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A 55-year-old man develops progressive muscle weakness, fasciculations, and atrophy. He has both upper motor neuron signs (spasticity, hyperreflexia) and lower motor neuron signs.
90% sporadic, ~10% familial
- AD: SOD1 (~20% of familial ALS), C9orf72 (repeat expansion, most common - also causes FTD), TARDBP, FUS
- Upper AND lower motor neuron degeneration
- Progressive weakness, fasciculations, atrophy
- Bulbar symptoms (dysarthria, dysphagia)
- Respiratory failure (primary cause of death)
- C9orf72: GGGGCC hexanucleotide repeat expansion - ALS/FTD spectrum
- Clinical diagnosis: combined upper and lower motor neuron signs with progression, per El Escorial / Gold Coast criteria
- EMG/nerve conduction studies confirm lower motor neuron involvement and exclude mimics; neuroimaging excludes structural causes
- Molecular testing (C9orf72 repeat expansion, then SOD1, TARDBP, FUS) in familial disease or when targeted therapy eligibility matters
- C9orf72 expansion testing uses repeat-primed PCR; cascade testing offered to at-risk relatives when a familial variant is found
- Multidisciplinary care (neurology, pulmonology, PT/OT, speech, nutrition) improves survival and quality of life
- Riluzole and edaravone are approved disease-modifying agents that modestly slow progression
- SOD1-targeted antisense therapy (tofersen) is indicated for confirmed SOD1-associated ALS
- Noninvasive ventilation for respiratory failure, PEG for dysphagia/weight loss; advance care planning is central
"A-myo-trophic" = "without muscle nourishment": Motor neurons degenerate, so muscles lose their nerve supply (nourishment) and waste away.
ALS vs Huntington's vs Alzheimer's vs Parkinson's: ALS = motor deficits (fasciculations, weakness). Huntington's = chorea (involuntary movements). Alzheimer's = memory loss. Parkinson's = rigidity and resting tremor.