| Disease | Distinguishing features |
| Multifocal motor neuropathy | Multifocal nerve conduction block, very high GM1 ganglioside antibody titers |
| Cervical spondylosis or extramedullary tumor with compressive radiculopathy and myelopathy | Sensory symptoms and signs, Lhermitte's symptom, LMN signs at level(s) of compression and UMN signs in legs, sphincter dysfunction, MRI of spine shows significant cord compression with intrinsic spinal cord signal abnormality |
| Benign fasciculations | No weakness or atrophy, no electromyographic abnormality of motor unit morphology |
| Inclusion body myositis | Disproportionate finger flexor weakness, no UMN signs, slow progression, diagnosis requires muscle biopsy, electromyography usually with myopathic features |
| Primary lateral sclerosis | A clinical variant of ALS: Spastic paraparesis, often with pseudobulbar palsy, prominent spasticity and hyperreflexia, no LMN signs |
| Progressive bulbar palsy | A clinical variant of ALS: Bulbar involvement predominates, pronounced dysarthria and dysphagia, limb musculature mostly spared |
| Progressive muscular atrophy | A clinical variant of ALS: Muscle weakness and atrophy with no UMN signs |
| Myasthenia gravis | Diplopia, ptosis, ocular dysmotility, weakness improved by acetylcholinesterase inhibitors, no UMN or LMN features |
| Monomelic (benign focal) amyotrophy | Onset usually in youth, slow and self limited course, no UMN features |
| Hereditary spinal muscular atrophy | Symmetric, slow course, no UMN signs, usually diagnostic changes detected in the survival motor neuron 1 gene (SMN1) |
| Hereditary spastic paraplegia | Slowly progressive lower extremity spastic UMN weakness, minimal or no LMN symptoms and/or signs, sphincter dysfunction, sensory symptoms and signs, HSP gene positive if available |
| Post-polio progressive muscular atrophy | Slow course, no UMN signs |
| Spinobulbar muscular atrophy (Kennedy disease) | X-linked recessive disorder, slow progression, expansion of a CAG trinucleotide repeat (>40 CAGs) in the androgen receptor gene |
| Late-onset Tay-Sachs disease (GM2 gangliosidosis) | Late adolescent and early adult onset, progressive atrophic paralysis, hexosaminidase A deficiency |
| Motor neuron syndromes with lymphoproliferative disorders | Lymphoma (Hodgkin or non-Hodgkin), multiple myeloma, chronic lymphocytic leukemia, Waldenström macroglobulinemia; some have paraproteinemia |
| Motor neuron syndromes in lung, breast, and other cancers | May improve on treatment of the tumor, may be paraneoplastic or coincidental |
| Radiation brainstem injury/radiation myelopathy | History of radiation therapy for cancer, location of injury within the radiation ports, delay of months to a few years from treatment, LMN symptoms and signs at the level of the injury, possible UMN symptoms and signs below the injury, possible sensory symptoms and signs below the level of the injury (eg, Lhermitte sign), self limited: does not progress to a diffuse LMN/UMN disorder |
| Thyrotoxic myopathy with fasciculations | Overt or covert hyperthyroidism |
| Intraspinal tumors and other lesions | Imaging studies show syringomyelia, syringobulbia, or intraspinal tumors |
