Autosomal Dominant Hereditary Spastic Paraplegia (Ad-Hsp), the Spast Gene Variations and Evidence For Anticipation

Background and aim: hereditary spastic paraplegia (hsp) is a heterogeneous neurodegenerative disorder with lower-limb spasticity and weakness in pure form, while neurological and non-neurological complications appear in complex form. different patterns of inheritance and >70 genes have been identified that contribute to the cause of hsp, so far. most of autosomal dominant-hsps (ad-hsps) are associated with mutations of the spast gene (spg4), which account for 17-79% of all ad-hsp cases, causing pure form, but sometimes with cognitive impairment. anticipation is the phenomenon whereby a genetic disorder is passed to next generation, it is manifested in earlier ages, such a decrease of age-at-onset (aao) is noted to be adherent with increased severity. here, we tried to present more evidence that anticipation is present in ad-hsp caused by spast mutations.methods: whole-exome sequencing (wes) was done on 14 ad-hsp unrelated iranian probands. data were analyzed and candidate variants were pcr-amplified and sequenced by sanger method subsequently checked in family members in order to co-segregation analysis. the families harboring mutations in spast were selected. clinical features of all affected individuals were recorded in details and the probable anticipation was checked in these families.results: our results showed that three of 14 probands, harbor mutations in the spast gene. these mutations co-segregated in the family members. clinical features of these families indicate decreasing aao and increasing of severity of the disease in successive generations. mean aaos in first-generations were 9±1, 47±5, >40 years and in second-generations were 3±0.9, 22.5±2, 16.5±10.5 years, respectively and the difference in the aao among generations were significant.conclusion: anticipation, a biological phenomenon mainly attributed to dynamic mutations, is occasionally attributed to static mutations. for instance, some missense and splice-site mutations insod1 which causes amyotrophic lateral sclerosis (als) have been associated with anticipation. it seems that this phenomenon is not repeat expansion-specific and can be seen in various static mutations in different genes such as the spast gene variations, indicating the importance of consideration of vast genetic, epigenetic and environmental factors. underlying mechanism of anticipation seems to be rather disease-related than general and deep understanding of disease mechanism in pivotal for interpreting anticipation. grant no=963846