Muscular Dystrophy Beyond DuchenneAnn Bubenzer

ObjectivesRecognize patients that require referral for diagnosis and management of muscular disorders.Perform the history and physical exam to screen for neuromuscular disorder for patients of all ages.Describe current methods of diagnostic testing for neuromuscular disorders. Discuss current therapy and treatment options available and the affect on prognosis

Presentations of patients with neuromuscular disorders Case 1Called to evaluate newborn infant with hypotonia. Pregnancy complicated only by flu-like illness in 2nd trimester and question of decreased strength of fetal movements compared to first pregnancy. Labor and delivery complicated by precipitous delivery.

Case 1 contPhysical exam reveals hypotonic infant with high arched palate. Physical exam is otherwise normal.

Laboratory such as CBC and electrolytes are normal.

Case 24 year old presents to clinic with chief complaint of toe walking and falling. The parents also state that he has trouble with stairs and running. Sat alone at 8 months, walking by 15 months.On physical exam he demonstrates walking up legs with hands in order to rise from seated position on floor. Calves are prominent.

Case 314 y/o with difficulty lifting arms above head. On review of symptoms, this adolescent states he has never been able to blow up a balloon.

On physical exam, scapular winging is noted.

Case 4Infant presents with narrow facies, ^ shaped upper lip, and respiratory distress after birth. Poor feeder requiring OG tube assistance.

Mother has similar facial features. When you shake her hand, she cant let go easily.

History and Physical Exam in the Newborn and OfficeHistoryNewborn floppy infant, term or preterm, poor head control, poor feeding, prolonged labor, maternal complicationsChildhood development delay in sitting, standing, walking, toe walking, difficulty stair climbing or runningTeen or adult difficulty in self-care, swallowing, athletic/endurance activity

Family HistoryInclude enough of family tree to pick up autosomal recessive disorders and X-linked or AD disorders with variable penetranceMany x-linked or AD represent new mutationsPast diagnoses in older family members may not be accurateReview of SystemsSchool functioning/cognitive developmentCardiac function/arrhythmias/syncopeRespiratory

Physical exam findingsMuscle mass: signs of wasting or hypertrophy/pseudohypertrophy Muscle strength: power generation of force against resistance or gravityObserve reaching, getting up from floorObserve trunk and head/neck controlTest specific proximal groups position so against gravityTone: resistance to passive movementNote hyper vs. hypotonia in weak areas Deep tendon reflexes: normal or decreased Normal sensation: remember proprioceptionJoint contracture: reduced passive range of motion not due to tone

What is Muscular Dystrophy?(MD) Muscular Dystrophy: group of genetic disorders that are characterized by progressive loss of muscle integrity, wasting, and weakness. Characterized by degeneration and regeneration of muscle fibers (in contrast with static or structural myopathies)Muscular Dystrophy Association Covers all muscular dystrophies and myopathiesMultisystem diseases : ALS or Friedreich AtaxiaNeuropathy : HSMN, CMTD

Dystrophinopathy: disorders involving dystrophinDuchenne MD and Becker MD are the muscular disorders the two most common and severe dystrophiesDystrophin is a very large gene on the X-chromosome, ubiquitous in the human body Dystrophin-Associated Protein (DAP) Complex composed of the extracellular, transmembrane, and intracellular components

The Lancet Neurology Volume 2 Number 5 May 2003 Copyright 2003 Elsevier

General Diagnostic Testing Creatine kinase : Aids in narrowing the differential diagnosis if greatly elevated (50 times normal)Increased in DMD, BMD, polymyositis, and rhabdomyolysisNonspecific if mildly elevated 2-3x normalLower late in MD course due to severely reduced muscle massNot helpful for carrier detection

Muscle biopsyDystrophic changes include necrosis, degeneration, regeneration, fibrosis and fatty infiltration, sometimes mild inflammation Specific diseases may have inflammation, intracellular vacuoles, rods, and other inclusions on biopsy Biochemical muscle protein analysisUseful for specific identified protein that is missing and many specific mutations may cause the same deficiency Immunohistochemical protein stainingWestern blot quantitates percent of normal protein present

Genetic analysisPCR for specific known defectsSouthern blot for nucleotide repeats Electromyography Useful if diagnosis not clear (biopsy has mixed features)Differentiates neuropathic vs. myopathicCharacteristic myotonic discharges in adults with myotonia dive bomber soundPerform after the CK

