Genetic Testing for Inborn Errors of Metabolism: What Does It Mean for Your Child?
Let’s break down what parents need to know about newborn screening, metabolic disorders, and the role of nutrition in managing them.
Inborn errors of metabolism affect 1 in every 1,500 births, and yet most parents have never heard of them until they are sitting in a doctor's office, trying to make sense of an unexpected test result. Whether you are a parent navigating a new diagnosis, an expectant parent who wants to be prepared, or simply someone who loves learning about how the body works, this post is for you.
As a result of advances in newborn screening testing, I have been seeing more infants newly diagnosed with inborn errors of metabolism than ever before in my private pediatric nutrition practice. This is a good thing, as it allows us to identify conditions earlier and help families learn to better manage the baby’s health from an early age.
Let's break down what inborn errors of metabolism actually are, how genetic testing helps detect them, and most importantly, what you can do about them.
What Are Inborn Errors of Metabolism?
Inborn errors of metabolism (IEMs) are a group of rare, inherited conditions in which the body cannot properly process certain nutrients, like proteins, fats, or carbohydrates, due to a missing or poorly functioning enzyme.
Enzymes are small, important proteins that play a key role in our metabolism, helping break down and transform the nutrients in our bodies into energy or other usable substances. When one or more of these enzymes are missing or not functional, the body cannot carry out these chemical processes normally, leading to the buildup of substances that can harm the body. This accumulation of harmful substrates can strongly affect early development and health outcomes.
The majority of IEMs are autosomal recessive disorders, meaning a child inherits one altered gene copy from each parent. Some of the most well-known IEMs include:
Phenylketonuria (PKU)
PKU is caused by a mutation in the PAH gene, which encodes the enzyme phenylalanine hydroxylase. When this enzyme is absent or insufficient, the amino acid phenylalanine builds up in the bloodstream. If left undetected and untreated, this can lead to seizures, intellectual disability, and even permanent brain damage.
Maple Syrup Urine Disease (MSUD)
MSUD affects the branched-chain α-ketoacid dehydrogenase (BCKAD) enzyme complex, resulting in the accumulation of branched-chain amino acids (BCAAs), namely leucine, isoleucine, and valine. Characterized by the distinctive sweet smell of maple syrup in the urine, high levels of these amino acids can result in neurological and developmental delays.
Galactosemia
Galactosemia is characterized by defects in the galactose-1-phosphate uridylyltransferase (GALT) enzyme, resulting in the inability to metabolize or break down galactose, a sugar found in dairy and breast milk, and convert it into glucose, which is the body’s primary source of energy. This build-up of galactose can cause liver damage, intellectual disability, and other serious complications if not identified early.
Hereditary Fructose Intolerance (HFI):
HFI is caused by the lack of the enzyme aldolase B, which is responsible for metabolizing fructose, found in many fruits, vegetables, and sweetened products. Without it, a toxic substance called fructose-1-phosphate accumulates, leading to vomiting, abdominal pain, hypoglycemia, jaundice, and, if left untreated, liver and kidney damage.
While these conditions are serious if left untreated, many of these IEMs (not including HFI) can be easily detected right at birth and are manageable with the right nutritional and medical care.
The Role of Genetic Testing in the Identification of Inborn Errors of Metabolism in Newborns
The cornerstone of early IEM detection in the United States is newborn screening. It is a routine and quick little heel-prick blood test performed on babies 24–48 hours after birth, which allows us to detect and begin treatment for IEM disorders before symptoms or permanent damage occur. The U.S. federal government recommends a standardized list of conditions for newborn screening known as the Recommended Uniform Screening Panel (RUSP). While each state ultimately decides which conditions to include in its program, most screen for most of the conditions on the RUSP.
Beyond the newborn heel-prick, genetic testing for IEMs can also include:
Preconception and carrier screening: The first opportunity to identify IEM risk happens before birth. Preconception carrier screening allows pregnant women and couples considering future pregnancies to learn whether they carry gene variants associated with IEMs.
Confirmatory genetic and biochemical testing: If a newborn screen comes back flagged positive, follow-up biochemical or DNA-based tests help confirm or rule out a diagnosis.
Diagnostic genetic testing for HFI in the newborn period: Unlike many other IEMs, HFI is not included in standard newborn screening panels. Instead, it can be identified through an additional genetic test, which analyzes the ALDOB gene for variants known to cause HFI.
