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

新生儿筛查(NBS)的目标是发现新生儿可能致命或致残的情况，从而为早期治疗提供机会之窗，通常是在儿童仍无症状的情况下。这种早期发现和治疗可能对受影响儿童的病情临床严重程度产生深远影响。如果不加以诊断和治疗，针对性疾病的后果可能是可怕的，许多疾病会导致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，并报告在核心评估中发现的26种次要疾病。这些建议已被卫生和卫生局新生儿和儿童遗传性疾病问题秘书咨询委员会(经2000年《儿童健康法》授权)和卫生和卫生局秘书接受。自接受核心条件以来，又增加了6个条件。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，已发现数千种罕见疾病，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错误，肝脏尿素循环的缺陷会导致体内氨的排出失败。过多的氨蓄积(高氨血症)具有神经毒性，会导致高氨性脑病和不可逆转的脑损伤。氨是由蛋白质分解产生的氮气产生的废物，并在尿素循环中通过一系列酶反应转化为危害较小的尿素，在肝脏中发生。尿素循环包含6种酶，它们催化一系列步骤，它们的缺乏定义了不同的UCDs：氨基甲酰磷酸合成酶(CPSI)缺乏；N-乙酰谷氨酸合成酶(NAGS)缺乏；鸟氨酸转氨甲基酶(OTC)缺乏；精氨酸琥珀酸合成酶缺乏，也称为瓜氨酸血症1型(CIT1)；精氨酸琥珀酸裂解酶缺乏，也称为精氨酸丁二酸血症(ASA)；以及精氨酸酶缺乏(ARG)。 UCDs分为近端尿素循环障碍(PUCD；NAGS、CPS1、OTC)和远端尿素循环障碍(CIT1、ASA、ARG)。一般来说，PUCDs的新生儿发病较早(出生后24小时到几天不等)，症状严重程度不一，有些人发病较晚，甚至是成人。最常见的PUCD，OTC，具有X连锁的遗传模式，因此男性通常受到更严重的影响，而女性可能没有症状，受影响较轻，或发病较晚。无论哪种类型，尿素循环的缺陷都可能导致婴儿不可逆转的脑损伤，包括智力残疾、发育迟缓、癫痫发作和/或昏迷，如果不立即治疗的话。由于积聚的程度和高氨状态的持续时间决定了神经系统的结果，因此早期发现并开始适当的治疗是极其重要的。

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.