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At least 19 recordsLinked to original sources
PubMed2004

Peripheral neuropathy, episodic myoglobinuria, and respiratory failure in deficiency of the mitochondrial trifunctional protein.

Mitochondrial trifunctional protein (TFP) deficiency is a rare disorder of the fatty acid beta-oxidation cycle with heterogeneous phenotypes and occurs secondary to either alpha- or beta-subunit mutations. We characterized the neuromyopathic phenotype of TFP deficiency through adolescence or adulthood in 11 patients, 8 with beta-subunit mutations and 3 with alpha-subunit mutations. Two independent clinical features occurred: infantile-onset progressive peripheral neuropathy and episodic exercise-, illness- or fasting-induced rhabdomyolysis accompanied by respiratory failure (in five patients). The combination of episodic rhabdomyolysis and peripheral neuropathy occurred in 10 of the 11 patients. The neuromyopathic phenotype is common in TFP deficiency (11 of 27 families from our cohort). Therefore, this disorder must be considered in the differential diagnosis of progressive peripheral neuropathy with or without episodic myoglobinuria.

Adolescent↗
PubMed1994

Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the alpha-subunit of the mitochondrial trifunctional protein.

Mitochondrial trifunctional protein is a newly identified enzyme involved in mitochondrial fatty acid beta-oxidation harbouring long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketothiolase activity. Over the last few years, we identified more than 26 patients with a deficiency in long-chain 3-hydroxyacyl-CoA dehydrogenase. In order to identify the molecular basis for the deficiency found in these patients, we sequenced the cDNAs encoding the alpha- and beta-subunits which revealed one G-->C mutation at nucleotide position 1528 in the 3-hydroxyacyl-CoA dehydrogenase encoding region of the alpha-subunit. The single base change results in the substitution of a glutamate for a glutamine at amino acid position 510. The base substitution creates a PstI restriction site. Using RFLP, we found that in 24 out of 26 unrelated patients only the C1528 was expressed. The other two patients were heterozygous for this mutation. This mutation was not found in 55 different control subjects. This indicates a high frequency for this mutation in long-chain 3-hydroxyacyl-CoA dehydrogenase deficient patients.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1997

Genomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency.

Mitochondrial trifunctional protein (TP), an enzyme of beta-oxidation, is a multienzyme complex composed of four molecules of the alpha-subunit (HADHA) containing the enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase domains and four molecules of the beta-subunit (HADHB) containing the 3-ketoacyl-CoA thiolase domain. An inborn error of this enzyme complex can cause sudden infant death syndrome, acute hepatic encephalopathy or liver failure, skeletal myopathy, or hypertrophic cardiomyopathy. TP deficiency is classified into two different biochemical phenotypes: one represents the existence of both subunits and the lack of only the 3-hydroxyacyl-CoA dehydrogenase activity and the other represents the absence of both subunits and the lack of all three TP activities, although their clinical features are similar. We have identified two Japanese patients with this disorder. Three enzyme activities of TP were undetectable in fibroblasts from these two patients. We detected two mutations in the HADHB gene from two Japanese patients, an exonic single T insertion which created a new cryptic 5' splice site and a G1331A transition (R411 K). Patient 1 was a compound heterozygote, while patient 2 was a homozygote of a G1331A transition.

Animals↗
PubMed1996

Hypoparathyroidism in mitochondrial trifunctional protein deficiency.

Mitochondrial trifunctional protein deficiency, a recently identified disorder of fatty-acid oxidation, may show characteristic features such as peripheral neuropathy, pigmentary retinopathy, and acute fatty liver degeneration in pregnant women with an affected fetus. We describe a patient with trifunctional protein deficiency whose clinical picture consisted of severe calcium and phosphate abnormalities caused by hypoparathyroidism.

Female↗
PubMed2003

Complete deficiency of mitochondrial trifunctional protein due to a novel mutation within the beta-subunit of the mitochondrial trifunctional protein gene leads to failure of long-chain fatty acid beta-oxidation with fatal outcome.

