Expanding the Genotype-phenotype Correlations in KIF5A-related Disorder: A Study on a Large Multigenerational Kindred
Jaroslaw Dulski1, Shan Ali1, Audrey Strongosky1, Zoe Parrales1, Judith Dunmore2, Zbigniew Wszolek1
1Department of Neurology, 2Department of Neuroscience, Mayo Clinic Florida
Objective:
To study genotype-phenotype correlations in KIF5A-related disorder.
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.
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.