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Arnold W. Strauss - One of the best experts on this subject based on the ideXlab platform.
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mutations in long chain 3 hydroxyacyl coenzyme a dehydrogenase are associated with placental maternal floor infarction massive perivillous fibrin deposition
Pediatric and Developmental Pathology, 2012Co-Authors: Adrienne Carruth Griffin, Michael J. Bennett, Arnold W. Strauss, Linda M ErnstAbstract:Maternal floor infarction/massive perivillous fibrin deposition (MFI/MPVFD) of the placenta has an unclear etiology. The placenta of an 8-month-old child diagnosed with long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency reportedly showed MFI, but no further evidence of a direct association between MFI/MPVFD and LCHAD deficiency has been documented. Three cases of MFI/MPVFD were studied. Paraffin blocks of placental tissue were retrieved, tissue scrolls were harvested, and DNA was extracted. The alpha-subunit of the Mitochondrial Trifunctional Protein containing the LCHAD coding region (HADHA) was subsequently amplified using specific primer sets and directly sequenced by the dideoxy chain termination method. All 3 placentas demonstrated heterozygous mutations in the HADHA gene. A sample from a 25-4/7 week gestation growth-restricted female infant revealed a heterozygous mutation in exon 11, 1072C>A (glutamine to lysine, Qln358Lys) with a heterozygous sequence difference in the intron fol...
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General Mitochondrial Trifunctional Protein (TFP) Deficiency as a Result of Either α- or β-Subunit Mutations Exhibits Similar Phenotypes Because Mutations in Either Subunit Alter TFP Complex Expression and Subunit Turnover
Pediatric Research, 2004Co-Authors: Ute Spiekerkoetter, Zaza Khuchua, Michael J. Bennett, Zou Yue, Arnold W. StraussAbstract:The Mitochondrial Trifunctional Protein (TFP) is a multienzyme complex of the β-oxidation cycle. Human TFP is an octamer composed of four α-subunits harboring long-chain enoyl-CoA hydratase and long-chain L-3-hydroxyacyl-CoA dehydrogenase and four β-subunits encoding long-chain 3-ketoacyl-CoA thiolase. Mutations in either subunit may result in general TFP deficiency with reduced activity of all three enzymes. We report five new patients with α-subunit mutations and compare general TFP deficiency caused by α-subunit mutations ( n = 15) to that caused by β-subunit mutations ( n = 13) with regard to clinical features, enzyme activity, mutations, thiolase expression, and thiolase Protein turnover. Among patients with α-subunit mutations, the same three heterogeneous phenotypes reported in patients with β-subunit mutations were observed: a lethal form with predominating cardiomyopathy; an infancy-onset, hepatic presentation; and a milder, later-onset, neuromyopathic form. Maternal HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurred with an incidence of 15 to 20%, as in families with β-subunit mutations. Enzyme assays in fibroblasts revealed an identical biochemical pattern in both groups. α-Subunit mutational analysis demonstrated molecular heterogeneity, with 53% (9 of 17) truncating mutations. In contrast, patients with β-subunit mutations had predominantly missense mutations. Thiolase expression in fibroblasts was as markedly reduced in α-subunit patients as in the β-subunit group with similarly increased thiolase degradation, presumably secondary to TFP complex instability. TFP deficiency as a result of either α- or β-subunit mutations presents with similar, heterogeneous phenotypes. Both α- and β-subunit mutations result in TFP complex instability, demonstrating that the mechanism of disease is the same in α- or β-mutation-derived disease and explaining the biochemical and clinical similarities.
