Submission Details

KIF5A was first linked to hereditary spastic paraplegia (SPG10) in 2002. However, over time the phenotypic spectrum of KIF5A has broadened to include disorders such as pure & complex HSP, autosomal dominant Charcot-Marie-Tooth type 2 (CMT2), Amyotrophic Lateral Sclerosis (ALS) and neonatal intractable myoclonus (NEIMY). Due to differences in phenotype and genotype clustering, we split ALS and NEIMY. However, the HSP and CMT2 phenotypes have suspicious genetic and phenotypic overlap. Variants in the motor domain of KIF5A have been presented as causing pure & complex HSP as well as CMT2. In some cases, the intra-familial variability of a variant can assign a primarily HSP phenotype without neuropathy to one sibling, and CMT2 with pyramidal signs to another. For these reasons, we have decided to lump SPG10 and CMT2. In this curation, we scored 10 variants from 10 families as well as segregation by linkage analysis to collect a genetic evidence score of 8 (PMID: 25008398, 18853458, 12355402). There were two animal models studied for KIF5A mutations. A (-/-) KIF5A mouse showed an axonal transport deficit affecting motor neurons more seriously than sensory neurons. A N256S drosophila HSP model also induced axonal transport and motor neuron disease. The results of these studies suggested a dominant-negative action of mutant KIF5A on the kinesin-1 complex. These animal models as well as functional evidence (immunoblot) scored 4.5 points of experimental evidence (PMID :10964943, 22466687, 23209432). These tally to 12.5 points: definitive with replication over time. While literature suggests the primary manifestation of mutations in this gene is HSP, there have been many cases, where the clinical presentation is CMT2, potentially with subclinical signs of HSP. It is likely that KIF5A mutations infer a continuum of phenotypic manifestations and signs for complex HSP and CMT2 should be studied in patients. In summary, KIF5A is definitively associated with autosomal dominant HSP and CMT2.