Summary Duchenne Muscular Dystrophy is a common congenital condition caused by an X-linked recessive mutation leading to the absence of dystrophin protein that affects young males who present with progressive muscle weakness, scoliosis, and cardiomyopathy. Diagnosis is made with DNA testing showing an absence of the dystrophin protein. 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 X-linked recessive 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 Becker's Muscular Dystrophy similarities to Duchenne's sex-linked recessive calf pseudohypertrophy is present CPK is elevated differences from Duchenne's dystrophin protein is decreased instead of absent (due to in-frame mutation) later onset with slower progression and longer life expectancy (average diagnosis at age 8 years compared to 2 years with Duchenne's) more prone to cardiomyopathy 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 triceps, biceps, teres major, supraspinatus, infraspinatus, 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 sartorius, gracilis, semitendinosus, semimembranosus, 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) Prone to cardiomyopathy 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 prednisone (0.75 mg/kg/day) deflazacort (0.9 mg/kg/day) 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) 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 oligonucleotide splicing modulators gene therapy agents eteplirsen (exon 51), golodirsen (exon 53), viltolarsen (exon 53), casimerson (exon 45) all 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 complication rates remain high regardless of correction construct type 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 Historically poor 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%