Pre-eclampsia in a woman whose child suffered from lethal carnitine-acylcarnitine translocase deficiency

Authors

  • WB Geven,

    Corresponding author
    1. a Department of Pediatrics, Martini Hospital, Groningen, the Netherlandsb Laboratory for Metabolic Diseases and c Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, d Department of Obstetrics, Martini Hospital, Groningen, the Netherlandse Department of Clinical Chemistry and Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlandsf Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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  • a KE Niezen-Koning,

    1. a Department of Pediatrics, Martini Hospital, Groningen, the Netherlandsb Laboratory for Metabolic Diseases and c Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, d Department of Obstetrics, Martini Hospital, Groningen, the Netherlandse Department of Clinical Chemistry and Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlandsf Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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  • b A Timmer,

    1. a Department of Pediatrics, Martini Hospital, Groningen, the Netherlandsb Laboratory for Metabolic Diseases and c Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, d Department of Obstetrics, Martini Hospital, Groningen, the Netherlandse Department of Clinical Chemistry and Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlandsf Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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  • c AJ Van Loon,

    1. a Department of Pediatrics, Martini Hospital, Groningen, the Netherlandsb Laboratory for Metabolic Diseases and c Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, d Department of Obstetrics, Martini Hospital, Groningen, the Netherlandse Department of Clinical Chemistry and Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlandsf Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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  • d RJA Wanders,

    1. a Department of Pediatrics, Martini Hospital, Groningen, the Netherlandsb Laboratory for Metabolic Diseases and c Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, d Department of Obstetrics, Martini Hospital, Groningen, the Netherlandse Department of Clinical Chemistry and Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlandsf Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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  • and e FJ Van Spronsen f

    1. a Department of Pediatrics, Martini Hospital, Groningen, the Netherlandsb Laboratory for Metabolic Diseases and c Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, d Department of Obstetrics, Martini Hospital, Groningen, the Netherlandse Department of Clinical Chemistry and Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlandsf Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Dr WB Geven, Department of Pediatrics, Martini Hospital, PO Box 30033,9700 RM Groningen, the Netherlands. Email w.b.geven@MZH.nl

Case report

We describe a newborn with carnitine-acylcarnitine translocase (CACT) deficiency whose mother experienced pre-eclampsia in her fifth pregnancy, after a normal first pregnancy and three miscarriages, all with the same partner. The parents are healthy, first cousins and of Dutch origin.

The mother’s first pregnancy was uneventful and normotensive. An otherwise healthy girl with situs inversus was born vaginally at 39 weeks. She was completely healthy at 3 years of age.

The mother experienced three subsequent 7–8 week miscarriages. A thrombophilia workup and anticardiolipin antibodies were negative.

This fifth pregnancy was normal until 35 weeks of gestation when a blood pressure of 130/90 mmHg was recorded. At 36+4 weeks, blood pressure rose to 152/92 mmHg. Proteinuria developed 3 days later, but liver function tests [aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), lactate dehydrogenase (LDH)], uric acid and platelet counts were all normal. All cardiotocograms were normal. Magnesium infusion was started, labour was induced and she underwent an uneventful vaginal delivery of a 3040 g boy. The baby initially appeared healthy and began bottle-feeding with no problems. Physical examination by a paediatrician 11 hours after birth showed no abnormalities, except for a rectal temperature of 36.3°C, which became normal thereafter. Twenty-seven hours after birth, the baby started grunting, was hypotonic and pale. He was admitted to the paediatric ward where a variable heart rate (between 40 and 100 beats/minutes) and a normal blood pressure (54/32 mmHg, mean of 40 mmHg) were noted. His respiratory status deteriorated, and he was intubated and artificially ventilated. Intravenous saline plus adrenalin were immediately given with a bolus of 6 ml glucose 10% (bedside glucose concentration was less than 1.0 mmol/l). Infusion of 6 mg glucose/kg/minutes raised glucose concentrations to 2.2 and 2.7 mmol/l in 1 and 3 hours later, respectively. Haemoglobin, total and differential leucocyte counts, platelets, capillary blood gas analysis and serum lactate were normal as was a chest X-ray. Leucocyte counts and glucose were also normal in cerebral spinal fluid. Antibiotics were started, and the boy was transferred to a neonatal intensive care unit in a tertiary referral centre. His heart rate continued to vary widely with normal pulse oximetry values (92–96%). The electrocardiogram (Figure 1) showed very abnormal broad and constantly changing QRS complexes on which no specific diagnosis could be made. Despite extra glucose intravenously, adrenaline, isoprenaline and calcium-gluconate, the circulation deteriorated and the boy died shortly after admission to the referral centre.

Figure 1.

The patient’s electrocardiogram showing abnormal broad and constantly changing QRS complexes, not diagnostic of any specific disorder.

An autopsy showed normal anatomy, however, on microscopic examination, using a stain specific for fat, cardiomyocytes, hepatocytes, myocytes and proximal tubular epithelial cells showed small fat droplets.

