Background

Monoallelic variants in the KIF1A gene are associated with a large set of clinical phenotypes including neurodevelopmental and neurodegenerative disorders, underpinned by a broad spectrum of central and peripheral nervous system involvement.

Methods

In a multicenter study conducted in patients presenting spastic gait or complex neurodevelopmental disorders, we analyzed the clinical, genetic and neuroradiological features of 28 index cases harboring heterozygous variants in KIF1A. We conducted a literature systematic review with the aim to comparing our findings with previously reported KIF1A-related phenotypes.

Results

Among 28 patients, we identified nine novel monoallelic variants, and one a copy number variation encompassing KIF1A. Mutations arose de novo in most patients and were prevalently located in the motor domain. Most patients presented features of a continuum ataxia-spasticity spectrum with only five cases showing a prevalently pure spastic phenotype and six presenting congenital ataxias. Seventeen mutations occurred in the motor domain of the Kinesin-1A protein, but location of mutation did not correlate with neurological and imaging presentations. When tested in 15 patients, muscle biopsy showed oxidative metabolism alterations (6 cases), impaired respiratory chain complexes II + III activity (3/6) and low CoQ10 levels (6/9). Ubiquinol supplementation (1gr/die) was used in 6 patients with subjective benefit.

Conclusions

This study broadened our clinical, genetic, and neuroimaging knowledge of KIF1A-related disorders. Although highly heterogeneous, it seems that manifestations of ataxia-spasticity spectrum disorders seem to occur in most patients. Some patients also present secondary impairment of oxidative metabolism; in this subset, ubiquinol supplementation therapy might be appropriate.

中文翻译：

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单等位基因 KIF1A 相关疾病：多中心横断面研究和系统文献综述

背景

KIF1A基因中的单等位基因变异与大量临床表型相关，包括神经发育和神经退行性疾病，受广泛的中枢和周围神经系统参与所支持。

方法

在对呈现痉挛步态或复杂神经发育障碍的患者进行的一项多中心研究中，我们分析了 28 个在KIF1A中携带杂合变异的指示病例的临床、遗传和神经放射学特征。我们进行了文献系统回顾，目的是将我们的发现与之前报道的KIF1A相关表型进行比较。

结果

在 28 名患者中，我们确定了九个新的单等位基因变异，一个包含KIF1A 的拷贝数变异。大多数患者的突变是从头发生的，并且普遍位于运动区。大多数患者表现出连续性共济失调-痉挛谱的特征，只有 5 例表现出普遍的单纯痉挛表型，6 例表现出先天性共济失调。17 个突变发生在 Kinesin-1A 蛋白的运动域，但突变位置与神经学和影像学表现无关。当对 15 名患者进行测试时，肌肉活检显示氧化代谢改变（6 例）、呼吸链复合物 II + III 活性受损（3/6）和辅酶 Q10 水平低（6/9）。6 名主观获益的患者使用泛醇补充剂（1gr/die）。

结论

这项研究拓宽了我们对KIF1A相关疾病的临床、遗传和神经影像学知识。尽管高度异质性，似乎共济失调-痉挛谱系障碍的表现似乎发生在大多数患者身上。部分患者还出现继发性氧化代谢障碍；在这个子集中，泛醇补充疗法可能是合适的。