Case 1: A newborn infant with cardiac arrest

A female term infant 40 h of age was found to be unresponsive, apneic and asystolic while being held by her father in the newborn nursery at the authors’ hospital.

She was born uneventfully to a nonconsanguineous Caucasian couple. Her birth weight was 2.6 kg and she was exclusively breastfed.

Cardiopulmonary resuscitation was initiated immediately, in addition to epinephrine, fluids and sodium bicarbonate. Within 25 min, her heart rate was stabilized. Initial work-up revealed profound hypoglycemia (serum glucose 0 mmol/L; normal 2.5 mmol/L to 5.0 mmol/L) and lactic acidosis (serum lactate 8.8 mmol/L; normal <2.5 mmol/L). She responded to glucose boluses but required intake up to 13 mg/kg/min to maintain euglycemia.

Physical examination on admission to the neonatal intensive care unit revealed a nondysmorphic infant who was obtunded, hypotonic and hyporeflexic. Pupils were dilated and sluggish. These findings were consistent with severe neonatal encephalopathy. She underwent 72 h of therapeutic hypothermia for neuroprotection. Clinical seizures were observed 12 h into hypothermia and controlled by phenobarbital. Hypotension was managed by dobutamine infusion. She remained on mechanical ventilation for 8 h and then extubated to continuous positive airway pressure for four days before being successfully weaned to room air.

Further work-up revealed the diagnosis.

CASE 1 DIAGNOSIS: LONG-CHAIN 3-HYDROXYACYL-COA DEHYDROGENASE DEFICIENCY

The initial working diagnosis was neonatal encephalopathy secondary to sudden unexpected postnatal collapse (SUPC). Potential causes considered included congenital heart disease, sepsis, inborn error of metabolism (IEM) and acute airway obstruction.

Magnetic resonance imaging of the brain four days post event demonstrated bilateral asymmetric areas of diffusion restriction, with abnormal signals in the globi pallidi and internal capsules. An electroencephalogram performed on the same day revealed marked suppression of brain activity consistent with severe diffuse encephalopathy. Echocardiography demonstrated normal cardiac anatomy and function, and screening for sepsis and meningitis did not yield a positive culture. In view of the profound and persistent hypoglycemia, a comprehensive metabolic work-up was performed. Liver enzymes, ammonia and coagulation profile were within normal range. Serum lactate was corrected to 2 mmol/L over a 36 h period. Toal serum and free carnitine levels were decreased. Acylcarnitine analysis demonstrated elevated long-chain and 3-hydroxy long-chain acylcarnitine levels; urine organic acid analysis revealed the presence of dicarboxylic acid and several other hydroxycarboxylic acids (Table 1). Results of the newborn screening and subsequent investigations were consistent with a diagnosis of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.

Table 1.

