1 Primary Muscle Diseases Comprise

Musculoskeletal 1a – Muscle Disease

Anil Chopra

1 Primary muscle diseases comprise:

- muscular dystrophies

- Congenital myopathies

2 Pathogenesis of muscle weakness - progressive muscle degeneration and fibro-adipose tissue substitution in muscular dystrophy:

- Reduced force generated by muscle in congenital myopathies but little or no change with time

3 Main group of proteins involved in muscular dystrophies
- the dystrophin-associated glycoprotein complex
- (laminin/ dystroglycan/ sarcoglycans/ dystrophin)

4 Main group of proteins involved in congenital myopathies
- Proteins of sarcomeres (actin, tropomyosin and nebulin)

5 Main clinical features of the muscular dystrophies:
- proximal weakness
- joint contractures

respiratory muscle involvement

Neuromuscular Disorders

v  Many are inherited

v  Various parts of the motor units affected

v  A defect in a motor neuron or nerve is a neuropathy

v  A defect at the neuromuscular junction is a myasthenia.

v  A defect of muscle is a myopathy.

Myopathies

1.  Congenital myopathies

2.  muscular dystrophies

Congenital Myopathies

General Features

-  non progressive

-  weakness from birth or infancy

-  generally, patients achieve the ability to walk independently

-  serum creatine kinase are normal only mildly elevated, indicating low degree of muscle damage.

-  Characterised by generalised muscle thinning and muscle weakness.

-  Respiratory muscle weakness can be out of proportion compared to limb muscle weakness.

There are 4 types of congenital myopathies

-  central core disease

o  disturbance of excitation contraction coupling

-  nemaline myopathy

o  sarcomeric protein diseases

-  myotubular myopathy

o  problems in cell-cell signalling and energy metabolism

-  minicore myopathy

o  disturbance of excitation contraction coupling

Severity depends on the degree of disruption of the excitation/contraction coupling or the degree of defect in the sarcomeric proteins.

Generally symptoms are mild:

v  Proximal muscle weakness:

o  difficulties in walking fast

o  difficulties in running

o  difficulties in getting up from the floor

v  Axial weakness:

o  scoliosis common

o  respiratory muscle weakness common even in ambulant patients

Proteins Affected

·  Nebulin

·  Alpha-actin

·  Beta tropomyosin (TPM2)

·  Alpha tropomyosin 3 (TMP3)

·  Troponin T1 (TNNT1)

Muscular Dystrophies

Histological Assessment

-  Wide variations in fibre size

-  Necrosis

-  Fibrosis, fat

-  Hypercontracted fibres

-  Split fibres whorled fibres

-  internal nuclei

-  basophilic fibres

Muscular dystrophies can be congenital or onset during childhood, and rarely in adulthood.

They are characterised by:

-  Often progressive weakness

-  Variable severity: from congenital to adult onset depending on the subtype (many subtypes recognised)

-  Weakness

o  usually proximal

o  rarely distal

-  Respiratory muscle weakness

-  Limitation of joint movements often accompanies the weakness

-  Muscle atrophy often with associated pseudohypertrophy in the same patient.

There are different muscle proteins involved with muscular dystrophies than with myopathies. The ones affected in muscular dystrophy include:

1.Transarcolemma (Duchenne, sarcoglycanopathies, others)

2. Enzymes

3. Nuclear envelope

4. Extracellular matrix

5. Sarcomere

6. Others (cytoskeleton; ER proteins of unknown)

Deficiencies in extracellular proteins cause congenital muscular dystrophies. E.g. merosin deficiency, collagen VI deficiency causes “Ulrich congenital muscular dystrophy”. They are characterised by random contractures at birth – arthrogryposis.

Sarcoglycanopathies: deficiencies in sarcoglycans.

Duchenne Muscular Dystrophy

Caused by a deficiency in the dystrophin molecule.

·  1 in 3500 male births

·  symptomatic <1 year - 5 years

·  loss of independent walking 6 -12 years

·  death mid teens - early twenties

·  30% significant learning difficulties

Molecular Basis

Duchenne is caused by abnomailities in chromosome 21 which codes for the dystrophin protein. An “in frame” deletion causes fewer complications than an “out of frame” deletion.

Clinical Presentation:

Ø  late walking - 50% >18 months

Ø  toe walking

Ø  unable to run or jump

Ø  falls

Ø  stairs and climbing hard

Ø  Gowers’ Manoeuvre – getting up by rolling onto their front and using their arms.

Ø  IQ shifted -1SD

Ø  30% IQ<70, mean IQ 85

Ø  verbal IQ < performance IQ

Ø  speech delay very common

Later Presentatons

Ø  Progressive joint contractures

Ø  Progressive scoliosis

Ø  Dilated cardiomyopathy

Ø  Weakness of the inspiratory and expiratory muscles: this is particularly dangerous as it can lead to

o  frequent respiratory infections

o  nocturnal hypoventilation

o  nocturnal hypoxia

o  nocturnal hypercarbia (too much CO2)

o  morning drowsiness, headaches, nausea, fatigue

o  respiratory insufficiency and sudden death

Diagnosis – the diagnosis of Duchenne’s is difficult and is often untreatable.

•  CK: 50 - 100x normal

•  deletion in gene detectable in 70%

•  muscle biopsy

–  histology dystrophic

–  immunocytochemistry shows absent dystrophin

Treatment

-  using ACE inhibitors can slow the onset of dilated cardiomyopathy

-  β- blockers are becoming increasingly used

Becker Muscular Dystrophy

Presentation

•  Mean age of onset of symptoms is around 11 yrs

•  Calf pains, slower than peers

•  Variable progression

•  Loss of walking ability – only in 18% (Mean age at loss of walking – 37 yrs)

•  Scoliosis extremely uncommon

•  Dilated cardiomyopathy however very common.

Molecular Basis

Generally only caused by “in frame” deletions leaving a partially functional protein.