Welcome to the ACMG Knowledge Nugget on newborn screening for the aminoacidemias detected through elevations of citrulline. This activity is intended for educational purposes only. Neither I nor the planning committee have any disclosures. This session is approved for 0.25 CME. To obtain CMEs for this activity, you will need to pass the quiz with a score of at least 80% and complete the evaluation. This session is a companion to the Elevated Citrulline Act Sheet, which is freely available at www.acmg.net slash ACT. Act Sheets are intended to be immediate resources for providers who encounter positive newborn screening results. Please keep in mind that a newborn screening result is just the first step in the diagnostic process. Further testing and evaluations are needed to determine if the newborn has the disease, a true positive result, or is unaffected, a false positive result. The Act Sheets are intended to provide an overview of the diseases identified by newborn screening and clear next steps for the management of a positive newborn screening result. This session will cover background information on those aminoacidemias detected through elevated citrulline, including the clinical features and underlying genetic causes, actions a primary care provider needs to take upon receiving a screen positive test result for a citrulline elevation, clinical considerations, and supplemental resources. Elevated citrulline is associated with a group of amino acid disorders caused by one of several defects affecting the urea cycle, the pathway that converts ammonia into urea. Each of the disorders is caused by a deficiency of the related enzyme. In these disorders, ammonia, a toxic metabolite, accumulates and leads to variable clinical presentations. The clinical spectrum of these disorders is vast, though all are likely to present in the neonatal period. A detailed list of diseases associated with elevated citrulline along with their clinical considerations can be found on the Act Sheet. These aminoacidemias are inherited in an autosomal recessive manner, meaning that only infants with a pathogenic variant in both of their relevant genes will be affected. Biologic parents with a child with one of these disorders are carriers and are unaffected, but have a 25% recurrence risk with any future children they have together. All states in the United States provide newborn screening for the aminoacidemias identified by examining levels of elevated citrulline. A good resource for checking a state's newborn screening panel is the newbornscreening.hrsa.gov website. Screening for these diseases is performed by examining levels of citrulline, which is elevated in individuals with these particular aminoacidemias. Now that you have a general understanding of the diseases detected through elevated citrulline levels, let's talk about what to do if you have a patient screened positive with a citrulline elevation during newborn screening. You will need to take the following actions. First, immediately contact the family and do the following. Inform them of the newborn screening result and that more testing is needed to determine if their child does or does not have one of these aminoacidemias. Ascertain clinical status, paying close attention to signs like poor feeding, vomiting, lethargy, or fast or shallow breathing, called tachypnea. Provide the family with basic information about the aminoacidemias associated with elevated citrulline. Arrange for a clinical evaluation, paying special attention to signs like poor feeding, vomiting, lethargy, tachypnea, decreased muscle tone or hypotonia, seizures, or signs of liver disease. If any of these are present or if the newborn is ill, facilitate transport to a hospital for further treatment in consultation with a metabolic specialist. Second, take a family history. Because the aminoacidemias associated with elevated citrulline are all inherited in an autosomal recessive manner, it is common for there to be no known family history of these disorders. Third, arrange an immediate same-day referral to a pediatric metabolic specialist for a comprehensive clinical evaluation, discussion of a treatment plan, and genetic counseling. The specialist should be a pediatric metabolic specialist. The clinical evaluations should include a comprehensive physical assessment by an experienced aminoacidemia specialist. Fourth, working with the appropriate specialist, take steps to ensure biochemical and or molecular confirmation of the newborn screening result. Confirmatory testing includes plasma ammonia levels, plasma aminoacid levels, and urine aminoacid levels, in addition to relevant gene sequencing. Fifth, report the final diagnostic outcome back to your state newborn screening program. Treatment is available for each of the aminoacidemias detected through elevated citrulline. In general, treatment often includes a low-protein diet and medications that assist with the removal of ammonia. Even with treatment, outcomes can be variable, and hospitalization may be necessary during episodes of hyperaminemia. As you continue to care for your patient with a positive newborn screen for an elevation of citrulline, it is likely additional questions and concerns will come up. Here are some resources where you can obtain information on elevated citrulline-related aminoacidemias, appropriate laboratories and tests, and genetic specialists. Before we end today's session, let's have a quick review. First, the aminoacidemias detected through elevated citrulline are serious conditions. An identification of affected individuals is essential for administration of early treatment. Second, newborn screening cannot distinguish between the various aminoacidemias that may cause a citrulline elevation, and more testing will be necessary. Third, ACT sheets are freely available on the ACMG website to review in the event of a screen-positive result. In addition to these aminoacidemias, ACT sheets are available for many other conditions that can be identified through newborn screening.

newborn screening

aminoacidemias

elevated citrulline

urea cycle defects

ACMG ACT sheets