UNLABELLED: The mitochondrial trifunctional protein (MTP) is a multienzyme complex which catalyses three of the four chain-shortening reactions in the beta-oxidation of long-chain fatty acids. Clinically, failure of long-chain fatty acid beta-oxidation leads to hypoketotic hypoglycaemia associated with coma, hepatopathy, skeletal myopathy and cardiomyopathy. We report on consanguineous parents with six children, four of whom had unexpectedly died in Egypt during the neonatal period due to cardiomyopathy of unknown aetiology and respiratory failure. After moving to Germany, two further children died at the age of 4 months and 12 h, respectively, with signs of respiratory and cardiac failure, hydrops fetalis and acidosis. Analysis of acylcarnitine profiles in dried blood spots of the last two children by electrospray tandem mass spectrometry was indicative of a long-chain fatty acid beta-oxidation disorder. Both infants were homozygous for a novel missense mutation (976G-->C) within a highly conserved region of the MTP beta-subunit gene. Immunoblot analysis in chorionic villi obtained during the subsequent pregnancy demonstrated absence of MTP. In fibroblasts and liver, activities of all three catalytic units of MTP were markedly decreased, further confirming the diagnosis of MTP deficiency. CONCLUSION: the detected mutation (976G-->C) within the beta-subunit of the mitochondrial trifunctional protein gene destabilises the protein, leading to complete deficiency and a poor prognosis. Immunoblot analysis of mitochondrial trifunctional protein in chorionic villi may be a valuable tool for the prenatal diagnosis of the disorder when the molecular genetic defect is unknown.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2005

Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency.

General mitochondrial trifunctional protein (TFP) deficiency leads to a wide clinical spectrum of disease ranging from severe neonatal/infantile cardiomyopathy and early death to mild chronic progressive sensorimotor poly-neuropathy with episodic rhabdomyolysis. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency resulting from the common Glu510Gln mutation usually gives rise to a moderately severe phenotype with multiorgan involvement with high morbidity and mortality. However, isolated LCHAD deficiency can also be consistent with long-term survival in patients identified and treated from an early age. We present biochemical, clinical and mutation data in 9 patients spanning the full spectrum of disease. Fibroblast acylcarnitine profiling shows good correlation with clinical phenotype using the ratio C18(OH)/(C14(OH)+C12(OH)). This ratio shows a gradation of values, from high in four patients with severe neonatal disease (2.5+/-0.8), to low in two neuromyopathic patients (0.35, 0.2). Fibroblast fatty acid oxidation flux assays also show correlation with the patient phenotype, when expressed either as percentage residual activity with palmitate or as a ratio of percentage activity of myristate/oleate (M/O ratio). Fibroblasts from four patients with severe neonatal disease gave an M/O ratio of 4.0+/-0.6 compared to 1.97 and 1.62 in two neuromyopathic patients. Specific enzyme assay of LCHAD and long-chain 3-ketothiolase activity in patient cells shows lack of correlation with phenotype. These results show that measurements in intact cells, which allow all determinative and modifying cellular factors to be present, better reflect patient phenotype. Mutation analysis reveals a number of alpha- and beta-subunit mutations. Peripheral sensorimotor polyneuropathy, often as the initial major presenting feature but usually later accompanied by episodic rhabdomyolysis, is a manifestation of mild TFP protein deficiency. The mild clinical presentation and relative difficulty in diagnosis suggest that this form of TFP is probably underdiagnosed.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed2006

Partial hypoparathyroidism associated with mitochondrial trifunctional protein deficiency.

The mitochondrial trifunctional protein (MTP) catalyzes the last three steps in the long-chain fatty acid beta-oxidation pathway. We report herein a patient with an inherited MTP deficiency and hypoparathyroidism that were both revealed at 4 months of age. Although parathyroid function appeared to be normalized following nutritional management of the fatty acid beta-oxidation defect, persistent gland dysfunction was suggested by frequent mild episodes of hypocalcaemia without increase in plasma intact parathyroid hormone (iPTH) levels during recurrent fasting-induced episodes of rhabdomyolysis and by our finding of a bilateral cataract at 5 years of age. An acute provocation test conducted to stimulate iPTH release with sodium bicarbonate infusion resulted in a subnormal rise in iPTH release, which further supported a partial hypoparathyroidism. This case is the third report of inherited MTP deficiency associated with hypoparathyroidism, thus raising the possibility of a link between these two rare disorders.

Calcium↗
PubMed1996

Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.

