NeoQuest June 2022: Term Infant with a Fatal Arrhythmia

A term infant with hepatomegaly develops emesis and respiratory distress 12 hours after birth. Six hours later, he becomes lethargic and develops acute bradycardia, hypotension, and hypoxemia requiring cardiopulmonary resuscitation. Initial laboratory tests reveal a metabolic acidosis and serum potassium of 8.5 mEq/L along with worsening renal function with a serum creatinine concentration of 1.9 mg/dL. His cranial ultrasound images are shown in the Figure. Additional investigation reveals a diagnosis of carnitine palmitoyltransferase II (CPT II) deficiency.

Figure 1. Coronal (left panel) and sagittal (right panel) views of a cranial ultrasound notes ventriculomegaly (green arrows) and vermian hypoplasia (yellow arrow). From: A Term Neonate with Multiorgan Dysfunction, Severe Metabolic Acidosis, and Hyperkalemia. Neoreviews. 2022;23(6):e409-e412¹

Of the following, the clinical feature LEAST likely associated with this infant’s diagnosis is:

1. Autosomal recessive inheritance
2. Cystic renal dysplasia
3. Hyperammonemia
4. Ketotic hypoglycemia

Answer: D. Ketotic hypoglycemia

Explanation:

The presentation of hypotonia and shock in a previously well infant should elicit a differential that includes sepsis, cardiac disease, and metabolic disorders.² The infant described in the question has an established diagnosis of carnitine palmitoyltransferase II (CPT II) deficiency.  That diagnosis involved deficient beta-oxidation of fatty acids, provoking an acute metabolic decompensation associated with hypoketotic hypoglycemia, not ketotic hypoglycemia (Option D).¹ Although ketosis and ketonuria are elements of some metabolic disorders, fatty acid oxidation disorders are associated with hypoketotic hypoglycemia as a result of  deficient hepatic ketogenesis and an impaired capacity to use stored fats in periods of prolonged fasting or increased metabolic demand.^2–4 The CPT system, which resides within the mitochondrial fatty acid oxidation pathway, is necessary for the transport of long-chain fatty acyl-coenzyme A (CoA) molecules into the mitochondrial matrix (Figure 2).⁵ The neonatal form of CPT II deficiency involves a severe clinical presentation within hours after birth, often triggered by fasting or acute illness, and it is characterized by acute hepatic failure, respiratory distress, cardiomyopathy, cardiac arrhythmias, seizures, and lethargy.^1,6,7

Figure 2. Overview of the mitochondrial fatty acid oxidation pathway. The enzyme carnitine palmitoyltransferase II (red) has an important role in the transport of long-chain fatty acyl-CoA molecules into the mitochondrial matrix from the cytoplasm. CACT = Carnitine-acylcarnitine translocase, CPT = carnitine palmitoyltransferase, TCA = tricarboxylic acid. Si W, Karbalivand H, Havranek T. Fatal arrhythmia in a 2-day-old full-term infant. Pediatr Rev. 2021;42(Supplement 1):S27–S29³

Fatty acid oxidation disorders such as CPT II deficiency are autosomal recessive conditions with an incidence of 1 in 5,000–10,000 live births (Option A).¹ Importantly, the biological parents of affected patients are likely to be carriers of mutations, and therefore there is a 25% recurrence risk in future pregnancies, if both individuals carry the mutation. Preimplantation genetic testing, prenatal diagnosis by chorionic villus sampling, or amniocentesis may be considered for future pregnancies.¹

Neonatal CPT II deficiency is associated with cystic renal dysplasia (Option B).^1,4,6 Notably, in some cases of infantile and adult CPT II deficiency, muscle involvement of the disease may result in myoglobinuria, elevated levels of serum creatinine and blood urea nitrogen, and acute renal failure.⁴

The disruption of the carnitine transport system (Figure 2) in CPT II deficiency results in the cytosolic accumulation of unoxidized fatty acyl-CoA molecules and is associated with laboratory features including increased serum aminotransferase and hyperammonemia (Option C).⁵ In general, the presence of metabolic acidosis and hyperammonemia should elicit concern for metabolic disorders such as CPT II deficiency and other mitochondrial energy metabolic defects (Figure 3).^5,7,8

Figure 3. Algorithm for evaluation of hyperammonemia in a neonate with a suspected inborn error of metabolism. Metab. = metabolism. Adapted from: Dagli A, Zori R, Heese B. Testing strategy for inborn errors of metabolism in the neonate. Neoreviews. 2008;9(7):e291–e298⁸

This month’s NeoQuest is based on the June case report A Term Neonate with Multiorgan Dysfunction, Severe Metabolic Acidosis, and Hyperkalemia.²

Did you know?

• The diagnosis of CPT II deficiency in a neonate should prompt investigation for neuronal migration defects and other structural malformations of the brain (Figure 1).^1,4,6 Neonatal CPT II deficiency has been associated with ventriculomegaly, agenesis of the corpus callosum, intraventricular calcifications, and cystic dysplasia of the brain.⁴
• Elevated C16 and C18:1 long-chain acylcarnitines on newborn screening or plasma acylcarnitine analysis by tandem mass spectrometry are suggestive of a diagnosis of CPT II deficiency.¹

An infant presents similarly to the infant in this vignette, with the exception of ketotic hypoglycemia. Does this change your management? To learn more about disorders of glycogen metabolism, refer to:  Rice GM, Steiner RD. Inborn errors of metabolism (metabolic disorders). Pediatr Rev. 2016;37(1):3–17⁹

How can you differentiate inborn errors of metabolism and metabolic acidosis based on the serum lactate level? To learn more about metabolic disorders with elevated versus normal lactic acid levels, refer to: Dagli, et al. Testing strategy for inborn errors of metabolism in the neonate. Neoreviews. 2008;9(7):e291–e298⁸

NeoQuest June Authors
Lila S. Nolan, MD, Washington University School of Medicine in St. Louis
Elizabeth Schulz, MD, Uniformed Services University

References

1. Monangi N, Shah M, DonnaMaria C. A Term neonate with multi organ dysfunction, severe metabolic acidosis, and hyperkalemia. Neoreviews. 2022;23(6):e409–e412
2. Tajima G, Hara K, Yuasa M. Carnitine palmitoyltransferase II deficiency with a focus on newborn screening. J Hum Genet. 2019;64(2):87–98
3. Si W, Karbalivand H, Havranek T. Fatal arrhythmia in a 2-day-old full-term infant. Pediatr Rev. 2021;42(Supplement 1):S27–S29
4. Sigauke E, Rakheja D, Kitson K, Bennett MJ. Carnitine palmitoyltransferase II deficiency: a clinical, biochemical, and molecular review. Lab Investig. 2003;83(11):1543­1554
5. Vishwanath VA. Fatty acid beta-oxidation disorders: a brief review. Ann Neurosci. 2016;23(1):51–55
6. Schneider S, DiBartolomeo M, Brennan G. Case 1: lethal pulmonary hemorrhage in a 3-day-old term infant. Neoreviews. 2019;20(12):e737–e739
7. Niemi A-K. Neonatal presentations of metabolic disorders. Neoreviews. 2020;21(10):e649–e662
8. Dagli AI, Zori RT, Heese BA. Testing strategy for inborn errors of metabolism in the neonate. Neoreviews. 2008;9(7):e291–e298
9. Rice GM, Steiner RD. Inborn errors of metabolism (metabolic disorders). Pediatr Rev. 2016;37(1):3–17