Late-onset Tay-Sachs disease (LOTS) is a rare neurodegenerative disorder caused by partial deficiency of the lysosomal enzyme β-hexosaminidase A from mutations in the HEXA gene. Unlike the infantile form, LOTS typically manifests in adolescence or adulthood with slowly progressive neuromuscular symptoms, including weakness, muscle atrophy, and fasciculations. Because these features mimic those of motor neuron diseases, particularly amyotrophic lateral sclerosis (ALS), LOTS is frequently underrecognized and misdiagnosed. The clinical overlap between these entities poses a diagnostic challenge, delaying appropriate genetic counseling and management. Expanding awareness of LOTS and its phenotypic spectrum is essential, as identifying metabolic and potentially treatable conditions within the group of motor neuron syndromes may have significant implications for patient care and prognosis.

Three adult patients with an initial diagnosis of ALS due to progressive distal weakness, fasciculations, and signs of lower motor neuron involvement presented to our clinic. In all cases, brain magnetic resonance imaging showed ventricular enlargement without focal lesions, and nerve conduction studies demonstrated active denervation compatible with a lower motor neuron pattern. However, enzyme activity determination revealed a significant reduction in β-hexosaminidase A, confirming that they were carriers of mutations in the HEXA gene. The patients did not present relevant cognitive alterations or family history of ALS. Clinical and genetic reevaluation established the final diagnosis of LOTS.

 LOTS can clinically simulate ALS, sharing motor symptoms and electrophysiological findings. The identification of this similarity is fundamental, as LOTS is a metabolic disease with potential diagnosis through enzymatic and genetic analysis, which allows for a differentiated prognostic and family approach. Clinicians should consider LOTS within the differential diagnosis of late-onset motor neuron diseases.