Neonatal carnitine palmitoyltransferase II deficiency: failure of treatment despite prolonged survival

BACKGROUND

We describe the first case of neonatal carnitine palmitoyltransferase (CPT) II deficiency surviving beyond the neonatal period.

CASE PRESENTATION

A 29-year-old woman, gravida 5 para 4, was referred to our hospital for prenatal diagnosis because of carriership of CPT II deficiency. Two of her children are healthy (a daughter of 8 years old and a son of 3 years old), while two other children died soon after birth. Her first son died 1 day after birth. Her second son died on day 2. Laboratory investigation showed accumulation of long-chain acylcarnitines. DNA revealed homozygosity for the p.Pro227Leu (c.680 C>T) mutation in the CPT II gene. Both children were thus diagnosed as having neonatal CPT II deficiency.

During the fifth pregnancy, antenatal diagnostic investigation for CPT II deficiency was performed in the 28th week of gestation. A similar genetic pattern with homozygosity in the p.Pro227Leu mutation of the CPT II gene was found in the DNA of cultured amniotic fluid cells, revealing that the fetus was also affected by CPT II deficiency. Antenatal fetal cerebral MRI performed after an abnormal fetal ultrasound scan showed abnormal enlargement of the posterior ventricular horns due to partial corpus callosum agenesis. The fatal outcome of this disease was discussed with the parents, who choose not to terminate the pregnancy.

A caesarean section was performed for obstetric reasons at 39 weeks. A boy was born with a birth weight of 3110 g (25th percentile for gestational age) and Apgar scores of 8, 9 and 10 at 1, 5 and 10 min, respectively. Physical examination showed microcephaly (head circumference: 32 cm, <5th percentile). Immediately after birth a glucose infusion was started to assure a glucose intake of 8 mg/kg/min.

After an initial period of continuous intravenous glucose administration, continuous nasogastric feeding with special long-chain fatty acid free milk (Basic F; Milupa, Friedrichsdorf, Germany) was introduced. Gradually, a regimen of seven daily feeds was started under strict control with regard to glucose values, which remained adequate.

On day 22, the patient was discharged with seven daily feedings with special formula that did not contain long-chain fatty acids, but only essential fatty acids enriched with medium-chain triglycerides and glucose polymers (Fantomalt; Nutricia, Zoetermeer, The Netherlands). The parents were taught how to administer continuous nasogastric feeding during the night and received clear instructions to avoid fasting and when to contact the hospital. Hyperkalaemia was treated with resonium, which was continued after discharge. Hyperkalaemia resolved after a month. The overnight nasogastric tube feeding was stopped by the parents at 4 weeks of age as they preferred to give an extra feeding during the night.

The child developed normally during the first few months, although there was some generalised hypertonia.

At the age of 6 months the child visited the outpatient clinic for a routine monthly check-up. He was well at that time, without recent episodes of fever, vomiting or prolonged fasting. Physical examination revealed normal heart sounds, no murmurs and the liver was within normal limits for age. At 2 days later his mother found him in bed with a strange breathing pattern. He had not been ill in the 2 days before. He was immediately transported to the emergency room of a local hospital with insufficient breathing and a weak, dying pulse, where he was intubated and ventilated, but he died after 45 min due to ventricular fibrillation, which did not respond to defibrillation. The parents did not consent to autopsy.

INVESTIGATIONS

Laboratory studies performed directly after birth showed severe plasma accumulation of long-chain acylcarnitines. Plasma levels were: C16-carnitine 10.6 μmol/litre (normal range 0.06–0.24 μmol/litre), C18-carnitine 2.2 μmol/litre (normal 0.02–0.1 μmol/litre) and C18:1-carnitine 7.2 μmol/litre (normal 0.06–0.28 μmol/litre). Plasma free carnitine was normal: 21.2 μmol/litre. Plasma ammonia was mildly elevated at 136 μmol/litre (normal <110 μmol//litre). Liver enzymes and renal functions were alanine aminotransferase 15 U/litre (normal <45 U/litre), aspartate aminotransferase 74 U/litre (normal <60 U/litre), lactate dehydrogenase 1583 U/litre (normal 170–580 U/litre), urea 2.5 mmol/litre (normal 3–7 mmol/litre) and creatinine 166 μmol/litre (normal 10–65 μmol/litre/litre).

Electrolytes, arterial blood gas and blood cell count were all normal. Serum creatinine levels gradually decreased from 166 to 88 μmol/litre before discharge.

