inherited disorders of skeletal muscle
TRANSCRIPT
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