NeurologyTier 2Disease (DEADMAN)

Myopathy, acquired and genetic

Description

Disease of muscle fibre -> symmetrical proximal weakness, no sensory loss, reflexes preserved until late
Wasting is disproportionately mild for the weakness; fasciculations absent

Weakness pattern is the first branch point

Pattern	Think
Proximal, symmetrical	Inflammatory myositis, endocrine, drug, limb-girdle, DMD/BMD
Distal	Myotonic dystrophy, distal myopathies, IBM (finger flexors)
Face + scapula + humerus	FSHD
Ptosis + ophthalmoplegia	Mitochondrial (CPEO), oculopharyngeal MD, myasthenia (fatigable)
Bulbar + eyes, fatigable	Myasthenia - not a myopathy
Episodic, normal between attacks	Periodic paralysis, metabolic myopathy
Asymmetric, quads + long finger flexors, age >50	Inclusion body myositis

Muscular dystrophies

	Inheritance	Gene	Pattern	Cardiac
Duchenne	XLR	DMD (dystrophin, Xp21) - out-of-frame	Proximal from age 3-5; calf + deltoid pseudohypertrophy, Gowers sign	DCM from ~age 10, universal
Becker	XLR	DMD - in-frame	Same but later, slower	DCM - may be out of proportion to the weakness
Limb-girdle	Mostly AR (some AD)	Sarcoglycans, calpain, dysferlin, FKRP	Shoulder/pelvic girdle, 2nd-3rd decade; face and heart usually spared	Some subtypes
FSHD	AD	D4Z4 contraction 4q35 (permissive 4qA)	Face, scapula (winging), humerus; deltoid hypertrophied and spared; asymmetric; foot drop	Rare. Retinal telangiectasia, SNHL
Myotonic (DM1)	AD, anticipation	DMPK CTG expansion 19q13	Distal + face + neck flexors; myotonia	Conduction disease -> sudden death
Oculopharyngeal	AD	PABPN1 GCG expansion	Ptosis + dysphagia, then proximal limb	No

DM1 is multisystem - the weakness is often not what kills
- Frontal balding, expressionless triangular facies, temporalis/masseter wasting, bilateral partial ptosis
- Cataracts (posterior subcapsular, "Christmas tree"), insulin resistance/diabetes, testicular atrophy, low IgG
- Sternomastoid wasting: weak neck flexion, normal extension
- Grip and percussion myotonia (slow relaxation of APB after tapping the thenar eminence)
- Conduction block, arrhythmia, sudden cardiac death; hypersomnolence, cognitive change
- *DM2 (CNBP CCTG) - proximal weakness, milder, later, no congenital form*

Epidemiology

DMD = commonest inherited muscle disease of childhood; ~1 in 3500-5000 male births; ~1/3 are de novo mutations
Myotonic dystrophy = commonest adult-onset muscular dystrophy; ~1 in 8000
FSHD ~1 in 8000-20,000; 3rd commonest dystrophy
Inclusion body myositis = commonest acquired myopathy over 50; M>F
Statin myalgia in 5-10% of users; true myositis <0.1%, rhabdomyolysis ~1-3/100,000 patient-years

Aetiopathogenesis

Acquired causes - PACE/PODS

Polymyositis / dermatomyositis (+ IBM, immune-mediated necrotising myopathy)
Alcohol; AIDS (HIV itself, and zidovudine)
Carcinoma - paraneoplastic; cachectic myopathy
Endocrine - thyrotoxicosis, hypothyroidism, Cushing's, acromegaly, hypopituitarism, hyperparathyroidism
Periodic paralysis - hypo-, hyper- or normokalaemic
Osteomalacia - proximal myopathy with bone pain and a waddling gait; CK normal
Drugs - statins, corticosteroids, colchicine, chloroquine/hydroxychloroquine, amiodarone, zidovudine, checkpoint inhibitors, alcohol
Sarcoidosis

Genetic

Dystrophinopathies - dystrophin links the actin cytoskeleton to the sarcolemma; its loss -> membrane tears on contraction -> Ca influx -> necrosis, fibrofatty replacement
- Reading-frame rule: frameshift/out-of-frame -> no dystrophin -> Duchenne; in-frame -> truncated but partly functional -> Becker
Myotonic dystrophy - expanded CUG repeat RNA sequesters MBNL splicing factors -> toxic RNA gain of function, widespread mis-splicing (explains the multisystem phenotype and the insulin receptor defect)
- Anticipation - repeat expands between generations; congenital DM1 is almost always maternally transmitted
Channelopathies - hypoKPP (CACNA1S, SCN4A), hyperKPP (SCN4A), myotonia congenita (CLCN1 - Thomsen AD, Becker AR), paramyotonia congenita (SCN4A, cold-induced, worsens with exercise)
Metabolic - McArdle (myophosphorylase; second-wind phenomenon, exercise-induced cramps + myoglobinuria), CPT2 deficiency (rhabdomyolysis after prolonged exercise or fasting), acid maltase/Pompe (diaphragm weakness out of proportion, respiratory failure at presentation)
Mitochondrial - maternal or nuclear; CPEO, Kearns-Sayre (+ retinitis pigmentosa + heart block), MELAS, MERRF