Late-onset IEM screening in children, adolescents, and adults: In cases where patients retain some enzyme activity, toxic substances can accumulate slowly over time, and some IEMs can present later in childhood, while others may not appear until adolescence or adulthood.
What Happens After a Positive Screening Test?
The results of a baby’s newborn heel-prick screening become available five to seven days after birth. There are three types of results possible:
In-range: Most babies do not have a condition detected by blood spot screening. Those with in-range results typically do not require further testing. In-range results are also referred to as “negative,” “normal,” or “low risk.”
Out-of-range: Babies with out-of-range results need more testing from a specialist. Out-of-range results are also known as “positive,” “abnormal,” or “high risk.”
Borderline: Babies with borderline results will also need more screening or testing. Another blood sample from the baby may be collected to repeat the original screening. Borderline results are also called “inconclusive” or “medium risk.”
If your baby screens positive, know that a positive screen is not a diagnosis. It is a sign that further evaluation is needed, and oftentimes, the follow-up testing comes back normal.
Here is what the follow-up process typically looks like:
Your baby's pediatrician is notified of the out-of-range result and contacts you directly.
Repeat or confirmatory blood tests are ordered. The initial newborn screening and follow-up screening are generally at no cost to parents (but may depend on state and insurance coverage).
If follow-up testing indicates a true positive, the family is referred to a metabolic specialist, who then performs additional laboratory and/or genetic tests to confirm the diagnosis.
Through a metabolic clinic, your baby receives a tailored treatment plan, and you receive education and support on the next steps.
The most important thing to know is that you will not be navigating any of this alone.
The Importance of Diet in Managing Inborn Errors of Metabolism
Collaboration between a multidisciplinary team is crucial. When medical geneticists, metabolic dietitians, genetic counselors, and primary care providers work together to create a comprehensive care plan, children with IEMs are diagnosed sooner, treated faster, and stay out of the hospital more often.
For the majority of IEMs, the treatment is not a pill or an injection. Dietary therapy and nutrition become medicine for those with IEM disorders, and experienced, credentialed registered dietitians are critical for their management. The main goals of dietary therapy in IEMs are to maintain normal growth and development, avoid the accumulation of harmful materials in the body, and prevent nutrient deficiencies. Depending on the specific condition, this might look like:
PKU: Restriction of phenylalanine, which is found in high-protein foods including animal meats, fish, nuts, beans, soy, and dairy. Specialized formulas and supplements for infants, children, and adults with PKU restrict phenylalanine while providing the protein and nutrients needed for growth.
MSUD: Strictly limiting the intake of BCAAs through a protein restriction and using specialized formulas consisting of amino acids without BCAA to meet protein, macro, and micronutrient needs safely.
Galactosemia: Removing galactose from the diet, which means an immediate transition away from breast milk and standard dairy-based formula to galactose-free alternatives such as soy-based formulas or elemental formulas.
HFI: Elimination of fructose, sucrose, sucralose, and sorbitol from the diet, including fruit, fruit juices, some vegetables (depending on fructose content), honey, sugar, and even certain medications and vitamin supplements. A dietitian can help caretakers learn to read labels carefully and identify hidden sources of fructose, find safe food substitutes, and ensure their child continues to meet all nutritional needs for healthy growth and development.
The good news is that nutritional therapy for IEMs is customized for the specific disorder and individualized for each patient to promote compliance and optimal outcomes.All diets prescribed for IEM should take into account the patient's clinical status, tolerances, metabolic stability, age, developmental abilities, and probable prognosis. Because dietary therapy for many of these conditions is lifelong, education about the diet and formula options must begin early and be adapted as your child grows.
Final thoughts…
Genetic testing and newborn screening are some of the best tools we have to protect our children's long-term health from the moment they are born. If you have received an abnormal newborn screen result or if you have concerns about your child's metabolic health, reach out to your pediatrician and ask for a referral to a metabolic specialist and pediatric dietitian.
Working with a registered dietitian who specializes in IEMs is the best way to ensure your baby’s diet supports their growth and safety. Book a pediatric nutrition consultation today, and let's build a plan that works for your child and your family.
Thank you to my dietetic intern, Stephanie Zhang, for her contributions to this article.