赖氨酸还原治疗与吡哆醇依赖性癫痫患者认知结局的关系。
Association Between Lysine Reduction Therapies and Cognitive Outcomes in Patients With Pyridoxine-Dependent Epilepsy.
机构信息
From the Section of Clinical Genetics and Metabolism (C.R.C., J.L.K.V.H.), Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora; Department of Pediatrics (L.A.T., F.A.W., C.v.K.), Emma Children's Hospital and Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam; United for Metabolic Diseases (L.A.T., C.v.K.); Department of Pediatrics and Neonatology (L.A.B.), Máxima Medical Center, Veldhoven, the Netherlands; Clinic for Pediatric Kidney (H.H.), Liver, and Metabolic Diseases, Hannover Medical School, Germany; Department of Metabolic Paediatrics (E.F.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology and Muscular Diseases Unit (P.S.), IRCCS "G. Gaslini" Institute, Genova; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (P.S.), University of Genova, Italy; Prince Sultan Military Medical City (B.M.T.), Riyadh, Saudi Arabia; Department of Paediatric Neurology (R.J.L.), University Medical Center Groningen, University of Groningen, the Netherlands; Division of Biochemical Genetics (S.S.-I.), BC Children's Hospital, University of British Columbia; BC Children's Hospital Research Institute (S.G.), Vancouver, British Columbia, Canada; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's Hospital, Orange, CA; Division of Medical Genetics (N.L., A.A.), Department of Pediatrics, University of Utah, Salt Lake City; Department of Internal Medicine (M.C.H.J.), Radboud University Medical Center, Nijmegen; Department of Gastroenterology and Hepatology (A.v.W.), Dietetics and Intestinal Failure, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands; Department of Pediatrics (C.P., A.N.P.), Western University, London, Ontario, Canada; Department of Epidemiology and Center for Global Health (M.M.L.), Colorado School of Public Health, Aurora; Departments of Neurology and Pediatrics (S.M.G.), University of Washington, Seattle; Seattle Children's Research Institute (S.M.G.), WA; Department of Pediatrics (S.M.G.), Duke University, Durham, NC; and Department of Human Genetics (C.v.K.), Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, the Netherlands.
出版信息
Neurology. 2022 Dec 5;99(23):e2627-e2636. doi: 10.1212/WNL.0000000000201222.
BACKGROUND AND OBJECTIVES
Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy characterized by seizure improvement after pyridoxine supplementation. Adjunct lysine reduction therapies (LRTs) reduce the accumulation of putative neurotoxic metabolites with the goal to improve developmental outcomes. Our objective was to examine the association between treatment with LRTs and cognitive outcomes.
METHODS
Participants were recruited from within the International Registry for Patients with Pyridoxine-Dependent Epilepsy from August 2014 through March 2021. The primary outcome was standardized developmental test scores associated with overall cognitive ability. The relationship between test scores and treatment was analyzed with multivariable linear regression using a mixed-effects model. A priori, we hypothesized that treatment in early infancy with pyridoxine and LRTs would result in a normal developmental outcome. A subanalysis was performed to evaluate the association between cognitive outcome and LRTs initiated in the first 6 months of life.
RESULTS
A total of 112 test scores from 60 participants were available. On average, treatment with pyridoxine and LRTs was associated with a nonsignificant increase of 6.9 points (95% CI -2.7 to 16.5) on developmental testing compared with treatment with pyridoxine alone. For the subanalysis, a total of 14 developmental testing scores were available from 8 participants. On average, treatment with pyridoxine and LRTs in the first 6 months of life was associated with a significant increase of 21.9 points (95% CI 1.7-42.0) on developmental testing.
DISCUSSION
Pyridoxine and LRTs at any age was associated with mild improvement in developmental testing, and treatment in early infancy was associated with a clinically significant increase in developmental test scores. These results provide insight into the mechanism of intellectual and developmental disability in PDE-ALDH7A1 and emphasize the importance of treatment in early infancy with both pyridoxine and LRTs.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that in PDE-ALDH7A1, pyridoxine and LRTs compared with pyridoxine alone is not significantly associated with overall higher developmental testing scores, but treatment in the first 6 months of life is associated with significantly higher developmental testing scores.
背景和目的
吡哆醇依赖性癫痫（PDE-ALDH7A1）是一种发育性癫痫性脑病，其特征是补充吡哆醇后癫痫发作改善。赖氨酸还原治疗（LRT）的辅助治疗可减少潜在神经毒性代谢物的积累，从而改善发育结局。我们的目的是研究 LRT 治疗与认知结果之间的关系。
方法
本研究参与者于 2014 年 8 月至 2021 年 3 月从国际吡哆醇依赖型癫痫患者登记处招募。主要结局是与整体认知能力相关的标准化发育测试评分。使用混合效应模型的多变量线性回归分析测试分数与治疗之间的关系。我们假设，在婴儿早期使用吡哆醇和 LRT 治疗会导致正常的发育结果。进行了一项亚分析，以评估在生命的前 6 个月开始的认知结果与 LRT 之间的关联。
结果
共有 60 名参与者的 112 项测试分数可用。平均而言，与单独使用吡哆醇相比，使用吡哆醇和 LRT 治疗与发育测试中无显著性增加 6.9 分（95%CI-2.7 至 16.5）相关。对于亚分析，从 8 名参与者中总共获得了 14 项发育测试评分。平均而言，在生命的前 6 个月使用吡哆醇和 LRT 治疗与发育测试中显著增加 21.9 分（95%CI1.7-42.0）相关。
讨论
任何年龄的吡哆醇和 LRT 治疗均与发育测试的轻度改善相关，婴儿早期的治疗与发育测试分数的临床显著增加相关。这些结果提供了 PDE-ALDH7A1 中智力和发育障碍机制的见解，并强调了在婴儿早期同时使用吡哆醇和 LRT 治疗的重要性。
证据分类
本研究提供了 IV 级证据，表明在 PDE-ALDH7A1 中，与单独使用吡哆醇相比，吡哆醇和 LRT 治疗与整体较高的发育测试评分无显著相关性，但在生命的前 6 个月内治疗与显著较高的发育测试评分相关。
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