Muscular Dystrophies

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

Symptoms

• Lack of coordination • Muscle weakness • Loss of mobility

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

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

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

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

General Diagnostic Testing

• Genetic analysis– PCR for specific known defects– Southern blot for nucleotide repeats

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– Limb-girdle muscular dystrophy– Fascioscapulohumeral muscular dystrophy

Differential Patterns of Initial Muscle Differential Patterns of Initial Muscle Weakness in MD Weakness in MD

Congenital MDDuchenne MD Limb Girdle MD FSHDFacio-Scapulo-humeral

Emery-Dreifuss MD

OPMDOculopharyngealMD

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

Duchenne Muscular Dystrophy

(DMD)

Duchenne Muscular Dystrophy

(DMD) • Clinical Manifestations

– - 36Onset : age years – PPPPPPPPPPP PPPPPPPP – Pseudohypertrophy of cal

P PPPPPPP – PPPPPP PPPPPPPPP – Cardiomyopathy– Respiratory – 30% mild to moderate

MR

•Pseudohypertrhophy of calf muscle, •Tip toe gaitforward tilt of pelvis, compensatory lordosis

Disappearance of lordosis while sitting

GOWER’S SIGN

Duchenne Muscular Dystrophy(DMD)

• Natural History– Progress slowly and

continuously– muscle weakness– -- lower >upper ext r emi t

i es– -unabletoambulate: 10year(7 12)– - deathfrompulmonary/ cardiacf ai l ur e: 2 3r d d

ecade

Duchenne Muscular Dystrophy Diagnosis

• Clinical Signs (Gower’s Sign)• Family history (pedigree analysis)• Increase CPK 200( x)• DNA mutation analysis (65%) or

haplotype analysis)• Myopathic change in EMG

Bx: m. degeneration• Muscle biopsy and Immunoblotting: Abs

ence dystrophin (if geneticist can’t find the mutation !!)

Prenatal diagnosis is available

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

DMD / BMD

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)

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

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

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

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

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)

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

– 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

Myotonic Dystrophy

• Genetics• 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

Myotonic Dystrophy (DM)

• Congenital: severe form– initial respiratory distress after birth

with ventilatory requirement or apnea, – feeding difficulty,– mental retardation, – club feet, scoliosis,– strabismus

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.

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

SummaryClinical DMD LGMD FSMD CMD

Incidence common less Not common

Rare

Age of onset

3-6 y 2nd decade

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

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

-

Summary

Clinical DMD LGMD FSMD CMDPseudohypertrophy

80% calf

< 33% Rare No

Contracture Common Late Mild, late Severe

ScoliosisKyphoscoliosis

Common, late

Late - ?

Heart Hypertrophytachycardia

Very rare

Very rare Not observed

Intellectual decrease Normal Normal ?

Course Stead, rapid

Slow Insidious Steady

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 !!!!?