Duchenne Muscular Dystrophy Presentation: 3-5 y/o with pseudohypertrophy of calf muscles, frequent falls, slow running, and waddling gait Prevalence of 1:3500 Other organs affected Heart cardiomyopathyRespiratory Intellect - 30 % with impairment IQ

Becker Muscular Dystrophy Slowly progressive form with same gene affected as Duchenne MD Muscle biopsy immunostaining for dystrophin with patchy stainingDisorder of function or decreased amount of dystrophin rather than absence of the protein

Congenital Muscular DystrophyPresentation: neonatal onset of severe weakness, delayed motor milestones, contracturesMerosin negative/CMD A1White matter hypodensities on brain scan but normal mental capacity Diagnosis by muscle biopsy immunohistochemistry showing loss of 2-laminin (AR-chromosome 6q22-23)

Neuronal Migration Disorders With neuronal migration disorders get mental retardation, brain malformations, and clinical eye involvementFukuyamas muscular dystrophy affects fukutin protein (AR chromosome 9q31) Muscle-eye-brain disease affects POMGnT1, (AR chromosome 1p32-34)Walker Warburg affects POMT1 (AR)Glycosyltransferases are also important in neuronal development

Other Merosin Positive CMD

Myotonic Muscular Dystrophy or Steinerts disease Presentation adult with multiple systems affectedPrimarily distal and facial weaknessFacial features: frontal balding in men, ptosis, low-set ears, hatchet jaw, dysarthria, swan neck, ^ shaped upper lipMyotonia: worse in cold weather, after age 20Heart: conduction block evaluate syncopeSmooth muscle: constipation, care with swallowing, gallstones, problems with childbirth, BP labilityBrain: learning disabilities, increased sleep requirementOphthalmology: cataractsEndocrine: insulin resistance, hypothyroidism, testicular atrophy

Genetics:Mothers can have adult or congenital onset offspring; fathers can have adult onset offspringParents may not be aware of own diagnosisMyotonin gene is affected as well as adjacent transcription factor gene SIX 5 by CTG repeat in noncoding region of chromosome 19q13.3, and anticipation seen with increased repeatsMuscle biopsy with internalized nuclei, type 1 fiber atrophy, ring fibers, and sarcoplasmic massesCongenital: severe form, initial respiratory distress after birth with ventilatory requirement or apnea, feeding difficulty, mental retardation, club feet, scoliosis, strabismus

FascioScapularHumeral Muscular Dystrophy Presentation:Facial weakness with trouble blowing up a balloon, sipping through a straw, whistling, trouble closing the eyes at night, scapular winging that may be asymmetric, painMay have absence of pectoralis, biceps, or brachioradialisAlso affected: mild high pitched hearing loss, retinal abnormalities, mental retardation in early onset Genetics/TestingSouthern blot testing available (chromosome 4q35) for decrease in repeats normally present Muscle biopsy may show lymphocytic infiltrates

Limb Girdle Muscular Dystrophy Presentation: variable age of onset with weakness and wasting of the limb-girdle May have calf hypertrophy, involvement of scapular muscle and deltoid in sarcoglycanopathiesMany types involve dysfunctional sarcoglycans transmembrane proteins of the DAP that interact with cytoplasmic proteinsTable 2 types of LGMD

TypeProteinChromosomeInheritance1AMyotilin5q22-34AD1BLaminin A/C1q21AD/allelic to EDMD1CCaveolin-33p25AD1D7qAD2ACalpain-315q15-21AR2BDysferlin2p13AR/allelic to Myoshi Myopathy2CGamma sarcoglycan13q12AR2DAlpha sarcoglycan17q12-21AR2EBeta sarcoglycan4q12AR2FDelta sarcoglycan5q33-34AR2GTelethonin17q11-12AR2H9Q33AR2IFukutin-related protein19q13AR/allelic to CMD 1C

Oculopharyngeal Muscular Dystrophy Presentation: mid-adult with ptosis, facial muscle weakness with difficulty swallowing, proximal muscle weakness, may have extraocular muscle weakness, more common in French-Canadian and Hispanic populationGenetics Muscle biopsy shows filamentous nuclear inclusions and ubiquitin containing vacuolesAffects poly A binding protein 2 (PABP2) by expansion of a GCG repeat without anticipation seen Southern blot (chromosome 14q11-13)

Emery-Dreifuss Muscular DystrophyScapuloperoneal MD Presentation: stiff joints, shoulder and upper arm weakness, calf weakness, cardiac conduction defects and arrhythmias, contracturesGeneticsX-linked type affects emerinDiagnose by protein analysis of leukocytes or skin fibroblastsDNA testing available (chromosome Xq28)AD affects lamin A or lamin C (chromosome 1q21)Nuclear membrane proteins

