Myopathies are a heterogeneous group of conditions with diverse aetiologies. They usually affect muscle without involving the nervous system or any disorder of the neuromuscular junction.

The muscular dystrophies are the most common of such disorders and Duchenne's muscular dystrophy (DMD) is the most common muscular dystrophy. However, the broad range of myopathies is outlined in the boxes below which include some of the rare primary disorders of muscle as well as acquired myopathies.

The subsequent sections put these conditions in context and highlight some contrasting diagnostic and clinical features. Most of the congenital myopathies are chronic and slowly progressive. However, metabolic, inflammatory, toxic and endocrine myopathies present subacutely or even acutely and this requires awareness amongst front-line physicians to recognise and diagnose myopathy.

Classification

The primary myopathies^1,2,3,4

• Muscular dystrophies - disorders of dystrophin:
  • Duchenne's muscular dystrophy (DMD) including Becker's muscular dystrophy.⁵
  • Fascioscapulohumeral muscular dystrophy.^6,7
  • Limb girdle muscular dystrophy.⁸
  • Emery-Dreifuss muscular dystrophy.
  • Rare forms of muscular dystrophy including:
    • Distal muscular dystrophy.
    • Oculopharyngeal muscular dystrophy.
    • Congenital muscular dystrophy (CMD) - caused by genetic mutations and generally autosomal recessive disorders:
      • Extracellular matrix protein defects:
        • Laminin-alpha 2 deficiency.
        • Ullrich's CMD.
      • Integrin alpha 7 deficiency.
      • Glycosyltransferases:
        • Walker-Warburg syndrome.⁶
        • Muscle-eye-brain (MEB) disease.
        • Fukuyama CMD - quite common in Japan (7-12 per 100,000).
        • CMD with laminin deficiency (two types).
        • CMD with mental retardation.
      • Proteins of the endoplasmic reticulum:
        • Rigid spine syndrome.
• Congenital myopathies - these are rare (unknown incidence) conditions, in which gene defects lead to muscle protein defects:
  • Nemaline rod myopathy.
  • Central core disease.
  • Centronuclear myopathy.
  • Minimulticore myopathy.
  • Type 1 fibre predominance.
• Metabolic myopathies:
  • Hereditary muscle disorders caused by enzymatic defects (usually considered to be inborn errors of metabolism affecting the three major pathways of ATP supply) and relatively rare (much less common than the muscular dystrophies):
    • Glycogen storage diseases:
      • Pompe's disease - acid maltase deficiency (prevalence 1 in 40,000).⁹
      • McArdle's disease - (prevalence 1 in 100,000).
      • Other forms.
    • Lipid storage disease:
      • Carnitine palmitoyltransferase deficiency - (relative deficiency identified in as many as 1 in 150 patients).
      • Myopathic carnitine deficiency.
    • Disorders of purine nucleotide metabolism (affects replenishment of ATP).
    • Mitochondrial disorders.

The acquired myopathies

• Secondary metabolic and endocrine myopathies:
  • Thyroid disease:
    • Myxoedema can present with myopathy.
    • Hyperthyroidism.
  • Parathyroid dysfunction:
    • Hypoparathyroidism - causes tetany.
    • Hyperparathyroidism - causes proximal myopathy.
  • Pituitary dysfunction - for example, Addison's disease (myopathy through either adrenal dysfunction or secondary thyroid dysfunction).
    
    
  • Corticosteroids:
    • Cushing's disease.
    • Exogenous steroids - especially high doses (over 25 mg per day).
  • Biochemical:
    • Hypokalaemia and hyperkalaemia can cause muscle weakness and myotonia (stiffness).
    • May be caused by varieties of acute periodic paralysis (genetic).
    • Secondary to acute gastrointestinal loss.
    • Secondary to endocrine disease.
    • Renal disease.
    • Excessive liquorice ingestion.
  • Diabetes mellitus.

Epidemiology

These are all relatively uncommon diseases:

• Duchenne's muscular dystrophy (DMD) is easily the most common childhood-onset muscular dystrophy and affects 1 in 3,300 boys.¹⁰ The prevalence of DMD is 63 cases per million.
• The prevalence of the Becker phenotype is 24 cases per million.
• Congenital muscular dystrophy (CMD) is approximately 50% as common as DMD.