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peripheral neuropathy episodic myoglobinuria and respiratory failure in deficiency of the Mitochondrial Trifunctional Protein
Muscle & Nerve, 2004Co-Authors: Ute Spiekerkoetter, Michael J. Bennett, Arnold W. Strauss, Bruria Benzeev, Ingrid TeinAbstract:Mitochondrial Trifunctional Protein (TFP) deficiency is a rare disorder of the fatty acid -oxidation cycle with heterogeneous phenotypes and occurs secondary to either -o r-subunit mutations. We characterized the neuromyopathic phenotype of TFP deficiency through adolescence or adulthood in 11 patients, 8 with -subunit mutations and 3 with -subunit mutations. Two independent clinical features occurred: infantile-onset pro- gressive peripheral neuropathy and episodic exercise-, illness- or fasting- induced rhabdomyolysis accompanied by respiratory failure (in five pa- tients). The combination of episodic rhabdomyolysis and peripheral neuropathy occurred in 10 of the 11 patients. The neuromyopathic pheno- type 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. Muscle Nerve 29: 66-72, 2004
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the early onset phenotype of Mitochondrial Trifunctional Protein deficiency a lethal disorder with multiple tissue involvement
Journal of Inherited Metabolic Disease, 2004Co-Authors: Ute Spiekerkoetter, Zaza Khuchua, Z Yue, Arnold W. StraussAbstract:Summary: 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.
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molecular and phenotypic heterogeneity in Mitochondrial Trifunctional Protein deficiency due to β subunit mutations
Human Mutation, 2003Co-Authors: Zaza Khuchua, Michael J. Bennett, Ute Spiekerkoetter, Arnold W. StraussAbstract:The Mitochondrial Trifunctional Protein (TFP) is a multienzyme complex of the fatty acid b-oxidation cycle. It is composed of four a-subunits (HADHA) harboring long-chain enoyl-CoA hydratase and longchain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) and four b-subunits (HADHB) harboring longchain 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 b-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. Hum Mutat 21:598–607, 2003. r 2003 Wiley-Liss, Inc.
Michael J. Bennett - One of the best experts on this subject based on the ideXlab platform.
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mutations in long chain 3 hydroxyacyl coenzyme a dehydrogenase are associated with placental maternal floor infarction massive perivillous fibrin deposition
Pediatric and Developmental Pathology, 2012Co-Authors: Adrienne Carruth Griffin, Michael J. Bennett, Arnold W. Strauss, Linda M ErnstAbstract:Maternal floor infarction/massive perivillous fibrin deposition (MFI/MPVFD) of the placenta has an unclear etiology. The placenta of an 8-month-old child diagnosed with long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency reportedly showed MFI, but no further evidence of a direct association between MFI/MPVFD and LCHAD deficiency has been documented. Three cases of MFI/MPVFD were studied. Paraffin blocks of placental tissue were retrieved, tissue scrolls were harvested, and DNA was extracted. The alpha-subunit of the Mitochondrial Trifunctional Protein containing the LCHAD coding region (HADHA) was subsequently amplified using specific primer sets and directly sequenced by the dideoxy chain termination method. All 3 placentas demonstrated heterozygous mutations in the HADHA gene. A sample from a 25-4/7 week gestation growth-restricted female infant revealed a heterozygous mutation in exon 11, 1072C>A (glutamine to lysine, Qln358Lys) with a heterozygous sequence difference in the intron fol...
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General Mitochondrial Trifunctional Protein (TFP) Deficiency as a Result of Either α- or β-Subunit Mutations Exhibits Similar Phenotypes Because Mutations in Either Subunit Alter TFP Complex Expression and Subunit Turnover
Pediatric Research, 2004Co-Authors: Ute Spiekerkoetter, Zaza Khuchua, Michael J. Bennett, Zou Yue, Arnold W. StraussAbstract:The Mitochondrial Trifunctional Protein (TFP) is a multienzyme complex of the β-oxidation cycle. Human TFP is an octamer composed of four α-subunits harboring long-chain enoyl-CoA hydratase and long-chain L-3-hydroxyacyl-CoA dehydrogenase and four β-subunits encoding long-chain 3-ketoacyl-CoA thiolase. Mutations in either subunit may result in general TFP deficiency with reduced activity of all three enzymes. We report five new patients with α-subunit mutations and compare general TFP deficiency caused by α-subunit mutations ( n = 15) to that caused by β-subunit mutations ( n = 13) with regard to clinical features, enzyme activity, mutations, thiolase expression, and thiolase Protein turnover. Among patients with α-subunit mutations, the same three heterogeneous phenotypes reported in patients with β-subunit mutations were observed: a lethal form with predominating cardiomyopathy; an infancy-onset, hepatic presentation; and a milder, later-onset, neuromyopathic form. Maternal HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurred with an incidence of 15 to 20%, as in families with β-subunit mutations. Enzyme assays in fibroblasts revealed an identical biochemical pattern in both groups. α-Subunit mutational analysis demonstrated molecular heterogeneity, with 53% (9 of 17) truncating mutations. In contrast, patients with β-subunit mutations had predominantly missense mutations. Thiolase expression in fibroblasts was as markedly reduced in α-subunit patients as in the β-subunit group with similarly increased thiolase degradation, presumably secondary to TFP complex instability. TFP deficiency as a result of either α- or β-subunit mutations presents with similar, heterogeneous phenotypes. Both α- and β-subunit mutations result in TFP complex instability, demonstrating that the mechanism of disease is the same in α- or β-mutation-derived disease and explaining the biochemical and clinical similarities.
