Mild cognitive impairment in novel SPG4/SPAST mutation‐related sporadic late onset hereditary spastic paraplegia: case series

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AbstractBackgroundMutations and deletions in the SPG4/SPAST gene cause for up to 50% of the autosomal dominant forms of hereditary spastic paraplegia (HSP) and for up to 15% of the sporadic cases. Affected individuals have pyramidal signs in the lower limbs and some present additional features. Cognitive impairment is common in late‐onset forms of HSPs.MethodsThis study examined the cognitive abilities of 20 sporadic late‐onset patients with HSP using next‐generation sequencing. We also used a combination of the Mini‐Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) to assess their cognition.ResultsThe present study led to the discovery of three new pathogenic mutations of the SPG4 gene through evolutionary conservation and analysis of structural models. We also confirmed mild cognitive impairment (MCI) with normal MMSE scores (≥27) and reduced MoCA scores (<26) in these HSP‐SPG4 mutant patients. Such individuals mainly present with impaired executive function, delayed memory, abstraction and language.ConclusionsThe results broaden the mutational space of SPG4‐associated HSP with sporadic late‐onset modality and indicate a combination of reduced MoCA and normal MMSE for diagnosis, indicating that clinicians should consider performing a MoCA to detect MCI in patients with HSP, particularly those with sporadic onset SPG4/SPAST‐HSP.