Distal Muscular DystrophyPresentation: weakness in forearms, hands, and lower legsclinically similar to a neuropathy but NCV normalMuscle biopsy with autophagocytic vacuoles/ inclusion bodiesTable 3 Types of DMD

MyopathiesCentral core disease: Ryanodine receptor, Ca channel that mediates excitation/contraction coupling, (AD chromosome 19q13)Associated with Malignant HyperthermiaMyotubular myopathyMyotubularin, important in myogenesis (Xq28)Nemaline MyopathyCaused by many defects, disorder of thin filamentsRod-like stuctures on muscle biopsyInflammatoryJuvenile DermatomyositisInclusion Body Myositis (usually distal)Adult Polymyositis (associated with malignancy)

Treatment - MedicationsSteroids Briefly increase strength, slow progression in dystrophinopathy for walking, arm use, and respiratory functionWeekend or 15-20/month as well as prednisolone/deflazacort may minimize SEDilantin and Tegretol raise the repolarization threshold and improve myotoniaMethylphenidate improves daytime somnolence in DMAlbuterol may help in FSH MDCreatine and glutamine may help delay progression/improve energy in youngest with DMD

Treatment future therapiesGenetic therapiesRepairing the mutated sequencesUsing cells own repair mechanisms but adding templateGentamicin trial for relaxation in stop codon recognition for DMD has not workedReplacing the mutated sequencesInserting truncated genes or whole gene with vectorUpregulation of similar functioning proteinsUtrophin in DMD

TherapyContracture preventionStretching exercises and postural changingStretch the most contracture prone groups (gastrocnemius, hip flexors, iliotibial bands, hamstrings)AFO at night to supplement

Strengthening/conditioning/enduranceGoal is to maintain or improve muscle strength and maximize functional ability slight improvement is possibleAdditional goal is to avoid muscular damage by overwork or injuryNo eccentric contraction or delayed sorenessVoluntary active exercise such as swimming/hydrotherapy or cycling in ambulatory children currently recommended

Mobility aidsWalking orthoses KAFOStanding frames, standing wheelchairs, swivel walker occasionally usedWalkers where arm strength less affectedTransfer boardWheelchair power needed for independencePlan for indoor lift, van with lift, roll in shower Improving daily activities of daily living Physical and Occupational Therapy teaching modified techniquesAntigravity orthoses are being developed to assist in daily living activitiesSplinting and therapy to prevent hand contractures

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Surgerynote the risk inherent to surgery malignant hyperthermia Palliative vs. rehabilitativeTendon releasesAchilles Need KAFO to walk post-opRelieves pain and allow shoe wearHamstring and iliotibial bandRelieves hip and knee pain or contractureAllows better gait compensation

Scoliosis spine stabilizationBracing is not effective with progressive neuromuscular diseaseTimely correction of scoliosis is important for patient comfort and respiratory ability Spine and scapular stabilization may aid function of armsOphthalmologyDeficient eye closure oculomaxillofacial MD and FSH MD may require artificial tears or tarsorrhaphyTreatment for cataracts in Myotonic MD

RespiratoryPatients with morning headache, nightmares, excessive daytime somnolence, mental dullness, difficulty concentrating, increased colds, coughing, or pneumonia should undergo evaluationInfluenza vaccine and pneumococcal vaccineIn-exsufflator for airway clearance, cough assistPulmonologist, pulmonary function testing

Assisted noninvasive ventilation Oxygen alone does not ventilate!Positive pressure ventilation vs. volume ventilation with pressure limitAssisted ventilation with tracheostomyTalk to patient about degree of desired intervention when respiratory status first starts to decline and before an acute event The goal is home ventilationCardiologyEKG pacemaker for conduction defects and arrhythmiasEchocardiogram afterload reduction, digoxin for cardiomyopathy

Nutrition/GIOverweight and underweight are common problemsOverweight impairs mobilityUnderweight decreases strength & healthProtein and calorie supplementsAssess for dysphagiaIntestinal hypomotility in DMD, CMD, and myotonic dystrophy can require a bowel regimen to prevent constipation

Osteopenia/OsteoporosisBegins before walking stops, fractures may end walkingWorsened by steroidsCalcium supplements, Miacalcin may helpPsychology/NeuropsychologicalEducation aid in planningSpecial education may not be needed with accomodation and modificationsProgressive loss of function affects patient and family

Thank youMy familyDr. Vikki StefansDr. Robert Warren