Mitochondrial trifunctional protein (MTP) is a recently identified enzyme involved in mitochondrial beta-oxidation, harboring long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain 3-ketothiolase activity. A deficiency of this protein is associated with impaired oxidation of long-chain fatty acids which can lead to sudden infant death. Furthermore, it is clear that this inborn error of fatty acid oxidation is very frequent, second to medium chain acyl-CoA dehydrogenase deficiency. In most patients only the LCHAD activity of MTP is deficient with near normal activity of the two other enzyme activities of the complex. We recently described the occurrence of a frequent G1528C mutation in the cDNA coding for the a subunit of MTP. Using S. cerevisiae for expression of wild type and mutant protein we show that the G1528C mutation is directly responsible for the loss of LCHAD activity. Furthermore, we describe a newly developed method allowing identification of the G1528C mutation in genomic DNA. The finding of an 87% allele frequency of the G1528C mutation in 34 LCHAD deficient patients makes this a valuable test for prenatal diagnosis. Finally, we show that the gene encoding the alpha subunit of MTP is located on chromosome 2p24.1-23.3.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2003

Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations.

The mitochondrial trifunctional protein (TFP) is a multienzyme complex of the fatty acid beta-oxidation cycle. It is composed of four alpha-subunits (HADHA) harboring long-chain enoyl-CoA hydratase and long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) and four beta-subunits (HADHB) harboring long-chain 3-ketoacyl-CoA thiolase (LKAT). Mutations in either subunit can result in TFP deficiency with reduced activity of all three TFP enzymes. We characterize 15 patients from 13 families with beta-subunit mutations by clinical, biochemical, and molecular features. Three clinical phenotypes are apparent: a severe neonatal presentation with cardiomyopathy, Reye-like symptoms, and early death (n=4); a hepatic form with recurrent hypoketotic hypoglycemia (n=2); and a milder later-onset neuromyopathic phenotype with episodic myoglobinuria (n=9). Maternal HELLP syndrome occurred in two mothers independently of the fetal phenotype. Mutational analysis revealed 16 different mutations, the majority being missense mutations (n=12). The predominance of missense mutations and the milder myopathic phenotype are consistent. Based upon homology to yeast thiolase that has been characterized structurally, the mutation localization within the protein correlates with the clinical phenotype. Outer loop mutations that are expected to alter protein stability less were only present in milder forms. The degree of reduction in thiolase antigen also correlated with the severity of clinical presentation. Although TFP deficiency is highly heterogeneous, there is genotype-phenotype correlation.

Adolescent↗
PubMed2005

Mitochondrial trifunctional protein defects: molecular basis and novel therapeutic approaches.

Mitochondrial trifunctional protein (MTP) is a complex protein that catalyzes the last three steps of long chain fatty acid oxidation. MTP defects have emerged recently as important inborn errors of metabolism because of their clinical implications. These disorders are recessively inherited and display a spectrum of clinical phenotypes in affected children including hepatic dysfunction, cardiomyopathy, neuro-myopathy, and may cause sudden unexpected infant death if undiagnosed and untreated. Interestingly, mothers who carry fetuses with MTP defects develop life-threatening complications during pregnancy. Recently, we delineated disease-causing mutations in MTP and reported the molecular basis for the pediatric and fetal-maternal genotype-phenotype correlations. Current management of patients with MTP defects include long-term dietary therapy of fasting avoidance, low fat diet with the restriction of long chain fatty acid intake and substitution with medium chain fatty acids. The long-term outcome of patients treated by dietary modifications remains unknown. Thus, treatment that aims at correcting the metabolic defect remains the therapy of choice for this disorder. Currently, we are exploring the potential use of protein transfection domains (PTD) for treatment of these disorders. We have shown that the transactivator of transcription (TAT) peptide from the human immunodeficiency virus can deliver proteins to mitochondria. We have further developed methods to localize these proteins to mitochondria by including a mitochondrial targeting in the fusion protein construct. Finally, we have shown that the fusion protein can cross the placenta and was detectable in the fetus and newborn pups. The practical therapeutic implications of this novel approach will be discussed.

Amino Acid Sequence↗
PubMed2001

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.

Animals↗
PubMed2004

The early-onset phenotype of mitochondrial trifunctional protein deficiency: a lethal disorder with multiple tissue involvement.

