Muscular dystrophies, inherited metabolic and acquired myopathies

Overview

A myopathy is a disease of skeletal muscle itself. It may be inherited (dystrophies, metabolic and channel disorders) or acquired (inflammation, endocrine disease, drugs, alcohol).

Typical picture:

• Proximal, symmetrical weakness: trouble climbing stairs, rising from a chair, combing hair.
• No sensory loss, no fasciculation.
• Reflexes preserved until the muscle is badly wasted.
• Some have pain (inflammation, metabolic), cramps or myoglobinuria.

Useful definitions

• Myositis: inflammation of muscle.
• Muscular dystrophy: an inherited, progressive degeneration of muscle fibres.
• Myotonia: slow relaxation after a contraction (for example, cannot let go after a handshake).
• Channelopathy: a disorder of ion channels in the muscle membrane (periodic paralysis, myotonia congenita).

Investigations in muscle disease

Muscular dystrophies

Duchenne muscular dystrophy (DMD)

• X-linked recessive; affects boys. About one-third are new mutations. Kumar and Clark give about 1 in 3000 male births.
• Usually a frameshift deletion in the dystrophin gene on Xp21 leading to complete absence of dystrophin.
• Dystrophin links the internal cytoskeleton to the cell membrane complex and extracellular laminin. Without it the membrane tears with contraction, fibres die and are replaced by fat and fibrous tissue.

Clinical features:

• Normal at birth; problems noticed by about 3–5 years: late walking, clumsiness, frequent falls, difficulty running and climbing stairs, waddling gait, toe walking.
• Gowers sign: to stand up from the floor the child turns prone and "climbs up his legs" with his hands, because of weak hip and thigh extensors.
• Calf pseudohypertrophy: big, firm calves from fat and fibrous tissue replacing muscle.
• Proximal weakness of legs before arms; lumbar lordosis.
• Loss of walking and wheelchair by around the early teens (severe disability typical by age 10).
• Scoliosis, contractures.
• Cardiomyopathy and respiratory failure; death often by around 20 (survival is improving with ventilation support).
• Mild learning difficulty in some.

Investigations:

• CK grossly raised: 100–200 times normal (even before symptoms).
• Genetic testing for the deletion (first-line diagnostic test).
• Muscle biopsy: fibre size variation, necrosis, regeneration, fat replacement, absent dystrophin on staining.

Management:

• No cure; corticosteroids (prednisolone or deflazacort) slow the loss of strength.
• Physiotherapy, night splints, scoliosis surgery, non-invasive ventilation, cardiac drugs (ACE inhibitors, beta-blockers).
• Carrier detection: sisters and mothers. The sister of an affected boy carries the gene with a 50% probability. CK is raised in about 70% of carriers; genetic testing and prenatal diagnosis are offered with counselling.

Becker muscular dystrophy

• Same gene, also X-linked recessive, but an in-frame mutation: dystrophin is present but reduced or abnormal.
• Milder and later: weakness becomes obvious in young adults; walking preserved into adult life; calf hypertrophy and cramps; cardiomyopathy may be the main problem.

Myotonic dystrophy (dystrophia myotonica)

• Autosomal dominant; the commonest adult muscular dystrophy.
• Type 1: expanded CTG trinucleotide repeat in the DMPK (protein kinase) gene on chromosome 19. Type 2: a CCTG (four-base) repeat in a different gene (CNBP).
• Anticipation: the repeat grows in successive generations, so onset is earlier and disease more severe; congenital myotonic dystrophy (floppy baby, talipes, breathing failure) occurs when the mother passes on a large expansion.
• Usually shows between 20 and 50 years.

Features (a multisystem disease):

• Distal limb weakness (unlike most myopathies), ptosis, long thin "hatchet" face, weak, wasted sternomastoids and temporalis.
• Myotonia: slow release of grip; percussion myotonia of the thenar muscles.
• Cataracts (early, iridescent).
• Frontal balding.
• Cardiac conduction defects and arrhythmias: sudden death can occur; needs regular ECGs and sometimes a pacemaker.
• Testicular atrophy / hypogonadism, glucose intolerance (diabetes), small pituitary fossa.
• Swallowing problems (oesophageal dysfunction, aspiration), mild cognitive impairment, hypersomnolence.
• Low IgG.
• Sensitive to general anaesthesia.

Myotonia congenita

• Chloride channel (CLCN1) mutation; dominant or recessive.
• Myotonia from childhood, worse after rest and in cold, eases with repeated movement ("warm-up").
• Diffuse muscle hypertrophy ("Herculean" build) but not much weakness.

Facioscapulohumeral and limb-girdle dystrophies

Inherited metabolic myopathies

McArdle disease (glycogen storage disease type V)

• Deficiency of muscle glycogen phosphorylase (myophosphorylase); autosomal recessive.
• Muscle cannot break down its glycogen for energy during short, intense exercise.
• Exercise-induced cramps, pain, early fatigue and myoglobinuria (dark urine) after strenuous effort, risking acute kidney injury.
• "Second wind": after a few minutes, exercise becomes easier as blood glucose and fatty acids are used.
• Ischaemic forearm exercise test: lactate fails to rise (ammonia rises normally).
• Diagnosis by muscle biopsy (absent phosphorylase) or genetic testing.
• Treatment: avoid intense exercise; sugar (sucrose) before exercise helps; normal life span.

