More than 30% of individuals with KAND have private variants, and there are likely many more variants that remain to be identified. In the existing literature, 71 variants have been described to date, and here we describe 48 additional variants 2- 34, 37- 39, 41, 43- 45. A novel feature of KAND is the large number of disease-causing variants, predominantly missense variants within the motor domain of the protein. Variants can be inherited dominantly or recessively, with de novo variants associated with the most severe phenotypes. KIF1A Associated Neurological Disorder (KAND) encompasses a recently identified group of rare progressive neurodegenerative conditions caused by pathogenic variants in KIF1A 1- 42. We propose a new way to describe KAND subtypes to better capture the breadth of disease severity. Our findings suggest the clinical phenotypic heterogeneity in KAND likely reflects and parallels diverse molecular phenotypes. The molecular rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced binding is associated with milder clinical phenotypes. We find all patient variants result in defects in transport, and describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. For a subset of identified variants, we generated recombinant mutant proteins which we used to assess transport in vivo by assessing neurite tip accumulation, and to assess MT binding, motor velocity, and processivity using total internal reflection fluorescence microscopy. We found increased severity is strongly associated with variants occurring in regions involved with ATP and MT-binding: the P-loop, switch I, and switch II. Focusing on 100 individuals, we compared the average clinical severity score for each variant with in silico predictions of deleteriousness and location in the protein. We developed a heuristic severity score using a weighted sum of common symptoms to assess disease severity. Here we characterize the natural history of KAND in 117 individuals using a combination of caregiver or self-reported medical history, a standardized measure of adaptive behavior, clinical records, and neuropathology. KIF1A Associated Neurological Disorder (KAND) encompasses a recently identified group of rare neurodegenerative conditions caused by variants in KIF1A, a member of the kinesin-3 family of microtubule (MT) motor proteins.
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