Welcome to the ACMG Knowledge Nugget on newborn screening for Gluteric Acidemia Type 2. 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 Gluteric Acidemia Type 2 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 Gluteric Acidemia Type 2, including clinical features and the underlying genetic cause, actions a primary care provider needs to take upon receiving a screen positive test result for Gluteric Acidemia Type 2, clinical considerations, and supplemental resources. Gluteric Acidemia Type 2, also known as Multiple Acyl-CoA Dehydrogenase Deficiency, or MAD, is caused by pathogenic variants in one of three genes, either the ETFA, ETFB, or the ETFDH genes. These genes give the body instructions for making certain enzymes called Electron Transfer Flavoprotein and Electron Transfer Flavoprotein Dehydrogenase. These enzymes are involved in mitochondrial fatty acid oxidation and other energy-producing pathways that help break down proteins and fats that the body uses for energy. The impairment of these enzymes can cause an accumulation of incompletely processed proteins and fats. This buildup causes the blood and tissues to become acidic, which is also called metabolic acidosis. The presentation of Gluteric Acidemia Type 2 can vary widely, ranging from mild to severe signs and symptoms. This condition typically presents during infancy or early childhood, though it can also present during adulthood. Typical signs and symptoms include lethargy, poor feeding, vomiting, facial dysmorphism, muscle weakness, and muscle pain. Typical problems include low blood sugar, or hypoglycemia, and high ammonia levels in the blood, or hyperammonemia. Fasting, stress, fever, and infectious illnesses can cause complications of this condition. Gluteric Acidemia Type 2 is inherited in an autosomal recessive manner, meaning that only infants with a pathogenic variant in both of their genes will be affected. Both of the inherited non-working genes must match, in other words, two variant ETFA genes, in order for the child to have this condition. Biologic parents with a child with Gluteric Acidemia Type 2 are carriers and are unaffected, but have a 25% recurrence risk with any future children they have together. Not all states in the United States provide newborn screening for Gluteric Acidemia Type 2. A good resource for checking a state's newborn screening panel is the newbornscreening.hrsa.gov website. Screening for Gluteric Acidemia Type 2 is performed by examining the levels of plasma acylcarnitines, particularly the C4 and C5 acylcarnitines, which are elevated in individuals with this condition. Now that you have an understanding of Gluteric Acidemia Type 2, let's talk about what to do if you have a patient screen positive for this condition during newborn screening. You will need to take the following actions. First, immediately contact the family and do the following. Inform the family of the newborn screening result and that more testing is needed to determine if their child does or does not have Gluteric Acidemia Type 2. Ascertain clinical status, paying close attention to signs like poor feeding, vomiting, lethargy, a sweaty feet odor, and difficulty breathing or respiratory distress. Arrange for a clinical evaluation, evaluating for signs of failure to thrive, lethargy, hypoglycemia, hyperammonemia, a sweaty feet odor, metabolic acidosis, and or facial abnormalities. If any of these findings are present or if the newborn is ill, transport to a hospital immediately for further treatment in consultation with a metabolic specialist. Provide the family with basic information about Gluteric Acidemia Type 2. Second, take a family history. Because Gluteric Acidemia Type 2 is inherited in an autosomal recessive manner, it is common for there to be no known family history of this condition. Third, arrange for an immediate referral to a Gluteric Acidemia Type 2 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 Gluteric Acidemia Type 2 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 acyl carnitines, urine organic acids, urine acyl glycines, and gene sequencing. Fifth, report the final diagnostic outcome back to your state newborn screening program. Treatment for Gluteric Acidemia Type 2 is lifelong and includes avoidance of fasting and supplementation with riboflavin, L-carnitine, and coenzyme Q10. Regular medical monitoring and avoidance of metabolic crisis is important to prevent irreversible damage. As you continue to care for your patient with a positive newborn screen result for Gluteric Acidemia Type 2, it is likely that additional questions and concerns will come up. Here are some resources where you can obtain information on Gluteric Acidemia Type 2, appropriate laboratories and tests, and genetic specialists. Before we end today's session, let's have a quick review. First, Gluteric Acidemia Type 2 is a serious condition, and identification of affected individuals is essential for administration of early treatment. Second, newborn screening helps provide early identification of Gluteric Acidemia Type 2, though not all states screen for this condition. Third, ACT sheets are freely available on the ACMG website to review in the event of a screen positive result. In addition to Gluteric Acidemia Type 2, ACT sheets are available for many other conditions that can be identified through newborn screening. Thank you for watching.

Gluteric Acidemia Type 2

genetic causes

diagnostic process

clinical management

mitochondrial enzymes