Presentation

Clinical features of myopathy

• The hallmark symptom of myopathy (and neuromuscular disease) is weakness.
• Weakness predominantly affecting proximal muscle groups (shoulder and limb girdles) is typical.
• Weakness manifests itself in different ways at different ages:
  • Decreased fetal movements in utero.
  • Floppy infant neonatally.
  • Motor delay in the toddler years.
  • Reduced muscle strength and power in older children and adults.
• Myalgia may occur in inflammatory myopathies.
• Muscle-stretch reflexes are preserved.
• Somatosensory reflexes are preserved.
• Variation of strength with exercise (either increasing or decreasing) can occur:
  • Fluctuating muscle power suggests metabolic myopathy (for example, McArdle's disease).
  • Fatigability (or progressive weakness with exertion, relieved by rest) is a feature of myasthenia gravis where the defect is in neuromuscular transmission.

History

• Common symptoms:
  • Symmetrical proximal muscle weakness.
  • Malaise.
  • Fatigue.
  • Absence of sensory symptoms (paraesthesia).
  • Atrophy of muscles (and reduced reflexes) occurs late with myopathies (early with neuropathy).
  • Waddling gait of Duchenne's muscular dystrophy (DMD) at age 3-6 years is typical.
• How acute are the symptoms?
  • Weakness over hours suggests toxic cause or episodic paralysis.
  • Weakness developing over days - consider dermatomyositis or rhabdomyolysis.
  • Weakness over weeks suggests polymyositis, steroid myopathy, endocrine myopathy.
• Pain and tenderness without weakness - consider other causes.
  
  
• Which muscle groups are affected?
  • Proximal muscle groups - difficulty rising from chair, climbing stairs, shaving, hair combing.
  • Distal muscles - difficulty walking (flapping gait), grasping, handwriting.
• Metabolic myopathies present with:
  • Difficulty with exercise.
  • Cramps and myalgia with exercise (early with glycogen storage disorders and after prolonged exercise with lipid storage disorders).
  • Myoglobinuria.
  • Progressive muscle weakness in some metabolic myopathies.
• Past medical history:
  • Autoimmune disease:
    • Systemic lupus erythematosus
    • Rheumatoid arthritis
    • Polyarteritis nodosa
  • Endocrine disease
  • Renal disease
  • Alcoholism
• Family history:
  • Muscular dystrophy.
  • Other relevant conditions or myopathies.
• Medication:
  • Steroids
  • Lipid-lowering drugs
  • Alcohol
  • Colchicine
  • Heroin
  • Zidovudine
• Occupational history:
  • Pottery industry - glazing salts can cause hypokalaemic paralysis.

Examination

• Symmetrical proximal muscle weakness.
• Muscle tenderness very rare with myopathy.
• Fever with inflammatory causes.
• There is usually no wasting but there may be hypertrophy of muscle (atrophy is a late sign).
• Reflexes and sensation usually normal.
• Hypotonia is common in some myopathies (for example, congenital myopathies).
• There may be helpful additional signs such as the skin changes of dermatomyositis.
• Urine should be examined - myoglobinuria in acute alcoholic myopathy can cause renal tubular necrosis.

Differential diagnosis

This list includes other conditions causing weakness:

• Guillain-Barré syndrome
• Eaton-Lambert myasthenic syndrome
• Myasthenia gravis
• Cerebral palsy
• Spinal muscular atrophy
• Congenital hypomyelinating neuropathies

• It may be difficult to distinguish myopathy from peripheral neuropathy. The distinguishing clinical features of peripheral neuropathy are:
  • Weakness affects distal muscles - although there are exceptions:
    • Myopathy where distal muscle groups are affected (myotonic dystrophy, myopathy of Welander).
    • Peripheral neuropathies which affect proximal muscles (diabetic amyotrophy, motor neurone disease).
  • Reduced muscle - stretch reflexes
  • Fasciculations
  • Somatosensory abnormalities
• Some complex cases may have both neurogenic and myopathic disorders which can lead to diagnostic confusion:
  • Diabetes mellitus can cause both neuropathy and inflammatory myopathy.
  • Cancer can cause dermatomyositis and chemotherapy peripheral neuropathy in the same patient.
  • Radiculopathy (from degenerative disc disease) can occur in patients with myopathy.

Investigations

Blood and urine tests

These, together with electrocardiogram (ECG) examination, are most useful in acute situations.

• Creatine kinase (with isoenzymes) - level may be 50-100 x normal reference range.
• Electrolytes including calcium and magnesium.
• Serum myoglobin.
• Urea and serum creatinine.
• Urinalysis and urine microscopy - myoglobinuria inferred by positive urinalysis with few red cells at microscopy.
• FBC.
• ESR.
• TFTs.
• Antinuclear antibodies.

ECG

May show:

• Changes of hypokalaemia - increased P-R interval, U waves, wide QRS and nonspecific ST-T changes.
• Sinus arrhythmias, deep Q waves and elevated R waves precordially (for example, in Duchenne's muscular dystrophy (DMD)).

