Hereditary spastic paraplegia (HSP) encompasses a heterogeneous and expanding group of neurodegenerative conditions in which the prominent clinical features are progressive spasticity and weakness of lower limbs, which may (complicated HSP) or may not (pure HSP) be associated with additional symptoms. To date more than 50 HSP loci (SPG1-SPG53) have been mapped and 29 genes identified. This project aim to genetically analyse six families (five Omani and one Turkish) presenting with HSP. Two main approaches were used in this project to identify the causative gene in each family; Homozygosity mapping technique and Exome sequencing. These methodologies led to the identification of 3 novel mutations (not reported before in dbSNP build 131) in 3 different genes in 3 of the families studied. A novel splice-site mutation (c.2351+2 C>A) in amyotrophic lateral sclerosis 2 (ALS2) gene (2933.1) in the Turkish family with four affected siblings was identified. Moreover, another novel mutation was identified in one of the Omani families with one affected child in solute carrier family 22, member 17 (SLC22A17) gene linked to 14q11.2. This missense mutation (c.499 G>A) gives a probability to which SLC22A17 gene would be a potential novel HỢP gene. Additionally, exome sequencing accompanied with homozygosity mapping identified a potential novel HSP gene in a third with three affected siblings. The mutation identified is a missense mutation in ethanolaminephosphotransferase 1 (EPTI) gene linked to 2p23.3. PCR-based direct sequencing of other family members revealed that the mutation c.335G>C in EPT1 gene co-segregates in the family and is absent in 100 Omani control chromosomes. Further analysis is recommended to prove SLC22A17 and EPT1 genes to be novel HSP causing genes added to the 29 genes previously identified. For TecOIIII! the other three families in this study, the causative genes could not be identified. However, direct sequencing excludes the known HSP variants in the coding regions and splice sites for all the known HSP genes in the homozygous regions.