Muscular Dystrophy Beyond Duchenne Ann Bubenzer Objectives n

Muscular Dystrophy Beyond Duchenne Ann Bubenzer

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

Case 1 con’t Physical exam reveals hypotonic infant with high arched palate. Physical exam is otherwise normal. Laboratory such as CBC and electrolytes are normal.

n Case 2 4 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.

n Case 3 14 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.

n Case 4 Infant 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 can’t let go easily.

History and Physical Exam in the Newborn and Office n History n n n Newborn – floppy infant, term or preterm, poor head control, poor feeding, prolonged labor, maternal complications Childhood development – delay in sitting, standing, walking, toe walking, difficulty stair climbing or running Teen or adult – difficulty in self-care, swallowing, athletic/endurance activity

n Family History n n Include enough of family tree to pick up autosomal recessive disorders and X-linked or AD disorders with variable penetrance Many x-linked or AD represent new mutations Past diagnoses in older family members may not be accurate Review of Systems n n n School functioning/cognitive development Cardiac function/arrhythmias/syncope Respiratory

n Physical exam findings Muscle mass: signs of wasting or hypertrophy/pseudohypertrophy n Muscle strength: power – generation of force against resistance or gravity n Observe reaching, getting up from floor n Observe trunk and head/neck control n Test specific proximal groups – position so against gravity n n Tone: resistance to passive movement n Note hyper vs. hypotonia in weak areas Deep tendon reflexes: normal or decreased n Normal sensation: remember proprioception n Joint contracture: reduced passive range of motion not due to tone n

What is Muscular Dystrophy? (MD) n n 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 n Covers all muscular dystrophies and myopathies Multisystem diseases : ALS or Friedreich Ataxia Neuropathy : HSMN, CMTD

n n Dystrophinopathy: disorders involving dystrophin Duchenne MD and Becker MD are the muscular disorders – the two most common and severe dystrophies Dystrophin is a very large gene on the Xchromosome, ubiquitous in the human body Dystrophin-Associated Protein (DAP) Complex – composed of the extracellular, transmembrane, and intracellular components

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General Diagnostic Testing n Creatine kinase : Aids in narrowing the differential diagnosis if greatly elevated (50 times normal) n Increased in DMD, BMD, polymyositis, and rhabdomyolysis n Nonspecific if mildly elevated 2 -3 x normal n Lower late in MD course due to severely reduced muscle mass n Not helpful for carrier detection n

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

n Genetic analysis n n n PCR for specific known defects Southern blot for nucleotide repeats Electromyography n n Useful if diagnosis not clear (biopsy has mixed features) Differentiates neuropathic vs. myopathic Characteristic myotonic discharges in adults with myotonia – “dive bomber” sound Perform after the CK

Duchenne Muscular Dystrophy n n n Presentation: 3 -5 y/o with pseudohypertrophy of calf muscles, frequent falls, slow running, and waddling gait Prevalence of 1: 3500 Other organs affected n n Heart – cardiomyopathy Respiratory Intellect - 30 % with impairment IQ <75 Testing n n Immunostaining with absence of dystrophin PCR testing available for common mutations (X 21. 2)

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

Congenital Muscular Dystrophy n n Presentation: neonatal onset of severe weakness, delayed motor milestones, contractures Merosin negative/CMD A 1 n n White matter hypodensities on brain scan but normal mental capacity Diagnosis by muscle biopsy immunohistochemistry showing loss of α 2 laminin (AR-chromosome 6 q 22 -23)

Neuronal Migration Disorders n n n With neuronal migration disorders get mental retardation, brain malformations, and clinical eye involvement Fukuyama’s muscular dystrophy – affects fukutin protein (AR – chromosome 9 q 31) Muscle-eye-brain disease – affects POMGn. T 1, (AR – chromosome 1 p 32 -34) Walker Warburg – affects POMT 1 (AR) Glycosyltransferases are also important in neuronal development

Other Merosin Positive CMD Disorder Protein Associated signs Inheri-tance Chromosome Rigid Spine Disease SEPN 1 (selenoprotein) Slowly progressive Spine contractures AR 1 p 36 Ullrich CMD COL 6 A 2 Rapidly progressive Joint hyperlaxity AR 21 q 22 Bethlem myopathy Type VI collagen subunits Slowly progressive Myopathy? AD 21 q 22 and 2 q 37 Integrin a 7 deficiency Integrin a 7 AR 12 q 13 CMD 1 C Fukutin-related Rapidly protein progressive Cardiomyopathy AR 19 q 13

