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Objective  Hereditary spastic paraplegias ( HSP s) are among the most genetically diverse inherited neurological disorders, with over 70 disease loci identified ( SPG 1‐71) to date.  SPG 15 and  SPG 11 are clinically similar, autosomal recessive disorders characterized by progressive spastic paraplegia along with thin corpus callosum, white matter abnormalities, cognitive impairment, and ophthalmologic abnormalities. Furthermore, both have been linked to early‐onset parkinsonism.    Methods  We describe two new cases of  SPG 15 and investigate cellular changes in  SPG 15 and  SPG 11 patient‐derived fibroblasts, seeking to identify shared pathogenic themes. Cells were evaluated for any abnormalities in cell division,  DNA  repair, endoplasmic reticulum, endosomes, and lysosomes.    Results  Fibroblasts prepared from patients with  SPG 15 have selective enlargement of  LAMP 1‐positive structures, and they consistently exhibited abnormal lysosomal storage by electron microscopy. A similar enlargement of  LAMP 1‐positive structures was also observed in cells from multiple  SPG 11 patients, though prominent abnormal lysosomal storage was not evident. The stabilities of the  SPG 15 protein spastizin/ ZFYVE 26 and the  SPG 11 protein spatacsin were interdependent.    Interpretation  Emerging studies implicating these two proteins in interactions with the late endosomal/lysosomal adaptor protein complex  AP ‐5 are consistent with shared abnormalities in lysosomes, supporting a converging mechanism for these two disorders. Recent work with  Zfyve26 −/− mice revealed a similar phenotype to human  SPG 15, and cells in these mice had endolysosomal abnormalities.  SPG 15 and  SPG 11 are particularly notable among  HSP s because they can also present with juvenile parkinsonism, and this lysosomal trafficking or storage defect may be relevant for other forms of parkinsonism associated with lysosomal dysfunction.

Lysosomal abnormalities in hereditary spastic paraplegia types SPG 15 and SPG 11