RARE DISEASE
Mitochondrial trifunctional protein deficiency
Mitochondrial trifunctional protein deficiency
Mitochondrial trifunctional protein deficiency
Synonyms: TFP deficiency, TFPD
Synonyms: TFP deficiency, TFPD
Synonyms: TFP deficiency, TFPD
Drug discovery
1
drug
With orphan designation
Overview
Mitochondrial Trifunctional Protein Deficiency (MTPD) is an autosomal recessive disorder caused by mutations in HADHA or HADHB genes, disrupting mitochondrial β-oxidation of long-chain fatty acids. Clinical manifestations range from severe neonatal-onset disease (hypoketotic hypoglycemia, cardiomyopathy, hepatic dysfunction) to later-onset neuropathy and rhabdomyolysis. Metabolic crises triggered by fasting or illness carry high mortality risks. Management includes fasting avoidance, low-fat/high-carbohydrate diets, and medium-chain triglyceride (MCT) supplementation [1][3][18].
Burden
Neonatal mortality >50% in severe cases; survivors face retinopathy (90%), recurrent rhabdomyolysis, and neuropathy [3][7][18].
Maternal carriers risk pregnancy complications (e.g., HELLP syndrome, AFLP) [7][15].
Persistent long-chain hydroxyacylcarnitine elevation may drive progressive organ damage despite therapy [3][8].
Therapies
Dietary: Restrict long-chain fats, supplement with MCTs, and ensure frequent carbohydrate intake [3][8][13].
Emergency Care: IV glucose during acute illness to prevent metabolic decompensation [8][13].
Adjuncts: Low-dose carnitine (25 mg/kg/day) to manage deficiency without exacerbating toxicity [3][8].
Categories: rare cardiac diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
64 drug discovery papers about Mitochondrial trifunctional protein deficiency, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
64 drug discovery papers about Mitochondrial trifunctional protein deficiency, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-01-08 | Elamipretide Improves Mitochondrial Function in Mitochondrial Trifunctional Protein-Deficient Mice and Human Fibroblasts.
Mitochondrial trifunctional protein (TFP) deficiency is an inherited disorder of long-chain fatty acid β-oxidation (FAO). TFP is a heteromeric enzyme composed of two α and two β-subunits. Despite early detection and dietary treatment, TFP deficiency patients often develop hypoglycemia, rhabdomyolysis, cardiomyopathy, and peripheral neuropathy. Degenerative retinopathy and milder peripheral neuropathy occur in patients with an isolated deficiency of the αTFP subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity. Triheptanoin treatment improves most complications, but not peripheral neuropathy and retinopathy. Notably, TFP also carries a fourth enzymatic function involved in cardiolipin remodeling, which we previously found to be impaired in TFP/LCHAD deficiency. We therefore tested whether elamipretide, a synthetic cardiolipin-binding peptide, could improve mitochondrial function and cardiolipin levels in βTFP-deficient mice and patient-derived fibroblasts. Mice were treated with elamipretide delivered by osmotic minipump and challenged with treadmill exercise or cold stress after fasting. βTFP-deficient mice treated with elamipretide showed improved exercise endurance, but cold tolerance was not altered. Liver mitochondria from male βTFP-deficient mice demonstrated improved FAO-ETC enzyme activities. However, cardiolipin content and composition were unchanged. In patient fibroblasts, elamipretide produced a possible genotype-dependent increase in mitochondrial bioenergetics and a reduction in ROS. These results support a mechanism in which elamipretide stabilizes between FAO enzymes and ETC complexes, thereby improving mitochondrial function independently of changes in cardiolipin levels. Elamipretide thus emerges as a potential therapeutic agent for TFP/LCHAD deficiency, warranting further preclinical studies.
