Hyperammonemia, Lactic Acidosis, and Arrhythmia in a Newborn

Clinical History

A full-term female baby was born to consanguineous parents with a family history of a sibling who died on Day 2 of life with no clear diagnosis. The pregnancy was complicated by placenta previa and fetal distress following induction of labor necessitating cesarean section. She was admitted to the intensive care unit at 1 h of age due to respiratory distress and initially diagnosed with transient tachypnea of newborn. On Day 3 of life, she developed grunting, hypoxia, and bradycardia, necessitating intubation and mechanical ventilation. Echocardiogram showed atrial septal defect, mild tricuspid regurgitation, and mild aortic insufficiency with low contractility and flow in left ventricle. On evaluation, she was found to have an increased plasma ammonia concentration at 424 µmol/L (reference interval: 18–72), lactic acid (5.2 mmol/L; reference interval: 0.5–2.2), hypoglycemia and metabolic acidosis (pH: 7.25; HCO₃ 14 mmol/L). Dried blood spot acylcarnitine analysis revealed a low free carnitine (C0) concentration and increased hexadecanoylcarnitine (C16), octadecenoylcarnitine (C18:1), and other long-chain acylcarnitines (LCACs) (Table 1). Urine organic acid analysis showed increased excretion of lactic acid. Thus, a disorder of long-chain fatty acid metabolism was suspected.

Diagnosis and Summary

Whole exome sequencing revealed a homozygous variant [NM_000387.5: c.713A>G (p.Gln238Arg)] in the SLC25A20 gene encoding the carnitine-acylcarnitine translocase (CACT). According to the American College of Medical Genetics guidelines, we classified this known Saudi mutation as pathogenic based on the published and unpublished clinical, segregation, functional, biochemical, allele frequency, and pathogenicity prediction data. CACT is required for shuttling long-chain fatty acyl-CoAs from the cytosol into the mitochondrial matrix (1,). CACT deficiency (OMIM# 212138) is a rare autosomal recessive disease of long-chain fatty acid oxidation that usually presents early in life with a rapidly progressive course and high mortality. It is a multisystem disease and may also present with respiratory distress, seizures, arrhythmias, cardiomyopathy, liver disease, coma, and sudden death, possibly explaining the previous neonatal death of the male sibling in this family (Fig. 1A) (2,). Biochemical abnormalities include hypoketotic hypoglycemia, deranged liver enzymes, hyperammonemia, increased creatine kinase activity, and increased LCAC concentrations. Increased concentrations of LCACs are associated with impaired cardiorespiratory functions, adverse clinical outcomes, and increased amplitude of the potassium channel that contributes to the development of cardiac arrhythmia (3, 4).

Long-chain acyl-CoAs are initially converted to their acylcarnitine equivalents through the action of carnitine palmitoyltransferase I (CPT I). The resulting acylcarnitines are then transported into the mitochondrial matrix by CACT. Finally, carnitine palmitoyltransferase II (CPT II) converts acylcarnitines back to acyl-CoA species and free carnitine, the latter of which is transported back to the intermembrane space by CACT to participate in another cycle (5,) (Fig. 1B). CACT deficiency is associated with increased concentrations of LCACs (most notably C16 and C18:1) and low free carnitine, as in this case (3). A similar biochemical pattern is also seen in CPT II deficiency. Therefore, either molecular testing and/or enzyme activity measurement is required to differentiate the two conditions.

The severe form of CACT deficiency is associated with high mortality and sudden death early in life (2). Treatment includes the avoidance of fasting and frequent feeding consisting of carbohydrate-rich foods with restriction of dietary lipids. In these patients the majority of lipids should be supplied from medium chain triglycerides. In our case, the management of hyperammonemia was initiated with arginine, Ammonul (250 mg/kg IV bolus over 2 h, followed by 250 mg/kg/day infusion over 24 h) and levocarnitine (100 mg/kg/day, divided every 6 h). Although the ammonia concentration decreased to 62 µmol/L within 12 h from admission, lactic acidosis persisted and she continued to be obtunded and developed focal seizures. Her course was complicated by ventricular tachycardia that was attributed to hyperkalemia (plasma potassium 7.24 mmol/L; reference interval: 3.7–5.5), which was managed medically. However, the next day, she experienced 2 events of cardiac arrest, the second of which did not respond to resuscitation.

Nonstandard Abbreviations

CPT I, carnitine palmitoyltransferase I; CACT, carnitine-acylcarnitine translocase; CPT II, carnitine palmitoyltransferase II.

Author Contributions

All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors’ Disclosures or Potential Conflicts of Interest

Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership

R.W.A. Peake, Clinical Chemistry, AACC.

Consultant or Advisory Role

None declared.

Stock Ownership

None declared.

Honoraria

None declared.

Research Funding

N.A.M. Almontashiri, R.W.A. Peake, Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia.

Expert Testimony

None declared.

Patents

None declared.

Acknowledgment

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number 821.

References