Progressive degeneration of upper and lower motor neurons producing mixed UMN/LMN signs without sensory involvement.
Also known as: ALS, Lou Gehrig disease, motor neuron disease, MND
Overview
A relentlessly progressive neurodegenerative disease characterized by simultaneous loss of upper motor neurons (corticospinal tract) and lower motor neurons (anterior horn cells and bulbar nuclei). Sensory, autonomic, and oculomotor function are typically spared.
Epidemiology
Incidence ~2 per 100,000 per year; peak onset in the sixth and seventh decades. Male predominance ~1.5:1. ~10% familial (SOD1, C9orf72, FUS, TARDBP); ~90% sporadic. Median survival 3-5 years from symptom onset, although ~10% live >10 years.
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Family history of ALS or frontotemporal dementia (especially C9orf72 hexanucleotide repeat expansion)
Smoking (modest)
Military service (associations reported but mechanism unclear)
Pathophysiology
Selective degeneration of motor neurons driven by multiple converging mechanisms: TDP-43 cytoplasmic aggregation, glutamate excitotoxicity, mitochondrial dysfunction, oxidative stress, impaired protein homeostasis, neuroinflammation, and disturbed RNA processing. C9orf72 GGGGCC repeat expansion is the most common genetic cause and overlaps with frontotemporal dementia.
Clinical presentation
Symptoms
Limb-onset (~70%): asymmetric weakness, foot drop, hand clumsiness, muscle wasting
Spinal muscular atrophy (adult-onset) — Pure LMN, more slowly progressive, SMN1 deletion
Kennedy disease (spinobulbar muscular atrophy) — X-linked, bulbar and proximal weakness with gynecomastia, infertility, perioral fasciculations; CAG repeat in AR gene
Lyme, HIV, syphilis, lead, heavy metals, hyperthyroidism — Reversible mimics — screen routinely to avoid missing a treatable cause
Diagnostic workup
Diagnostic criteria
Gold Coast criteria (2020): progressive motor impairment + UMN and LMN dysfunction in ≥1 body region OR LMN dysfunction in ≥2 body regions + exclusion of mimics. EMG demonstrates active denervation (fibrillations, positive sharp waves) and chronic reinnervation (large motor unit potentials) in multiple body regions.
Labs
CK (mildly elevated in many), TSH, B12, HIV, RPR, Lyme serologies
SPEP/immunofixation to exclude paraproteinemia-related neuropathy
Anti-GM1 antibodies if MMN suspected
Genetic testing (SOD1, C9orf72, FUS, TARDBP) particularly with family history or before tofersen consideration
Imaging
MRI brain and full spine to exclude structural mimics (compression, demyelination, syrinx)
Diagnostic algorithm
flowchart TD
A[Progressive painless<br/>weakness in adult] --> B[Exam: UMN + LMN<br/>signs, no sensory loss]
B --> C[MRI brain/spine<br/>+ labs to exclude mimics]
C --> D[EMG/NCS:<br/>denervation in<br/>multiple regions]
D --> E{Gold Coast<br/>criteria met?}
E -->|Yes| F[ALS diagnosis]
E -->|No| G[Re-evaluate;<br/>consider mimics]
F --> H[Multidisciplinary clinic<br/>+ riluzole ± edaravone<br/>± tofersen if SOD1]
H --> I[Serial FVC,<br/>BiPAP, PEG,<br/>palliative care]
ALS diagnostic and longitudinal management pathway.
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