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peripheral neuropathy episodic myoglobinuria and respiratory failure in deficiency of the Mitochondrial Trifunctional Protein
Muscle & Nerve, 2004Co-Authors: Ute Spiekerkoetter, Michael J. Bennett, Arnold W. Strauss, Bruria Benzeev, Ingrid TeinAbstract:Mitochondrial Trifunctional Protein (TFP) deficiency is a rare disorder of the fatty acid -oxidation cycle with heterogeneous phenotypes and occurs secondary to either -o r-subunit mutations. We characterized the neuromyopathic phenotype of TFP deficiency through adolescence or adulthood in 11 patients, 8 with -subunit mutations and 3 with -subunit mutations. Two independent clinical features occurred: infantile-onset pro- gressive peripheral neuropathy and episodic exercise-, illness- or fasting- induced rhabdomyolysis accompanied by respiratory failure (in five pa- tients). The combination of episodic rhabdomyolysis and peripheral neuropathy occurred in 10 of the 11 patients. The neuromyopathic pheno- type 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. Muscle Nerve 29: 66-72, 2004
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molecular and phenotypic heterogeneity in Mitochondrial Trifunctional Protein deficiency due to β subunit mutations
Human Mutation, 2003Co-Authors: Zaza Khuchua, Michael J. Bennett, Ute Spiekerkoetter, Arnold W. StraussAbstract:The Mitochondrial Trifunctional Protein (TFP) is a multienzyme complex of the fatty acid b-oxidation cycle. It is composed of four a-subunits (HADHA) harboring long-chain enoyl-CoA hydratase and longchain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) and four b-subunits (HADHB) harboring longchain 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 b-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. Hum Mutat 21:598–607, 2003. r 2003 Wiley-Liss, Inc.
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molecular and phenotypic heterogeneity in Mitochondrial Trifunctional Protein deficiency due to β subunit mutations
Human Mutation, 2003Co-Authors: Ute Spiekerkoetter, Zaza Khuchua, Michael J. Bennett, Bin Sun, Arnold W. StraussAbstract: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.
Ute Spiekerkoetter - One of the best experts on this subject based on the ideXlab platform.