Mitochondrial trifunctional protein (TFP) deficiency is a clinically heterogeneous disorder with phenotypes of different severity. Early onset, severe forms predominantly exhibit cardiomyopathy, life-threatening arrhythmias and liver dysfunction; the later-onset, milder phenotype is mainly characterized by neuromyopathic features. The mechanisms that determine these heterogeneous presentations are unknown. We performed multiple tissue immunoblots from a patient with early-onset, lethal TFP deficiency and demonstrated absent TFP antigen in all. The predominant cardiac manifestation of severe TFP deficiency reflects its essential role in myocardial energetics, not its tissue-specific expression.

Cardiomyopathies↗
PubMed2003

Morphological investigation of two sibling autopsy cases of mitochondrial trifunctional protein deficiency.

Two sibling autopsy cases of type 2 mitochondrial trifunctional protein (MTP) deficiency are described. MTP is an enzyme complex involved in the mitochondrial beta-oxidation of fatty acids, which is the major pathway for energy production in heart and skeletal muscle. Both cases showed similar pathological findings. Numerous small foci of degeneration of muscle cells and cardiac myocytes were detected. Some of these cells had condensed or fragmented nuclei and most of them were positively stained using the deoxyuridine triphosphate nick-end labeling method. The lipid staining of both cases showed a small- to medium-sized fatty, vesicular morphology for liver cells, muscle cells, cardiac myocytes and proximal tubular cells of the kidney. Bone marrow was severely hypoplastic, and cortical thymocytes were markedly reduced in number. Neither case had hepatic fibrosis nor cirrhosis. The definitive diagnosis of type 2 MTP deficiency was made by verifying completely defective MTP-alpha and MTP-beta subunits in cultured skin fibroblasts of one of 2 patients. Our patients' signs indicate that there is a wider pathological spectrum of type 2 MTP deficiency, while very few autopsy cases of type 2 MTP deficiency have been confirmed. Pathologists should consider the possibility of type 2 MTP deficiency or other beta-oxidation defects in cases of sudden infant death, fatty infiltration of viscera or cardiomyopathy.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1999

Genes for the human mitochondrial trifunctional protein alpha- and beta-subunits are divergently transcribed from a common promoter region.

Human HADHA and HADHB genes encode the subunits of an enzyme complex, the trifunctional protein, involved in mitochondrial beta-oxidation of fatty acids. Both genes are located in the same region of chromosome 2p23. We isolated genomic clones, including 5' flanking regions, for HADHA and HADHB. Sequencing revealed that both of these genes are linked in a head-to-head arrangement on opposite strands and have in common a 350-bp 5' flanking region. The 5' flanking region has bidirectional promoter activity within this region; two cis elements proved critical for the activity. Transcription factor Sp1 functions as an activator for the bidirectional promoter by binding to both elements. Therefore, expression of trifunctional protein subunits are probably coordinately regulated by a common promoter and by Sp1.

Base Sequence↗
PubMed2007

Identification of novel mutations of the HADHA and HADHB genes in patients with mitochondrial trifunctional protein deficiency.

Patients with long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency manifest hypoketotic hypoglycemia, hepatomegaly, hypotonia, lactic acidemia, acute renal failure, cardiomyopathy, and sudden death. We describe four novel mutations of the alpha- and beta-subunits of the mitochondrial trifunctional protein in four patients from three unrelated families. Their plasma acylcarnitine profiles suggested the presence of LCHAD deficiency by demonstrating highly elevated 3-hydroxyacyl carnitines by tandem mass spectrometry (MS/MS). Patients 1 and 2 had siblings who had died of lactic acidemia during the neonatal period. These patients also manifested lactic acidemia and died in the neonatal period. Patient 3 had a family history of Reye-like syndrome. She exhibited acute renal failure, rhabdomyolysis, pericardial effusion, and myopathy at the age of 12 years. DNA analysis of patients 1 and 2 revealed homozygosity for a c.1689+2T>G mutation of the HADHA gene, resulting in the skipping of exon 16 with an in-frame 69-bp deletion. Patient 3 was a compound heterozygosity of the HADHB gene, N307D/N389D. Patient 4, a 25-month-old baby, manifested recurrent episodes of lethargy, metabolic acidosis, elevated liver enzymes, and dark urine from the age of 10 months. Mutation analysis of the HADHB gene of patient 4 identified compound heterozygosity of N114D/N307D.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

Molecular prenatal diagnosis in families with fetal mitochondrial trifunctional protein mutations.

