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.