Diagnosis

Clinical

Difficulty rising from a chair, climbing stairs, washing hair, hanging washing
Waddling gait, exaggerated lumbar lordosis, Gowers sign, cannot stand from squatting with arms folded
Normal or reduced reflexes, flexor plantars, no sensory loss
- Any sensory loss -> not a pure myopathy: think neuropathy, or a paraneoplastic/CTD process affecting both
Look for the cause on inspection: Cushingoid habitus, heliotrope rash + Gottron papules, sclerodactyly, thyrotoxic signs, ptosis and fatigability

Bedside discriminators

Myotonia - percuss the thenar eminence (delayed APB relaxation); slow grip release; warms up with repetition, except paramyotonia which worsens with repetition
Winged scapula + facial weakness + hypertrophied deltoid -> FSHD
Neck flexion weak, extension normal -> DM1
Head drop -> IBM, MND, myasthenia, DM2

Investigation

Test	Yield
CK	Hugely raised (>10x) in DMD/BMD, rhabdomyolysis, immune-mediated necrotising myopathy; modest in myositis; normal in steroid myopathy, osteomalacia, thyrotoxic myopathy
ALT/AST/LDH	Rise from muscle - "abnormal LFTs" in a child is often undiagnosed DMD; check CK before a liver work-up
EUC, Ca/PO4/Mg, vitamin D, PTH	Hypokalaemia, hypophosphataemia, osteomalacia
TSH	Both hyper- and hypothyroid myopathy
ESR/CRP, ANA, ENA, myositis-specific antibodies	Jo-1/anti-synthetase, Mi-2, MDA5 (rapidly progressive ILD, amyopathic), TIF1-gamma / NXP2 (malignancy), SRP and HMGCR (necrotising)
EMG/NCS	Short-duration, low-amplitude, polyphasic units + early recruitment = myopathic. Myotonic discharges ("dive-bomber") in DM1/2, myotonia congenita; distinguishes from the decrement of myasthenia
MRI muscle with STIR	Oedema (active inflammation) vs fatty replacement (chronic); guides biopsy site
Genetic testing	First-line where the phenotype is characteristic - DMD/BMD deletion-duplication (MLPA) then sequencing; DMPK CTG repeat (gold standard for DM1); D4Z4 for FSHD; panel/exome for LGMD
Muscle biopsy	When genetics non-diagnostic or inflammatory myopathy suspected. Dystrophin immunostain; rimmed vacuoles + inclusions in IBM; ragged red fibres in mitochondrial disease

Every dystrophy diagnosis needs

ECG + echocardiogram (DMD/BMD, DM1, LGMD 2C-F/2I, Emery-Dreifuss); DM1 also needs Holter
Spirometry sitting and supine (>10% fall = diaphragm weakness), sleep study
OGTT/HbA1c and slit lamp in DM1

Management

A. Reversible acquired causes - find and correct

Stop the drug (statin, steroid, colchicine, chloroquine); correct thyroid, K+, PO4, vitamin D
Statin myopathy: stop, recheck CK; if CK stays high or weakness progresses off the drug, test anti-HMGCR -> immune-mediated necrotising myopathy needing immunosuppression, not simple statin intolerance
Steroid myopathy: painless, proximal, normal CK, no EMG irritability -> reduce dose, switch to alternate-day or a non-fluorinated steroid, resistance exercise

B. Inflammatory myopathy

Prednisolone 1 mg/kg/day with an early steroid-sparing agent (methotrexate or azathioprine); IVIg for severe/dysphagic or MDA5 disease; rituximab if refractory
Age-appropriate malignancy screen - especially dermatomyositis with anti-TIF1-gamma or anti-NXP2
IBM does not respond to immunosuppression - exercise, dysphagia management and aids only

