Jamal A. Ibdah

A FETAL FATTY-ACID OXIDATION DISORDER AS A CAUSE OF LIVER DISEASE IN PREGNANT WOMEN

Background Acute fatty liver of pregnancy and the HELLP syndrome (hemolysis, elevated liver-enzyme levels, and a low platelet count) are serious hepatic disorders that may occur during pregnancy in...

Lack of mitochondrial trifunctional protein in mice causes neonatal hypoglycemia and sudden death

Mitochondrial trifunctional protein (MTP) is a hetero-octamer of four alpha and four beta subunits that catalyzes the final three steps of mitochondrial long chain fatty acid beta-oxidation. Human MTP deficiency causes Reye-like syndrome, cardiomyopathy, or sudden unexpected death. We used gene targeting to generate an MTP alpha subunit null allele and to produce mice that lack MTP alpha and beta subunits. The Mtpa(-/-) fetuses accumulate long chain fatty acid metabolites and have low birth weight compared with the Mtpa(+/-) and Mtpa(+/+) littermates. Mtpa(-/-) mice suffer neonatal hypoglycemia and sudden death 6-36 hours after birth. Analysis of the histopathological changes in the Mtpa(-/-) pups revealed rapid development of hepatic steatosis after birth and, later, significant necrosis and acute degeneration of the cardiac and diaphragmatic myocytes. This mouse model documents that intact mitochondrial long chain fatty acid oxidation is essential for fetal development and for survival after birth. Deficiency of MTP causes fetal growth retardation, neonatal hypoglycemia, and sudden death.

Inherited long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and a fetal-maternal interaction cause maternal liver disease and other pregnancy complications

Fetal-maternal interactions are critical determinants of maternal health during pregnancy and perinatal outcome. This review explores the causative relationship of a fetal disorder of mitochondrial fatty acid oxidation, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and the serious maternal liver diseases of pregnancy-preeclampsia, the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet counts), and acute fatty liver of pregnancy. Features of the metabolic adaptation necessitated during the fetal-neonatal transition; common phenotypes of pediatric fatty acid oxidation disorders, including neonatal hypoketotic, hypoglycemia and hepatic crisis; and clinical abnormalities of HELLP and acute fatty liver of pregnancy are presented. Evidence that a common mutation in the alpha-subunit (LCHAD) of trifunctional protein, E474Q, is always one of the mutant alleles in fetal isolated LCHAD deficiency associated with these disorders of pregnancy that cause high maternal, fetal, and newborn morbidity and mortality is reviewed. Recommendations for molecular testing for LCHAD deficiency in families with life-threatening maternal liver disease are given.

Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.

Human mitochondrial trifunctional protein (TFP) is a heterooctamer of four alpha- and four beta-subunits that catalyzes three steps in the beta-oxidation spiral of long-chain fatty acids. TFP deficiency causes a Reye-like syndrome, cardiomyopathy, or sudden, unexpected death. We delineated the molecular basis for TFP deficiency in two patients with a unique phenotype characterized by chronic progressive polyneuropathy and myopathy without hepatic or cardiac involvement. Single-stranded conformation variance and nucleotide sequencing identified all patient mutations in exon 9 of the alpha-subunit. One patient is homozygous for the T845A mutation that substitutes aspartic acid for valine at residue 246. The second patient is a compound heterozygote for the T914A that substitutes asparagine for isoleucine at residue 269 and a C871T that creates a premature termination at residue 255. Allele-specific oligonucleotide hybridization studies revealed undetectable levels of the mRNA corresponding to the mutant allele carrying the termination codon. This study suggests a novel genotype-phenotype correlation in TFP deficiency; that is, mutations in exon 9 of the alpha-subunit, which encodes a linker domain between the NH2-terminal hydratase and the COOH-terminal 3-hydroxyacyl-CoA dehydrogenase, result in a unique neuromuscular phenotype.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: Variable expressivity of maternal illness during pregnancy and unusual presentation with infantile cholestasis and hypocalcaemia

Patients with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency present with a Reye-like syndrome, cardiomyopathy, or sudden unexpected death. We describe an unusual presentation in a patient with unsuspected LCHAD deficiency. The proband presented at 2 months of age with an acute infantile hypocalcaemia and vitamin D deficiency associated with occult, unexplained cholestatic liver disease. Sudden, unexpected death occurred at 8 months. Molecular analysis revealed homozygosity for the prevalent LCHAD (1528G>C, E474Q) mutation. The mother had pre-eclampsia during the third trimester of her pregnancy. In a subsequent pregnancy, she developed severe acute fatty liver of pregnancy (AFLP) and intrauterine fetal death at 33 weeks of gestation. In conclusion, infantile hypocalcaemia is an unusual phenotype associated with LCHAD deficiency. The maternal pregnancy history documents that fetal LCHAD deficiency is associated with a spectrum of maternal illnesses ranging from pre-eclampsia to life-threatening AFLP.

Late presentation of esophageal injury after transesophageal echocardiography.

