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

丙酮酸脱氢酶复合体缺乏症(PDCD)是线粒体的一种主要类型 疾病，限制碳水化合物的氧化以产生能量，这一点特别重要 在大脑里。在NAMDC注册表中，PDCD是注册表中第二常见的条目 患有多种线粒体酶缺陷的受试者。最好的生存预测者和 受PDCD影响的患者的认知结局似乎与发病年龄、新生儿有关 通常与早逝有关的表现，以及与以下相关的儿童期发病病例 存活率较高，且有正常或轻度至严重的认知障碍。平均年龄和中位年龄 诊断PDCD的时间分别为31个月和12个月。我们有细分的PDC 不足的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措施，但 可能对其他亚类的受试者无效和/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“在一定程度上是对 我们在之前的《PDC的自然历史和高级遗传学研究》中所做的工作 缺陷“，其中我们发现了与丙酮酸相关的新的和已知的基因 新陈代谢，b)将自然历史和分子数据与NAMDC登记处和 其他数据库，c)将PDCD受试者细分为三组--初级具体-- 原发的泛发性和继发性的PDCD，以及d)注意到患者诊断为原发的特异性 PDCD将是从生酮饮食开始中受益最大的人。我们的第一个目标 是继续利用已建立的高级遗传学来鉴定PDCD的新的遗传病因 在需要时与功能确认相结合的分析技术，这将 有助于更好地了解这种疾病的病理生理学机制，以供将来临床对照 治疗性干预试验。我们的第二个目标是首次试行新生儿筛查(NBS) 使用生物标记物和特定分子测试的方案，目的是诊断新生儿 用于生酮饮食早期干预的初级特异性PDCD，以获得更好的长期健康和 认知结果。该试点NBS PDC协议是俄亥俄州范围内的努力，包括两个 其他NAMDC位点，加起来约占所有线粒体新兵的20% NAMDC注册表中的疾病。

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.