VRK1 encodes a serine/protein kinase possibly involved in pathways related to amyotrophic lateral sclerosis (ALS) pathogenesis. Pathogenic variants in VRK1 have been related to different phenotypes. We describe the clinical phenotype of two unrelated Portuguese patients with different VRK1 variants. Both patients presented a bilateral distal weakness in lower limbs beginning in childhood slowly progressing to upper limbs, associated with pyramidal signs, without bulbar, respiratory or cognitive involvement, according to probable ALS. Imaging and nerve conduction studies were unremarkable in both patients. Genetic testing in patient 1 identified two VRK1 variants in heterozygosity: c.265C > T, p.(Arg89*) and c.769G > A, p.(Gly257Ser), classified as pathogenic and variant of uncertain significance, respectively. In patient 2, two probably pathogenic variants in VRK1 were identified in heterozygosity: c.710-14T > C in intron 8 and c.721C > T, p.(Arg241Cys) in exon 9. We report two unrelated patients with different variants in VRK1 displaying a similar childhood-onset motor neuron disease/ALS, further expanding the phenotypic spectrum associated to VRK1 variants.

VRK1编码可能与肌萎缩性侧索硬化症（ALS）发病机制有关的通路中的丝氨酸/蛋白激酶。VRK1中的致病变异与不同的表型有关。我们描述了具有不同VRK1变异的两名无关葡萄牙患者的临床表型。根据可能的ALS，这两名患者均从儿童期开始出现下肢双侧远端无力，逐渐发展为上肢，伴有锥体束征，无延髓，呼吸或认知障碍。影像学和神经传导研究在这两名患者中均无异常。患者1的基因检测发现两个VRK1杂合性变异体：c.265C> T，p。（Arg89 *）和c.769G> A，p。（Gly257Ser），分别分类为致病性和不确定意义的变异体。在患者2中，在杂合性中鉴定出VRK1的两个可能的致病变异：内含子8中的c.710-14T> C和外显子9中的c.721C> T，p。（Arg241Cys）。VRK1显示出类似的儿童期发作性运动神经元疾病/ ALS，进一步扩大了与VRK1变体相关的表型谱。