Muscular Dystrophies

What is Muscular Dystrophy?(MD)

• MD is an inherited muscle disease with many different forms.

• In most cases muscle progressively become weaker.

• Some types of MD affect voluntary muscles such as the heart.

• Muscular Dystrophy: group of genetic disorders that are characterized by progressive loss of muscle integrity, wasting, and weakness. Characterized by degeneration and regeneration of muscle fibers (in contrast with static or structural myopathies)

• Muscular Dystrophy Association – Covers all muscular dystrophies and myopathies– Multisystem diseases : ALS or Friedreich Ataxia– Neuropathy : HSMN, CMTD

• Muscular dystrophy refers to a group of genetic, hereditary muscle diseases that cause progressive muscle weakness.

• Muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue

Symptoms

• Lack of coordination • Muscle weakness • Progressive crippling • 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

• 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

• 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

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

• 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

CLASSIFICATION

X-linked muscular dystrophy• Duchenne muscular dystrophy• Becker muscular dystrophy• Emery-Dreifuss syndrome

CLASSIFICATION

Autosomal recessive muscular dystrophy

• Limb-girdle muscular dystrophy

Autosomal dominant 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

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)

Duchenne Muscular Dystrophy

• Presentation: 3-5 y/o with frequent falls, slow running

• Prevalence of 1:3500 • Etiology– single gene defect (65% deletions, 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

Duchenne Muscular Dystrophy

• 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

• 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 mut at i on anal ysi s (65%) or haplotype

analysis)• Myopathic change in EMG

Bx: m. degener at i on• Muscle biopsy and Immunoblotting: Absenc

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

Prenatal diagnosis is available

Becker Muscular Dystrophy

• 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

• 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)

Limb Girdle Muscular Dystrophy

• 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

FascioScapularHumeral Muscular Dystrophy (AD)

• 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• 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

Huntington Disease• 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

• The earliest onset of Huntington’s ever documented was a two year old boy.

• The symptoms of HD can also develop at 55 or later, in which case it is harder to recognize.

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

Summary

Clinical DMD LGMD FSMD DD CMD

Incidence common less Not common

Rare Rare

Age of onset

3-6 y 2nd decade

2nd decade

20-77 y At/ after birth

Sex Male Either sex M = F Either sex Both

Inheritance

Sex-linked recessive

AR, rare AD

AD AD Unknown

Muscle involve.

Proximal to distal

Proximal to distal

Face & shoulder to pelvic

Distal Generalized

Muscle spread until late

Leg, hand, arm, face, larynx,eye

Upper ex, calf

Back ext, hip abd, quad

Proximal -

Summary

Clinical DMD LGMD FSMD DD CMDPseudohypertrophy

80% calf

< 33% Rare no No

Contracture Common Late Mild, late Mild, late Severe

ScoliosisKyphoscoliosis

Common, late

Late - - ?

Heart Hypertrophytachycardia

Very rare

Very rare Very rare Not observed

Intellectual decrease Normal Normal Normal ?

Course Stead, rapid

Slow Insidious benign 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