Muscular Dystrophy

Objectives

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

Case 1 Called 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 cont Physical exam reveals hypotonic infant with high arched palate. Physical exam is otherwise normal.
Laboratory such as CBC and electrolytes are normal.

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.

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.

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 cant let go easily.

History and Physical Exam in the Newborn and Office

History

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

Family History

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 School functioning/cognitive development Cardiac function/arrhythmias/syncope Respiratory

Review of Systems

Physical exam findings

Muscle mass: signs of wasting or hypertrophy/pseudohypertrophy Muscle strength: power generation of force against resistance or gravity
Observe reaching, getting up from floor Observe trunk and head/neck control Test specific proximal groups position so against gravity

Tone: resistance to passive movement

Note hyper vs. hypotonia in weak areas

Deep tendon reflexes: normal or decreased Normal sensation: remember proprioception Joint 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 myopathies Multisystem diseases : ALS or Friedreich Ataxia Neuropathy : HSMN, CMTD

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

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 rhabdomyolysis Nonspecific if mildly elevated 2-3x normal Lower late in MD course due to severely reduced muscle mass Not helpful for carrier detection

Muscle biopsy

Dystrophic 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 Useful for specific identified protein that is missing and many specific mutations may cause the same deficiency Immunohistochemical protein staining Western blot quantitates percent of normal protein present

Biochemical muscle protein analysis

Genetic analysis

PCR for specific known defects Southern blot for nucleotide repeats 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

Electromyography

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 cardiomyopathy Respiratory Intellect - 30 % with impairment IQ <75

Testing
Immunostaining with absence of dystrophin PCR testing available for common mutations (X21.2)

Becker Muscular Dystrophy

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

Presentation: neonatal onset of severe weakness, delayed motor milestones, contractures Merosin negative/CMD A1

White matter hypodensities on brain scan but normal mental capacity Diagnosis by muscle biopsy immunohistochemistry showing loss of 2laminin (AR-chromosome 6q22-23)

Neuronal Migration Disorders

With neuronal migration disorders get mental retardation, brain malformations, and clinical eye involvement Fukuyamas 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

Disorder Rigid Spine Disease Protein SEPN1 (selenoprotein) Associated signs Inheri-tance Slowly progressive Spine contractures Rapidly progressive Joint hyperlaxity Slowly progressive Myopathy? AR Chromosome 1p36

Ullrich CMD

COL6A2

AR

21q22

Bethlem myopathy Integrin a7 deficiency

Type VI collagen subunits Integrin a7

AD

21q22 and 2q37

AR

12q13

CMD 1C

Fukutin-related Rapidly protein progressive Cardiomyopathy

AR

19q13

Myotonic Muscular Dystrophy or Steinerts disease

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

Genetics:
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 19q13.3, 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

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, 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
Southern 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 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

1A
1B 1C 1D

Myotilin
Laminin A/C Caveolin-3

5q22-34
1q21 3p25 7q

AD
AD/allelic to EDMD AD AD

2A
2B 2C 2D 2E 2F 2G 2H 2I

Calpain-3
Dysferlin Gamma sarcoglycan Alpha sarcoglycan Beta sarcoglycan Delta sarcoglycan Telethonin Fukutin-related protein

15q15-21
2p13 13q12 17q12-21 4q12 5q33-34 17q11-12 9Q33 19q13

AR
AR/allelic to Myoshi Myopathy AR AR AR AR AR AR AR/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 population Genetics
Muscle biopsy shows filamentous nuclear inclusions and ubiquitin containing vacuoles Affects poly A binding protein 2 (PABP2) by expansion of a GCG repeat without anticipation seen Southern blot (chromosome 14q11-13)

Emery-Dreifuss Muscular Dystrophy Scapuloperoneal MD

Presentation: stiff joints, shoulder and upper arm weakness, calf weakness, cardiac conduction defects and arrhythmias, contractures Genetics
X-linked type affects emerin

Diagnose by protein analysis of leukocytes or skin fibroblasts DNA testing available (chromosome Xq28)

AD affects lamin A or lamin C (chromosome 1q21) Nuclear membrane proteins

Distal Muscular Dystrophy

Presentation: weakness in forearms, hands, and lower legs

Muscle biopsy with autophagocytic vacuoles/ inclusion bodies Table 3 Types of DMD
Welander distal myopathy Anterior tibial/MarkesberyGriggs/Udd Nonaka/Inclusion body myopathy 2 Gowers/Laing distal myopathy Miyoshi myopathy Distal myopathy with vocal cord and pharyngeal weakness AD/2p13 AD/2q31-33 AR/9p13 AD/14q11 AR/2p13 AD/5 Affects dysferlin Rimmed vacuoles, inclusion bodies, affects GNE hands first

clinically similar to a neuropathy but NCV normal

Myopathies

Central core disease:

Myotubular myopathy

Ryanodine receptor, Ca channel that mediates excitation/contraction coupling, (AD chromosome 19q13) Associated with Malignant Hyperthermia

Nemaline Myopathy

Myotubularin, important in myogenesis (Xq28)

Caused by many defects, disorder of thin filaments Rod-like stuctures on muscle biopsy Juvenile Dermatomyositis Inclusion Body Myositis (usually distal) Adult Polymyositis (associated with malignancy)

Inflammatory

Treatment - Medications

Steroids

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

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

Treatment future therapies

Genetic therapies

Repairing the mutated sequences

Using cells 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

Replacing the mutated sequences

Upregulation of similar functioning proteins

Utrophin in DMD

Therapy

Contracture prevention
Stretching exercises and postural changing

Stretch the most contracture prone groups (gastrocnemius, hip flexors, iliotibial bands, hamstrings)

AFO at night to supplement

Strengthening/conditioning/endurance

Goal is to maintain or improve muscle strength and maximize functional ability slight improvement is possible Additional goal is to avoid muscular damage by overwork or injury

No eccentric contraction or delayed soreness

Voluntary active exercise such as swimming/hydrotherapy or cycling in ambulatory children currently recommended

Mobility aids
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

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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Surgery

note the risk inherent to surgery malignant hyperthermia

Palliative vs. rehabilitative Tendon releases

Achilles

Need KAFO to walk post-op Relieves pain and allow shoe wear Relieves hip and knee pain or contracture Allows better gait compensation

Hamstring and iliotibial band

Scoliosis spine stabilization

Bracing

is not effective with progressive neuromuscular disease Timely correction of scoliosis is important for patient comfort and respiratory ability Spine and scapular stabilization may aid function of arms

Ophthalmology
Deficient

eye closure oculomaxillofacial MD and FSH MD may require artificial tears or tarsorrhaphy Treatment for cataracts in Myotonic MD

Respiratory
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

Assisted noninvasive ventilation

Oxygen alone does not ventilate! Positive pressure ventilation vs. volume ventilation with pressure limit

Assisted ventilation with tracheostomy

Talk to patient about degree of desired intervention when respiratory status first starts to decline and before an acute event The goal is home ventilation

Cardiology

EKG pacemaker for conduction defects and arrhythmias Echocardiogram afterload reduction, digoxin for cardiomyopathy

Nutrition/GI

Overweight and underweight are common problems

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

Osteopenia/Osteoporosis

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

Psychology/Neuropsychological

Thank you

My family Dr. Vikki Stefans Dr. Robert Warren