NEWBORN SCREENING PILOT STUDY FOR PROXIMAL UREA CYCLE DISORDERS (PUCD)

新生儿近端尿素循环障碍筛查试点研究 (PUCD)

• 批准号: 10013409
• 负责人: WILLIAM WILCOX
• 金额: $ 14.16万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2021-03-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013409
• 关键词: Adult; Advisory Committees; Affect; American; Ammonia; Argininosuccinate lyase deficiency; Biochemical Reaction; Birth; Brain Injuries; CYP21A2 gene; Carbamyl Phosphate; Cessation of life; Child; Child Health; Citrulline; Citrullinemia type 1; Clinical; Coma; Defect; Development; Developmental Delay Disorders; Developmental Disabilities; Disease; Distal; Early Diagnosis; Early treatment; Encephalopathies; Enzymes; Evaluation; Excision; Failure; Female; Goals; Heritability; Hour; Hyperammonemia; Hyperargininemia; Inborn Errors of Metabolism; Individual; Infant; Intellectual functioning disability; Left; Link; Liver; Medical Genetics; N acetyl L glutamate; Neonatal; Neonatal Screening; Nervous System Trauma; Neurological outcome; Newborn Infant; Nitrogen; Onset of illness; Ornithine Carbamoyltransferase; Ornithine carbamoyltransferase deficiency; Physically Handicapped; Pilot Projects; Proteins; Rare Diseases; Recommendation; Reporting; Seizures; Severities; Symptoms; Technology; Urea; Urea cycle disorders; Waste Products; argininosuccinate synthase; male; medical schools; neurotoxic; screening guidelines; urea cycle

The goal of newborn screening (NBS) is to detect potentially fatal or disabling conditions in newborns, thereby providing a window of opportunity for early treatment, often while the child is still asymptomatic. Such early detection and treatment can have a profound impact on the clinical severity of the condition in the affected child. If left undiagnosed and untreated, the consequences of the targeted disorders can be dire, many causing irreversible neurological damage, intellectual, developmental and physical disabilities, and even death. In 2006, the American College of Medical Genetics (ACMG) developed newborn screening guidelines that recommend that all newborn infants be screened for 29 "core conditions" and that 26 secondary conditions identified during the core evaluations be reported. These recommendations have been accepted by the HHS Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) (authorized by the Children's Health Act of 2000), and by the Secretary of HHS. Since acceptance of the core conditions, 6 additional ones have been added. Most states now use this or very similar panels for newborn screening. Currently, there are thousands of rare disorders that have been identified and hundreds that could potentially benefit from newborn screening. Urea cycle disorders (UCD) are a group of rare inborn errors of metabolism where a defect in the liver urea cycle leads to a failure in the removal of ammonia from the body. Excessive ammonia accumulation (hyperammonemia) is neurotoxic and leads to hyperammonemic encephalopathy and irreversible brain damage. Ammonia is generated as a waste product from nitrogen resulting from the breakdown of proteins and is converted to less harmful urea through a sequence of enzymatic reactions in the urea cycle which takes place in the liver. The urea cycle contains 6 enzymes that catalyze sequential steps, and their deficiency defines distinct UCDs: carbamyl phosphate synthase (CPSI) deficiency; N- acetylglutamate synthase (NAGS) deficiency; ornithine transcarbamylase (OTC) deficiency; argininosuccinate synthase deficiency, also known as citrullinemia type 1 (CIT1); argininosuccinate lyase deficiency, also known as argininosuccinic acidemia (ASA); and arginase deficiency (ARG). UCDs are classified into proximal urea cycle disorders (PUCD; NAGS, CPS1, OTC) characterized by low levels of the intermediary citrulline, and distal urea cycle disorders (CIT1, ASA, ARG). In general, PUCDs have an early neonatal-onset (anywhere from 24 hours to few days after birth) and symptoms vary in severity, with some individuals with later or even adult onset of disease. The most common PUCD, OTC, has an X-linked mode of inheritance such that males are typically more severely affected, and females may be asymptomatic, mildly affected, or have a later onset of disease. Regardless of the type, defects in the urea cycle can result in irreversible brain damage in infants, including intellectual disability, developmental delays, seizures, and/or coma if not treated immediately. Since the extent of accumulation and the duration of the hyperammonemic state determine neurological outcomes, early detection and initiation of appropriate treatment are extremely important.

新生儿筛查（NBS）的目标是检测新生儿中潜在的致命或致残性疾病，从而为早期治疗提供机会，通常在儿童仍无症状时进行。这种早期发现和治疗可以对受影响儿童的临床严重程度产生深远影响。如果得不到诊断和治疗，目标疾病的后果可能是可怕的，许多会造成不可逆转的神经损伤，智力，发育和身体残疾，甚至死亡。2006年，美国医学遗传学学会（ACMG）制定了新生儿筛查指南，建议对所有新生儿进行29种“核心疾病”的筛查，并报告在核心评估期间确定的26种次要疾病。这些建议已被卫生和公众服务部新生儿和儿童遗传性疾病秘书咨询委员会（ACHDNC）（经2000年《儿童健康法》授权）和卫生和公众服务部秘书接受。自接受核心条件以来，又增加了6项。大多数州现在使用这种或非常类似的面板进行新生儿筛查。目前，已经发现了数千种罕见疾病，数百种可能从新生儿筛查中受益。 尿素循环障碍（UCD）是一组罕见的先天性代谢缺陷，其中肝脏尿素循环缺陷导致氨从体内排出失败。过量的氨积累（高氨血症）是神经毒性的，并导致高氨性脑病和不可逆的脑损伤。氨是由蛋白质分解产生的氮作为废物产生的，并通过肝脏中发生的尿素循环中的一系列酶促反应转化为危害较小的尿素。尿素循环含有催化连续步骤的6种酶，并且它们的缺乏定义了不同的UCD：氨甲酰磷酸合酶（CPSI）缺乏; N-乙酰谷氨酸合酶（NAGS）缺乏;鸟氨酸转氨甲酰酶（OTC）缺乏;氨基琥珀酸合酶缺乏，也称为瓜氨酸血症1型（CIT 1）;氨基琥珀酸裂解酶缺乏，也称为氨基琥珀酸血症（阿萨）;和精氨酸酶缺乏症（ARG）。 UCD分为近端尿素循环障碍（PUCD; NAGS、CPS 1、OTC）和远端尿素循环障碍（CIT 1、阿萨、ARG），近端尿素循环障碍的特征是中间瓜氨酸水平低。一般来说，PUCD具有早期的胎盘发病（出生后24小时至几天），症状的严重程度各不相同，有些个体的发病时间较晚，甚至是成人发病。最常见的PUCD，OTC，具有X-连锁遗传模式，使得男性通常受到更严重的影响，女性可能无症状，轻度影响或具有较晚的发病。无论哪种类型，尿素循环缺陷都可能导致婴儿不可逆的脑损伤，包括智力残疾，发育迟缓，癫痫发作和/或昏迷，如果不立即治疗。由于高氨血症的累积程度和持续时间决定了神经系统的结果，因此早期发现和开始适当的治疗是非常重要的。