Background: Motor neuron disease (MND) incorporates a spectrum of neurodegenerative syndromes involving both upper and lower motor neurons to a variable degree. Amyotrophic lateral sclerosis (ALS) is the most prevalent MND, but its atypical forms can make ALS a diagnostic challenge. Material and methods: Ambidirectional analysis of three atypical ALS cases diagnosed on the basis of clinical signs and electromyography results. Results: We report one case of pseudopolyneuritic ALS: a 60-year-old male with predominantly lower motor neuron lesion signs restricted to the lower limbs for a year, followed by cranial progression, upper motor neuron signs, cognitive deficit, which led to significant motor impairment, dysphagia, breathing difficulties and a fatal outcome within 3 years. Electrophysiological studies showed indirect signs of upper motor neuron damage and diffuse fasciculations. We also report the case of a 44-year-old female presenting with dysarthria, dysphonia and dysphagia followed by a progressive muscle weakness of the right limbs, whose electromyography showed spontaneous motor activity; and the case of a 78-year-old female presenting with isolated bulbar dysfunction and a false-positive edrophonium test, who was ultimately diagnosed with progressive bulbar palsy. Conclusions: These cases illustrate the diagnostic challenges associated with ALS and the extensive differential diagnosis that is required. Simplified diagnostic criteria (such as the recently proposed Gold Coast Criteria) are more inclusive for heterogeneous phenotypes, a fact that speeds the diagnostic process and the initiation of treatme