Metabolic Disorders

This episode will help you better prepare for and manage children with inborn errors of metabolism in the Emergency Department. Consider it a supplement to what you remember from Biochemistry and the instructions on the family’s laminated care plan sheet. My special guest podcaster, Emily Groopman, is an actual Pediatric Geneticist in training and we hope that you will find this episode useful.


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Emily Groopman, MD, PhD

Emily Groopman, MD, PhD is a first-year resident in the Combined Pediatrics-Medical Genetics Residency Program at Children’s National Hospital/NIH. She did her MD/PhD at Columbia University, where she investigated the diagnostic utility of exome sequencing for kidney disease. She is a member of the Clinical Genome Resource Inborn Errors of Metabolism (IEM) Clinical Domain Working Group, where as a biocurator she assesses the pathogenicity of variants in IEM-associated genes to facilitate expedited genetic diagnosis for IEMs. She aims to become a physician-scientist in pediatrics and medical genetics, engaging in bench-to-bedside research that utilizes multi-omics-based approaches to provide a molecular diagnosis and support personalized care for individuals with suspected rare genetic diseases and their families. You can contact her via email at


Jeanmonod R, Asuka E, Jeanmonod D. Inborn Errors of Metabolism. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from:

Rice GM, Steiner RD. Inborn Errors of Metabolism (Metabolic Disorders). Pediatr Rev. 2016 Jan;37(1):3-15; quiz 16-7, 47. doi: 10.1542/pir.2014-0122. PMID: 26729777.

Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics. 1998 Dec;102(6):E69. doi: 10.1542/peds.102.6.e69. PMID: 9832597.


Note: This transcript was partially completed with the use of the Descript AI

Welcome to PEM Currents, the Pediatric Emergency Medicine Podcast. As always, I’m your host, Brad Sobolewski, and this episode focuses on the management of children with metabolic disorders who present to the emergency department. I know that this is a subject that makes us all a little bit nervous, and you’re just hoping that the parents have a good laminated sheet to tell you everything that you need to do.

Unfortunately, that’s not always the case. And, let’s face it, there are some great principles that you can apply across metabolic diseases to make sure that you are safely taking care of these children. And you’re thinking, hey! Brad’s not a pediatric medical geneticist. No, I’m not. So I called in a ringer.

Or, well, the ringer called me. So my special guest host on this episode is a trainee in pediatrics and medical genetics. Her name is Emily Groopman, and she’s a current resident at Children’s National Hospital. After doing her MD PhD at Columbia University, where she investigated the genetic diagnosis of kidney disease, she started her residency training with the long term goal of being a physician scientist caring for patients with rare genetic disorders.

She came to me with the idea for this episode based on a recognized need to reinforce key principles in the management of children with inborn errors of metabolism who present to the emergency department. I put a lot more information about Dr. Groopman and how to contact her in the show notes. But now I’m going to pass the mic.

Take it away, Emily.

Inborn errors of metabolism, or IEMs, refer to a diverse group of disorders that result from mutations in genes that are involved in pathways responsible for breaking down nutrients and generating energy. In other words, metabolism. While each of these conditions is individually rare, when considered as a group, they are IEMs occur in approximately 1 in 2, 500 births and can have severe health consequences, including ketoacidosis, cardiac arrhythmias, and encephalopathy.

Therefore understanding these diseases, their presentations and their evaluation is critical for emergency medicine providers. So first, a little bit about their etiology and epidemiology. IEMs are primarily caused, as I mentioned, by mutations in genes involved in metabolism. In other words, genes that include enzymes and other proteins that are involved in breaking down nutrients like carbs, proteins, and fats, and generating energy.

IEMs vary in their inheritance. Most IEMs are inherited in an autosomal recessive manner. Meaning that an individual must inherit two copies of the mutation, so one from each of his or her parents, to be affected. Since an individual must have two copies of the mutation to be affected, the parents and other family members who have one copy, which are known as carriers, will be unaffected.

So, importantly, you may not have a positive family history. Other factors, such as environmental influences, epigenetic changes, the microbiome, and additional genes, may also impact the penetrance of IEMs. In other words, whether or not individuals with a disease causing mutation manifest the associated genetic disease, and also the expressivity.

In other words, which features of the disease individuals with the mutation show for these conditions. Now, newborn screening, or NBS, includes testing newly born infants for certain IEMs.

Since which IEMs are tested for vary state by state, the tests used do not, and the tests do not have perfect sensitivity. And not all IEMs are included on NBS, NBS can miss individuals with IEMs. Therefore, and I want to stress this again, negative results on NBS do not rule out the possibility of IEM.

And it’s always worth considering IEM among children, including among older children and teens, who present with suggestive symptoms. So what’s the pathophysiology of IEMs? Now, IEMs result from disruption of major metabolic processes in our body. And these major metabolic processes include carbohydrate metabolism, protein metabolism, fatty acid oxidation, and glycogen storage.