Myotonic Muscular Dystrophy or Steinert’s disease n Presentation – adult with multiple systems affected n Primarily distal and facial weakness n Facial features: frontal balding in men, ptosis, lowset ears, hatchet jaw, dysarthria, swan neck, ^ shaped upper lip n Myotonia: worse in cold weather, after age 20 n Heart: conduction block – evaluate syncope n Smooth muscle: constipation, care with swallowing, gallstones, problems with childbirth, BP lability n Brain: learning disabilities, increased sleep requirement n Ophthalmology: cataracts n Endocrine: insulin resistance, hypothyroidism, testicular atrophy

n Genetics: n n n Mothers can have adult or congenital onset offspring; fathers can have adult onset offspring Parents may not be aware of own diagnosis Myotonin gene is affected as well as adjacent transcription factor gene SIX 5 by CTG repeat in noncoding region of chromosome 19 q 13. 3, and anticipation seen with increased repeats Muscle biopsy with internalized nuclei, type 1 fiber atrophy, ring fibers, and sarcoplasmic masses Congenital: severe form, initial respiratory distress after birth with ventilatory requirement or apnea, feeding difficulty, mental retardation, club feet, scoliosis, strabismus

Fascio. Scapular. Humeral Muscular Dystrophy n Presentation: n n n 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, pain May have absence of pectoralis, biceps, or brachioradialis Also affected: mild high pitched hearing loss, retinal abnormalities, mental retardation in early onset Genetics/Testing n n n Southern blot testing available (chromosome 4 q 35) for decrease in repeats normally present Muscle biopsy may show lymphocytic infiltrates

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

Type Protein Chromosome Inheritance 1 A Myotilin 5 q 22 -34 AD 1 B Laminin A/C 1 q 21 AD/allelic to EDMD 1 C Caveolin-3 3 p 25 AD 7 q AD 1 D 2 A Calpain-3 15 q 15 -21 AR 2 B Dysferlin 2 p 13 AR/allelic to Myoshi Myopathy 2 C Gamma sarcoglycan 13 q 12 AR 2 D Alpha sarcoglycan 17 q 12 -21 AR 2 E Beta sarcoglycan 4 q 12 AR 2 F Delta sarcoglycan 5 q 33 -34 AR 2 G Telethonin 17 q 11 -12 AR 9 Q 33 AR 19 q 13 AR/allelic to CMD 1 C 2 H 2 I Fukutin-related protein

Oculopharyngeal Muscular Dystrophy n n 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 population Genetics n n Muscle biopsy shows filamentous nuclear inclusions and ubiquitin containing vacuoles Affects poly A binding protein 2 (PABP 2) by expansion of a GCG repeat without anticipation seen – Southern blot (chromosome 14 q 11 -13)

Emery-Dreifuss Muscular Dystrophy Scapuloperoneal MD n n Presentation: stiff joints, shoulder and upper arm weakness, calf weakness, cardiac conduction defects and arrhythmias, contractures Genetics n X-linked type affects emerin n n Diagnose by protein analysis of leukocytes or skin fibroblasts DNA testing available (chromosome Xq 28) AD affects lamin A or lamin C (chromosome 1 q 21) Nuclear membrane proteins

Distal Muscular Dystrophy n Presentation: weakness in forearms, hands, and lower legs n n n clinically similar to a neuropathy but NCV normal Muscle biopsy with autophagocytic vacuoles/ inclusion bodies Table 3 – Types of DMD Welander distal myopathy AD/2 p 13 Anterior tibial/Markesbery. Griggs/Udd AD/2 q 31 -33 Nonaka/Inclusion body myopathy 2 AR/9 p 13 Gowers/Laing distal myopathy AD/14 q 11 Miyoshi myopathy AR/2 p 13 Distal myopathy with vocal cord and pharyngeal weakness AD/5 hands first Rimmed vacuoles, inclusion bodies, affects GNE Affects dysferlin

