OBJECTIVE: To determine the cause and course of a novel syndrome with progressive @entity75 and @entity1010 in @entity1 . METHODS: Clinical whole-exome sequencing was performed for @entity245 and @entity717 ; some @entity1 also had @entity3500 and evidence of clinical regression. Six @entity1 were identified with de novo missense mutations in the kinesin gene @entity19572 . The predicted functional disruption of these mutations was assessed in silico to compare the calculated conformational flexibility and estimated efficiency of @entity855 binding to kinesin motor domains of wild-type (WT) versus mutant alleles. Additionally, an in  vitro microtubule gliding assay was performed to assess the effects of de novo dominant, inherited recessive, and polymorphic variants on @entity19572 motor function. RESULTS: All six subjects had severe @entity245 , @entity2421 , and varying degrees of @entity427 and @entity3500 . @entity4242 , cortical @entity227 , @entity1781 , @entity1897 , @entity2055 , @entity302 , and @entity717 were also observed. All six @entity1 had a @entity179 with progressive cerebral and @entity76 seen on sequential magnetic resonance imaging scans. Computational modeling of mutant protein structures when compared to WT kinesin showed substantial differences in conformational flexibility and @entity855 -binding efficiency. The de novo @entity19572 mutants were nonmotile in the microtubule gliding assay. INTERPRETATION: De novo mutations in @entity19572 cause a @entity179 with @entity1010 . Computational and in  vitro assays differentiate the severity of dominant de novo heterozygous versus inherited recessive @entity19572 mutations. The profound effect de novo mutations have on axonal transport is likely related to the cause of progressive @entity16 in these @entity1 .

De novo mutations in @entity19572 cause progressive @entity75 and XXXX .

@entity1 :: ('9606', 'Species') :: ['children', 'patients'] @entity227 :: ('MESH:D014786', 'Disease') :: ['visual impairment'] @entity75 :: ('MESH:D001927', 'Disease') :: ['encephalopathy'] @entity3500 :: ('MESH:D020336', 'Disease') :: ['spastic paraparesis'] @entity16 :: ('MESH:D009422', 'Disease') :: ['neurologic impairment'] @entity19572 :: ('547', 'Gene') :: ['KIF1A'] @entity245 :: ('MESH:D002658', 'Disease') :: ['developmental delay', 'global developmental delay'] @entity2055 :: ('MESH:D001259', 'Disease') :: ['ataxia'] @entity1010 :: ('MESH:C566985', 'Disease') :: ['brain atrophy'] @entity1897 :: ('MESH:D010523', 'Disease') :: ['peripheral neuropathy'] @entity2421 :: ('MESH:D009123', 'Disease') :: ['hypotonia'] @entity1781 :: ('MESH:D009901', 'Disease') :: ['optic neuropathy'] @entity302 :: ('MESH:D004827', 'Disease') :: ['epilepsy'] @entity179 :: ('MESH:D019636', 'Disease') :: ['degenerative neurologic course', 'degenerative neurologic syndrome'] @entity4242 :: ('MESH:D008831', 'Disease') :: ['Microcephaly'] @entity76 :: ('MESH:D002526', 'Disease') :: ['cerebellar atrophy'] @entity717 :: ('MESH:D009069', 'Disease') :: ['movement disorders', 'intellectual disability'] @entity427 :: ('MESH:D012021', 'Disease') :: ['hyperreflexia'] @entity855 :: ('MESH:D000255', 'Chemical') :: ['ATP']
@entity1010 :: (MESH:C566985,Disease) :: ['brain atrophy']