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the spectrum of peripheral neuropathy in disorders of the Mitochondrial Trifunctional Protein
Journal of Inherited Metabolic Disease, 2021Co-Authors: Sarah C Grunert, Matthias Eckenweiler, Dorothea Haas, Martin Lindner, Konstantinos Tsiakas, Rene Santer, Sara Tucci, Ute SpiekerkoetterAbstract:Peripheral neuropathy is a known irreversible long-term complication of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and Mitochondrial Trifunctional Protein deficiency (MTPD), two inherited disorders of Mitochondrial long-chain fatty acid oxidation. The underlying pathophysiology of neuropathy is still not fully understood. We report electrophysiological studies and neurological findings in a series of 8 LCHAD-deficient and 11 MTP-deficient patients. The median age at time of the study was 8.0 years (0.5-25 years). The overall prevalence of neuropathy was 58% with neuropathic symptoms being slightly more common in MTPD compared to LCHADD (70% vs 50%, respectively). Onset of neuropathy was significantly earlier in MTPD patients compared to LCHADD patients (median age at onset 4.7 vs 15.3 years, respectively, P = .047). In four patients, isolated peripheral neuropathy was the first and only presenting symptom, and in all four the diagnosis was missed by newborn screening. About half of the patients (45.5%) had a sensorimotor neuropathy, while 27.3% showed a pure motor form and another 27.3% an isolated sensory form. Despite early diagnosis by newborn screening and early initiation of therapy, peripheral neuropathy cannot be prevented in all patients with LCHADD/MTPD and has severe impact on the life of affected patients. Electrophysiology classifies LCHADD/MTPD neuropathy as axonal with secondary demyelination. A novel observation is that in patients with acute, fulminant onset of neuropathy, symptoms can be partly reversible. Further studies are needed to elucidate the underlying pathophysiology of axonal damage and possible therapeutic targets.
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outcome in six patients with Mitochondrial Trifunctional Protein disorders identified by newborn screening
Molecular Genetics and Metabolism, 2010Co-Authors: Astrid Sperk, Martina Mueller, Ute SpiekerkoetterAbstract:Before the newborn screening era, disorders of the Mitochondrial Trifunctional Protein (TFP) complex including long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) presented with high morbidity and mortality. Data on outcome and prognosis of TFP deficiency disorders since implementation of screening are scarce. We here characterize 6 screened patients with a disorder of the TFP complex (3 of those with LCHADD) with respect to clinical presentation and molecular features. Three of 6 patients were symptomatic prior availability of screening results on days 4-5 of life. Of the three asymptomatic patients recognised by screening, one acutely died at 3months at home during an infection. Two patients remained asymptomatic with preventive measures during follow-up until the age of 3years. One of them had an older sibling with identical genotype born before the screening era, who became symptomatic with 15months. We conclude that newborn screening for disorders of the TFP complex allows identification of asymptomatic cases; however, the acute presentation in 3/6 babies before screening is noteworthy and troublesome. TFP and LCHAD deficiencies remain life-threatening disorders. This is in clear contrast to other defects of long-chain fatty acid oxidation after identification by newborn screening.
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intrauterine cardiomyopathy and cardiac Mitochondrial proliferation in Mitochondrial Trifunctional Protein tfp deficiency
Molecular Genetics and Metabolism, 2008Co-Authors: Ute Spiekerkoetter, Martina Mueller, Eva Cloppenburg, Reinald Motz, Ertan Mayatepek, Burkhard Bueltmann, Christoph KorenkeAbstract:Because of a switch in energy-producing substrate utilization from glucose in the fetal period to fatty acids postnatally, intrauterine morbidity of fatty acid oxidation defects has widely been denied. We report the intrauterine development of severe cardiomyopathy in a child with Mitochondrial Trifunctional Protein deficiency after 27 weeks of gestation. The child was born at 31 weeks of gestation and died on day 3 of life. Severe cardiac Mitochondrial proliferation was observed. Molecular analysis of both TFP genes was performed and confirmed a homozygous mutation in the TFP α-subunit introducing a stop codon at amino acid position 256 (g.871C>T, p.R256X). Despite severe intrauterine decompensation in our patient, no HELLP-syndrome or acute fatty liver of pregnancy was observed in the mother. In the pathogenesis of maternal HELLP-syndrome, toxic effects of accumulating long-chain hydroxy-acyl-CoAs or long-chain hydroxy-acylcarnitines are suspected. In our patient, acylcarnitine analysis on day 2 of life during severest metabolic decompensation did not reveal massive accumulation of long-chain hydroxy-acylcarnitines in blood, suggesting other pathogenic factors than toxic effects. The most important pathogenic mechanism for the development of intrauterine cardiomyopathy appears to be significant cardiac energy deficiency. In conclusion, our report implicates that fatty acid oxidation does play a significant role during intrauterine development with special regard to the heart. Severe cardiac Mitochondrial proliferation in TFP deficiency suggests pathophysiologically relevant energy deficiency in this condition.