2024-01-23 | Neurological outcome in long‐chain hydroxy fatty acid oxidation disorders
Abstract Objective This study aims to elucidate the long‐term benefit of newborn screening (NBS) for individuals with long‐chain 3‐hydroxy‐acyl‐CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide. Methods German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long‐term clinical outcomes. Results Sixty‐seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved. Interpretation While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long‐term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course‐altering treatment.
2023-09-04 | Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients
Abstract Background Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients—if untreated—are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients. Results We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients. Conclusions We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.
2020-09-07 | Faculty Opinions recommendation of The pivotal role of protein acetylation in linking glucose and fatty acid metabolism to β-cell function.
Protein acetylation has a crucial role in energy metabolism.Here we performed the first large-scale profiling of acetylome in rat islets, showing that almost all enzymes in core metabolic pathways related to insulin secretion were acetylated.Label-free quantitative acetylome of islets in response to high glucose revealed hyperacetylation of enzymes involved in fatty acid β-oxidation (FAO), including trifunctional enzyme subunit alpha (ECHA).Acetylation decreased the protein stability of ECHA and its ability to promote FAO.The overexpression of SIRT3, a major mitochondrial deacetylase, prevented the degradation of ECHA via decreasing its acetylation level in β-cells.SIRT3 expression was upregulated in rat islets upon exposure to low glucose or fasting.SIRT3 overexpression in islets markedly decreased palmitate-potentiated insulin secretion, whereas islets from SIRT3 knockout mice secreted more insulin, with an opposite action on FAO.ECHA overexpression partially reversed SIRT3 deficiency-elicited insulin hypersecretion.Our study highlights the potential role of protein acetylation in insulin secretion.
2019-08-19 | Regulation of mitochondrial trifunctional protein modulates nonalcoholic fatty liver disease in mice.
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.
small molecules
2025-11-19 | The Hidden Metabolic Threat: A Case of Fatty Acid Oxidation Disorder Masquerading as Viral Myocarditis.
Fatty acid oxidation disorders (FAODs) are rare inherited metabolic diseases that can present with various features including cardiomyopathy, arrhythmias, hypoketotic hypoglycemia, and liver dysfunction. Their clinical and radiological manifestations may at times overlap with acquired conditions such as viral myocarditis and multisystem inflammatory syndrome in children (MIS-C), making timely diagnosis challenging. We describe a 10-month-old infant boy with undiagnosed long-chain FAOD (LC-FAOD) who presented with sudden cardiac arrest following a viral illness. The patient's family history was significant for cardiac disease and sudden death. The infant displayed early symptoms of cardiac dysfunction at three months and was misdiagnosed with COVID-19-related myocarditis at the age of six months. Despite initial cardiac recovery and metabolic stabilisation, the child remained comatose and succumbed to refractory respiratory distress syndrome. The initial workup identified metabolites suggestive of LC-FAOD and whole-exome sequencing (WES) identified a homozygous variant in HADHA gene, ultimately confirming the diagnosis of mitochondrial trifunctional protein deficiency (TFPD). Early recognition through newborn screening and genetic testing, coupled with timely initiation of targeted metabolic management, remains crucial to improving outcomes and preventing fatal consequences.
2024-09-10 | Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency.
Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting CL metabolism might be dependent on patient genotype.
2023-07-10 | Molecular targets of spermidine: implications for cancer suppression
Spermidine is a ubiquitous, natural polyamine with geroprotective features. Supplementation of spermidine extends the lifespan of yeast, worms, flies, and mice, and dietary spermidine intake correlates with reduced human mortality. However, the crucial role of polyamines in cell proliferation has also implicated polyamine metabolism in neoplastic diseases, such as cancer. While depleting intracellular polyamine biosynthesis halts tumor growth in mouse models, lifelong external spermidine administration in mice does not increase cancer incidence. In contrast, a series of recent findings points to anti-neoplastic properties of spermidine administration in the context of immunotherapy. Various molecular mechanisms for the anti-aging and anti-cancer properties have been proposed, including the promotion of autophagy, enhanced translational control, and augmented mitochondrial function. For instance, spermidine allosterically activates mitochondrial trifunctional protein (MTP), a bipartite protein complex that mediates three of the four steps of mitochondrial fatty acid (β-oxidation. Through this action, spermidine supplementation is able to restore MTP-mediated mitochondrial respiratory capacity in naïve CD8+ T cells to juvenile levels and thereby improves T cell activation in aged mice. Here, we put this finding into the context of the previously described molecular target space of spermidine.
