibly due to lack of efficacy, financial challenges, side effects, or other health issues
      • ACE inhibitor, beta-blockers
        • slow progression of cardiomyopathy and heart failure
        • regular EKC/echocardiogram surveillance
          • once every 2 years until age 10 years, every year afterwards
          • every 6 months in the setting of cardiomyopathy
      • pulmonary care with nightly ventilation
      • rehabilitation
        • techniques
          • physical therapy for range of motion exercises
          • adaptive equipment
          • power wheelchairs
          • KAFO bracing (controversial)
      • nutrition
        • risk of malnutrition, obesity, osteoporosis
    • Operative
      • soft tissue releases to prolong ambulation
        • indications
          • ambulatory child with Duchenne's
        • techniques
          • hip abduction contractures treated by release of iliotibial band
          • Hip flexion contractures treated by release of sartorius, rectus femoris, and tensor fascia lata
          • hamstring releases
          • Achilles tendon and posterior tibialis lengthenings
        • postoperative care
          • early mobilization and ambulation to prevent deconditioning
      • scoliosis surgery (see below)
  • Scoliosis
    • Introduction
      • considered a neurogenic curve
      • curve progresses rapidly from age 13 to 14 years
        • begins with mild hyperlordosis
        • progresses with general kyphosis and scoliosis with varying degrees of pelvic obliquity
          • as opposed to lordosis normally seen in idiopathic scoliosis
        • progresses 1° to 2° per month starting at age 8 to 10 years
        • patients may become bedridden by age 16
      • cardiac and pulmonary function studies should be obtained pre-operatively as significant declines in function of both organ systems may make spinal fusion too high-risk
      • treatment is complicated by restrictive pulmonary disease (significant decrease in forced vital capacity)
    • Treatment
      • nonoperative
        • bracing is contraindicated
          • may interfere with respiration
        • maintain ambulation for as long as possible
          • reduce risk of development and severity of scoliosis
          • multidisciplinary team approach critical
      • operative
        • instrumented posterior spinal fusion is the mainstay of treatment for Duchenne-associated scoliosis
        • indications
          • early posterior spinal fusion with instrumentation
            • curve 20-30° in non-ambulatory patient
              • treat early before pulmonary function declines
              • can wait longer ~40° if responding well to corticosteroids
            • rapidly progressive curve
            • FVC drops ≤ 35%
              • portends poor outcomes
              • reduced reserve
              • increased risk of ventilatory compromise, complications, and need for ventilation support
          • early posterior spinal fusion with instrumentation to pelvis 
            • curves ≥ 40°
            • pelvic obliquity ≥ 10°
            • lumbar curve where apex is lower than L1
          • combined anterior and posterior spinal fusion
            • generally avoid anterior approach
              • requires lung deflation
              • increased pulmonary complications and blood loss
            • indications
              • rarely for stiff curves
        • preoperative considerations
          • cardiac and pulmonary function studies should be obtained as significant declines in function of both organ systems may make spinal fusion too high-risk
          • cessation of ACE inhibitors/beta-blockers
            • ACE inhibitors can be stopped 2-3 days prior to surgery
            • beta blockers should be stopped in a phased manner over a few weeks
          • normal vs controlled hypotensive anesthesia
            • hypotensive anesthesia will reduces blood loss but may not be tolerated in the setting of cardiomyopathy
            • risk of anesthesia-induced rhabdomyolysis
          • TXA
            • reduces blood loss
        • Techniques
          • early PSF with instrumentation
            • techniques
              • pedicle screws
                • effective corrective power
                • improves and maintains pelvic obliquity
                • allows early mobilization
                • reduces development of respiratory complications
            • complications
              • complication rates remain high regardless of correction construct type
              • intraoperative cardiac events
          • early PSF with instrumentation to pelvis
            • complications
              • intraoperative cardiac events
  • Equinovarus Foot
    • Introduction
      • common foot deformity seen with Duchenne muscular dystrophy
    • Pathoanatomy
      • muscle imbalance secondary to muscle replacement with fibrofatty tissue
    • Diagnosis
      • made upon clinical exam
    • Treatment
      • nonoperative
        • stretching, physical therapy, and night time AFO use
      • operative
        • Tendinoachilles lengthening with posterior tibialis tendon transfer, toe flexor tenotomies
  • Prognosis
    • Historical prognosis
      • Most unable to ambulate independently by age 10
      • Most wheelchair dependent by age 15
      • Most die from respiratory weakness or cardiomyopathy by age 20
      • 5-, 10, and 15-year survival rates without steroid therapy
        • 100%, 72.1%, 27.9%
    • With >1 year of steroid treatment
      • Delays loss of ambulation by 3-4 years
      • Delays loss of hand to mouth function by 5 years
      • Delays loss of distal hand function by 6-8 years
      • 76% lower mortality rate
        • 5-, 10, and 15-year survival rates with steroid therapy
          • 100%, 98%, 78.6%
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