Long-term clinical outcome, therapy and mild mitochondrial dysfunction in hyperprolinemia
Long-term clinical outcome, therapy and mild mitochondrial dysfunction in hyperprolinemia
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DOI：
10.1007/s10545-013-9660-9
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发表时间：
2014-05-01
影响因子：
4.2
通讯作者：
Morava, Eva
中科院分区：
文献类型：
--
作者：
van de Ven, Steffi;Gardeitchik, Thatjana;Morava, Eva
尽管高脯氨酸血症II型具有辨别性的代谢表型，并经常与神经系统受累有关，但除了继发性B6缺乏症外，代谢异常与临床特征之间的因果关系一直存在着频繁的争论。为了评估疾病频率和神经代谢结果，我们搜索了1992至2010年间的实验室数据库，包括20,991个尿有机酸谱。从这些人那里获得了16,720个平行的血液样本，并通过血清氨基酸分析进行了调查。我们还评估了临床、神经、心理特征、实验室数据和维生素水平以及代谢确诊的高脯氨酸血症的治疗效果。由于ALDH4A1和PROSH的线粒体定位，我们评估了线粒体酶复合体的活性，并测量了耗氧量来评估患者-成纤维细胞中ATP的产生。用线粒体疾病评分评估临床线粒体功能障碍。儿童行为检查表被用来筛查精神病理学。我们发现4例尿P5C升高的患者被诊断为II型高脯氨酸血症，只有1例患者患有I型高脯氨酸血症。所有II型高脯氨酸血症儿童的B6浓度都很低，其中3例患者有提示线粒体功能障碍的生化标志物。在一例肌肉活组织检查中证实线粒体功能障碍。在两名青少年患者中发现了智力障碍。所有患者都表现出癫痫发作和严重的行为问题，包括焦虑和幻觉。临床病程无进展，不受B6浓度和B6治疗的影响。高脯氨酸血症是一种罕见的先天错误。由于经常出现行为问题，高脯氨酸血症患者应该受到密切监测。
Although hyperprolinemia type-II has a discriminative metabolic phenotype and is frequently associated with neurological system involvement, the casual relation between the metabolic abnormalities and the clinical features, except for those of the secondary B6 deficiency, has been frequently debated. In order to evaluate disease frequency and the neuro-metabolic outcome we searched our laboratory database between 1992 and 2010, including 20,991 urinary organic acid profiles. From these individuals 16,720 parallel blood samples were available, and were investigated by serum amino acid analysis. We also evaluated the clinical, neurological, psychological features, laboratory data and vitamin levels and therapeutic effect in metabolically confirmed hyperprolinemia. Due to the mitochondrial localization of both ALDH4A1 and PRODH mitochondrial enzyme complex activity was evaluated and oxygen consumption was measured to assess ATP production in patient-fibroblasts. The Mitochondrial Disease Score was used to evaluate clinical mitochondrial dysfunction. The child behavior checklist was used to screen for psychopathology. We found four patients with increased urinary P5C diagnosed with hyperprolinemia type II, and only one patient had hyperprolinemia type I. All children with hyperprolinemia type II had low normal B6 concentration, and three of the patients had biochemical markers suggesting mitochondrial dysfunction. Mitochondrial dysfunction was confirmed in a muscle biopsy in one case. Intellectual disability was found in two adolescent patients. All patients showed seizures and significant behavioral problems, including anxiety and hallucinations. The clinical course was non-progressive and independent from the B6 concentration and B6 therapy. Hyperprolinemia is a rare inborn error. Individuals with hyperprolinemia should be monitored closely due to their frequent behavioral problems.