Muscular Dystrophy

Omid yaghini

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 α2-laminin (AR-chromosome 6q22-23)

Other Merosin Positive CMDDisorder Protein Associated signs Inheri-tance Chromosome

Rigid Spine Disease

SEPN1 (selenoprotein)

Slowly progressiveSpine contractures

AR 1p36

Ullrich CMD COL6A2 Rapidly progressiveJoint hyperlaxity

AR 21q22

Bethlem myopathy

Type VI collagen subunits

Slowly progressiveMyopathy?

AD 21q22 and 2q37

Integrin a7 deficiency

Integrin a7 AR 12q13

CMD 1C Fukutin-related protein

Rapidly progressiveCardiomyo-pathy

AR 19q13

Myotonic Muscular Dystrophy or Steinert’s disease

Presentation – adult with multiple systems affected

Primarily distal and facial weakness Facial features: frontal balding in men, ptosis,

low-set 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

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)

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 Inheritance1A Myotilin 5q22-34 AD1B Laminin A/C 1q21 AD/allelic to EDMD1C Caveolin-3 3p25 AD1D 7q AD2A Calpain-3 15q15-21 AR2B Dysferlin 2p13 AR/allelic to Myoshi

Myopathy2C Gamma

sarcoglycan13q12 AR

2D Alpha sarcoglycan 17q12-21 AR2E Beta sarcoglycan 4q12 AR2F Delta sarcoglycan 5q33-34 AR2G Telethonin 17q11-12 AR2H 9Q33 AR2I Fukutin-related

protein19q13 AR/allelic to CMD 1C

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 clinically similar to a neuropathy but NCV normal

Muscle biopsy with autophagocytic vacuoles/ inclusion bodies

Table 3 – Types of DMDWelander distal myopathy AD/2p13 hands first

Anterior tibial/Markesbery-Griggs/Udd

AD/2q31-33

Nonaka/Inclusion body myopathy 2

AR/9p13 Rimmed vacuoles, inclusion bodies, affects GNE

Gowers/Laing distal myopathy AD/14q11

Miyoshi myopathy AR/2p13 Affects dysferlin

Distal myopathy with vocal cord and pharyngeal weakness

AD/5

Treatment - Medications Steroids

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 Genetic therapies

Repairing the mutated sequences Using cell’s own repair mechanisms but adding

template Gentamicin trial for relaxation in stop codon

recognition for DMD has not worked Replacing the mutated sequences

Inserting truncated genes or whole gene with vector 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

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

Hamstring and iliotibial band Relieves hip and knee pain or contracture Allows better gait compensation

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

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

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

Osteopenia/Osteoporosis Begins before walking stops, fractures

may end walking Worsened by steroids Calcium supplements, Miacalcin may

help Psychology/Neuropsychological

Education – aid in planning Special education may not be needed

with accomodation and modifications Progressive loss of function affects

patient and family