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潜在的致命或致残状况，从而为早期治疗提供机会（通常是在孩子还没有症状时）。这种早期发现和治疗可以对受影响儿童病情的临床严重程度产生深远的影响。如果不及时诊断和治疗，目标疾病的后果可能是可怕的，许多会导致不可逆的神经损伤、智力、发育和身体残疾，甚至死亡。 2006年，美国医学遗传学学院（ACMG）制定了新生儿筛查指南，建议对所有新生儿进行29种“核心病症”筛查，并报告核心评估期间发现的26种次要病症。这些建议已被 HHS 秘书新生儿和儿童遗传性疾病咨询委员会 (ACHDNC)（经 2000 年《儿童健康法》授权）和 HHS 秘书接受。自核心条件获得通过后，又新增6项。现在大多数州都使用此或非常类似的面板进行新生儿筛查。目前，已发现数千种罕见疾病，还有数百种可能受益于新生儿筛查。 尿素循环障碍 (UCD) 是一组罕见的先天性代谢错误，肝脏尿素循环缺陷导致无法从体内清除氨。过量的氨积累（高氨血症）具有神经毒性，会导致高氨性脑病和不可逆的脑损伤。氨是蛋白质分解产生的氮的废物产物，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。尿素循环包含 6 种催化连续步骤的酶，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；精氨基琥珀酸合酶缺乏症，也称为 1 型瓜氨酸血症 (CIT1)；精氨基琥珀酸裂解酶缺乏症，也称为精氨基琥珀酸血症（ASA）；和精氨酸酶缺乏症（ARG）。 UCD 分为以中间瓜氨酸水平低为特征的近端尿素循环障碍（PUCD；NAGS、CPS1、OTC）和远端尿素循环障碍（CIT1、ASA、ARG）。一般来说，PUCD 会在新生儿早期发病（出生后 24 小时到几天内），症状严重程度各异，有些个体发病较晚，甚至是成人发病。最常见的 PUCD（OTC）具有 X 连锁遗传模式，因此男性通常受到更严重的影响，而女性可能无症状、受到轻微影响或较晚发病。无论哪种类型，如果不立即治疗，尿素循环缺陷都可能导致婴儿不可逆转的脑损伤，包括智力障碍、发育迟缓、癫痫发作和/或昏迷。由于积累的程度和高氨状态的持续时间决定神经系统结果，因此早期发现和开始适当的治疗极其重要。