1. Muscular Dystrophies

2. What is Muscular Dystrophy? (MD)
Muscular Dystrophy is a group of genetic disorders that cause progressive muscle weakness.
MD is caused by a genetic mutation. The protein in the muscle is deformed which causes the patients muscle to deteriorate.
MD is characterized by degeneration and regeneration of muscle fibers (in contrast with static or structural myopathies) progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue

3. Symptoms
Lack of coordination
Muscle weakness
Loss of mobility

4. General Diagnostic Testing
Creatine kinase :
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

5. General Diagnostic Testing
Electromyography
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

6. General Diagnostic Testing
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

7. General Diagnostic Testing
Biochemical muscle protein analysis
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

8. General Diagnostic Testing
Genetic analysis
PCR for specific known defects
Southern blot for nucleotide repeats

9. CLASSIFICATION X-linked muscular dystrophy
Duchenne muscular dystrophy
Becker muscular dystrophy
Emery-Dreifuss syndrome
Autosomal recessive muscular dystrophy
Congenital muscular dystrophy
Limb-girdle muscular dystrophy
Autosomal dominant muscular dystrophy
Fascioscapulohumeral muscular dystrophy

10. Differential Patterns of Initial Muscle Weakness in MD
Duchenne MD
Emery-Dreifuss MD
Congenital MD
Limb Girdle MD
FSHD
Facio-
Scapulo-
humeral
OPMD
Oculopharyngeal MD

11. Duchenne Muscular Dystrophy (DMD)
Presentation: 3-5 y/o with frequent falls, slow running,
Prevalence of 1:3500
Etiology
single gene defect (65% deletions in hot spot regions , 7-10% duplications, 25% point mutations, small deletions or insertions)
1/3 new mutation
2/3 family history
Xp21.2 region
absent dystrophin

12. Duchenne Muscular Dystrophy (DMD)

13. Duchenne Muscular Dystrophy (DMD)
Clinical Manifestations
Onset : age 3-6 years
Progressive weakness
Pseudohypertrophy of calf muscles
Spinal deformity
Cardiomyopathy
Respiratory
30% mild to moderate MR

14. Pseudohypertrhophy of calf muscle,
Tip toe gait
forward tilt of pelvis, compensatory lordosis

15. Disappearance of lordosis while sitting

16. GOWER’S SIGN

17. Duchenne Muscular Dystrophy (DMD)
Natural History
Progress slowly and continuously
muscle weakness
lower --> upper extremities
unable to ambulate: 10 year (7-12)
death from pulmonary/ cardiac failure: 2-3rd decade

18. Duchenne Muscular Dystrophy Diagnosis
Clinical Signs (Gower’s Sign)
Family history (pedigree analysis)
Increase CPK (200x)
DNA mutation analysis (65%) or haplotype analysis)
Myopathic change in EMG Bx: m. degeneration
Muscle biopsy and Immunoblotting: Absence dystrophin (if geneticist can’t find the mutation !!)
Prenatal diagnosis is available

19. Becker Muscular Dystrophy (BMD)
Slowly progressive form with same gene affected as Duchenne MD
Etiology
single gene defect
short arm X chromosome
altered size & decreased amount of dystrophin
Muscle biopsy immunostaining for dystrophin with patchy staining
Disorder of function or decreased amount of dystrophin rather than absence of the protein

20. DMD / BMD

21. Emery-Dreifuss Muscular Dystrophy (EDMD)
Presentation: This disorder is characterized by a triad
Early contractures of the Achilles tendon, elbows and posterior cervical muscles
Slowly progressive muscle wasting and weakness with a humeroperoneal distribution
Cardiomyopathy arises , which usually presents as cardiac conduction defects.
Genetics
X-linked type affects emerin (STA gene at chromosome Xq28)
Diagnose by protein analysis of leukocytes or skin fibroblasts
DNA testing available
AD affects lamin A or lamin C (chromosome 1q21)

22. Congenital Muscular Dystrophy (CMD)
Presentation: neonatal onset of severe weakness, delayed motor milestones, contractures
Classification
Merosin-negative
Merosin-positive
Neuronal migration
Fukuyama
Muscle eye-brain
Wlaker-Warburg

23. Limb Girdle Muscular Dystrophy (LGMD)
Presentation: variable age of onset with weakness and wasting of the limb-girdle
15 genetically different types (genetical and clinical heterogenic)
AD forms are rare but more less severe than AR forms
Several of these disorders are associated with clinically significant cardiac involvment

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

25. FascioScapuloHumeral Muscular Dystrophy (FSMD)
Presentation:
Facial and shoulder girdle are first affected muscle group
Later foot extensors and pelvic girdle muscles become involved
The heart is not implicated in most cases.
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

26. 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
Affects poly A binding protein 2 (PABP2) by expansion of a GCG repeat without anticipation seen – Southern blot (chromosome 14q11-13)

27. Myotonic Dystrophy (DM)
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

28. 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

29. Myotonic Dystrophy Genetics 4-37 repeats Normal
Myotonic dystrophy is caused by a triple nucleotide (triplet) expansion (CTG) in the noncoding region of the myotonin gene at chromosome 19q13.3.
The condition is characterized by extreme variability, anticipation and differential expansion in the maternal and paternal germline.
4-37 repeats Normal
>50 repeats Affected

30. Myotonic Dystrophy (DM)
Congenital: severe form
initial respiratory distress after birth with ventilatory requirement or apnea,
feeding difficulty,
mental retardation,
club feet, scoliosis,
strabismus

31. Huntington Disease (HD)
Presentation
Mood Swings
Impaired cognitive functions
Chorea
Huntington’s Disease is an Autosomal Dominant “Tri-nucleotide Repeat” Disorder caused by a mutation of a gene on the 4th chromosome which is responsible for producing the protein Huntingtin, that creates excess copies of the CAG codon which genetically program the degeneration of the neurons of the brain.
Age of onset is found generally in adults around the age of 40 but varies based on the number of repeats.
The earliest onset of Huntington’s ever documented was a two year old boy who was found to have nearly 100 CAG repeats.
The symptoms of HD can also develop at 55 or later, in which case it is harder to recognize.

32. Huntington Disease (HD)
The number of CAG codons varies and so does the severity of the disease
>40 repeats you develop HD, children 50% chance of developing disease
36-39 repeats “Grey Zone” May develop HD, children may or may not develop HD
29-35 repeats the individual will not develop HD, children may
<29 repeats, the individual will not develop HD, children will not develop HD

33. Summary Clinical DMD LGMD FSMD CMD Incidence common less Not common
Rare
Age of onset
3-6 y
2nd decade
At/ after birth
Sex
Male
Either sex
M = F
Both
Inheritance
Sex-linked recessive
AR, rare AD AD
Unknown
Muscle involve.
Proximal to distal
Face & shoulder to pelvic
Generalized
Muscle spread until late
Leg, hand, arm, face, larynx,eye
Upper ex, calf
Back ext, hip abd, quad -

34. Summary Clinical DMD LGMD FSMD CMD Pseudo hypertrophy 80% calf
< 33%
Rare No
Contracture
Common
Late
Mild, late
Severe
Scoliosis
Kyphoscoliosis
Common, late - ?
Heart
Hypertrophytachycardia
Very rare
Not observed
Intellectual
decrease
Normal
Course
Stead, rapid
Slow
Insidious
Steady

35. Treatment There is no cure for MD
Medications that are prescribed for MD patients
Steroids
Braces for support
Mobility chairs
Surgery is also an option to release contractures
STEM CELL THERAPY !!!!?