2023-06-13 | Case report: Mitochondrial trifunctional protein deficiency caused by HADHB gene mutation (c.1175C>T) characterized by higher brain dysfunction followed by neuropathy, presented gadolinium enhancement on brain imaging in an adult patient
Mitochondrial trifunctional protein (MTP) deficiency is an autosomal recessive disorder caused by impaired metabolism of long-chain fatty acids (LCFAs). Childhood and late-onset MTP deficiency is characterized by myopathy/rhabdomyolysis and peripheral neuropathy; however, the features are unclear. A 44-year-old woman was clinically diagnosed with Charcot-Marie-Tooth disease at 3 years of age due to gait disturbance. Her activity and voluntary speech gradually decreased in her 40s. Cognitive function was evaluated and brain imaging tests were performed. The Mini-Mental State Examination and frontal assessment battery scores were 25/30 and 10/18, respectively, suggesting higher brain dysfunction. Peripheral nerve conduction studies revealed axonal impairments. Brain computed tomography showed significant calcification. Magnetic resonance imaging revealed an increased gadolinium contrast-enhanced signal in the white matter, suggesting demyelination of the central nervous system (CNS) due to LCFAs. The diagnosis of MTP deficiency was confirmed through genetic examination. Administration of L-carnitine and a medium-chain fatty triglyceride diet was initiated, and the progression of higher brain dysfunction was retarded within 1 year. This patient's presentation was suggestive of CNS demyelination. The presence of brain calcification, higher brain dysfunction, or gadolinium enhancement in the white matter in patients with peripheral neuropathy may be suggestive of MTP deficiency.
2022-06-25 | Recurrent metabolic alkalosis following ketone body treatment of adult mitochondrial trifunctional protein deficiency: A case report
Recent studies have reported the potential for the therapeutic use of ketones in the form of ketone salts (KSs) in pediatric patients with fatty acid oxidation disorders (FAODs). We report a case of ketone salt administration in an adult patient with mitochondrial trifunctional protein deficiency (MTPD), an ultra-rare inborn error of the fatty acid metabolism. This patient was treated with oral KSs during an episode of sepsis of unknown origin. Before KS supplementation was initiated, he had developed severe rhabdomyolysis as well as a respiratory insufficiency that did not respond to emergency treatment aimed at stabilizing the metabolic decompensation by promoting anabolism. Therefore, KS supplementation was attempted twice to support his energy production and help regain metabolic stability. In both instances, KS supplementation led to a considerable metabolic alkalosis, which prompted its discontinuation. This adverse event could have been caused by an increase in extracellular sodium load due to KS administration. Therefore, the clinical applicability of KSs in adults may be limited. Alternative chemical forms of beta-hydroxybutyrate (βHB), such as ketone esters, might provide a more acceptable safety profile for future research into the therapeutic benefits of ketone body supplementation in adult patients with FAODs.
gene therapies
2024-09-16 | iPSC-Derived LCHADD Retinal Pigment Epithelial Cells Are Susceptible to Lipid Peroxidation and Rescued by Transfection of a Wildtype AAV-HADHA Vector.