And together, these processes help store us store nutrients from the food we eat and use it to generate energy. Now, carbs are our body’s preferred source of energy. When we eat, our bodies break down carbohydrates into glucose, which can be used by our cells to generate energy, aka ATP, via cellular respiration.

The glucose that is not immediately used to generate energy is stored in the liver and muscle cells as glycogen. When we’re between meals, in other words, we’re not eating, we’re not fasting, our bodies break down glycogen into glucose so that we can continue to generate the energy our cells need to function.

And altogether, we have enough stored glycogen to last for approximately 24 hours without food. Now, let’s say you fasted for that 24 hours, and at this point your glycogen stores will be depleted. At this point, our bodies have to shift to alternate pathways, first going down the hierarchy of gluconeogenesis, where you can make glucose from amino acids and other non sugar compounds, and then fatty oxidation.

In other words, breaking down fatty acids into the compound acetyl CoA, which can be used to generate energy. Now importantly, fatty oxidation yields ketone bodies. And when the body is in a state that it’s relying primarily on fatty oxidation to generate glucose. You’ll need to get, you’ll accumulate high amounts of ketones leading to ketoacidosis, which is a metabolic emergency.

Now IEMs can disrupt any of these pathways and importantly can have severe health consequences. So what are you going to see? On clinical presentation. Now, first off, realize that most IEMs present with very nonspecific clinical features. You won’t be able to diagnose them on history and physical alone.

And biochemical testing is really needed in most cases to independently diagnose a specific IEM. Therefore, in the ED, the goal is really to recognize the science and symptoms on history and physical exam that are suggestive of metabolic disease. identifying which specific IEM the patient has is part of the later long term evaluation, typically with the help of your friendly geneticist.

It is not the job or the expectation of the EM provider. So what are some of these suggestive clinical features? They include neurologic dysfunction, which is one of the most common that includes things like developmental delay, regression, AKA loss of developmental milestones, hypotonia, encephalopathy, or seizures.

GI symptoms are the second most common, and they include vomiting, food intolerance, food aversion, GERD, refractory to normal antireflux measures, diarrhea, and dehydration. You should also think about IEM in cases where you have failure to thrive, exercise intolerance, or autonomic instability. Now, as I mentioned earlier, since these are autosomal recessive disorders, where you need to have two copies of the mutate, of a mutation to manifest disease, oftentimes family history is negative.

However, sometimes you might hear of siblings or other relatives who had early onset neurologic or GI dysfunction or died early in life, and this can often be attributed to sepsis or sudden infant death syndrome because the symptoms of these overlap with IEMs. You also might see a family history of multiple miscarriages and or constant infinity.

Now typically, IEMs involved in glucose, protein, or fat breakdown, which are, the formal term for them is called intermediary metabolism, will have a short asymptomatic interval. They would kind of like there’s a honeymoon period of days to weeks depending on the IEM after birth. And then they’ll present with acute metabolic decompensation in the neonatal period.

And these neonates typically present looking really, really unwell. So they’re lethargic, they might vomit, they’re hypotonic, hypothermic, they might have fever or seizures. And this is due to buildup of the toxic intermediates of the stalled metabolic pathway. Now the important thing for EM providers to know is that this can mimic the presentation of sepsis.

So you should consider IEM on your differential, especially when the ID workup is negative. And the neonate’s symptoms are refractory to standard measures. In these children, in children, IEMs can present with acute metabolic or neurologic decompensation, like vomiting, coma, or seizures, oftentimes precipitated by episode, things that are metabolically stressful.

So think infection, exercise, or change in diet. Now IEMs involving excretion pathways will generally present with symptoms related to the buildup of the toxic metabolites that cannot be excreted. Now, this, because this gets a lot of buzz, hyperammonemia is a very common feature of a number of different IEMs.

And so it’s important to know its presentation. Hyperammonemia presents with difficulty feeding, lethargy, altered mental status, seizures, vomiting, and vital symptoms of anomalies, most commonly loss of regulation or low core temperature. Now, in contrast, individuals with IEMs that involve pathways for accessing stored energy Can be asymptomatic or well appeared for long periods of time as long as they have a steady supply of energy.

So for instance, in infants who often follow a regular feeding schedule, they can slip under their radar as they’re getting enough energy and in a period in routine forms, and they don’t need to then have any kind of tapping into their stored energy. But again, metabolic GI illness, interrupt other interruptions in feeding schedule, intense exercise.

will result in symptoms. And depending on the specific IEM, these can range from severe metabolic decompensation like hypoglycemia or ketoacidosis, to more subtle features like muscle cramps. So to summarize, consider IEM for neonates with severe unexplained progressive or refractory illness shortly after birth, children who have severe neurologic or GI dysfunction, neglects associated with vomiting.

