Welcome to the ACMG Knowledge Nugget on newborn screening for proprionic acidemia. 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 Proprionic Acidemia 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 proprionic acidemia, as well as the associated disease methylmalonic acidemia, including clinical features and the underlying genetic causes. Actions a primary care provider needs to take upon receiving a screen positive test result for either proprionic acidemia or methylmalonic acidemia, clinical considerations, and supplemental resources. Proprionic acidemia, or PA, is a genetic condition caused by pathogenic variants found in the PCCA and PCCB genes. Methylmalonic acidemia, or MMA, is a related condition caused by pathogenic variants in one of several different genes, the most common being the MMUT gene. These genes provide instructions for the creation of an enzyme that assists in the breakdown of amino acids, certain fats, and cholesterol. Individuals with PA or MMA have decreased amounts of working enzymes, which results in a buildup of propionyl-CoA in proprionic acidemia, or methylmalonic acid in MMA, and other toxic compounds. The buildup of these acids and toxic compounds causes damage to the brain and nervous system. Both PA and MMA can present during infancy. Usually within the first few days to weeks after birth. Symptoms include vomiting, lethargy, slow growth rate or failure to thrive, poor feeding, and dehydration. Some infants may also develop seizures. Laboratory studies include metabolic ketoacidosis, high ammonia levels, or hyperammonemia, and low blood sugar, or hypoglycemia. Symptoms can worsen after infections and after eating high amounts of protein. PA and MMA are both inherited in an autosomal recessive manner, meaning that only infants with a pathogenic variant in both of the matching genes will be affected. Parents with a child with PA or MMA deficiency 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 both proprionic acidemia and methylmalonic acidemia. A good resource for checking a state's newborn screening panel is the newbornscreening.hrsa.gov website. Screening for PA and MMA is performed by examining the level of C3 acylcarnitine, which is elevated in both of these conditions. Now that you have an understanding of what PA and MMA is, let's talk about what to do if you have a patient screen positive for one of these conditions 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 proprionic acidemia or methylmalonic acidemia. Next, ascertain the clinical status, paying close attention to signs like poor feeding, lethargy, vomiting, and fast breathing or tachypnea. Arrange for a clinical evaluation, evaluating for signs of vomiting, hypoglycemia, failure to thrive, dehydration, and ketonuria. If any of these are present or if the newborn is ill, transport to a hospital immediately for further treatment in consultation with a metabolic specialist. Second, take a family history. Because both propionic acidemia and methylmalonic acidemia are inherited in an autosomal recessive manner, it is common for there to be no known family history of either of these diseases. Third, arrange for an immediate same-day referral to a pediatric metabolic specialist for a comprehensive clinical evaluation, discussion of a treatment plan, and genetic counseling. Fourth, working with the appropriate specialist, take steps to ensure biochemical and or molecular confirmation of the newborn screening result. Diagnostic tests include plasma acylcarnitine and urine organic acid levels. Molecular genetic testing may be required to confirm the diagnosis. Fifth, report the final diagnostic outcome back to your state newborn screening program. Early and long-term treatment of both propionic acidemia and methylmalonic acidemia is essential as complications are common. Management includes diets low in certain proteins and fats, vitamin B12 supplements, and in some cases, L-carnitine supplementation. During acute episodes, treatment may include intravenous fluid and glucose, and in severe cases, hemodialysis. As you continue to care for your patient with a positive newborn screening for either PA or MMA, it is likely additional questions and concerns will come up. Here are some resources where you can obtain information on propionic acidemia and methylmalonic acidemia, appropriate laboratories and tests, and genetic specialists. Before we end today's session, let's have a quick review. First, both propionic acidemia and methylmalonic acidemia are serious conditions, and identification of affected individuals is essential for the administration of early treatment. Second, newborn screening may identify both propionic acidemia and methylmalonic acidemia prior to symptom onset. This allows for earlier management and can help prevent symptoms and complications. Third, app sheets are freely available on the ACMG website to review in the event of a screen-positive result. In addition to propionic acidemia and methylmalonic acidemia, app sheets are available for many other conditions that can be identified through newborn screening.

newborn screening

propionic acidemia

methylmalonic acidemia

genetic conditions

clinical management