Welcome to the ACMG Knowledge Nugget on newborn screening for Glutaric Acidemia Type 1. 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 Glutaric Acidemia Type 1 Act Sheet, which is freely available at www.acmg.net slash A-C-T. 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 Glutaric Acidemia Type 1, including clinical features and the underlying genetic cause, actions a primary care provider needs to take upon receiving a screen positive test result for Glutaric Acidemia Type 1, clinical considerations, and supplemental resources. Glutaric Acidemia Type 1 is caused by pathogenic variants in the GCDH gene. This gene gives instructions for making glutaral-CoA dehydrogenase, an enzyme that helps break down certain proteins, particularly those that contain the amino acids lysine, hydroxylysine, and tryptophan. Usually, a functioning glutaral-CoA dehydrogenase enzyme allows the body to either use or remove these proteins. The decreased production of this enzyme that occurs in Glutaric Acidemia Type 1 can cause the metabolites glutaric acid and glutaral carnitine to build up to toxic levels in the blood, urine, and tissues. This buildup causes acidemia, or a buildup of acid in the blood, aciduria, a buildup of acid in the urine, and damage to the baby's organs, particularly the brain. The symptoms and conditions of Glutaric Acidemia Type 1 can vary widely, ranging from mild to severe cases. This condition typically presents between four months and two years of age, though rarely can present at birth or even later in childhood. Typical signs and symptoms include an unusually large head or macrocephaly, poor feeding, sleep disturbances, decreased muscle tone or hypotonia, and muscle spasms and rigidity. Fasting, stress, and infectious illnesses can cause complications of this condition, including neurological abnormalities like dizziness or vertigo, headaches, loss of balance or coordination, known as ataxia, and dementia. It is important to note that Glutaric Acidemia Type 1 can cause bleeding in the eyes and brain, called a subdural hematoma, that mimics that of child abuse and shaken baby syndrome. Glutaric Acidemia Type 1 is inherited in an autosomal recessive manner, meaning that only infants with a pathogenic variant in both of their GCDH genes will be affected. Infants with a child with Glutaric Acidemia Type 1 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 Glutaric Acidemia Type 1. A good resource for checking a state's newborn screening panel is the newbornscreening.hrsa.gov website. Screening for Glutaric Acidemia Type 1 is performed by examining the levels of glutaryl carnitine, also known as C5dc acyl carnitine, which is elevated in individuals with this condition. Now that you have an understanding of Glutaric Acidemia Type 1, 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 Glutaric Acidemia Type 1. To ascertain clinical status, pay close attention to signs like poor feeding and decreased muscle tone. Arrange for clinical evaluation, evaluating for poor feeding, decreased muscle tone or hypotonia, and an unusually large head or macrocephaly. Provide the family with basic information about Glutaric Acidemia Type 1. Second, take a family history. Because Glutaric Acidemia Type 1 is inherited in an autosomal recessive manner, it is common for there to be no known family history of this disease. Third, arrange an immediate referral to a Glutaric Acidemia Type 1 specialist for a comprehensive clinical evaluation, discussion of a treatment plan, and genetic counseling. The specialist should be a pediatric metabolic specialist. The clinical evaluation should include a comprehensive physical assessment by an experienced Glutaric Acidemia Type 1 specialist. Fourth, working with the appropriate specialist, take steps to ensure biochemical and or molecular confirmation of the newborn screening result. Primary testing includes urine organic acids, urine glutaral carnitine, plasma acyl carnitines, and GCDH gene sequencing. Fifth, report the final diagnostic outcome back to your state newborn screening program. Treatment for Glutaric Acidemia Type 1 is necessary to avoid irreversible neurological damage. It is important to start this treatment as soon as possible, ideally before symptoms begin. Treatment includes a diet low in lysine, carnitine supplementation, and emergency treatment during intercurrent illnesses with the goal of preventing catabolism or metabolic breakdown. Children who receive early and ongoing treatment can have healthy development and growth. As you continue to care for your patient with a positive newborn screen result for Glutaric Acidemia Type 1, it is likely additional questions and concerns will come up. Here are some resources where you can obtain information on Glutaric Acidemia Type 1, appropriate laboratories and tests, and genetic specialists. Before we end today's session, let's have a quick review. First, Glutaric Acidemia Type 1 is a serious condition, and identification of affected individuals is essential for administration of early treatment. Second, newborn screening helps provide early identification of Glutaric Acidemia Type 1 so that treatment can begin prior to presentation of symptoms. Third, ACT sheets are freely available on the ACMG website to review in the event of a screen positive result. In addition to Glutaric Acidemia Type 1, ACT sheets are available for many other conditions that can be identified through newborn screening.

newborn screening

Glutaric Acidemia Type 1

genetic mutation

neurological damage prevention

early intervention