From the Department of Pediatrics (B.P., L.A.), Division of Child Neurology, University Hospital Zurich, Switzerland; the Department of Pediatrics (B.P.), Division of Neurology and Inborn Errors of Metabolism, Medical University Graz, Austria; radiz-"Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich" (B.P., L.A.); CRC Clinical Research Center (B.P.), University Childrens' Hospital Zurich, Switzerland; the Laboratory of Metabolic Diseases (K.P., E.P., D.H.), Department of Pediatrics, University Hospital Graz, Austria; UCL Institute of Child Health (P.M., P.C.), Clinical and Molecular Genetics Unit, London, UK; Childrens Hospital St. Gallen (O.M., O.H.), Switzerland; the Department of Pediatrics (G.H.), Klinikum Esslingen; the Department of Pediatrics (S.K.), St. Marien Hospital, Landshut, Germany; the Division of Child Neurology (M.C.) and Division of Biochemical Diseases (S.S.), Department of Pediatrics, University of British Columbia, Vancouver, Canada; the Department of Pediatrics, Division of Child Neurology (N.W.), VU University Medical Center and Neuroscience Campus Amsterdam; and the Department of Clinical Chemistry (E.S.), Vrije Universiteit Amsterdam, the Netherlands.
Neurology. 2014 Apr 22;82(16):1425-33. doi: 10.1212/WNL.0000000000000344. Epub 2014 Mar 21.
To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations.
We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria.
We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5'-phosphate (PLP).
This study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5'-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug-resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis.
确定是否存在吡哆醇反应性癫痫但 antiquitin 缺乏的生物标志物正常且 ALDH7A1 基因测序正常的患者可能存在 PNPO 突变。
我们对符合上述标准的 31 名患者进行了 PNPO 基因测序。
我们能够鉴定出 11 名患者携带 PNPO 基因的 3 种新突变。在 6 个家族中，鉴定出 7 号外显子的纯合错义突变 p.Arg225His，而 1 个家族为 5 号外显子的新型错义突变 p.Arg141Cys 和 3 号外显子的缺失 c.279_290del 的复合杂合子。通过在 100 个对照等位基因中不存在和在 CHO-K1 细胞系中的表达研究证明了各自突变的致病性。4 名患者对吡哆醇的反应迅速，2 名患者反应延迟，2 名患者仅在脑电图上反应，另 2 名患者最初无反应。2 名携带 p.Arg225His 突变的无关患者在转换为吡哆醛 5'-磷酸（PLP）时发生癫痫持续状态。
本研究挑战了吡哆醇 5'-磷酸氧化酶缺乏症患者中仅 PLP 反应的范式，并强调了在抗癫痫药物耐药性癫痫的新生儿中连续测试吡哆醇和 PLP 的重要性。对吡哆醇有反应但 antiquitin 缺乏的生物标志物正常的患者应进行 PNPO 突变分析。
