NIPA1 Gene Mutations Cause Spastic Paraplegia Type 6 in Four Families

Abstract Objective Spastic paraplegia type 6 (SPG6) is a rare subtype caused by Non-imprinted in Prader-Willi/Angelman syndrome region protein 1 ( NIPA1 ) mutations. We reported four unrelated SPG6 families, reviewed related cases worldwide, and summarized the genotype-phenotype correlations. Methods We examined four probands, aged between 15 and 43 years, all presenting with progressive spasticity in the lower limbs and walking difficulty. Physical examinations consistently revealed hypertonia, hyperreflexia, and Babinski signs in lower limbs. We identified NIPA1 mutations through whole exome sequencing, validated these findings using Sanger sequencing or MLPA, and subsequently conducted family co-segregation analysis along with a reevaluation of the phenotypes. Results Four SPG6 cases from different families were enrolled. One of these patients showed additional features of demyelination neuropathy. Two heterozygous mutations c.316G > A (p.Gly106Arg) in NIPA1 and 15q11.2 BP1-BP2 microdeletion (harboring full-length NIPA1 ) were disclosed respectively. Conclusion Two various NIPA1 mutations were found in four unrelated SPG6 families, leading to distinct phenotypes. While most cases presented as pure forms, one of them exhibited complicated features including demyelination neuropathy. This variability supports the notion of inter- and intra-family heterogeneity in SPG6 and indicates that the clinical boundaries of NIPA1 -related conditions are still broadening.