Approach to inborn errors of metabolism (acute): Clinical sciences

Inborn errors of metabolism, or IEMs, are genetic conditions that result from alterations within a biochemical or metabolic pathway. IEMs that present with acute onset during infancy are typically caused by single gene defects that impair enzymes involved in the urea cycle, amino acid and carbohydrate metabolism, glycogen storage, or peroxisomal or mitochondrial activity. When you suspect an acute IEM, you can use results of an initial laboratory evaluation to guide confirmatory testing.

Now, if a pediatric patient presents with a chief concern suggesting an IEM with acute onset, first perform an ABCDE assessment to determine if they are stable or unstable. If unstable, stabilize their airway, breathing, and circulation; and you may need to intubate your patient. Next, obtain intravenous access and consider starting IV fluids. Then, begin continuous vital sign monitoring, and if needed, provide supplemental oxygen. Finally, since patients with IEMs can present with signs and symptoms that mimic sepsis, consider starting IV antibiotics.

Now, after you’ve stabilized your patient, obtain a focused history and physical examination and order an ABG, CBC, CMP, ammonia level, and urinalysis. Most patients present during infancy with poor feeding, vomiting, and irritability. Affected infants have no obvious infection; no history of trauma; and no known central nervous system or other anomalies. History may also reveal a positive newborn screen, a sibling with an unexplained death or similar symptoms, or a family history of a metabolic disorder.

On exam, you’re likely to see an altered mental status; rapid, deep breathing or apnea; and hepatosplenomegaly. With these findings, consider an inborn error of metabolism, and assess the ABG for respiratory alkalosis.

If the ABG shows a decreased partial pressure of arterial carbon dioxide, or PaCO2, which indicates respiratory alkalosis, this is the first clue that you should consider a urea cycle disorder.

Your next step is to check the serum ammonia level. The presence of marked hyperammonemia indicates that you’re dealing with a urea cycle disorder, characterized by impaired conversion of neurotoxic ammonia into a more excretable compound called urea. Initially, hyperammonemia stimulates chemoreceptors in the brain, resulting in an increased respiratory rate and subsequent respiratory alkalosis. If left untreated, hyperammonemia can lead to encephalopathy, seizures, and coma.

Now, the most common urea cycle disorder is ornithine transcarbamylase, or OTC deficiency. To identify it, check plasma amino acid levels. If glutamine and alanine are elevated, and if citrulline and arginine levels are decreased, diagnose OTC deficiency.

Alright, let’s move on to conditions that are not associated with respiratory alkalosis, meaning the PaCO2 is not decreased. Unlike urea cycle disorders, many other IEMs commonly present with hypoglycemia, metabolic acidosis, or a combination of both.

So, let’s look at some other lab findings, starting with blood glucose levels. If the glucose is normal, look at your patient’s acid-base status to investigate further.

Here’s your first clinical pearl! Many IEMs are characterized by metabolic acidosis with an elevated anion gap. The anion gap is the difference between measured anions and cations in the blood, and the “gap” represents unmeasured ions. To calculate it, take the serum sodium and subtract the sum of serum chloride and bicarbonate. An anion gap above 12 milliequivalents per liter indicates the presence of unmeasured anions such as ketones or lactate.

Now back to our patient!

If labs demonstrate an elevated anion gap metabolic acidosis with elevated serum lactate levels, consider disorders of pyruvate metabolism such as pyruvate dehydrogenase complex deficiency, or PDC deficiency, characterized by lactic acidosis without organic acid abnormalities. Patients typically have low birth weight and later develop psychomotor delays. Characteristic exam findings resemble those seen in fetal alcohol syndrome, including short palpebral fissures; a smooth philtrum; a thin vermillion border; microcephaly; and hypotonia.

To confirm the diagnosis, order a genetic analysis. If there’s a defect in a gene that codes for one of the three critical enzymes in the pyruvate dehydrogenase complex, diagnose PDC deficiency. Because the pyruvate dehydrogenase complex is a part of the citric acid cycle and aerobic respiration, disorders of this complex lead to decreased ATP production during times of stress.

Okay, now let’s talk about cases with no acidosis and a normal serum lactate. Here, consider infantile Pompe disease, also known as Glycogen storage disease type II. History typically reveals profound Muscle weakness and Inadequate growth, while the exam demonstrates severe generalized Hypotonia, an enlarged Tongue, and Hepatomegaly. Labs typically demonstrate Elevated LFTs. To confirm the diagnosis, order a creatine kinase, or CK level, chest X-ray, and echocardiogram. The CK is typically elevated, the chest X-ray reveals massive Cardiomegaly, and the Echocardiogram often demonstrates Hypertrophic cardiomyopathy. These results confirm infantile Pompe disease which is also considered a lysosomal storage disease due to glycogen accumulation within lysosomes. You can remember the characteristics of this disease by using the mnemonic MIGHTY HECK!

Okay, let’s switch gears and discuss conditions that are characterized by hypoglycemia. Many IEMs can cause hypoglycemia, but you can narrow your differential by assessing the timing of hypoglycemia in relation to feedings.

Postprandial hypoglycemia should make you consider an inborn error of carbohydrate metabolism. To pinpoint the underlying cause, check urine non-glucose reducing substances, or NGRs; and order a galactose-1-phosphate uridyltransferase, or GALT activity assay as well as molecular genetic testing. If NGRs are elevated, and you identify an ALDOB gene mutation, diagnose hereditary fructose intolerance. Infants with this condition typically experience hypoglycemia when they first consume fruits and vegetables.