Three Iranian Patients With Rare Subtypes of Hereditary Spastic Paraplegia (Hsp): Spg76, Spg56, and Spg69 Publisher Pubmed



Sadr Z¹ ; Ghasemi A² ; Rohani M³ ; Khorram Khorshid HR¹ ; Habibikavashkohie MR^{1, 4} ; Mohammadi Y¹ ; Alavi A^{1, 2} Show Affiliations
Source: Neurogenetics Published:2025

Abstract

Some subtypes of hereditary spastic paraplegia (HSP), especially with autosomal recessive inheritance (AR-HSP), have been reported rarely. In this study, we report the clinical features and molecular results of three unrelated Iranian patients with rare subtypes of HSP, including SPG76, SPG56, and SPG69; thereafter, we compare them to other reported cases. Three patients who were clinically diagnosed with HSP and born to consanguineous parents underwent molecular assessment by whole-exome sequencing (WES), followed by Sanger sequencing and co-segregation analysis. Two patients carried biallelic pathogenic variants in CAPN1, or CYP2U1, resulting in SPG76, and SPG56, respectively. Additionally, another patient presented with a variant of uncertain significance (VUS) in the gene associated with SPG69, known as RAB3GAP2. Variants of CAPN1 and RAB3GAP2 are novel while the CYP2U1 variant has been previously reported. The patient with the RAB3GAP2 variant is the second reported SPG69 case. Our findings emphasize that the rare forms of AR-HSP may be more prevalent in communities with a high rate of consanguineous marriages, and WES can be a highly effective tool for identifying pathogenic variants in these communities. Also, the CYP2U1 variant seems to be a founder mutation because it was previously reported in 8 patients of three families from the Middle East. These results expand the variant spectrum of the CAPN1 and RAB3GAP2 genes. Also, given the association of variants in CAPN1 and RAB3GAP2 with a diverse array of phenotypes, we propose the use of the terms CAPN1-related disorders and RAB3GAP2-related disorders as alternatives to HSP76 and HSP69, respectively. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.