Advanced Genetic Study and Pilot Newborn Screening for Disorders of Pyruvate Metabolism

丙酮酸脱氢酶复合物缺陷（PDCD）是线粒体损伤的主要类型。 疾病，限制碳水化合物的氧化以产生能量，这是特别重要的 在大脑里。PDCD是NAMDC登记系统中第二个最常见的条目， 参与者有多种线粒体酶缺陷。生存率的最佳预测指标， PDCD患者的认知结果似乎与发病年龄有关，新生儿 通常与早逝相关的表现，以及与 更好的生存率和正常或轻度至重度认知障碍。平均年龄和中位年龄 诊断为PDCD的时间分别为31和12个月。我们有次级PDC 缺陷受试者分为三个不同的组，具有重要的临床后果。使用 生酮饮食目前是PDCD特定亚类的主要治疗干预，但 在其他亚类的受试者中可能无效和/或致命。建议的“先进 PDC缺乏症的遗传研究和新生儿筛查试点”是 我们在以前的“PDC的自然历史和高级遗传研究”中完成的工作 缺陷”，其中我们a）鉴定了与丙酮酸相关的新的和已知的基因， 代谢，B）已将自然史和分子数据与NAMDC登记处相结合， 其他数据库，c）将PDCD受试者细分为三组-主要特异性- 原发性全身性和继发性PDCD，和d）注意到患者诊断为原发性特异性 PDCD将是从生酮饮食开始获益最多的人。我们的目标#1 继续使用已建立的先进遗传学方法鉴定PDCD的新遗传病因， 分析技术，并在需要时进行功能确认， 使我们能够更好地了解这种疾病的病理生理学，以便将来控制临床 治疗干预试验。我们的目标#2是首次试点新生儿筛查（NBS） 使用生物标志物和特定分子测试的协议，目的是诊断新生儿 初级特异性PDCD，用于生酮饮食的早期干预，以改善长期健康， 认知结果。这个试点NBS PDC协议是俄亥俄州范围内的奋进，包括两个 其他NAMDC站点，它们总共占所有线粒体 NAMDC登记处的疾病。

Pyruvate dehydrogenase complex deficiencies (PDCD) are a major class of mitochondrial diseases, limiting oxidation of carbohydrate for energy production, which is especially important in the brain. PDCD is the second most common entry within the NAMDC Registry among registry participants with multiple mitochondrial enzyme defects. The best predictor of survival and cognitive outcome in those affected with PDCD appears to be the age of onset, with neonatal presentations typically associated with early death, and childhood onset cases associated with better survival and with normal or mild to severe cognitive disability. The mean and median ages of diagnosis of PDCD are about 31 and 12 months, respectively. We have sub-classified PDC deficient subjects into three different groups with important clinical consequences. Use of ketogenic diets is currently the main therapeutic intervention in a specific subclass of PDCD, but can be ineffective and/or lethal in subjects from the other subclasses. The proposed "Advanced Genetic Study and Pilot Newborn Screening for PDC deficiency" is in part a continuation of the work we have accomplished in our previous "Natural History and Advanced Genetic Study of PDC deficiencies", where we have a) identified novel and known genes associated with pyruvate metabolism, b) have integrated natural history and molecular data with the NAMDC Registry and other databases, c) have sub-classified PDCD subjects into three groups - primary specific- primary generalized- and secondary-PDCD, and d) noted that patients diagnosed primary-specific PDCD would be the ones who would benefit most from initiation of a ketogenic diet. Our Aim #1 is to continue identifying novel genetic etiologies for PDCD using established advanced genetic analysis technologies in conjunction with functional confirmation when needed, which would enable better understanding of the pathophysiology of this disorder for future controlled clinical therapeutic intervention trials. Our Aim #2 is to pilot for the first time a newborn screening (NBS) protocol using biomarkers and specific molecular tests with the goal of diagnosing newborns with primary-specific PDCD for early intervention with ketogenic diet for better long-term health and cognitive outcomes. This pilot NBS PDC protocol is an Ohio-wide endeavor that includes two other NAMDC sites, which together constitute about 20% of all recruits with mitochondrial disorders in the NAMDC Registry.