![]() We generated a KAND clinical severity score and correlate the clinical phenotype with genotype and molecular phenotype of the KIF1A motor. Here we describe the natural history of KAND in 117 individuals with 68 different variants in KIF1A, provide detailed medical and neurodevelopmental phenotypes, and demonstrate a wide range of clinical severity with associated neuropathology on autopsy. More recently, individuals with clinically diagnosed Rett Syndrome were identified with de novo KIF1A variants in individuals who did not have variants in the genes that predominantly cause Rett syndrome ( MECP2, CDKL5 and FOXG1) 35, 40. Heterozygous variants in KIF1A have been associated with NESCAV syndrome (Neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment, formerly mental retardation autosomal dominant 9) (MIM:614255), PEHO syndrome (Progressive encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy) and with inherited cases of both simple and complicated HSP 4- 34, 37- 39, 41, 43- 45. Individuals with biallelic missense variants in the motor domain were found to have HSP 30 3, a condition consisting of peripheral nerve degeneration and severe distal sensory loss with distal motor involvement. KIF1A has been associated with two different autosomal recessive conditions: hereditary spastic paraplegia (HSP, MIM:610357) and hereditary sensory and autonomic neuropathy (HSAN, MIM:614213) 2, 3. The progression of kinesins along MTs requires ATP binding and hydrolysis, which cause conformational changes within the motor domain that power the forward motion of the motor 46. It predominately functions as a dimer and is responsible for anterograde transport of multiple cargos including synaptic vesicle precursors and dense core secretory vesicles on axonal and dendritic MTs 46, 47. KAND has a broad phenotypic spectrum, which can include spasticity, neurodevelopmental delay, intellectual disability, autism, microcephaly, progressive spastic paraplegia, autonomic and peripheral neuropathy, optic nerve atrophy, cerebral and cerebellar atrophy, and seizures 2- 34, 37- 39, 41, 43- 45.Īt the cellular level, KIF1A is a neuron-specific member of the kinesin-3 family of ATP-dependent microtubule (MT) molecular motor proteins. 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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