Welcome to the ACMG Knowledge Nugget on newborn screening for carnitine palmitoyltransferase 2 or CPT2 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 CPT2 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 CPT2 deficiency, along with the associated disease, carnitine acylcarnitine translocase, or CACT deficiency, including the clinical features and underlying genetic cause, actions a primary care provider needs to take upon receiving a screen positive test result for CPT2 or CACT deficiency, clinical considerations, and supplemental resources. CPT2 deficiency is a genetic condition caused by pathogenic variants found in the CPT2 gene. CACT deficiency is a related condition caused by pathogenic variants found in the SLC25A20 gene. These genes provide instructions for the creation of an enzyme that assists in fatty acid oxidation or the breakdown of fats into energy. Individuals with CPT2 or CACT deficiency have decreased amounts of working enzymes, which results in decreased fat metabolism. The reduction in fat metabolism caused by CPT2 and CACT deficiency results in lowered energy production, particularly during episodes of prolonged fasting or increased energy demands like those during fever, illness, or stress. There are two types of CPT2 deficiency, a neonatal form and a muscular form. The neonatal form of CPT2 deficiency is similar to that of CACT deficiency. Both neonatal CPT2 deficiency and CACT deficiency can present during infancy. Symptoms include very low blood sugar or hypoglycemia, metabolic acidosis, abnormal heart rhythms or cardiac arrhythmias, heart muscle disease, cardiomyopathy, liver disease, facial abnormalities, and brain and kidney deformities. These infants rarely survive. The muscular form is much more common and less severe than the neonatal form of CPT2. The muscular form presents during early adolescence or adulthood. Symptoms of this form include muscle weakness and muscle pain or myalgia, exercise intolerance, and the breakdown of muscle tissue or rhabdomyolysis. Both CPT2 and CACT deficiency are inherited in an autosomal recessive manner, meaning that only infants with a pathogenic variant in both of their CPT2 or SLC25A20 genes will be affected. Parents with a child with either CPT2 or CACT deficiency 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 CPT2 and CACT deficiency. A good resource for checking a state's newborn screening panel is the newbornscreening.hrsa.gov website. Screening for CPT2 and CACT deficiency is performed by examining levels of C16 and or C18.1 acylcarnitines, which are elevated in these conditions. Now that you have an understanding of what CPT2 and CACT 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 CPT2 or CACT deficiency. Paying close attention to signs like poor feeding, lethargy, and vomiting. Elicit a history of sudden unexpected death in any siblings. Arrange for a clinical evaluation, evaluating for signs of hypoglycemia, liver dysfunction, cardiac insufficiency, or seizures. 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. Provide the family with basic information about CPT2 and CACT deficiency, including possible early signs and symptoms of either of these conditions. Second, take a family history. Because CPT2 and CACT deficiency are inherited in an autosomal recessive manner, it is common for there to be no known family history of either CPT2 or CACT deficiency. 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 and differentiate between CPT2 deficiency and CACT deficiency. Fifth, report the final diagnostic outcome back to your state newborn screening program. Management of CPT2 and CACT deficiency includes regular and frequent meals, avoidance of fasting, a low-fat, high-carbohydrate diet, and medium-chain triglyceride supplementation. In some cases, L-carnitine supplements and avoidance of cold weather can be helpful. As you continue to care for your patient with a positive newborn screening result for CPT2 or CACT deficiency, it is likely additional questions and concerns will come up. Here are some resources where you can obtain information on CPT2 and CACT deficiency, appropriate laboratories and tests, and genetic specialists. Before we end today's session, let's have a quick review. First, CPT2 and CACT deficiency are serious conditions, and identification of affected individuals is essential for the administration of early treatment. Although management is available, the neonatal form is very severe, and treatment may not be successful. Second, newborn screening may identify CPT2 or CACT 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 CPT2 and CACT deficiency, ACT sheets are available for many other conditions that can be identified through newborn screening.

newborn screening

CPT2 deficiency

CACT deficiency

genetic counseling

fat metabolism