For metabolic stressors like fever or fasting, and children who are presenting with acidosis or hypoglycemia. Now, what should we do for evaluation and next steps in management? So, again, to reinforce, since IEMs have very specific non specific presentations, the goal in the ER is not to specifically diagnose the IEM.

Rather, it’s recognizing the child in front of you may have an IEM and do what you need to do to acute, for acute stabilization for their associated symptoms. So first, like pretty much many presentations, do ABC, get your PALS as indicated, and get IV access. Next, you want to stop the intake of potentially toxic compounds like protein, fat, glucose, and fructose, and this includes NG or G tube feeds if the child does have them.

Make them NPO and give IV, and give IV fluids with 10 percent dextrose, normal saline, or half normal saline. So D10NS or D10 half NS at one and a half times their maintenance rate. And the goal here is to give glucose, which is that, you know, number one, pure substrate for energy iteration metabolic pathways at a sufficient volume or rate so that this patient does not need to use the other metabolic pathways that might be causing their presentation.

Next, get stat labs, look at metabolic anomalies for blood labs. You want to get some lights, you can get a BMP or CMP glucose, LFT, CRP. CK, urea, and also assess their acid base status, so venous, capillary, or arterial blood gas, and also get COAGs. you want to look at their ammonia and lactate and importantly, if you can, , you want to get a plasma sample for some more sophisticated metabolic tests that can be done later.

So those would be a plasma sample for plasma amino acids, organic acids, acyl carnitine, other compounds, which your friendly geneticist, when you consult them will be incredibly happy you got. Now you also want to get some urine samples. You want to check the color and odor with a urine analysis. Look at the pH, whether there’s glucose, protein, ketones in there.

And you can also store some urine sample for downstream testing. As certain metabolic disorders, you want to look at organic acids in the urine. Now, if you end up needing to get an LP, you can also freeze some extra CSF for downstream testing. Aim for around two to five mils. And then, aside from these tests, There are some additional studies that might be indicated by clinical symptomatology.

So for instance, if they’re having cardiac issues, think about getting an EKG or an echocardiogram. If they’re encephalopathic, you want to consider neural imaging, CT or MRI. And importantly, call a stat genetics consult for further guidance or management. These patients typically do need to be admitted, even if it’s just for monitoring, and if they’re very much deranged in their ABCs, their mental status, they may need to be admitted to the ICU.

So you’ve done your initial workup, nothing’s really conclusive yet, and this patient’s still in the ED. your genetics consult hasn’t responded yet. What should you do? First, continue the glucose infusion. Then, once you get the go ahead from your genetics consult, send samples for specialized metabolic evaluation, including plasma amino acids and acyl carnitines, urine amino acids and organic acids, and whatever else your consult recommends.

Keep an eye on their labs. Again, your consult can give you some helpful tips on the frequency of monitoring, including their lights, glucose, lactate, acid base status, and ammonia. And importantly, if you’re at a referring facility, the most important things are really the basics. So get the ABCs, start D10.

If the patient has a metabolic plan, whether it’s in their electronic medical record and or in their carrier gibbous fans. Follow it. This was made by people who know them very well. If labs are very difficult to get, let’s say the kid’s a difficult stick, at least get a finger stick glucose, get IV access, and start those fluids, D10, either NS or half NS, at one and a half times maintenance.

An obtundate or somnolent child can still tolerate intraosseous access, especially if you put the lidocaine in, 0. 5 mg per kg, max 20 mg. You can use 1 or 2 percent Lido. this video. And really get that access in so you can start those fluids and stabilize the child. Make plans to safely transport the child to a tertiary care after stabilization.

and connect and contact genetics and the accepting ED as soon as you can. Emily, thank you so much. I really appreciate you sharing your knowledge and information and hopefully this was a helpful refresher and primer for the next time that you see a child with a metabolic disorder in the emergency department.

If there’s other topics that you want to hear on the podcast, reach out and let me know. I will take an email. I will take a direct message on X. I will take a comment on Facebook or the blog. If you have the time, leave a review. It helps more people find the show, and therefore more people learn about the care of ill and injured children in the emergency department.

And if you’re like Dr. Groopman, And you’re wondering, Hey, can I record a podcast? The answer is yes, you can. If there’s a topic that you’re interested in learning and teaching about, and it relates to the care of children in the emergency department, send it my way. For PEM Currents, the pediatric emergency medicine podcast.

This has been Brad Sobolewski. See you next time.

By bradsobo

Brad Sobolewski, MD, MEd is a Professor of Pediatric Emergency Medicine and an Associate Director for the Pediatric Residency Training Program at Cincinnati Children's Hospital Medical Center. He is on Twitter @PEMTweets and authors the Pediatric Emergency Medicine site PEMBlog and produces and hosts the PEM Currents: The Pediatric Emergency Medicine Podcast.

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