Inherited disorders of skeletal muscle

INHERITED DISORDERS OF

SKELETAL MUSCLE

Muscular DystrophyDuchenne/

BeckerEmery-Dreifuss,

CongenitalLimb-Girdle,

Distal Myopathy

Onset 2-6 years Childhood to early teens, infancy

Late childhood-middle age

Muscle groups affected

Life expectancy Rarely beyond 20’s varies Middle age +

Inheritance X-linked recessive X-linked recessive, autosomal dom & rec.

Autosomal dominant & recessive

Genetic linkage Dystrophin Emerin, lamin, merosin, etc.

Calpain-3, Dysferlin, Caveolin-3, α-

sargoglycans, etc.Source: www.mdausa.org

X-linked: Dystrophinopathies

Groupe of hereditary myopathies Pathophysiology: defective or absent Dystrophin Dystrophin:

– Has integral role in sarcolemmal stability– Consist in 2 globular heads with flexible rod-shaped center – Associated in a complex with sarcoglycans & dystroglycans

(transmembrane proteins & glycoproteins)

– Coding gene: on Chromosom X short arm : Xp21 location

– Function loss: cascade of events (including loss of other

components of dystrophin-associated glycoprotein complex, sarcolemmal breakdown with attendant Ca ion influx phosphlipase activation, oxidative cellular injury) and ultimately myonecrosis

X- Linked: Ducenne, Beker..

X- linked, recessive transmissionAffects malesFemales are CarrierOnset: 2-5 years in Duchenne, end 1st decade in

Becker)Proximal muscles: mainly , (early)Severe disease (+ other systemes: cardiac..) death in the 2d decade

DUCHENNE MDprogressive skeletal muscle weakness.Absence of the dystrophin protein weakens the

connections between proteins in the muscle fibers & the cell membrane. (?the cell membrane becomes weaker & ruptures)

As a result: ions such as Ca can move in & out of the ruptured cell membrane contraction at the damaged site the muscle fibers will break the muscle will begin to waste away.

Clinically: onset of DMD

Delayed developmental milestones

Loss of motor skills

Characteristic gait

Calf “hypertrophy” (pseudohypertrophy)

Clumsiness/frequent falls

Symptoms of DMD

Muscle weakness: Difficulty in walking/running

Difficulty climbing stairs or hills

& Difficulty in rising (Gower’s sign)

DIAGNOSIS: Clinical,

Lab Invest.: CPK

Neurophysiol. (EMG): myogenic changes

Muscle biopsy

Genetic study (Immunoblot homogenate allow diffenrentiation between Duchenne & Becker)

Asymptomatic female Foetus diagnsis possible (as early as 8 weeks)

DMD: where is the Gene?The gene for dystrophin production sits on the X

chromosome.

If a normal gene for dystrophin is present, then the protein will be made.

If the gene is missing or altered, dystrophin may not be produced at all or only in abnormal forms, resulting in Duchenne muscular dystrophy

Dystrophinopathies. Dystrophic muscle

Dystrophinopathies: dystrophin staining

Normal dystrophin

Intermediate dystrophin Becker MD

Duchenne dystrophy

Treatments for DMD

To improve breathing:– O2 therapy

– Ventilator

– Scoliosis surgery

– Tracheotomy

Treatments (cont.)

To improve mobility:– Physical therapy

– Surgery on tight joints

– Prednisone

– Non-steroidal medications

– Wheelchair

Other MD

Limb Girdle MD

Common features– Expression in either male or female sex – Onset usually in the late first or second decade of

life (but also middle age) – Usually autosomal recessive and less frequently

autosomal dominant – Involvement of shoulder or pelvic-girdle muscles

with variable rates of progression – Severe disability within 20-30 years – Muscular pseudohypertrophy and/or contractures

uncommon

Limb Girdle MD

LGMD may show an autosomal recessive (autosomal dominant forms reported)

or sporadic method of inheritance.

Some forms of LGMD dramatically affect young adults, while other types progress so slowly that they are not detected until much later in life.

LGMD protein defects occur in several pathways

proteins associated with the sarcolemma

proteins associated with the contractile apparatus

Various enzymes involved in muscle function.

Autosomal recessive LGMD

This childhood form

Affects both males and females

First decade of life. In general

The course is of gradual progression over years.

Distribution of weakness is typically in the pelvis (80-90% of cases)

later in life, involvement of the shoulder girdle (30%)

No hypertrophy of the calves (contrast to other forms of MD

Scapulo-humeral dystrophy (Erb)

Involves mainly the upper extremities. Autosomal recessive in some cases. starts later in life (second to the fifth decades), “Benign” (years before it is diagnosed). Weakness generally is asymmetric: may spare the

deltoid, supra-spinatus, and infra-spinatus muscles. lower extremities involvement very late in life show The progression: very slow (normal life

expectancy). Minimal, disability

autosomal-recessive disease

Severe proximal weakness at birth (or within 6/12) Slowly progressive or nonprogressive. Contractures are common

central nervous system (CNS) abnormalities can occur.

Biopsy: signs of dystrophy, a marked in endomysial and perimysial connective tissue, and fiber size variability with small round & immature fibers, less commonly, necrosis

No distinguishing features (as in congenital myopathies)

Congenital Muscular Dystrophy

Congenital Muscular DystrophyThe pathophysiology of CMD depend on specific

associated genetic defect (known with 4 of the CMDs)

Functions of the disrupted proteins: defined in 2:– Deficiency of laminin-alpha2 (merosin), a skeletal

muscle extracellular matrix protein that binds the dystrophin-associated glycoprotein complex (see Picture 1)

– Deficiency of integrin-alpha7 beta1, a skeletal muscle membrane protein that binds laminin-2

The pathophysiology of the other CMDs is unknown