Progressive choroid and retinal pigment epithelial (RPE) degeneration causing vision loss is a unique characteristic of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a fatty acid oxidation disorder caused by a common c.1528G>C pathogenic variant in HADHA, the α subunit of the mitochondrial trifunctional protein (TFP). We established and characterized an induced pluripotent stem cell (iPSC)-derived RPE cell model from cultured skin fibroblasts of patients with LCHADD and tested whether addition of wildtype (WT) HAHDA could rescue the phenotypes identified in LCHADD-RPE. We constructed an rAAV expression vector containing 3' 3xFLAG-tagged human HADHA cDNA under the transcriptional control of the cytomegalovirus (CMV) enhancer-chicken beta actin (CAG) promoter (CAG-HADHA-3XFLAG). LCHADD-RPE were cultured, matured, and transduced with either AAV-GFP (control) or AAV-HADHA-3XFLAG. LCHADD-RPE express TFP subunits and accumulate 3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones than WT-RPE. When LCHADD-RPE are exposed to docosahexaenoic acid (DHA), they have increased oxidative stress, lipid peroxidation, decreased viability, and are rescued by antioxidant agents potentially explaining the pathologic mechanism of RPE loss in LCHADD. Transduced LCHADD-RPE expressing a WT copy of TFPα incorporated TFPα-FLAG into the TFP complex in the mitochondria and accumulated significantly less 3-hydroxy-acylcarnitines, released more ketones in response to palmitate, and were more resistant to oxidative stress following DHA exposure than control. iPSC-derived LCHADD-RPE are susceptible to lipid peroxidation mediated cell death and are rescued by exogenous HADHA delivered with rAAV. These results are promising for AAV-HADHA gene addition therapy as a possible treatment for chorioretinopathy in patients with LCHADD.
2024-08-06 | Newborn screening for long-chain fatty acid oxidation disorders
Long-chain fatty acid oxidation disorders (lcFAOD) are a group of metabolic disorders where the body cannot properly use dietary long-chain fatty acids (LCFAs) for energy. LCFAs are crucial energy sources, particularly during fasting, fever, or exercise. Genetic variants in the proteins or enzymes involved in the long-chain fatty acid oxidation pathway can cause lcFAOD, leading to the accumulation of specific long-chain acyl-CoAs and their carnitine derivatives, known as long-chain acylcarnitines. Symptoms of lcFAOD include hypoglycemia, myopathy, rhabdomyolysis, exercise intolerance, cardiomyopathy, and arrhythmia, which typically manifest during metabolic stress. Mitochondrial trifunctional protein (MTP) disorders uniquely present with pigmentary retinopathy and peripheral neuropathy. Newborn screening (NBS) aims to promptly diagnose conditions that can cause irreversible harm early in life, preventing severe outcomes through early treatment. Mass spectrometry allows for the detection of multiple metabolites in dried blood spots, enabling the inclusion of numerous disorders in NBS programs worldwide. In 2007, the Netherlands included two lcFAOD, very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), in their NBS program, showing benefits in preventing severe hypoglycemia. Despite its benefits, NBS also presents several challenges. Utilizing a wide variety of methods, including in vitro experiments, innovative monitoring techniques, testing protocols, questionnaires, and retrospective chart research, the research described in this thesis aimed to identify and clarify some of the challenges introduced by NBS with a focus on lcFAOD. One of the discussed challenges is the risk of over- and underdiagnosis. Sensitive methods detect minor biochemical abnormalities, potentially identifying mildly affected or asymptomatic individuals, raising questions about the benefits of NBS for these cases. Conversely, some patients, particularly those with thermo-sensitive lcFAOD may be missed due to the absence of characteristic acylcarnitine abnormalities at normal temperatures. To enhance early recognition, genetic screening may be beneficial. Predicting prognosis after NBS diagnosis is crucial to balance early disease detection and avoiding unnecessary treatment, but remains difficult. Studies identified candidate biomarkers for disease severity, such as C18:2-carnitine for VLCADD, which can predict severe phenotypes, and lysophosphatidylcholine (LPC)(14:1), a potential severity marker for VLCADD. For LCHADD, a novel lipid class, S-(3-hydroxyacyl)cysteamines, was discovered as a specific biomarker. Understanding the natural history of NBS-diagnosed lcFAOD patients is vital for prognosis and personalized treatment. Research involving exercise tests and quantitative MRI (qMRI) in adolescent lcFAOD patients revealed variable exercise capacities and potential disease markers. These insights may help tailor monitoring and treatment strategies, though long-term monitoring remains necessary to understand the disease course and develop evidence-based guidelines. Current treatments, such as dietary management and preventing catabolism, do not completely prevent symptoms in all lcFAOD patients. Future approaches may involve gene therapy, aiming to correct the genetic root cause of the disorders. The ultimate goal is personalized treatment and early disease stratification to provide optimal care while minimizing unnecessary interventions and burden.
