5 Yo Boy with Falls

Case 5 yo boy referred from primary care doctor for gross motor delay, increasing falls at school, difficulty keeping up with peers PMH: Born full term, no complications, no illnesses or developmental concerns in first year of life. Did not start walking until about 22 months, has always been a toe-walker. Family History: Maternal uncle died in his teens, mother not sure why but thinks it was a heart problem, also had difficulty walking

Differential Diagnosis Chronic Gait Problems in Childhood – Central vs. Peripheral: Associated Cognitive Deficits, Seizures, Spasticity, Prominent Bowel/Bladder Symptoms Suggest Central – Static vs. Progressive: Cerebral Palsy/Injury-related do not progress Myasthenia gravis, CIDP, Juvenile Dermatomyositis, Episodic Ataxias, Periodic Paralyses, Migraine equivalents episodic and usually non-progressive Inherited Myopathies, Leukodystrophies, HSP, Inherited Neuropathies, SMA Chronic and Progressive – Symmetric Typical of CMT, Myopathies, SMA, Leukodystrophies, Hereditary Spastic Paraplegia; Asymmetric More Typical in CP, Myasthenia, Autoimmune Neuropathies Features to Pay Close Attention to on Exam – Cognitive/Social Abnormalities Relative to Age Norms – Spasticity, Tone, Contractures, Pes Cavus, Fasiculations – Presence of Sensory Findings Localizing to CNS or Peripheral Nerve – Reflexes Increased in CNS Disorders, May be Decreased or Absent in PN or MN Diseases, Proportional to Weakness in NMJ and Muscle Disease – Cerebellar Signs – Gait, Gower’s sign

Exam General Exam Unremarkable MS: Alert, shy, but cooperates with most of exam, knows several colors, ABCs, follows 2-step commands CN: Fundoscopy, Pupils, EOM, Facial Movements Articulation Normal Motor: Normal Bulk, relatively large calves, Mild deltoid, illiopsoas, hamstring, quadriceps weakness (4/5) bilaterally, limited dorsiflexion of ankle, otherwise 5/5, mildly decreased tone Sensory: Intact light touch, pinprick, vibration, proprioception, cold DTRs: Present throughout, 2+, toes plantar Coord.: No FTN dysmetria Gait: Toe walks, waddling, with exaggerated lordosis, abdomen protruding; when asked to lie on floor and stand up, pushes up on floor, then thighs

Wicklund, M. Continuum (Minneapolis) 2013;19(6):1535– Calf Pseudohypertrophy Abnormal Gait Gower’s Sign

Approach to Weakness BrainSpinal CordMotor NeuronPeripheral Nerve Neuromuscular Junction Muscle PatternPyramidal (UE Extensors, LE Flexors), Usually Asymmetric, Multiple CN Often Bilateral, Pyramidal Proximal> Distal Distal> Proximal Ptosis, Ophthalmoplegia Proximal>Distal Proximal> Distal, Symmetric SensoryAll Modalities, CN Affected Sensory LevelNone (Cramps)Usually, Distal> Proximal NoneNone (Myalgias) ReflexesIncreasedIncreased (May be Decreased Early) DecreasedDecreased/ Absent Normal until severe weakness Other FeaturesAphasia, Altered Mental Status, Field Cut Bowel/ Bladder, Decreased Rectal Tone Fasciculations, Atrophy Autonomic Symptoms, Pes Cavus, Hammer Toes Fatiguability, Improves with Ice (MG) Myotonia, Myokymia, Pseudo- Hypertrophy

Localization: Likely Myopathy Consider Congenital Myopathies, Muscular Dystrophies, Mitochondrial Disorders First Test?... Serum CK – >3,000 Indicates likely Duchenne’s/Becker’s, Though Sarcoglycanopathy, Several Rare LGMD Can Cause Similar Elevation – Genetic Testing for Dystrophin Mutations is Next Test in Setting of Markedly Elevated CK Muscle Biopsy Indicated if CK normal or slightly elevated (several times upper limit of normal) EMG can confirm myopathy, exclude large fiber nerve involvement, identify muscles most involved, but painful, should be used mostly in cases of diagnostic uncertainty Muscle U/S may also identify subtle structural abnormalities, help in identifying biopsy site

Duchenne’s Muscular Dystrophy 1:3500 Incidence of Dystrophinopathies in Boys Spectrum of Dystrophin Mutations from Milder (Becker’s) to Severe: Loss of Ambulation by 12 yrs= Duchenne’s, Preserved Ambulation After 16 yrs= Becker’s Inflammatory Component with Chronic Inflammation Leading to Fatty Replacement of Muscle Tissue Affects Cardiac Muscle, so ECHO, EKG, Cardiologist are Essential Non-Invasive Ventilation Can Prolong Life, So Pulmonologist is Essential, As Well; Scoliosis Affects Pulmonary Function Cognitive Delays, ADHD, Autistic Features are Common

Duchenne’s Pathophysiology and Exon Skipping Therapy Dystrophin Links Actin Cytoskeleton to Extracellular Matrix DMD Genotype with Exon 51 Deletion Leads to Truncated Dystrophin: Antisense Oligonucleotide (AON) Skips Exon 51, Splices Together In-frame Exons 49, 51 to Create Smaller, but Functional Dystrophin: Fairclough, RJ et al. Nature Reviews Genetics Volume: 14, Pages: 373–378 Year published: (2013) Muscle Biopsy: variability in fiber size, increased endomysial connective tissue, regenerating and hypercontracted fibers, inflammatory infiltrate Wicklund, M. Continuum (Minneapolis) 2013;19(6):1535–1570

Management Daily (0.75 mg/kg/d) or Weekend (10 mg/kg/wk) Corticosteroids Delay Loss of Ambulation by 1-3 Years ACE Inhibitors Slow Development of Cardiomyopathy Orthotics, PT can Prevent or Slow Development of Contractures, though Exercise does not Lead to Strengthening Gene Therapy Complicated by Size of Dystrophin Gene, but Antisense Oligonucleotides May Help Convert Duchenne’s to Becker’s by Skipping Premature Stop Codons