Because no ketones or elevated concentrations of dicarboxylic acids were detected in the urine sample collected before death, a defect in the oxidation of fatty acids, possibly at the level of the oxidation of long-chain fatty acids, seemed probable. Acylcarnitine analysis of cultured fibroblasts loaded with palmitate showed a markedly elevated palmitoylcarnitine level of 46.1 nmol/hour/mg protein (normal <1.0).1 Subsequent fibroblast studies showed normal activities for all beta-oxidation enzymes except for mitochondrial CACT, which showed a near complete deficiency with 2.3 pmol/minutes/mg (control 68 ± 30).2 The mother conceived for the sixth time and this pregnancy again ended in a 7-week miscarriage. Unfortunately, no fetal tissue was collected.

Discussion

Hypertensive disorders complicate 12–22% of pregnancies, while in 3–14% pre-eclampsia is diagnosed.3 Pre-eclampsia after an uneventful previous pregnancy with the same father is unusual.4 The obligatory presence of trophoblastic tissue makes pre-eclampsia a disease specific to pregnancy.

Recent data have shown that fatty acid oxidation (FAO) may play an important role in energy generation by the placenta.5,6 The combination of heterozygosity for a particular defect in the mitochondrial FAO in the mother combined with homozygosity for this defect in the fetus, and consequently in the placenta, may lead to the production of toxic metabolites and/or reduced energy metabolism in both the placenta and the fetus. Defects in long-chain FAO of the fetus (especially long-chain 3-hydroxyl-CoA dehydrogenase [LCHAD]) are associated with pregnancy complications varying from mild hypertension, mild or severe pre-eclampsia to recurrent HELLP (haemolysis, elevated liver enzymes and low platelet count) syndrome or acute fatty liver of pregnancy (AFLP).7–9 One case with short-chain acyl-CoA dehydrogenase deficiency10 and one with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency,11 have been described in HELLP syndrome.12,13

While short- and medium-chain fatty acids can enter the mitochondrion directly, long-chain fatty acids can only pass the mitochondrial inner membrane as carnitine esters before being beta-oxidised. In CACT deficiency, the transport of acylcarnitine esters across the inner mitochondrial membrane into the matrix of the mitochondrion is blocked due to a deficiency of the carrier protein. The severe and generalised impairment in mitochondrial beta-oxidation is reported to cause fasting induced hypoglycaemia in all patients and cardiovascular collapse in approximately 50% of them.14 In most of the CACT-deficient patients presenting as neonates, hypoglycaemia occurred and has until now been explained by insufficient breastfeeding during the first days. However, in our patient, severe hypoglycaemia developed despite sufficient early bottle-feeding without vomiting in the first day of life. Cardiac arrhythmia was one of the presenting signs.

During autopsy, our patient showed fat droplets in the cardiomyocytes and steatosis of the liver and kidneys, as reported in other CACT-deficient patients.14 The presence of these abnormalities so soon after birth strongly suggests prenatal accumulation of these fatty acid metabolites. As in LCHAD deficiency, it may be expected that in our patient with CACT deficiency, long-chain acylcarnitines have accumulated also.15 Shekhawat et al.8 showed a cytotoxic effect of these metabolites as they inhibit mitochondrial FAO, impair ATP production and are known to damage sarcolemmal membranes.16 In addition, peroxidative injury during ischaemia/hypoxaemia is potentiated.17 Because of the low oxygen tension in utero, the fetus with a defective beta-oxidation may be even more susceptible to these cytotoxic effects.

The common concept that glucose and amino acids from the maternal circulation provide the majority of energy necessary for the placenta and fetus may have to be changed to the notion that energy provided by placental fatty acid metabolism is important too.8,9,11 The association between pre-eclampsia, HELLP or AFLP and different fetal deficiencies of enzymes involved in the mitochondrial beta-oxidation of long-chain fatty acids5,9,16 suggests a common pathway that has not been unravelled yet. Thiele et al.18 have shown increased plasma carnitine and acylcarnitine in pre-eclampsia, possibly indicating disturbed FAO.

In carriers (heterozygotes) of an FAO defect, the acylcarnitine profile is not disturbed. It may be possible that pre-eclampsia, HELLP or AFLP18 can cause disturbances in the acylcarnitine profile of a pregnant woman undependent of her eventual FAO defect carrier status. Theoretically, the acylcarnitine profile in the mother would not be a reliable screening method for fetuses with a homozygous FAO defect. Newborn screening for the most common FAO disorders; long-chain acyl-CoA dehydrogenase deficiency (LCAD), MCAD and very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) has been started in several countries.

It is possible that the repeated early miscarriages in this mother were related to CACT deficiency as well. We therefore suggest that a lack of energy supply in the placenta and fetus with a defect in the beta-oxidation may be not only a pathophysiological mechanism of pre-eclampsia, HELLP and AFLP but also of miscarriage.

Further studies are needed to elucidate the role of beta-oxidation in early fetal development and maternal complications during pregnancy.

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