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General Mitochondrial Trifunctional Protein (TFP) Deficiency as a Result of Either α- or β-Subunit Mutations Exhibits Similar Phenotypes Because Mutations in Either Subunit Alter TFP Complex Expression and Subunit Turnover
Pediatric Research, 2004Co-Authors: Ute Spiekerkoetter, Zaza Khuchua, Michael J. Bennett, Zou Yue, Arnold W. StraussAbstract:The Mitochondrial Trifunctional Protein (TFP) is a multienzyme complex of the β-oxidation cycle. Human TFP is an octamer composed of four α-subunits harboring long-chain enoyl-CoA hydratase and long-chain L-3-hydroxyacyl-CoA dehydrogenase and four β-subunits encoding long-chain 3-ketoacyl-CoA thiolase. Mutations in either subunit may result in general TFP deficiency with reduced activity of all three enzymes. We report five new patients with α-subunit mutations and compare general TFP deficiency caused by α-subunit mutations ( n = 15) to that caused by β-subunit mutations ( n = 13) with regard to clinical features, enzyme activity, mutations, thiolase expression, and thiolase Protein turnover. Among patients with α-subunit mutations, the same three heterogeneous phenotypes reported in patients with β-subunit mutations were observed: a lethal form with predominating cardiomyopathy; an infancy-onset, hepatic presentation; and a milder, later-onset, neuromyopathic form. Maternal HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurred with an incidence of 15 to 20%, as in families with β-subunit mutations. Enzyme assays in fibroblasts revealed an identical biochemical pattern in both groups. α-Subunit mutational analysis demonstrated molecular heterogeneity, with 53% (9 of 17) truncating mutations. In contrast, patients with β-subunit mutations had predominantly missense mutations. Thiolase expression in fibroblasts was as markedly reduced in α-subunit patients as in the β-subunit group with similarly increased thiolase degradation, presumably secondary to TFP complex instability. TFP deficiency as a result of either α- or β-subunit mutations presents with similar, heterogeneous phenotypes. Both α- and β-subunit mutations result in TFP complex instability, demonstrating that the mechanism of disease is the same in α- or β-mutation-derived disease and explaining the biochemical and clinical similarities.
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the early onset phenotype of Mitochondrial Trifunctional Protein deficiency a lethal disorder with multiple tissue involvement
Journal of Inherited Metabolic Disease, 2004Co-Authors: Ute Spiekerkoetter, Zaza Khuchua, Z Yue, Arnold W. StraussAbstract:Summary: 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.
Jamal A Ibdah - One of the best experts on this subject based on the ideXlab platform.
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regulation of Mitochondrial Trifunctional Protein modulates nonalcoholic fatty liver disease in mice
Journal of Lipid Research, 2018Co-Authors: Fatiha Nassir, Justin J Arndt, Sarah A Johnson, Jamal A IbdahAbstract:Mitochondrial Trifunctional Protein (MTP) plays a critical role in the oxidation of long-chain fatty acids. We previously reported that aging mice (>9 months old) heterozygous for an MTP defect (MTP+/−) develop nonalcoholic fatty liver disease (NAFLD). We tested whether a high-fat diet (HFD) accelerates NAFLD in young MTP+/−mice, and whether overexpression of the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuin 3 (SIRT3) deacetylates MTP and improves Mitochondrial function and NAFLD. Three-month-old WT and MTP+/− mice were fed HFD (60% cal fat) for 16 weeks and livers were assessed for fatty acid oxidation (FAO) and NAFLD. Compared with WT, MTP+/− mice displayed reduced hepatic SIRT3 levels and reduced FAO, with increased hepatic steatosis and the inflammatory marker CD68. Hepatic overexpression of SIRT3 in HFD-fed MTP+/− mice increased hepatic MTP Protein levels at the posttranscriptional level. Immunoprecipitation of MTP from liver mitochondria followed by Western blot with acetyl-lysine antibody showed higher acetylation of MTP in MTP+/− compared with WT mice. Overexpression of SIRT3 in MTP+/− mice significantly reduced the acetylation of MTP compared with β-galactosidase controls, increased Mitochondrial FAO, and reduced hepatic steatosis, CD68, and serum ALT levels. Taken together, our data indicate that deacetylation of MTP by SIRT3 improves Mitochondrial function and rescues NAFLD in MTP+/− mice.