Muscle biopsy

Muscle biopsy is important in diagnosis but findings under the microscope are rarely pathognomonic. Interpretation requires close consideration of the clinical history in conjunction with the microscopic features to make a diagnosis.

Electromyography

• Excludes primarily neurogenic processes (for example, spinal muscular atrophy).
• Proximal muscles of lower extremities often exhibit the most prominent features.
• Often helps to confirm diagnosis but not in itself diagnostic.

Magnetic resonance imaging (MRI)

• May help to exclude neurological disease.
• May help in assessing complications (musculoskeletal or involving other organs).

Genetic testing

The genetic basis of the primary myopathies means that genetic testing can be essential to the specific diagnosis. As defects are identified, repair strategies have been developed. Many are now at the stage of clinical testing.¹¹

Management

This depends on the diagnosis as well as the severity and extent of disease.

Emergency management

Myopathy can, rarely, present acutely or with acute complications. Examples include:

• Respiratory difficulties:
  • Respiratory failure can occur in a number of the myopathies.
  • Aspiration pneumonia may be associated with this.
  • Cardiac complications may be associated including cardiomyopathy and conduction defects.
• Some metabolic myopathies:
  • Hypokalaemia:
    • Oral supplements.
    • Cautious use of IV potassium.
    • Prophylactic drugs (spironolactone and acetazolamide).
  • Hyperkalaemia:
    • Carbohydrate loading (for example, early in attacks with hyperkalaemic periodic paralysis).
    • Glucose and insulin.
• Rhabdomyolysis:
  • Causes life-threatening renal complications and associated metabolic problems (hyperkalaemia).
  • Usually requires intensive care management.
• Polymyalgia rheumatica:
  • Treatment with corticosteroids.
  • Be aware of associated temporal arteritis.

Long-term care

• Myopathy associated with respiratory failure:
  • Monitor pulmonary function (early restrictive pattern may occur before onset of symptoms).
  • Beware of symptoms of nocturnal hypoxia (poor sleep, nightmares, headaches).
  • Physiotherapy.
  • May require tracheostomy and permanent ventilation.
• Specific medication may be useful in particular situations for particular myopathies.
• Genetic counselling.
• Surgery:
  • Tendon release surgery - for example, to prolong the ability to walk.
• Physical aids:
  • Walking aids
  • Wheelchairs
  • Adaptive devices
• Family support.
• Dietary advice:
  • General, for example to prevent obesity.
  • Specific.

Complications

• Respiratory failure.
• Aspiration pneumonia.
• Musculoskeletal problems:
  • Many associated deformities can occur.
  • Joint contractures.
  • Chest deformities.
  • Spinal deformities including scoliosis.
• Malignant hyperthermia can occur with central core disease.

Prognosis

This depends on the specific diagnosis. The primary disorders are incurable conditions with varied prognosis. Secondary myopathy may be corrected by treating the underlying cause.

Prevention

Genetic counselling is, in some of the most common myopathies such as Duchenne's muscular dystrophy (DMD), the only intervention that can prevent disease. In general:

• Give genetic counselling early.
• Test early for carrier status where appropriate.
• Consider prenatal diagnostic testing where appropriate.
• Advances in molecular genetics may help in the future.

Document references

1. Mellion ML et al, Dystrophinopathies, Medscape, Dec 2010
2. Lopate G, Congenital Muscular Dystrophy, Medscape, Aug 2011
3. Lopate G, Congenital Myopathies, Medscape, Oct 2011
4. Katiriji B, Metabolic Myopathies, Mar 2009
5. Spies S, Schipper K, Nollet F, et al; Duchenne muscular dystrophy. BMJ. 2010 Sep 7;341:c4364. doi: 10.1136/bmj.c4364.
6. Fascioscapulohumeral muscular dystrophy 1A, Online Mendelian Inheritance in Man (OMIM)
7. Padberg GW, van Engelen BG; Facioscapulohumeral muscular dystrophy. Curr Opin Neurol. 2009 Oct;22(5):539-42. [abstract]
8. Limb Girdle Muscular Dystrophy (search), Online Mendelian Inheritance in Man (OMIM)
9. van der Ploeg AT, Reuser AJ; Pompe's disease. Lancet. 2008 Oct 11;372(9646):1342-53. [abstract]
10. Muscular Dystrophy, Duchenne Type; DMD, Online Mendelian Inheritance in Man (OMIM)
11. Sahenk Z, Mendell JR; The muscular dystrophies: distinct pathogenic mechanisms invite novel therapeutic Curr Rheumatol Rep. 2011 Jun;13(3):199-207. [abstract]

Internet and further reading

• EFNS guideline on diagnosis and management of limb girdle muscular dystrophies, European Federation of Neurological Societies (2007)