Cardiac echography showed a normal heart structures with hypertrophic ventricular walls. Renal ultrasound revealed enlarged dysplastic kidneys with lined cysts and decreased corticomedullary differentiation. Cranial ultrasound showed a partial corpus callosum agenesis and abnormal echodensities in the basal ganglia, suggestive of calcifications. MRI of the cerebrum confirmed these abnormalities.

Plasma levels of acylcarnitines gradually decreased during regular check-ups. Free carnitine became extremely low (4.1 μmol/litre, normal 22.3–54.8 μmol/litre) and carnitine supplementation (20 mg/kg/day) was started at 2 months of age. Monthly measurements of free carnitine levels showed after an initial rise to a low to normal value (22.7 μmol/litre), but all other values were below 10 μmol/litre.

OUTCOME AND FOLLOW-UP

During the last months at home, we instructed the parents to avoid fasting at all times. Low-dose carnitine supplementation was started after the plasma carnitine levels had dropped below 10 μmol/litre. An initial rise in plasma carnitine was followed by extremely low values, due to non-compliance. However, the acute cause of death, without any signs of chronic cardiac failure and a normal echocardiographic exam 3 months before, is probably not the result of these low plasma carnitine levels. In carnitine deficiency, due to a carnitine transporter defect (OCTN2 deficiency) most patients present after 1 year of age with hypertrophic cardiomyopathy, and can even be asymptomatic. The most probable cause of death in this case was cardiac conduction disturbances caused by slow accumulation of toxic long-chain acyl-CoA esters or acylcarnitines. Since permission for autopsy was not granted, the exact cause of death remains uncertain.

DISCUSSION

We report a patient antenatally diagnosed as having the neonatal form of CPT II deficiency with involvement of several organ systems (brain, kidneys and heart), who survived for a relatively long time (6 months) in comparison to previously reported cases. All previously reported cases died within 6 weeks after birth. The atypical clinical course can be due to the timing of diagnosis. Because the diagnosis CPT II deficiency was available antenatally, we were able to initiate treatment immediately after birth by starting an intravenous glucose infusion to prevent hypoglycaemia.1

In a few cases, including our patient, cerebral malformations have been detected antenatally.2^,3 The importance of FAO during early human development has been discussed by Oey et al.2^,4^,5 Defective organogenesis can be explained by defective mitochondrial β-oxidation leading to deficiency in essential materials for phospholipid synthesis. Alternatively, accumulation of intermediary metabolism products in utero may lead to toxic effects on the developing fetus.

The causative p.Pro227Leu (c.680 C>T) mutation in the CPT II gene is a well known mutation, first described by Taroni et al.6 Thuillier et al described a correlation between genotype, metabolic data and clinical presentation in CPT II deficiency.7 This mutation is associated with the severe neonatal form of CPT II deficiency.

We performed a review of the literature and identified 18 cases of neonatal CPT II deficiency. Including the family reported in this article, we have data for 21 cases from 13 different families. Results of clinical features, laboratory investigations and outcome of all reported patients with CPT II deficiency are summarised in table 1. Death occurred before 45 days in all patients, except for the case in the present report. In two cases2^,8 prenatal diagnosis resulted in termination of pregnancy. In our case prenatal diagnosis did not lead to termination of pregnancy because of parental refusal. In 1999 Pierce et al9 published a review of patients with CPT II deficiency, but included five cases of infantile CPT II deficiency presenting at the age of 1 month or older, as well as six neonatal cases. In this article we did not include patients with infantile CPT II deficiency.

A characteristic feature is that all patients except our case died during the neonatal period. Cardiomegaly was mentioned in 76% of the cases, with cardiac arrhythmias in 62%. The kidneys showed cystic dyplasia in 54%. In half of the cases the causative mutation is known. Residual CPT II activity in fibroblasts was <20%. Seizures are mentioned in four cases.1^,9^–11 Dysmorphic features included atypical minor abnormalities, such as microcephaly, long tapering fingers and hypoplastic toenails. In four cases7^,12^,13 (including our case), death of affected siblings was reported. Remarkable features included, among others, hyperammonaemia and sepsis due to coagulase negative staphylococci sepsis,10 bilateral cataracts and liver calcifications,4 and Staphylococcus aureus sepsis (our case). Hyperkalaemia was noted in four cases2^,3^,14 (including our case). The origin of the hyperkalaemia is probably multifactorial14 and related to renal disease, metabolic acidosis and hypoaldosteronism. In our case hyperkalaemia was asymptomatic and treated with resonium enemas for a month.