Intrafamilial Variable Phenotype of Complicated Hereditary Spastic Paraplegia, Ataxia and Motor Neuron Disease Linked to a Novel KIF5A C-Terminal Domain Mutation

Abstract

Objectives: To genetically investigate a hereditary neurodegenerative disease in a kindred with an intra-familial variable phenotype of complicated hereditary spastic paraplegia with and without cerebellar ataxia and motor neuron disease. Methods: With a detailed clinical evaluation, five members of a family with autosomal dominant inherited neurological illness were subjected for whole exome sequencing. The identified disease causing variation was validated functionally by demonstration of exon skipping on cDNA based amplification of KIF5A. Results: We have identified a kindred with multiple affected individuals who manifested complicated hereditary spastic paraplegia (proband), a maternal uncle manifested Amyotrophic lateral sclerosis/Ataxia phenotype and another symptomatic individuals with cerebellar ataxia phenotype. Genetic investigations by whole exome sequencing revealed a novel heterozygous c.3020+3 A>T variant in KIF5A gene segregating with only affected individuals. The variant resides near 3’splice site junction of exon 27 of KIF5A gene. KIF5A transcript was demonstrated to be have skipped exon 27 in RNA extracted from peripheral whole blood. Conclusions: It has also been documented that C-terminal variants of KIF5A are exclusively associated with the ALS phenotype. We reported a family carrying a C-term mutation with a very complex phenotype affecting spinal cord and cerebellar axis, which is contrary to the reported observation with other C-terminal KIF5A mutant allele. This findings allows an understanding of the role of this important family of gene to have a converging molecular alterations leading to Neurodegenration.