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selective hepatic insulin resistance in a murine model heterozygous for a Mitochondrial Trifunctional Protein defect
Hepatology, 2013Co-Authors: Scott R Rector, Suzanne Ridenhour, Matthew E Morris, Grace M Meers, John Turk, Jamal A IbdahAbstract:Earlier reports suggest a link between Mitochondrial dysfunction and development of hepatic insulin resistance. Here we used a murine model heterozygous (HET) for a Mitochondrial Trifunctional Protein (MTP) gene defect to determine if a primary defect in Mitochondrial long-chain fatty acid oxidation disrupts hepatic insulin action. Hyperinsulinemic-euglycemic clamps and signaling studies were performed for assessment of whole-body and hepatic insulin resistance/signaling. In addition, hepatic fatty acid oxidation and hepatic insulin action were assessed in vitro using primary hepatocytes isolated from HET and wildtype (WT) mice. In both hepatic mitochondria and isolated primary hepatocytes, heterozygosity of MTP caused an ∼50% reduction in Mitochondrial fatty acid oxidation, a significantly impaired glucose disposal during the insulin clamp, and a markedly lower insulin-stimulated suppression of hepatic glucose production. HET mice also exhibited impaired insulin signaling, with increased hepatic phosphorylation of IRS2 (ser731) and reduced Akt phosphorylation (ser473) in both hepatic tissue and isolated primary hepatocytes. Assessment of insulin-stimulated FOXO1/phospho-FOXO1 Protein content and PEPCK/G6Pase messenger RNA (mRNA) expression did not reveal differences between HET and WT mice. However, insulin-induced phosphorylation of GSK3β was significantly blunted in HET mice. Hepatic insulin resistance was associated with an increased methylation status of the catalytic subunit of Protein phosphatase 2A (PP2A-C), but was not associated with differences in hepatic diacylglycerol content, activated Protein kinase C-ϵ (PKC-ϵ), inhibitor κB kinase β (IKK-β), c-Jun N-terminal kinase (JNK), or phospho-JNK Protein contents. Surprisingly, hepatic ceramides were significantly lower in the HET mice compared with WT. Conclusion: A primary defect in Mitochondrial fatty acid β-oxidation causes hepatic insulin resistance selective to hepatic glycogen metabolism that is associated with elevated methylated PP2A-C, but independent of other mechanisms commonly considered responsible for insulin resistance. (HEPATOLOGY 2013;)
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Mitochondrial Trifunctional Protein defects: clinical implications and therapeutic approaches.
Advanced Drug Delivery Reviews, 2008Co-Authors: R. Scott Rector, R. Mark Payne, Jamal A IbdahAbstract:Abstract The Mitochondrial Trifunctional Protein (MTP) is a heterotrimeric Protein that consists of four α-subunits and four β-subunits and catalyzes three of the four chain-shortening reactions in the Mitochondrial β-oxidation of long-chain fatty acids. Families with recessively inherited MTP defects display a spectrum of maternal and fetal phenotypes. Current management of patients with MTP defects include long-term dietary therapy of fasting avoidance, low-fat/high-carbohydrate diet with restriction of long-chain fatty acid intake and substitution with medium-chain fatty acids. These dietary approaches appear promising in the short-term, but the long-term outcome of patients treated with dietary intervention is largely unknown. Potential therapeutic approaches targeted at correcting the metabolic defect will be discussed. We will discuss the potential use of Protein transduction domains that cross the Mitochondrial membranes for the treatment of Mitochondrial disorders. In addition, we discuss the phenotypes of MTP in a heterozygous state and potential ways to intervene to increase hepatic fatty acid oxidative capacity.