Other metabolic myopathies

• Pompe disease (acid maltase deficiency, glycogen storage type II): infant form with cardiomyopathy and floppiness; adult form with proximal and respiratory weakness. Enzyme replacement exists.
• Carnitine palmitoyltransferase (CPT) deficiency: fatty acid oxidation defect; myoglobinuria after prolonged exercise or fasting, unlike McArdle.

Mitochondrial myopathies

• Defects in mitochondrial DNA, inherited from the mother (maternal inheritance); variable severity (heteroplasmy).
• Biopsy: ragged red fibres; blood or CSF lactate often raised.
• Syndromes: MELAS (encephalomyopathy, lactic acidosis, stroke-like episodes), MERRF (myoclonus, epilepsy and ragged red fibres), chronic progressive external ophthalmoplegia (CPEO) with ptosis, Kearns–Sayre syndrome (with heart block), and Leber hereditary optic neuropathy.

Periodic paralyses (channelopathies)

• Thyrotoxic periodic paralysis: a hypokalaemic form linked with hyperthyroidism, more common in Asian men; cured by treating the thyroid.

Malignant hyperthermia (hyperpyrexia)

• Inherited (often autosomal dominant) defect of the ryanodine receptor (RYR1) calcium-release channel in the sarcoplasmic reticulum.
• Triggered by volatile anaesthetics and suxamethonium: muscle rigidity, rapid rise in temperature, rising end-tidal CO2, tachycardia, acidosis, hyperkalaemia, rhabdomyolysis.
• Treatment: stop the trigger, cool, and give dantrolene.

Acquired myopathies

Inflammatory myopathies

• Antisynthetase syndrome (anti-Jo-1 antibody): myositis with interstitial lung disease, Raynaud's, arthritis and "mechanic's hands".
• Dermatomyositis is linked to malignancy (lung, ovary, breast, stomach and others), especially in older patients; screen for cancer at diagnosis and in follow-up.
• Treatment of PM and DM: prednisolone (about 0.5–1 mg/kg to start), tapered slowly, with steroid-sparing drugs (methotrexate, azathioprine, mycophenolate); IVIG or rituximab for resistant cases.

Endocrine and electrolyte myopathies

• Corticosteroids and Cushing syndrome: proximal weakness (especially hip girdle); CK normal; biopsy shows type 2 fibre atrophy. Fluorinated steroids (dexamethasone) are the worst. Improves on reducing the dose.
• Hyperthyroidism: proximal myopathy; links with myasthenia and hypokalaemic periodic paralysis; exophthalmos from swollen extraocular muscles.
• Hypothyroidism: muscle pain, stiffness, cramps, slow-relaxing reflexes, proximal weakness, raised CK.
• Osteomalacia, vitamin D deficiency and hypocalcaemia: proximal weakness with bone pain and a waddling gait.
• Hypokalaemia (for example from diuretics): flaccid weakness; corrected by slow potassium replacement.
• Hyperparathyroidism and acromegaly can also cause a proximal myopathy.

Drug- and toxin-induced myopathies

Infections and other causes

• Viral myositis (influenza, Coxsackie): pain, raised CK, sometimes rhabdomyolysis.
• Parasites: cysticercosis, trichinosis; pyomyositis (Staphylococcus aureus) in tropical countries.
• Sarcoidosis (granulomas in muscle).
• Critical illness myopathy in ICU patients with sepsis and steroid and neuromuscular-blocker use.

Quick revision

• Myopathy: proximal symmetrical weakness, no sensory loss; CK, EMG, biopsy, genetics.
• Duchenne: X-linked recessive, absent dystrophin, Gowers sign, calf pseudohypertrophy, CK 100–200× normal, cardiomyopathy, steroids slow it.
• Becker: same gene, some dystrophin, later and milder.
• Myotonic dystrophy: AD CTG repeat (DMPK), anticipation; distal weakness, myotonia, ptosis, cataracts, frontal balding, heart block, diabetes, hypogonadism.
• FSHD: AD, face, scapular winging, asymmetric, normal life span.
• McArdle: myophosphorylase deficiency, exercise cramps, myoglobinuria, flat lactate, second wind.
• Mitochondrial: maternal, ragged red fibres, MELAS, MERRF, CPEO.
• Hypokalaemic periodic paralysis: carbohydrate meal, low K; thyrotoxic form in Asian men.
• PM/DM: high CK, steroids; DM rash and cancer; IBM in older men, poor steroid response.
• Steroid myopathy: normal CK, type 2 fibre atrophy. Statin + fibrate or macrolide → rhabdomyolysis.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).

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