Case report: A newborn infant with cardiac arrest

Background

Mitochondrial fatty acid β-oxidation disorders (FAODs) are a group of about more tan 20 defects in fatty acid transport and mitochondrial β-oxidation that are inherited as autosomal recessive disorders. FAODs have a varied presentation, with either neonatal onset with hyperammonemia, transient hypoglycemia, metabolic acidosis, cardiomyopathy and sudden death or late onset with neuropathy, myopathy and retinopathy. Most cases with FAODs are now identified using newborn screening by mass spectrometry of blood spots. Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare fatty acid oxidation disorder which presents with different phenotypes. Early onset type, usually presents within the first months of life, with hypoglycemia, liver disease, cardiomyopathy, arrhythmias, pericardial effusion and sudden death mainly initiated by fasting, exercise, sickness and fever. Very long-chain fatty acids and carnitine need to be transported across the sarcolemma, as fatty acids are the major source of energy for myocardial cells. Any disturbance in energy production in this disorder results in low availability of glucose (hypoglycemia) and formation of ketone bodies, especially during periods of fasting and sickness. On the other hand, accumulation of toxic metabolites is cardiotoxic and can explain cardiomyopathy following toxic metabolite accumulation.

Case Study

A 36 hours-old boy was the first child of a non consanguineous couple, born through an uneventful pregnancy and delivery at term (40 weeks +3 days). Anthropometric index were normal at birth (weight: 3495 g, height: 50 cm, and head circumference: 36 cm). During admission, he experienced a cardiac arrest at hospital room so he was transferred to neonatal intensive care unit. Reanimation was made during 7 minutes and mechanic ventilation was neccesary. Empirical intravenous antibiotics were started, although septic screen was negative.

Chest X-ray and electroencephalogram revealed no significant findings. Ultrasound scan of brain showed germ matrix hemorrhage. Sinus tachycardia appeared on electrocardiography. Echocardiography do not showed chambers dilation, neither pulmonary hypertension and normal ejection fraction after cardiac arrest. Five days later another echocardiography was made and showed-up a mild septal hypertrophy.

He was found to have episodes of hypoglycemia with a blood glucose of 3 mg/dl, severe lactoacidosis (lactate= 13,80 mmol/L (0.5-1.6 mmol/L), arterial blood gas analysis revealed pH= 7.35 (7.35–7.45), pCO2= 21.5 mmHg (35–48 mmHg), HCO3= 12 mmol/L (22–29 mmol/L), and anion gap 26.2 mEq/L (8–16 mEq/L), suggestive of high anion gap metabolic acidosis. Urine ketone bodies were negative and serum ammonia 298 µg/dl so was evaluated for inherit error of metabolism. He appeared normoglycemic when receiving glucose infusion 4.5 mg/kg/min. With the glucose infusion and under therapeutic hypothermia during 72 hours, glucose infusion was tapered.

Laboratory tests demonstrated normal leukocyte count and differential for his age. Acute phase reactants were within normal range, but liver function tests were disrupted (aspartate aminotransferase (AST) = 1285 IU/l (<120 IU/L), alanine aminotransferase (ALT) = 179 IU/L (<40 IU/L), total bilirubin = 7.64 mg/dl (6-10 mg/dl), and direct bilirubin = 1.33 mg/dl (<0.3 mg/dl) and also high concentration of serum creatine phosphokinase 27803 IU/l.

Metabolic work-up revealed high concentrations of most of the serum amino acid and normal urine organic acid profile, but increased acylcarnitines in serum. The profile showed specific feature compatible with VLCAD or LCHAD.

C0= 40.31 µmol/L (21.5- 64.58 µmol/L), C12= 2,47 µmol/L (<0,18), C12:1= 3,14 µmol/L (<0,019), C14= 8,43 µmol/L (<0,11), C14:1= 13,99 µmol/L (<0,16), C14:2= 1,15 µmol/L (<0,09), C16= 13,70 µmol/L (<0,36), C16-OH= 0,26 µmol/L (<0,1), C16:1= 7,48 µmol/L (<0,15), C18= 2,58 µmol/L (<0,1), C18:1-OH= 0,18 µmol/L (<0,03), C18:1= 13,51 µmol/L (<0,25), C18:2= 0,91 µmol/L (<0,12), thus, MCT-based formula, low-fat and high-carbohydrate diet was started. Galactose 1-phosphate uridyl transferase activity was within normal limit.

On day 23 of life, the baby had been discharged from the neonatal intensive care unit. Follow-up echocardiogram was normal.

Further cultured lymphocytes enzyme activity demonstrated decreased Very long chain acyl-CoA dehydrogenase (VLCAD) activity and sequence analysis of ACADVL gene revealed heterozygous NM_000018.4:c.1273G>A; p.(Ala425Thr) y NM_000018.4:c.358_360del; p.(Ala120del) likely pathogenic variant based on the American College of Medical Genetics and Genomic guidelines (ACMG), which confirmed the diagnosis of VLCADD.

Up to 5 months of age, the baby had adequate weight gain without any cardiac event or hypoglycemic events.

Discussion

Inherit erros of metabolism are consequences of absence or abnormal levels of specific enzymes or enzyme cofactors, resulting in accumulation or deficiency of particular metabolites, mostly inherited as autosomal recessive traits. VLCAD deficiency is the second most commonly diagnosed disorder of fatty acid oxidation, and associated with a range of phenotypes, varying from asymptomatic patients to severe early-onset multiorgan failure and death.

Clinical phenotypes of VLCADD vary depending on the age at presentation. Early-onset, cardiac type, which is a severe form, often presents during the neonatal period or early infancy, involves cardiomyopathy and liver dysfunction and has high mortality. Our patient had the features of severe phenotype which is associated with mutations that result in poor residual VLCAD activity.

Biochemical examination and acylcarnitine analysis are useful for initial screening tools, usually abnormal during metabolic crisis and normal in levels between the episodes. Hypoketonemic hypoglycemia, high anion gap metabolic acidosis, deranged liver profile, and elevated CPK and plasma ammonia levels are the common biochemical abnormalities.

Acylcarnitine analysis by liquid tandem mass spectrometry is included in the routine newborn screening programs of most of the developed countries. The findings in plasma include an increase in free fatty acids C14:1 and lower proportions of C14:2 and C16:2 as specific markers of VLCADD. Other long-chain acylcarnitine species (C14, C16, C16:1, C16:2, C18:0, C18:1 and C18:2) are also elevated. Urine organic acid analysis may reveal hypoketonemic dicarboxylic aciduria, although normal urine organic acid profile cannot exclude the diagnosis of VLCADD, like in our patient who was genetically confirmed VLCADD but repeatedly had completely normal urine organic acid profile.

Conclusion

VLCADD can be a severe life-threatening disorder, if diagnosed late. This case demonstrates the importance of early diagnosis and management of this fatty acid oxidation deficiency in improving the outcome of the patients.