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mice heterozygous for a defect in Mitochondrial Trifunctional Protein develop hepatic steatosis and insulin resistance
Gastroenterology, 2005Co-Authors: Jamal A Ibdah, Dietrich Matern, Yiwen Zhao, Piero Rinaldo, Jerry J. Angdisen, Peter S Perlegas, Hermina Borgerink, Melanie K Shadoan, Janice D Wagner, Mark J ClineAbstract:Background & Aims: Little is known about the role of Mitochondrial β-oxidation in development of nonalcoholic fatty liver disease (NAFLD). Mitochondrial Trifunctional Protein (MTP) catalyzes long-chain fatty acid oxidation. Recently, we generated a mouse model for MTP deficiency and reported that homozygous ( MTPa −/− ) mice suffer neonatal death. In this study, we investigated effects of heterozygosity for the MTP defect on hepatic oxidative stress, insulin resistance, and development of NAFLD in mice. Methods: We evaluated liver histopathology, serum alanine aminotransferase (ALT), glucose, fatty acids, and insulin levels in MTPa +/− and MTPa +/+ littermates. Insulin resistance was evaluated using glucose tolerance test (GTT) and insulin tolerance test (ITT). Liver tissues were used to measure triglyceride and fatty acid content, activity of superoxide dismutases (SOD) and glutathione peroxidase (GPx), glutathione (GSH), and cytochrome P-450 2E1 expression. Results: Aging but not young MTPa +/− mice developed hepatic steatosis with elevated ALT, basal hyperinsulinemia, and increased insulin area under curve (AUC) on GTT compared with MTPa +/+ littermates. In response to insulin challenge, aging MTPa +/− mice had slower rate of glucose disappearance and increased glucose AUC. Significant hepatic steatosis and insulin resistance developed concomitantly in the MTPa +/− mice at 9–10 months of age. Aging MTPa +/− mice had higher antioxidant activity of total SOD and GPx, lower GSH, and increased expression of cytochrome P-450 2E1, consistent with increased hepatic oxidative stress. Conclusions: Heterozygosity for β-oxidation defects predisposes to NAFLD and insulin resistance in aging mice. Impairment of Mitochondrial β-oxidation may play an important role in pathogenesis of NAFLD.
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Mitochondrial Trifunctional Protein defects: molecular basis and novel therapeutic approaches.
Current Drug Targets - Immune Endocrine & Metabolic Disorders, 2005Co-Authors: Jerry J. Angdisen, R. Mark Payne, V. D.g. Moore, J. M. Cline, Jamal A IbdahAbstract: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.
Ronald J A Wanders - One of the best experts on this subject based on the ideXlab platform.
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necrotizing enterocolitis and respiratory distress syndrome as first clinical presentation of Mitochondrial Trifunctional Protein deficiency
Journal of Inherited Metabolic Disorders, 2013Co-Authors: Eugene F Diekman, M Duran, Ronald J A Wanders, Frits A Wijburg, Hans R. Waterham, Carolien C A Boelen, Berthil H C M T Prinsen, Lodewijk Ijlst, Tom J De Koning, Gepke VisserAbstract:Background: Newborn screening (NBS) for long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency does not discriminate between isolated LCHAD deficiency, isolated long-chain keto acyl-CoA (LCKAT) deficiency and general Mitochondrial Trifunctional Protein (MTP) deficiency. Therefore, screening for LCHAD deficiency inevitably comprises screening for MTP deficiency, which is much less amenable to treatment. Furthermore, absence of a clear classification system for these disorders is still lacking.
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Mitochondrial Trifunctional Protein deficiency with recurrent rhabdomyolysis.
Pediatric neurology, 2009Co-Authors: Oded Scheuerman, Ronald J A Wanders, Hans R. Waterham, Gal Dubnov-raz, Ben-zion GartyAbstract:Rhabdomyolysis is an important clinical diagnosis. The differential diagnosis is extensive and includes various etiologies, such as infection, inflammation, trauma, endocrinopathies, and congenital muscular and metabolic disorders. Reported here is the case of an infant with recurrent rhabdomyolysis diagnosed as suffering from Mitochondrial Trifunctional Protein deficiency—a rare β oxidation defect. The clinical course was unique, and a new mutation in the Mitochondrial Trifunctional Protein gene was identified.
