PDXK encodes for a pyridoxal kinase, which converts inactive B6 vitamers to the active cofactor pyridoxal 5'-phosphate (PLP). Recently, biallelic pathogenic variants in PDXK were shown to cause axonal Charcot-Marie-Tooth disease with optic atrophy that responds to PLP supplementation. We present two affected siblings carrying a novel biallelic missense PDXK variant with a similar phenotype with earlier onset. After detection of a novel PDXK variant using Whole Exome Sequencing, we confirmed pathogenicity through in silico protein structure analysis, determination of pyridoxal kinase activity using liquid chromatography-tandem mass spectrometry, and measurement of plasma PLP concentrations using high performance liquid chromatography. Our in silico analysis shows a potential effect on PDXK dimer stability, as well as a putative effect on posttranslational ubiquitination that is predicted to lead to increased protein degradation. We demonstrate that the variant leads to almost complete loss of PDXK enzymatic activity and low PLP levels. Our patients' early diagnosis and prompt PLP replacement restored the PLP plasma levels, enabling long-term monitoring of clinical outcomes. We recommend that patients presenting with similar phenotype should be screened for PDXK mutations, as this is a rare opportunity for treatment.

中文翻译：

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由于 PDXK 变异导致维生素 B6 代谢受损导致视神经萎缩的遗传性多发性神经病

PDXK 编码吡哆醛激酶，将无活性的 B6 维生素转化为活性辅因子吡哆醛 5'-磷酸 (PLP)。最近，PDXK 中的双等位基因致病变异被证明会引起轴突 Charcot-Marie-Tooth 病，并伴有对 PLP 补充有反应的视神经萎缩。我们介绍了两个受影响的兄弟姐妹，它们携带一种新型双等位基因错义 PDXK 变体，具有相似的表型且发病较早。在使用全外显子组测序检测到一种新的 PDXK 变异后，我们通过计算机蛋白质结构分析、使用液相色谱-串联质谱法测定吡哆醛激酶活性以及使用高效液相色谱法测量血浆 PLP 浓度来确认致病性。我们的计算机分析显示对 PDXK 二聚体稳定性的潜在影响，以及对翻译后泛素化的推定影响，预计会导致蛋白质降解增加。我们证明该变体导致几乎完全丧失 PDXK 酶活性和低 PLP 水平。我们患者的早期诊断和及时的 PLP 更换恢复了 PLP 血浆水平，从而能够长期监测临床结果。我们建议对表现出相似表型的患者进行 PDXK 突变筛查，因为这是一个难得的治疗机会。能够长期监测临床结果。我们建议对表现出相似表型的患者进行 PDXK 突变筛查，因为这是一个难得的治疗机会。能够长期监测临床结果。我们建议对表现出相似表型的患者进行 PDXK 突变筛查，因为这是一个难得的治疗机会。