Muscular dystrophies
- Heterogeneous group of diseases characterised by progressive muscle weakness and wasting
- Histological in advanced cases muscle fibres are replaced by fibrofatty tissue (distinguishes dystrophies from myopathies)
X-Linked Muscular Dystrophy; Duchenne MD and Becker MD
- DMD is more severe and more common than BMD
- Incidence is 1 in every 3500 male births
- Weakness begins around 5 years, resulting in wheelchair dependency by 10-12 and death in the early 20s
- BMD involves the same genetic locus but is less common and less severe
Pathogenesis
- Caused by abnormalities in the gene that encodes the protein dystophin
- Female carriers are clinically asymptomatic but often have a raised CK and histologcal abnormalities on muscle biopsy
- Dystrophin is a cytoplasmic protein which is part of a complex that corrects actin to the extracellular CT matrix and therefore involved in transferring the force of contraction
Morphology
- Histological abnormalities common to both DMD and BMD are;
- Variations in fibre diameter
- Increased numbers of internalised nuclei
- Degeneration, necrosis and phagocytosis of muscle fibres
- Proliferation of the endomysial CT
- In later stages the muscle fibres become totally replaced with fat and CT
Clinical course
Normal at birth but walking is often delayed- Weakness begins in the pelvic girdle muscles and extends to the shoulder girdle
- An important clinical finding is pseudohypertrophy – enlargement of the calf muscles associated with weakness
- Heat may be affected – heart failure or arrhythmias
- Some patients may develop some cognitive impairment
- Serum CK is elevated at the onset of disease but returns to normal as muscle mass decreases
- Death is due to;
- Respiratory insufficiency
- Pulmonary infection
- Cardiac decompensation
- Respiratory insufficiency
- Boys with BMD develop symptoms later with a slower more variable rate of progression
Autosomal Muscular Dystrophies
- Many different types depending on gene mutation involved
- Share features with DMD and BMD
- Some affect specific muscle groups
- The ones that affect the proximal muscles similar to DMD and BMD are called ‘limb girdle muscular dystrophies’
- These can be autosomal dominant or recessive
Myotonic Dystrophy
- Myotonia is sustained involuntary contraction
- Patients complain of stiffness
- Myotonic can often be elicited by percussion of the thenar eminence
Pathogenesis
- Autosomal dominant inheritance
- Associated with a CTG repeat expansion on chromosome 19 encoding for the protein dystrophila myotonia-protein kinase (DMPK)
- The more repeats, the greater the severity of disease which is why with succeeding generations disease occurs earlier and is more severe (anticipation)
Morphology
- Variations in skeletal muscle fibre size
- Increased number of internal nuclei
- Fibre splitting, necrosis and regeneration
- ‘ring fibre’ abnormality where there is a subsarcolemmal band of cytoplasm that appears distinct from the centre of the fibre. It contains circumferentially orientated myofibrils which are wound around the longitudinally orientated fibrils of the rest of the fibre
- The ring fibre may be associated with a sarcoplasmic mass extending outward from the ring
Clinical course
- Presents late in childhood with gait abnormalities due to weak foot dorsiflexion and progressive weakness of the intrinsic muscles of the hand and wrist extensors
- Atrophy of face muscles and ptosis
- Cataracts
- Frontal balding
- Gondal atrophy
- Cardiomyopathy
- Smooth muscle involvement
- Decreased IgG
- Abnormal glucose tolerance test