Results of metabolic investigations

	Day		Reference range, µmol/L
	10	15
Acylcarnitines
Acetyl C2	3.17	3.01	4.65–35.39
Propionyl C3	0.12	0.09	<1.08
Butyrl/isobutyryl C4	0.26	0.09	<0.68
Tiglyl C5:1	0.02	0.01	<0.09
Isovaleryl/2-methylbutyryl C5	0.12	0.07	<0.47
Hexanoyl C6	0.19	0.26	<0.32
OH Isoval/methylOHbutyryl C5OH	0	0.02	<0.14
Octenoyl C8:1	0.06	0.1	<0.68
Octanoyl C8	0.26	0.25	<0.30
Malonyl C3DC	0.02	0	<0.13
Decenoyl C10:1	0.09	0.07	<0.29
Decanoyl C10	0.06	0.11	<0.38
Methylmalonyl/succinyl C4DC	0	0	<0.13
Glutaryl/3-OH decanoyl C5DC	0.1	0.09	<0.14
Dodecenoyl C12:1	0.13	0.09	<0.19
Dodecanoyl C12	0.23	0.26	<0.19
Adipyl/3MeGlutaryl C6DC/C53MDC	0.03	0	<0.14
3OHDodecanoyl C12OH	0.08	0.06	<0.05
Tetradecadienoyl C14:2	0.37	0.26	<0.09
Tetradecenoyl C14:1	0.49	0.48	<0.21
Tetradecanoyl C14	0.23	0.28	<0.11
3OHTetradecenoyl C14:1OH	0.13	0.09	<0.05
3OHTetradecanoyl C14OH	0.29	0.17	<0.04
Palmitoleoyl C16:1	0.3	0.16	<0.09
Palmitoyl C16	0.29	0.23	<0.31
3OHPalmitoleoyl C16:1OH	0.13	0.11	<0.13
3OHPalmitoyl C16OH	0.37	0.24	<0.05
Linoleoyl C18:2	0.97	0.54	<0.14
Oleoyl C18:1	1.06	0.82	<0.28
Stearoyl C18	0.27	0.13	<0.10
3OHLinoleoyl C18:2OH	0.45	0.17	<0.03
3OHOleoyl C18:1OH	1.1	0.67	<0.04
Carnitine
Total	8.3	8.5	12–60
Free	12.8	12.8	23–84

Acylcarnitine and carnitine profiles, initially performed on day 10, and confirmed on day 15

The patient’s neurological status improved progressively over the following week and a repeat electroencephalogram revealed normalization of cerebral activities. She became increasingly alert and responsive, achieving full oral feeds by day 14, and was discharged home at 25 days of age. She was followed closely postdischarge, and the diagnosis of LCHAD was confirmed by serum enzyme assays. Her parents have diligently adhered to frequent and appropriate dietary management including food intake high in medium-chain triglycerides. She has not experienced any recurrence of cardiopulmonary collapse. Motor development appeared normal at the two years’ assessment; at three years of age, she appeared to demonstrate average cognitive skills on neurodevelopmental testing, although a significant expressive language delay was identified. Genetic counselling has been provided to the family.

SUPC is a rare condition in the newborn period that includes apparent life-threatening events and sudden unexpected death in infancy. The reported frequencies range from 1.6 to 133 per 100,000 live births during the first week of life, although the defining criteria varies widely in different reports (1). Recent literature suggests that skin-to-skin contact and prone positioning may be associated with these events in the immediate newborn period; however, such association is often difficult to interpret.

LCHAD deficiency is a rare form of fatty acid oxidation defect (FAOD). Mitochondrial oxidation of fatty acids plays an essential role in energy metabolism during periods of fasting. After birth, when the infant is separated from the placenta, mobilization of fatty acids is essential to maintain energy supply until enteral feeding is well established. The inability to oxidize fatty acids would explain why infants with FAOD may present with significant hypoketotic hypoglycemia during the first days of life. Initial clinical presentation of LCHAD deficiency is variable. Severe hypoglycemia, cardiomyopathy, encephalopathy, liver dysfunction, myopathy, pigmentary retinopathy and sudden unexpected death in infancy have been reported. This condition has also been associated with maternal HELLP syndrome (2).

Although uncommon, clinicians should always maintain a high index of suspicion for any IEM. Early diagnosis of conditions such as FAOD is vital because institution of dietary management strategies, including avoidance of starvation and appropriate dietary restrictions, will minimize the potential risk for ongoing neurological injury. In infants who have died and autopsy is not possible, postmortem blood sampling for at least an acylcarnitine analysis should be performed. Diagnosis is important for family counselling for future pregnancies.

CLINICAL PEARLS

• FAOD, such as LCHAD deficiency, can present with SUPC in the immediate newborn period.

• A thorough diagnostic work-up should always be performed in newborns and infants presenting with SUPC and, in cases in which IEM is suspected, a full metabolic work-up should be performed.

• Early identification of IEM may facilitate effective treatment to optimize outcomes in survivors.