OBJECTIVES: To evaluate the feasibility of molecular prenatal diagnosis in families with mitochondrial trifunctional protein (TFP) mutations and prospectively study the effects of fetal genotype on pregnancy outcome. TFP catalyzes the last 3 steps in mitochondrial long-chain fatty acid oxidation. STUDY DESIGN: We performed molecular prenatal diagnosis in 9 pregnancies, 8 in 6 families with isolated long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency and one in a family with complete TFP deficiency. Analyses were performed on chorionic villous samples in 7 pregnancies and on amniocytes in 2. RESULTS: Molecular prenatal diagnosis successfully identified the fetal genotype in all 9 pregnancies. Two fetuses were affected, and both pregnancies were terminated by family decision. Two other fetuses had normal genotype and 5 others were heterozygotes. These 7 pregnancies were uncomplicated, and all the offspring are alive and apparently healthy. Genotypes of the aborted fetuses and neonates were confirmed by molecular analysis and enzymatic assays. CONCLUSIONS: Molecular prenatal diagnosis is possible and valid in guiding management of pregnancies in families with known TFP defects. Women heterozygous for TFP alpha-subunit mutations who carry fetuses with wild-type or heterozygous genotypes have uncomplicated pregnancies.

Amniocentesis↗
PubMed2002

Fetal genotypes and pregnancy outcomes in 35 families with mitochondrial trifunctional protein mutations.

OBJECTIVE: The purpose of this study was to evaluate the effects of fetal genotype on maternal and fetal outcomes in families with mitochondrial trifunctional protein mutations in the United States. Trifunctional protein has 3 enzymatic activities that include long-chain 3-hydroxyacyl-CoA dehydrogenase, which catalyzes long-chain fatty acid beta-oxidation. STUDY DESIGN: We analyzed pregnancy history and offspring genotypes in 35 families with heterogeneous mutations. The fetal genotype was determined in utero in 11 pregnancies and after birth in 50 pregnancies. RESULTS: Forty-nine percent of the women who carried affected fetuses had acute fatty liver of pregnancy. Another 11% of the women had the syndrome of hemolysis, elevated liver enzymes, and low platelets, or preeclampsia. All women who had the maternal illness carried fetuses with isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Sixty-eight percent and 43% of the affected pregnancies also were associated with premature delivery and intrauterine growth retardation, respectively. No maternal or fetal complications were associated with heterozygous or wild-type fetal genotypes. CONCLUSION: Fetal mitochondrial trifunctional protein defects should be considered a cause for maternal liver disease, preterm labor, and intrauterine growth retardation.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2006

ENU mutagenesis identifies mice with cardiac fibrosis and hepatic steatosis caused by a mutation in the mitochondrial trifunctional protein beta-subunit.

Using the metabolomics-guided screening coupled to N-ethyl-N-nitrosourea-mediated mutagenesis, we identified mice that exhibited elevated levels of long-chain acylcarnitines. Whole genome homozygosity mapping with 262 SNP markers mapped the disease gene to chromosome 5 where candidate genes Hadha and Hadhb, encoding the mitochondria trifunctional protein (MTP) alpha- and beta-subunits, respectively, are located. Direct sequencing revealed a normal alpha-subunit, but detected a nucleotide T-to-A transversion in exon 14 (c.1210T>A) of beta-subunit (Hadhb) which resulted in a missense mutation of methionine to lysine (M404K). Western blot analysis showed a significant reduction of both the alpha- and beta-subunits, consistent with reduced enzyme activity in both the long-chain 3-hydroxyacyl-CoA dehydrogenase and the long-chain 3-ketoacyl-CoA thiolase activities. These mice had a decreased weight gain and cardiac arrhythmias which manifested from a prolonged PR interval to a complete atrio-ventricular dissociation, and died suddenly between 9 and 16 months of age. Histopathological studies showed multifocal cardiac fibrosis and hepatic steatosis. This mouse model will be useful to further investigate the mechanisms underlying arrhythmogenesis relating to lipotoxic cardiomyopathy and to investigate pathophysiology and treatment strategies for human MTP deficiency.

Adipose Tissue↗