Myopathies n Central core disease: n n n Myotubular myopathy n n Myotubularin, important in myogenesis (Xq 28) Nemaline Myopathy n n n Ryanodine receptor, Ca channel that mediates excitation/contraction coupling, (AD – chromosome 19 q 13) Associated with Malignant Hyperthermia Caused by many defects, disorder of thin filaments Rod-like stuctures on muscle biopsy Inflammatory n n n Juvenile Dermatomyositis Inclusion Body Myositis (usually distal) Adult Polymyositis (associated with malignancy)

Treatment - Medications n Steroids n n n Briefly increase strength, slow progression in dystrophinopathy for walking, arm use, and respiratory function Weekend or 15 -20/month as well as prednisolone/deflazacort may minimize SE Dilantin and Tegretol raise the repolarization threshold and improve myotonia Methylphenidate improves daytime somnolence in DM Albuterol may help in FSH MD Creatine and glutamine may help delay progression/improve energy in youngest with DMD

Treatment – future therapies n Genetic therapies n Repairing the mutated sequences n n n Replacing the mutated sequences n n Using cell’s own repair mechanisms but adding template Gentamicin trial for relaxation in stop codon recognition for DMD has not worked Inserting truncated genes or whole gene with vector Upregulation of similar functioning proteins n Utrophin in DMD

Therapy n Contracture prevention n Stretching exercises and postural changing n n Stretch the most contracture prone groups (gastrocnemius, hip flexors, iliotibial bands, hamstrings) AFO at night to supplement

n Strengthening/conditioning/endurance Goal is to maintain or improve muscle strength and maximize functional ability – slight improvement is possible n Additional goal is to avoid muscular damage by overwork or injury n n n No eccentric contraction or delayed soreness Voluntary active exercise such as swimming/hydrotherapy or cycling in ambulatory children currently recommended

n Mobility aids n n n n Walking orthoses – KAFO Standing frames, standing wheelchairs, swivel walker occasionally used Walkers where arm strength less affected Transfer board Wheelchair – power needed for independence Plan for indoor lift, van with lift, roll in shower Improving daily activities of daily living n n n Physical and Occupational Therapy – teaching modified techniques Antigravity orthoses are being developed to assist in daily living activities Splinting and therapy to prevent hand contractures

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n Surgery n note the risk inherent to surgery – malignant hyperthermia Palliative vs. rehabilitative Tendon releases n Achilles n n n Need KAFO to walk post-op Relieves pain and allow shoe wear Hamstring and iliotibial band n n Relieves hip and knee pain or contracture Allows better gait compensation

n Scoliosis – spine stabilization n Bracing is not effective with progressive neuromuscular disease n Timely correction of scoliosis is important for patient comfort and respiratory ability n Spine and scapular stabilization may aid function of arms n Ophthalmology n Deficient eye closure oculomaxillofacial MD and FSH MD may require artificial tears or tarsorrhaphy n Treatment for cataracts in Myotonic MD

Respiratory n n n Patients with morning headache, nightmares, excessive daytime somnolence, mental dullness, difficulty concentrating, increased colds, coughing, or pneumonia should undergo evaluation Influenza vaccine and pneumococcal vaccine In-exsufflator for airway clearance, cough assist Pulmonologist, pulmonary function testing

n Assisted noninvasive ventilation Oxygen alone does not ventilate! n Positive pressure ventilation vs. volume ventilation with pressure limit n n Assisted ventilation with tracheostomy Talk to patient about degree of desired intervention when respiratory status first starts to decline and before an acute event n The goal is home ventilation n n Cardiology EKG – pacemaker for conduction defects and arrhythmias n Echocardiogram – afterload reduction, digoxin for cardiomyopathy n

n Nutrition/GI n Overweight and underweight are common problems n n n Overweight impairs mobility Underweight decreases strength & health Protein and calorie supplements Assess for dysphagia Intestinal hypomotility in DMD, CMD, and myotonic dystrophy can require a bowel regimen to prevent constipation

n Osteopenia/Osteoporosis Begins before walking stops, fractures may end walking n Worsened by steroids n Calcium supplements, Miacalcin may help n n Psychology/Neuropsychological Education – aid in planning n Special education may not be needed with accomodation and modifications n Progressive loss of function affects patient and family n

Thank you n n n My family Dr. Vikki Stefans Dr. Robert Warren