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INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, vol.85, no.5, 2025 (SCI-Expanded)
Hereditary spastic paraplegia (HSP) represents a genetically heterogeneous group of neurodegenerative disorders characterized by progressive axonal degeneration of corticospinal upper motor neurons, leading to lower limb-predominant spasticity and weakness. To date, 83 HSP subtypes have been reported, exhibiting either pure or complicated phenotypes. Among these, spastic paraplegia type 64 (SPG64) is an ultra-rare form of complicated HSP caused by biallelic variants in ENTPD1, which encodes an ectonucleotidase involved in purine metabolism. In this study, we report a proband presenting with neurodevelopmental regression, dysmorphic features and sensorimotor polyneuropathy, followed comprehensively for 6 years. Genetic analysis identified a novel homozygous NM_001776:c.1174C>T;p.Gln392Ter variant in ENTPD1. A literature review reveals that 39 individuals with SPG64 have been reported, with clinical manifestations including cognitive decline (38/39), speech abnormalities (30/39) and brain malformations (16/31). However, aspects of the full phenotypic spectrum remain to be fully characterized. Notably, this case represents the first documented patient with long-term follow-up, providing valuable clinical insights into disease progression over time. Neuroimaging in the proband demonstrated the involvement of the posterior limb of the internal capsule and the 'ear of the lynx' sign, which was not previously reported in SPG64. Furthermore, the presence of sensorimotor polyneuropathy supports that neuropathy may be a previously unappreciated component of SPG64. Our findings highlight the importance of deep phenotyping and long-term follow-up in fully understanding the nature of this unique HSP subtype.