Muscular Dystrophy Omid yaghini
Dec 17, 2015
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 Inheritance
1A Myotilin 5q22-34 AD
1B Laminin A/C 1q21 AD/allelic to EDMD
1C Caveolin-3 3p25 AD
1D 7q AD
2A Calpain-3 15q15-21 AR
2B Dysferlin 2p13 AR/allelic to Myoshi Myopathy
2C Gamma sarcoglycan
13q12 AR
2D Alpha sarcoglycan 17q12-21 AR
2E Beta sarcoglycan 4q12 AR
2F Delta sarcoglycan 5q33-34 AR
2G Telethonin 17q11-12 AR
2H 9Q33 AR
2I Fukutin-related protein
19q13 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