Experience in the clinical and genetic diagnosis of a series of Algerian patients with hereditary spastic paraplegias.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative diseases that include more than 90 genetic forms. The diagnosis of HSPs is challenging owing to their exceptional clinical and genetic heterogeneity. Using whole exome sequencing (WES), we investigated the genetic and clinical features of 29 patients from 16 Algerian families diagnosed with HSPs. The prevalence of complicated forms was higher than that of pure forms, with interfamilial clinical variability. We identified pathogenic variants in 11 HSPs-causing genes with a diagnostic rate of 81.2%. The diagnosed families mainly presented an autosomal recessive inheritance pattern due to the high frequency of consanguineous marriages in Algeria. Five novel causative variants were identified in the homozygous state: GBA2:c.1351 C > T/p.Arg451Ter in two sisters with the standard SPG46 phenotype; SPG11:c.6530_6534del in three siblings with a complicated HSP phenotype without thin corpus callosum; HPDL:c.862T > C/p.Tyr288His in a patient with complicated HSP; AMFR:c.707 + 1G > A in a patient with a complicated form extending the clinical spectrum of SPG89; and SPAST:c.1076T > C in two sisters with a pure HSP form overlapping with the classical SPG4 phenotype associated with dominant pathogenic variants in the same gene. In one family, reverse phenotyping revealed a case of Kufor-Rakeb syndrome after ATP13A2 variants were identified, showing the importance of dialogue between clinicians and geneticists. This study is the first series of HSPs consisting exclusively of Algerian families. Our findings broaden the clinical and genetic spectrum of HSPs, confirm their high heterogeneity in Algeria, and underline the efficiency of WES as a diagnostic tool for genetically heterogeneous diseases.