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Background and purpose: Microtubule defects are a common feature in several neurodegenerative disorders, including hereditary spastic paraplegia. The most frequent form of hereditary spastic paraplegia is caused by mutations in the SPG4/SPAST gene, encoding the microtubule severing enzyme spastin. To date, there is no effective therapy available but spastin‐enhancing therapeutic approaches are emerging; thus prognostic and predictive biomarkers are urgently required. Methods: An automated, simple, fast and non‐invasive cell imaging‐based method was developed to quantify microtubule cytoskeleton organization changes in lymphoblastoid cells and peripheral blood mononuclear cells. Results: It was observed that lymphoblastoid cells and peripheral blood mononuclear cells from individuals affected by SPG4‐hereditary spastic paraplegia show a polarized microtubule cytoskeleton organization. In a pilot study on freshly isolated peripheral blood mononuclear cells, our method discriminates SPG4‐hereditary spastic paraplegia from healthy donors and other hereditary spastic paraplegia subtypes. In addition, it is shown that our method can detect the effects of spastin protein level changes. Conclusions: These findings open the possibility of a rapid, non‐invasive, inexpensive test useful to recognize SPG4‐hereditary spastic paraplegia subtype and evaluate the effects of spastin‐enhancing drug in non‐neuronal cells. [ABSTRACT FROM AUTHOR]