Epilepsy in hereditary spastic paraplegia associated with NIPA1 gene

Boysen, Sebastian; Elumalai, Vimala; ElSheikh, Reem H; Aravindhan, Akilandeswari; Veerapandiyan, Aravindhan

doi:10.1016/j.jocn.2022.02.013

Cited by 1 publication

(2 citation statements)

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“…18,19,21,24 Interestingly, SPG6 with complex HSP is usually caused by NIPA1 c.316G>A mutation, but may be infrequently found in patients with NIPA1 c.316G>C, c.134C>G (p.T45R), or c.249C>G (p.N83K) mutation, too. 11,28,35 De novo NIPA1 mutation had also been reported in few SPG6 patients with apparently sporadic phenotype. 10,24 In this study, both SPG6 patients had no family history, and one had pure HSP and the other had HSP with epilepsy and schizophrenia.…”

Section: Discussionmentioning

confidence: 97%

“…The additional neurological manifestations in SPG6 could be epilepsy, 10,14,20,24,27,28 ataxia, 24,25 cognitive impairment, 14,17,21 motor neuron disease, 27 and/or peripheral neuropathy 18,19,21,24 . Interestingly, SPG6 with complex HSP is usually caused by NIPA1 c.316G>A mutation, but may be infrequently found in patients with NIPA1 c.316G>C, c.134C>G (p.T45R), or c.249C>G (p.N83K) mutation, too 11,28,35 . De novo NIPA 1 mutation had also been reported in few SPG6 patients with apparently sporadic phenotype 10,24 .…”

Section: Discussionmentioning

confidence: 99%

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Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia

Fang

Chou

Hsu

et al. 2023

Ann Clin Transl Neurol

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Objective NIPA1 mutations have been implicated in hereditary spastic paraplegia (HSP) as the cause of spastic paraplegia type 6 (SPG6). The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort. Methods We screened 242 unrelated Taiwanese patients with HSP for NIPA1 mutations. The clinical features of patients with a NIPA1 mutation were analyzed. Minigene‐based splicing assay, RT‐PCR analysis on the patients' RNA, and cell‐based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression. Results Two patients were identified to carry a different heterozygous NIPA1 mutation. The two mutations, c.316G>A and c.316G>C, are located in the 3′ end of NIPA1 exon 3 near the exon–intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring NIPA1 c.316G>A manifested spastic paraplegia, epilepsy and schizophrenia since age 17 years, whereas the individual carrying NIPA1 c.316G>C had pure HSP since age 12 years. We reviewed literature and found that epilepsy was present in multiple individuals with NIPA1 c.316G>A but none with NIPA1 c.316G>C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G>A mutation was associated with a significantly reduced NIPA1 protein expression. Interpretation SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The NIPA1 c.316G>A and c.316G>C mutations are associated with adolescent‐onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy.

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