Esophageal injury is a rare complication of intraoperative transesophageal echocardiography (TEE) associated with cardiac surgery. We report two cases of delayed presentation (2 and 6 days after surgery) of esophageal injury that were likely due to TEE. The differential diagnosis of postoperative pleural effusion or anemia must include esophageal injury from TEE, even 6 days after the procedure.

Post-mortem analysis for two prevalent β-oxidation mutations in sudden infant death

Background: Fatty acid oxidation disorders may cause sudden and unexpected infant death and are associated with the histological hallmark of hepatic steatosis. The goal of the present study was to assess the value of post‐mortem molecular analysis for medium‐chain acyl‐coenzyme A dehydrogenase (MCAD) and mitochondrial trifunctional protein (MTP) defects in unexplained sudden infant death (SID) associated with fatty infiltration of the liver. MCAD catalyzes the first step of medium‐chain fatty acid oxidation while MTP catalyzes the last three steps of long‐chain fatty acid oxidation.

Liver Disease in Children: Inborn Errors of Mitochondrial Fatty Acid Oxidation

Mitochondrial fatty acid β-oxidation plays a major role in energy production and homeostasis once glycogen stores are depleted because of fasting, illness, and increased muscular activity [1]. The mitochondrial β-oxidation of fatty acids provides nearly 80% of energy for cardiac and hepatic functions at all times [2]. In the liver, the β-oxidation of fatty acids generates the precursors of ketone bodies, 3-hydroxybutyrate, and acetoacetate which are used as alternate fuel by the brain and peripheral tissues, such as cardiac and skeletal muscle, when glucose supply is low [3]. Defects in the mitochondrial fatty acid oxidation pathway are inherited as autosomal recessive disorders. The first well-documented genetic defect of fatty acid oxidation (FAO), described in 1973, was carnitine palmitoyl transferase (CPT) deficiency, presenting as a skeletal muscle disorder with exercise-induced rhabdomyolysis and myoglubinuria [4]. More than 20 defects have since been discovered [2]. The growing number of FAO disorders covers a wide spectrum of phenotypes, and the disorders are characterized by a wide array of clinical presentations. FAO disorders have become an important group of inherited metabolic disorders causing morbidity and mortality. FAO disorders, if unrecognized and untreated, may cause sudden unexpected death. Previously described clinical entities such as Reyes syndrome, certain cases of sudden infant death syndrome (SIDS), cyclic vomiting syndrome, unexplained cases of liver failure, and maternal complications of pregnancy are examples of disorders associated with defects in FAO [2].

A Fetal Fatty-Acid Oxidation Disorder as a Cause of Liver Disease in Pregnant Women

BACKGROUND Acute fatty liver of pregnancy and the HELLP syndrome (hemolysis, elevated liver-enzyme levels, and a low platelet count) are serious hepatic disorders that may occur during pregnancy in women whose fetuses are later found to have a deficiency of long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase. This enzyme resides in the mitochondrial trifunctional protein, which also contains the active site of long-chain 2,3-enoyl-CoA hydratase and long-chain 3-ketoacyl-CoA thiolase. We undertook this study to determine the relation between mutations in the trifunctional protein in infants with defects in fatty-acid oxidation and acute liver disease during pregnancy in their mothers. METHODS In 24 children with 3-hydroxyacyl-CoA dehydrogenase deficiency, we used DNA amplification and nucleotide-sequence analyses to identify mutations in the alpha subunit of the trifunctional protein. We then correlated the results with the presence of liver disease during pregnancy in the mothers. RESULTS Nineteen children had a deficiency only of long-chain 3-hydroxyacyl-CoA dehydrogenase and presented with hypoketotic hypoglycemia and fatty liver. In eight children, we identified a homozygous mutation in which glutamic acid at residue 474 was changed to glutamine. Eleven other children were compound heterozygotes, with this mutation in one allele of the alpha-subunit gene and a different mutation in the other allele. While carrying fetuses with the Glu474Gln mutation, 79 percent of the heterozygous mothers had fatty liver of pregnancy or the HELLP syndrome. Five other children, who presented with neonatal dilated cardiomyopathy or progressive neuromyopathy, had complete deficiency of the trifunctional protein (loss of activity of all three enzymes). None had the Glu474Gln mutation, and none of their mothers had liver disease during pregnancy. CONCLUSIONS Women with acute liver disease during pregnancy may have a Glu474Gln mutation in long-chain hydroxyacyl-CoA dehydrogenase. Their infants are at risk for hypoketotic hypoglycemia and fatty liver.

NOVEL GENOTYPE-PHENOTYPE CORRELATIONS IN PEDIATRIC MITOCHONDRIAL TRIFUNCTIONAL PROTEIN DEFICIENCY. • 606

NOVEL GENOTYPE-PHENOTYPE CORRELATIONS IN PEDIATRIC MITOCHONDRIAL TRIFUNCTIONAL PROTEIN DEFICIENCY. • 606