Welcome to the ACMG Knowledge Nugget on newborn screening for long-chain 3-hydroxyacyl-CoA dehydrogenase or LCHAD deficiency. 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 LCHAD Deficiency 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 LCHAD deficiency, as well as the associated disease, mitochondrial trifunctional protein, or TFP deficiency, including clinical features and the underlying genetic cause, actions a primary care provider needs to take upon receiving a screening positive test result for either LCHAD or TFP deficiency, clinical considerations, and supplemental resources. LCHAD deficiency is a genetic condition caused by pathogenic variants found in the HADHA gene. Mitochondrial trifunctional protein, or TFP deficiency, is a related condition caused by pathogenic variants found in either the HADHA or the HADHB gene. These genes provide instructions for the creation of a complex enzyme that is responsible for breaking down a certain group of fats called long-chain fatty acids, specifically the C16OH acylcarnitine. The metabolism of these fats helps to make energy for the heart, liver, and muscles. Pathogenic variants in these genes lead to a decreased amount of working enzyme, which then results in decreased fat metabolism. The decreased fat metabolism causes a decrease in energy production, particularly during episodes of prolonged fasting or increased energy demands, like those that occur during fever, illness, or stress. LCHAD and TFP deficiency present during infancy and require immediate treatment. Symptoms include poor feeding, vomiting, lethargy, an enlarged liver or hepatomegaly, heart muscle disease or cardiomyopathy, abnormal heart rhythms or arrhythmias, a breakdown of muscle tissue or rhabdomyolysis, and low blood sugar or hypoglycemia. Early studies will reveal elevated liver enzymes, elevated creatine phosphokinase or CPK, and lactic acidosis. Some forms of these diseases may present later in life with milder symptoms. LCHAD and TFP deficiency are inherited in an autosomal recessive manner, meaning that only infants with a pathogenic variant in both of their HADHA or HADHB genes will be affected. Parents with a child with LCHAD or TFP 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 LCHAD and TFP deficiency. A good resource for checking a state's newborn screening panel is the newbornscreening.hrsa.gov website. Screening for LCHAD and TFP deficiency is performed by examining levels of C16OH and C18OH acylcarnitines, which are elevated in these conditions. Now that you have an understanding of what LCHAD and TFP deficiencies are, 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 LCHAD or TFP deficiency. Ascertain clinical status, paying close attention to signs like poor feeding, lethargy, vomiting, and weak muscle tone or hypotonia. Inquire about acute fatty liver disorder and or severely high blood pressure or preeclampsia in the mother during pregnancy. Also inquire about sudden unexpected deaths of any siblings. Arrange for a clinical evaluation, evaluating for lethargy, hepatomegaly, hypoglycemia, arrhythmias, and cardiac insufficiency. If any of these are present or if the newborn is ill, transport to a hospital immediately for further treatment and consultation with a metabolic specialist. Provide the family with basic information about LCHAD and TFP deficiency, including the need to avoid fasting, especially for newborns. Second, take a family history. Because LCHAD and TFP deficiency are inherited in an autosomal recessive manner, it is common for there to be no known family history of either of these conditions. 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. Fourth, working with the appropriate specialist, take steps to ensure biochemical and or molecular confirmation of the newborn screening result. Molecular genetic testing is required to confirm the diagnosis. Fifth, report the final diagnostic outcome back to your state newborn screening program. Management of LCHAD and TFP deficiency includes regular and frequent meals and avoidance of fasting, medium chain triglyceride supplementation, and IV Klugos administration if severely ill. As you continue to care for your patient with a positive newborn screen for LCHAD or TFP deficiency, it is likely additional questions and concerns will come up. Here are some resources where you can obtain information on LCHAD and TFP deficiency, appropriate laboratories and tests, and genetic specialists. Before we end today's session, let's have a quick review. First, LCHAD and TFP deficiencies are serious conditions, and identification of affected individuals is essential for the administration of early treatment. Second, newborn screening may identify LCHAD or TFP deficiency prior to symptom onset. This allows for earlier management and can help prevent symptoms and complications. Third, act sheets are freely available on the ACMG website to review in the event of a screen positive result. In addition to LCHAD and TFP deficiency, act sheets are available for many other conditions that can be identified through newborn screening.

newborn screening

LCHAD deficiency

TFP deficiency

clinical management

ACMG resources