Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases

Abstract

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic inframe deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of

Expanding the Knowledge of KIF1A-Dependent Disorders to a Group of Polish Patients

“…Interestingly, contrary to the literature, ataxia was not observed at the last assessment of our patients [24,25]. In one individual (patient 1), cerebellar atrophy was noted in neuroimaging, and he presented with dystonia.…”

“…Comparisons of our patients with the available literature data are shown in Tables 3-5. KIF1A-related disorders probably remain underdiagnosed because of the dominant relation with HSP and less known coincidence with a multisystem and progressive course with upper motor neuron dysfunction and extrapyramidal signs with neuropathy [24][25][26][27][28][29][30][31].…”

Autosomal dominant neurodevelopmental disorders associated with <italic>KIF1A</italic> gene variants in 6 pediatric patients

“…基于 KIF1A 基因变异引起的临床表型异质性较强，且NESCAVS、SPG30和HSN2C的表型互有重叠，临床难以作出精准分型，近年来已有文献将其统一归类为 KIF1A 基因相关神经系统疾病 ［ 14 ］ 。有学者建议根据基因型（以表型作为参考）对 KIF1A 基因变异病例进行分类，而不是传统的根据表型（以基因型作为参考）分类的模式；即将重点放在患者变异位点和特定表型上，而不是单纯型或复杂型综合征的诊断上 ［ 15 ］ 。这一分类依据已在部分变异位点得以验证，如p.S58L、p.T99M、p.E253K和p.T258M变异的患者往往行走困难且伴有癫痫，而p.S69L、p.A255V、p.R350G等变异的患者主要表现为痉挛性截瘫 ［ 14 ］ 。…”

“…目前已鉴定到的 KIF1A 变异主要集中在运动结构域，且大部分源自散发病例；目前已报道的200余例 KIF1A 基因变异患者中 ［ 2 ， 15 - 16 ， 27 ， 29 - 30 ］ ，近70%为患儿自发新生突变。除上述少数变异位点外，大部分 KIF1A 基因变异尚未建立显著的基因型-临床表型关联，仍需积累更多病例数据观察。最近有假说提出了一种变异特异性的剂量效应：一些变异可能仅涉及远端轴突顺行运输的轻微损伤，导致较轻微的表型；而另一些变异可能损害近端轴突及其他神经元群体，导致严重的表型；少数已报道的功能丧失型变异会造成KIF1A蛋白水平降低而导致运输减少 ［ 3 ］ 。然而即使是同一变异的患者也存在临床异质性，或许需要考虑其他驱动蛋白的补偿机制以及其他未知的遗传或环境因素。…”

KIF1A-Associated Neurological Disorder: An Overview of a Rare Mutational Disease

“…The molecular motor KIF1A affects the survival and development of sensory neurons in our body as well as the movement of membrane-bound cargo [ 7 ]. If there are any disturbances in these neuronal trafficking pathways, which are strictly controlled due to the functional compartmentalization of neurons and connect the neuron’s body, dendrites, and axons, neurodegenerative diseases would result [ 8 ].…”