Abstract Details

Title Expanding the Genotype-phenotype Correlations in KIF5A-related Disorder: A Study on a Large Multigenerational Kindred

Topic Movement Disorders

Presentation(s) S35 - Movement Disorders: Hyperkinetic Movement Disorders (4:18 PM-4:30 PM)

Poster/Presentation
Number 005

Background KIF5A mutations are a well-established cause of amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia type 10 (HSP10), and sensory neuropathy type 2 (Charcot-Marie-Tooth disease type 2, CMT2). It was suggested that the phenotype is determined by the mutation location within the KIF5A gene, with the C-terminal mutations (amino acids 907-1032) manifesting primarily with ALS and N-terminal mutations resulting in HSP10 or CMT2.

Objective

To study genotype-phenotype correlations in KIF5A-related disorder.

Design/Methods

A large American five-generation pedigree (n=52) was studied. We personally examined 10 (men n=4) family members. The evaluation included detailed history taking, neuropsychological assessment (MoCA), clinical evaluation (neurological examination, scales: MDS-UPDRS, ALS Functional Rating Scale Revised, Rasch Overall ALS Disability Scale), video documentation, and specimen collection (plasma and skin). Whole-exome sequencing (WES) was performed in the proband, whereas targeted genetic testing was done in other family members.

Results

We observed heterogeneity in clinical presentation among the individual family members, with variable isolated or combined signs of spastic paraplegia, ALS, parkinsonism, sensory neuropathy, and dementia. WES found KIF5A c.3020G>A (p.Arg1007Lys) mutation in the proband. The targeted genetic testing in the two other affected individuals confirmed the presence of the variant. Genetic testing in other family members, as well as a more detailed analysis of neuropsychological and clinical (including scales) characteristics, was underway at the moment of abstract submission.

Conclusions There is substantial heterogeneity in the clinical presentation of the KIF5A p.Arg1007Lys mutation, even among the members of the same family. Therefore, other genetic and environmental factors most likely contribute to the clinical variability of KIF5A-related disorders. As most affected cases develop an overlap syndrome of different neurological disorders (ALS, HSP10, and CMT2), family history suggestive of co-occurrence of these disorders should direct the differential diagnosis toward KIF5A mutations.

Authors/Disclosures
Jaroslaw Dulski, MD, PhD PRESENTER	Dr. Dulski has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for VM Media Ltd.. Dr. Dulski has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Radoslaw Lipinski 90 Consulting. Dr. Dulski has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Ipsen. Dr. Dulski has received research support from Polish Neurological Society. Dr. Dulski has received research support from Polish National Agency for Academic Exchange. Dr. Dulski has received intellectual property interests from a discovery or technology relating to health care.
Shan Ali, MD (Mayo Clinic)	Mr. Ali has nothing to disclose.
Audrey Strongosky	No disclosure on file
Zoe Parrales (Mayo Clinic)	No disclosure on file
Judith Dunmore (Mayo Clinic)	No disclosure on file
Zbigniew K. Wszolek, MD, FAAN (Mayo Clinic- Jacksonville)	Dr. Wszolek has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Polish Neurological Society/Via Medica.