Heterozygosity for the Common LCHAD Mutation (1528G&gt;C) Is Not a Major Cause of HELLP Syndrome and the Prevalence of the Mutation in the Dutch Population Is Low

Boer, Margarethe E. J. den; IJlst, Lodewijk; Wijburg, Frits A.; Oostheim, W.; Werkhoven, M. A. Van; Pampus, Maria G. van; Heymans, H. S. A.; Wanders, Ronald J. A.

doi:10.1203/00006450-200008000-00006

Cited by 55 publications

(20 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutation analysis in patients in China, Japan and Korea reveals zero patients carrying this mutation [17,34,36–41]. In contrast, European countries report allele frequencies from as low as 1:680 in the Netherlands to a high of 1:79 in one region of Poland [30,32]. The carrier rate in the United States has never been investigated to our knowledge.…”

Section: Hadha or Hadhb Mutations And Retinopathymentioning

confidence: 99%

Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies

Fletcher

Pennesi

Harding

et al. 2012

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

Although the retina is thought to primarily rely on glucose for fuel, inherited deficiency of one or more activities of mitochondrial trifunctional protein results in a pigmentary retinopathy leading to vision loss. Many other enzymatic deficiencies in fatty acid oxidation pathways have been described, none of which results in retinal complications. The etiology of retinopathy among patients with defects in trifunctional protein is unknown. Trifunctional protein is a heteroctomer; two genes encode the alpha and beta subunits of TFP respectively, HADHA and HADHB. A common mutation in HADHA, c.1528 G>C, leads to a single amino acid substitution, p. Glu474Gln, and impairs primarily long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity leading to LCHAD deficiency (LCHADD). Other mutations in HADHA or HADHB often lead to significant reduction in all three enzymatic activities and result in trifunctional protein deficiency (TFPD). Despite many similarities in clinical presentation and phenotype, there is growing evidence that they can result in different chronic complications. This review will outline the clinical similarities and differences between LCHADD and TFPD, describe the course of the associated retinopathy, propose a genotype/phenotype correlation with the severity of retinopathy, and discuss the current theories about the etiology of the retinopathy.

show abstract

Section: Hadha or Hadhb Mutations And Retinopathymentioning

confidence: 99%

Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies

Fletcher

Pennesi

Harding

et al. 2012

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

show abstract

“…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 .…”

Section: Discussionmentioning

confidence: 88%

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

Geven

Niezen-Koning

Timmer

et al. 2007

BJOG

View full text Add to dashboard Cite

We describe a newborn with carnitine-acylcarnitine translocase (CACT) deficiency whose mother experienced preeclampsia 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. Twentyseven 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.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 ox...

show abstract

“…5 ). Accumulation of acylcarnitines has been linked to fatty acid oxidation deficiency due to a defect in carnitine-acylcarnitine translocase [55] , and acylcarnitines directly reflect the oxidation rate of fatty acid [56] , [57] . Previously, a clinical report of a mother who has had previous miscarriages but gave birth to a baby with a lethal deficiency of CACT indicated that maternal heterozygosity for CACT deficiency with fetal homozygosity for the same deficiency may contribute to impaired metabolism and toxic metabolites formation in both fetus and placenta [58] .…”

Section: Discussionmentioning

confidence: 99%

Spontaneous miscarriage in first trimester pregnancy is associated with altered urinary metabolite profile

Tan

Lim

et al. 2017

BBA Clinical

View full text Add to dashboard Cite

Threatened miscarriage is the most common gynecological emergency, occurring in about 20% of pregnant women. Approximately one in four of these patients go on to have spontaneous miscarriage and the etiology of miscarriage still remains elusive. In a bid to identify possible biomarkers and novel treatment targets, many studies have been undertaken to elucidate the pathways that lead to a miscarriage. Luteal phase deficiency has been shown to contribute to miscarriages, and the measurement of serum progesterone as a prognostic marker and the prescription of progesterone supplementation has been proposed as possible diagnostic and treatment methods. However, luteal phase deficiency only accounts for 35% of miscarriages. In order to understand the other causes of spontaneous miscarriage and possible novel urine biomarkers for miscarriage, we looked at the changes in urinary metabolites in women with threatened miscarriage. To this end, we performed a case-control study of eighty patients who presented with threatened miscarriage between 6 and 10 weeks gestation. Urine metabolomics analyses of forty patients with spontaneous miscarriages and forty patients with ongoing pregnancies at 16 weeks gestation point to an impaired placental mitochondrial β-oxidation of fatty acids as the possible cause of spontaneous miscarriage. This study also highlighted the potential of urine metabolites as a non-invasive screening tool for the risk stratification of women presenting with threatened miscarriage.

show abstract

Heterozygosity for the Common LCHAD Mutation (1528G>C) Is Not a Major Cause of HELLP Syndrome and the Prevalence of the Mutation in the Dutch Population Is Low

Cited by 55 publications

References 23 publications

Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies

Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies

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

Spontaneous miscarriage in first trimester pregnancy is associated with altered urinary metabolite profile

Contact Info

Product

Resources

About