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neonatal screening for defects of the Mitochondrial Trifunctional Protein
Molecular Genetics and Metabolism, 2005Co-Authors: Johannes Sander, Ulrike Steuerwald, Ronald J A Wanders, Stefanie Sander, Nils Janzen, Michael Peter, Iris Marquardt, Christoph G Korenke, Anibh M. DasAbstract:Long-chain l-3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has been included in the routine neonatal screening program by the German screening commission. As tandem mass spectrometry (TMS) does not discriminate between the different defects of the Mitochondrial Trifunctional Protein (MTP) screening for isolated LCHAD deficiency includes the detection of long-chain 3-ketoacyl-CoA thiolase and complete MTP deficiencies as well. We identified 11 patients with abnormalities of the MTP out of 1.2 million newborns screened in our laboratory during the last 6 years. Treatment was started on the day the screening result was obtained (day 3 to day 9 of life). Seven of these newborns developed satisfactorily during an observation period of up to 64 months. They had isolated LCHAD deficiency, four of them caused by the typical mutation (1528 G>C), three others had no molecular genetic analysis done or were shown to have previously unknown mutations. Four children did not survive, two of them showing complete deficiency of MTP and two showing deficiency of long-chain 3-ketoacyl-CoA thiolase. We conclude that, despite the rarity of the disease, screening for MTP deficiencies is justified based on the following criteria: improved quality of life for patients with isolated LCHAD deficiency, absence of stigmatisation of babies showing mild variants without necessity of treatment, no significant increase of the total number of false positive screening results, no false negative results to our knowledge. Finally, extension of analysis to MTP deficiencies is achieved without additional costs for screening laboratories already using TMS.
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Mitochondrial Trifunctional Protein deficiency a severe fatty acid oxidation disorder with cardiac and neurologic involvement
The Journal of Pediatrics, 2003Co-Authors: Margarethe Den E J Boer, Ronald J A Wanders, Carlo Dionisivici, Anupam Chakrapani, Anders O J Van Thuijl, Frits A WijburgAbstract:Abstract Objective To determine the spectrum of presentation, including both clinical and biochemical abnormalities, and the clinical course in a cohort of patients with complete Mitochondrial Trifunctional Protein (MTP) deficiency, a rare inborn error of Mitochondrial fatty acid oxidation. Study design A questionnaire was sent to the referring physicians from 25 unselected MTP-deficient patients. Results Twenty-one patients could be included. Questionnaires about four patients were not returned. Nine (43%) patients presented with rapidly progressive clinical deterioration; six (67%) of them had hypoketotic hypoglycemia. The remaining 12 patients presented with a much more insidious disease with nonspecific chronic symptoms, including hypotonia (100%), cardiomyopathy (73%), failure to thrive, or peripheral neuropathy. Ten patients (48%) presented in the neonatal period. Mortality was high (76%), mostly attributable to cardiac involvement. Two patients who were diagnosed prenatally died despite treatment. Conclusion Complete MTP deficiency often presents with nonspecific symptomatology, which makes clinical recognition difficult. Hypotonia and cardiomyopathy are common presenting features, and the differential diagnosis of an infant with these signs should include MTP deficiency. In spite of early diagnosis and treatment, only a few patients with this condition have survived. (J Pediatr 2003;142:684-9)
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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
European Journal of Pediatrics, 2003Co-Authors: Karl Otfried Schwab, Dietrich Matern, Ronald J A Wanders, Regina Ensenauer, Gokhan Uyanik, Birgit Schnieders, W LehnertAbstract:The Mitochondrial Trifunctional Protein (MTP) is a multienzyme complex which catalyses three of the four chain-shortening reactions in the β-oxidation of long-chain fatty acids. Clinically, failure of long-chain fatty acid β-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 β-oxidation disorder. Both infants were homozygous for a novel missense mutation (976G→C) within a highly conserved region of the MTP β-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 β-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.