Objective: We present clinical, electrophysiological and genomic data of a consanguineous family with two affected siblings suffering from spasticity and severe ataxia.

Background: Mutations in the KIF1C gene cause autosomal recessive spastic ataxia type 2 (SPAX2) also termed hereditary spastic paraplegia type 58 (SPG58). Both are very rare diseases with until now only five published affected families caused by four known different mutations. Severe cerebellar ataxia with dysarthria and pyramidal tract dysfunction are the main symptoms. Additional peripheral neuropathy was suggested in one family but electrophysiological data are not available.

Methods: We performed extensive clinical and electrophysiological investigations in one affected sibling. Genomic DNA of the index patient was used for analysis of spastic ataxia associated genes by exome enrichment using the Nextera Rapide Capture Exome Kit followed by next generation sequencing (NGS) on a NextSeq desktop sequencer (Illumina). Data analysis was done by the software GensearchNGS (PhenoSystems), pathogenicity and splice predictions were carried out using the algorithms embedded in Alamut (Interactive Biosoftware).

Results: The parents of the female proposita are consanguineous and originate from Turkey. Their daughter reported first symptoms of progressive gait disturbance and coordination problems at the age of 8 years. Physical examination at age 21 exhibited cerebellar dysarthria, complex oculomotor dysfunction, spasticity and proximal paresis of the lower limbs as well as severe cerebellar ataxia resulting in wheelchair-dependency. The family reported that the 5 years older brother suffers from similar symptoms. Electrophysiological investigations of the index patient showed severe sensorimotor neuropathy and highly pathologic evoked potentials. NGS analysis revealed a homozygous new sequence variant c.864+1G>A at the donor splice site of exon 10 in the KIF1C gene. This variant was consistently predicted by multiple algorithms to disrupt the splice site resulting in skipping of exon 10 and (probable) subsequent protein dysfunction. Autosomal recessive inheritance was proven by segregation analysis.

Conclusions: We present a new splice site mutation in KIF1C causing a disease phenotype consistent with spastic ataxia type 2 and we extend the clinical spectrum to additional sensorimotor neuropathy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-homozygous-splice-site-mutation-in-the-kif1c-gene-spax2-spg58-found-in-a-consanguineous-turkish-family/