MUSCLE DISEASES Patrick C.J. Ward, MB.BCh. Summer 2008.

MUSCLE DISEASES

Patrick C.J. Ward, MB.BCh.

Summer 2008

MUSCLE DISEASES

• Duchenne Muscular Dystrophy

• Becker Muscular Dystrophy

• Myotonic Dystrophy

• Dermatomyositis

• Polymyositis

• Myasthenia Gravis

MUSCLE DISEASES

• Duchenne Muscular Dystrophy

Duchenne Dystrophy

Autographed copy of: De la Paralysie Musculaire Pseudo-hypertrophique...1868 From NLM

Guillaume-Benjamin

Duchenne de Boulogne

DUCHENNE MUSCULAR DYSTROPHY: CLINICAL

• 1/3500 live male births

• Walking often delayed in infancy

• Weakness: pelvic extending to shoulder girdle

• Wheelchair dependence by 10-12 yrs.

• Untreated, death by early 20’s

• Treated, death by 25-35 yrs

DMD: HISTOPATHOLOGY

• Variation in fiber size

• Increased internalization of nuclei

• Evidence of fiber regeneration (blue fibers)

• Proliferation of endomysial connective tissue

• ± necrosis / phagocytosis

• ± subendocardial interstitial fibrosis

DMD: PSEUDOHYPERTROPHY OF CALF

• Definition: enlargement of calf ‘muscles’

classic feature of DMD are muscles really hypertrophied?

• CPK initially elevated, then normal. Why?

Ewing EP, Jr., CDC

From: A Kornberg

Duchenne muscular dystrophyStanding from supine position

Pestronk, A., Neuromuscular Disease Center, Washington University, St. Louis, MO

Gowers’ Sign in Patient with Duchenne Muscle Dystrophy

DMD: BIOCHEMISTRY

• Dystrophin: juxtasarcolemmal cytoplasmic protein

conc. at plasma membrane over Z–bands

• strong mechanical link to cytoplasmic actin

• Superficially attached to sarcolemmal proteins

thence by laminin–2 to outside connective tissue

• When dystrophin is absent or defective:

connecting forces (actin–CT) are missing

• Muscle degenerates (into what?)

DMD: GENETICS

• Abnormalities of dystrophin gene on Xp21

deletions (majority of cases)

frameshift mutations

point mutations

• Familial (2/3) versus spontaneous (1/3)

• In familial disease, females are carriers but

their CPK levels are elevated and they are

at risk for dilated cardiomyopathy later in life

van Deutekom J et al. N Engl J Med 2007;357:2677-2686

Schematic Representation of Exon Skipping

MUSCULOSKELETAL SYSTEM

• Duchenne Muscular Dystrophy

• Becker Muscular Dystrophy

BECKER MUSCULAR DYSTROPHY (BMD)

• Lesion at same genetic locus as DMD

• Later age of onset, even adolescence

• Some dystrophin present, but mol. size is altered

• Nearly normal life span

Becker, adult

Becker

From: A Kornberg

Pestronk, A., Neuromuscular Disease Center, Washington University, St. Louis, MO

Pestronk, A., Neuromuscular Disease Center, Washington University, St. Louis, MO

MUSCULOSKELETAL SYSTEM

• Duchenne Muscular Dystrophy

• Becker Muscular Dystrophy

• Myotonic Dystrophy

MYOTONIC DYSTROPHY: CLINICAL

• Onset in late childhood

• Sustained invol. contraction of muscle groups

complaints of ‘stiffness’

cannot say goodbye easily (why?)

• Thenar tap sign

• Gait problems: dorsi-flexor weakness of foot

• Hand muscle and wrist extensor atrophy

• Facial atrophy, ptosis

MYOTONIC DYSTROPHY: ASSOC. FEATURES

• Cataracts

• Frontal balding

• Gonadal atrophy

• Cardiomyopathy

• Decreased IgG

• Abnormal glucose tolerance

• ± dementia

Can you remember these?

MYOTONIC DYSTROPHY: PATHOLOGY

• Massive internalization of nuclei

• Ring fibers

• Sarcoplasmic masses

MYOTONIC DYSTROPHY: MOLECULAR BIOLOGY

• Trinucleotide repeat of CTG on 19q13.2 - 13.3

• Normal: 30 repeats

• Increased numbers lead to disease

• In severe disease, may be several 1000 repeats

these adversely affect mRNA for DMPK

• More and more protein product is formed

• Anticipation (as in what other disease you studied?)

Neil Miller, Johns Hopkins

MUSCULOSKELETAL SYSTEM

• Duchenne Muscular Dystrophy

• Becker Muscular Dystrophy

• Myotonic Dystrophy

• Dermatomyositis

DERMATOMYOSITIS: MAJOR FINDINGS

• Proximal muscle weakness, myalgias

• Dysphagia

• Heart / lung inflammation

• Scaling, erythematous rash

• Heliotrope upper eyelids with periorbital edema

• Göttron lesions

DERMATOMYOSITIS: MUSCLE PATHOLOGY

• Hypoperfusion resulting from endothelial injury

• Associated with perimysial atrophy / inflammation

• ± necrosis

• ± regeneration throughout fascicle

MUSCULOSKELETAL SYSTEM

• Duchenne Muscular Dystrophy

• Becker Muscular Dystrophy

• Myotonic Dystrophy

• Dermatomyositis

• Polymyositis

POLYMYOSITIS: CLINICAL

• Predominantly in adults presenting with subacute or chronic proximal weakness elevated CPK

• Is a cell-mediated autoimmune disorder

POLYMYOSITIS:GENERAL

• Non-infectious, inflammatory myopathy

• Two manifestations:

myopathy is isolated

component of more systemic disease (10% of SS)

• Pathology:

endomysial CD8+ cells, MФs

necrotic / regenerating fibers throughout fascicle

Rx: immunosuppressive therapy is beneficial

MUSCULOSKELETAL SYSTEM

• Duchenne Muscular Dystrophy

• Becker Muscular Dystrophy

• Myotonic Dystrophy

• Dermatomyositis

• Polymyositis

• Myasthenia Gravis

MYASTHENIA GRAVIS: GENERAL STATS

• 3 / 100,000 population

• < 40 years

• ♀ > ♂

• Thymus hyperplasia thymoma (in 15%)

• Electrophysiologic tests diagnostic

MYASTHENIA GRAVIS: CLINICAL

• Ptosis

• Diplopia (ΔΔ?)

• Generalized weakness, curiously fluctuating

• Anticholinesterase as diagnostic test (tensilon)

Rx: prostigmine, prednisone, plasmapheresis

• Surgery : thymectomy

• With therapy, 95% five year survival

Myasthenia Gravis Foundation Coalition of Canada, 2008

Esterase stain

Esterase stain

Neuromuscular Junctions

Posey & Spiller

Fatigue (Ptosis) in a patient with MG

Repetitive nerve stimulation: Decrement

Pestronk, A., Neuromuscular Diseases Center, Washington, University, St. Louis, MO

Myasthenia Gravis Foundation of California, Los Angeles, CA