“…The remaining set of variants have only been reported with CNS involvement; out of these variants causing CNS involvement, the variant associated with the most severe phenotype is p.Glu253Lys-also present in subject BG3associating with severe developmental delay (nonambulatory, nonverbal), optic nerve atrophy, seizures, and cerebellar atrophy (Esmaeeli Nieh et al, 2015;Lee et al, 2015;Muir et al, 2019;Samanta & Gokden, 2019). Thus, there is a striking distinction between variants that tend to cause pure HSP versus those causing the vast majority of HSP cases with CNS involvement, indicative of been reported as causal for both "pure" and "complicated" AD HSP, MRD9, PEHO syndrome, and optic atrophy (Cheon et al, 2017;Esmaeeli Nieh et al, 2015;Lee et al, 2015;Pennings et al, 2020;Raffa et al, 2017;Samanta & Gokden, 2019). Some clinical features are shared between these entities: lower-extremity spasticity, hypotonia, intellectual disability, cerebellar and optic atrophy, hyperreflexia, and convulsion/seizures.…”