A 50-year-old man presented with two years of progressive speech and gait difficulties. Neurological examination revealed spastic dysarthria, tongue fasciculations, ankle and foot weakness, generalized hyperreflexia and bilateral Hoffman’s sign. His father and paternal uncle had ALS. Within one year of his presentation, he had progressed to needing intermittent BiPAP at night and a rolling walker for ambulation. ALS-FRS at presentation was 40 and had declined to 30 within 1.5 years. An EMG/NCS of the right upper and lower extremities as well as the tongue and thoracic paraspinal muscles was normal except for fasciculations noted in the triceps.
Genetic testing revealed heterozygosity for the NM_004984.4 c.3019A>G (p.Arg1007Gly) Kinesin family member 5A (KIF5A) gene mutation (KIF5AdeltaExon27). This variant has a missense mutation upstream of the splice donor site of exon 27 producing a protein with an altered tail region. In vitro, this altered protein forms neurotoxic cytoplasmic aggregates. Kinesin-1 family proteins form a dimeric heavy chain structure responsible for antegrade axonal trafficking along microtubules. The proteins have three domains, the motor domain is on the N-terminus and contains the ATP and microtubule binding sites, the alpha-helical coiled-coiled region stalk domain is the central part of the protein and is responsible for heavy chain dimerization, and the globular tail domain on the C-terminus with binds to cargos and kinesin light chains. This is the second report of the c.3019A>G KIF5A mutation in familial ALS, but the first report of bulbar-onset upper motor neuron predominant familial ALS with this mutation.