C. Muscular dystrophy - anticipatory multisystem care, not a cure

Corticosteroids are standard of care in ambulant DMD - prednisone or deflazacort, prolonging ambulation ~2-3 years and delaying scoliosis and respiratory decline
- Vamorolone - a dissociative steroid, similar efficacy with less growth suppression and bone loss
- Bone protection, growth, weight, cataract and adrenal-suppression monitoring on any regimen
Givinostat (HDAC inhibitor) - approved for ambulant DMD >=6 years as an add-on to steroid
Mutation-specific: exon-skipping antisense oligonucleotides (eteplirsen, golodirsen, viltolarsen, casimersen) for amenable exon-51/53/45 deletions; delandistrogene moxeparvovec micro-dystrophin gene transfer
- Approvals are accelerated and functional benefit is contested; serious hepatotoxicity reported. Not PBS-funded in Australia - know they exist, not the detail
Cardiac: ACE inhibitor +/- beta blocker started before EF falls in DMD/BMD; MRA added; screen female DMD carriers - up to 10-20% develop cardiomyopathy
Respiratory: annual FVC, cough assist, non-invasive ventilation - the single largest driver of improved survival
Scoliosis surgery, contracture prevention, PT/OT, dietitian, genetic counselling and carrier testing

D. Myotonic dystrophy - what actually causes harm

Cardiac surveillance is the priority: annual ECG; pacemaker for conduction disease - low threshold, PR >240 ms or QRS >120 ms; ICD if indicated
Anaesthetic risk - profound sensitivity to opioids, benzodiazepines, propofol and neuromuscular blockers; avoid depolarising agents; prolonged post-op apnoea and aspiration
Myotonia if disabling: mexiletine (ECG first)
Modafinil for hypersomnolence; treat diabetes, cataracts, dysphagia; SLT and PEG discussion
Genetic counselling: anticipation; congenital DM1 risk if the mother carries the expansion

E. Periodic paralysis and metabolic myopathy

HypoKPP: oral K+ for the attack, acetazolamide/dichlorphenamide for prevention, avoid carbohydrate loads and rest after exercise
HyperKPP: carbohydrate and mild exercise abort attacks; thiazide or acetazolamide for prevention
Thyrotoxic periodic paralysis - treat the thyrotoxicosis; cautious K+ replacement, rebound hyperkalaemia
McArdle: pre-exercise sucrose, aerobic conditioning, avoid maximal isometric exertion
Pompe: enzyme replacement (alglucosidase/avalglucosidase alfa)

Associations

Proximal myopathy + peripheral neuropathy -> paraneoplastic, alcohol, hypothyroidism, connective tissue disease, critical illness
Dermatomyositis - malignancy (ovarian, lung, GI, nasopharyngeal), ILD (anti-synthetase, MDA5)
Myotonic dystrophy - diabetes, cataracts, cardiac conduction disease, hypogonadism, hypersomnolence, pilomatrixoma, dysphagia
DMD/BMD - dilated cardiomyopathy, scoliosis, learning difficulty, carrier females
FSHD - Coats disease/retinal telangiectasia, high-frequency sensorineural hearing loss
Sarcoidosis, amyloidosis, HIV, hepatitis C
Myotonia differential: myotonic dystrophy, myotonia congenita, paramyotonia congenita, hyperkalaemic periodic paralysis, drug-induced (statin, colchicine); acquired neuromyotonia (Isaacs, anti-CASPR2/VGKC) is nerve, not muscle

Natural history & complications

Duchenne

Presents 3-5 yrs -> wheelchair by ~10-13 (later on steroids) -> scoliosis -> respiratory and cardiac failure
Dilated cardiomyopathy from ~age 10 in essentially all
Historic survival to late teens; with steroids, NIV and cardiac therapy median survival now into the 30s
Becker: ambulant into adulthood; cardiac disease may dominate and can be the presenting or fatal problem

Myotonic dystrophy

Slowly progressive; death most often from respiratory failure or sudden cardiac death
Sudden death occurs at any stage and is not predicted by the severity of the weakness
Congenital DM1 - hypotonia, talipes, respiratory failure at birth, intellectual disability

Others

FSHD - normal lifespan; ~20% eventually wheelchair-dependent; very variable, even within a family
IBM - relentless, no effective therapy; falls from quadriceps weakness and aspiration from dysphagia dominate
Inflammatory myopathy - most improve with immunosuppression; relapse common on withdrawal; ILD and malignancy drive mortality
Endocrine, drug and electrolyte myopathies recover fully once the cause is corrected (may take months)

Monitor

Serial FVC (sitting and supine), ECG +/- Holter, echocardiogram, scoliosis, swallow, bone density
Rhabdomyolysis risk at anaesthesia, sepsis, extreme exertion - CK, K+, renal function

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