proteins
2026-01-08 | Elamipretide Improves Mitochondrial Function in Mitochondrial Trifunctional Protein-Deficient Mice and Human Fibroblasts.
Mitochondrial trifunctional protein (TFP) deficiency is an inherited disorder of long-chain fatty acid β-oxidation (FAO). TFP is a heteromeric enzyme composed of two α and two β-subunits. Despite early detection and dietary treatment, TFP deficiency patients often develop hypoglycemia, rhabdomyolysis, cardiomyopathy, and peripheral neuropathy. Degenerative retinopathy and milder peripheral neuropathy occur in patients with an isolated deficiency of the αTFP subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity. Triheptanoin treatment improves most complications, but not peripheral neuropathy and retinopathy. Notably, TFP also carries a fourth enzymatic function involved in cardiolipin remodeling, which we previously found to be impaired in TFP/LCHAD deficiency. We therefore tested whether elamipretide, a synthetic cardiolipin-binding peptide, could improve mitochondrial function and cardiolipin levels in βTFP-deficient mice and patient-derived fibroblasts. Mice were treated with elamipretide delivered by osmotic minipump and challenged with treadmill exercise or cold stress after fasting. βTFP-deficient mice treated with elamipretide showed improved exercise endurance, but cold tolerance was not altered. Liver mitochondria from male βTFP-deficient mice demonstrated improved FAO-ETC enzyme activities. However, cardiolipin content and composition were unchanged. In patient fibroblasts, elamipretide produced a possible genotype-dependent increase in mitochondrial bioenergetics and a reduction in ROS. These results support a mechanism in which elamipretide stabilizes between FAO enzymes and ETC complexes, thereby improving mitochondrial function independently of changes in cardiolipin levels. Elamipretide thus emerges as a potential therapeutic agent for TFP/LCHAD deficiency, warranting further preclinical studies.
2024-01-23 | Neurological outcome in long‐chain hydroxy fatty acid oxidation disorders
Abstract Objective This study aims to elucidate the long‐term benefit of newborn screening (NBS) for individuals with long‐chain 3‐hydroxy‐acyl‐CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide. Methods German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long‐term clinical outcomes. Results Sixty‐seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved. Interpretation While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long‐term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course‐altering treatment.
2023-09-04 | Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients
Abstract Background Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients—if untreated—are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients. Results We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients. Conclusions We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.
2020-09-07 | Faculty Opinions recommendation of The pivotal role of protein acetylation in linking glucose and fatty acid metabolism to β-cell function.
Protein acetylation has a crucial role in energy metabolism.Here we performed the first large-scale profiling of acetylome in rat islets, showing that almost all enzymes in core metabolic pathways related to insulin secretion were acetylated.Label-free quantitative acetylome of islets in response to high glucose revealed hyperacetylation of enzymes involved in fatty acid β-oxidation (FAO), including trifunctional enzyme subunit alpha (ECHA).Acetylation decreased the protein stability of ECHA and its ability to promote FAO.The overexpression of SIRT3, a major mitochondrial deacetylase, prevented the degradation of ECHA via decreasing its acetylation level in β-cells.SIRT3 expression was upregulated in rat islets upon exposure to low glucose or fasting.SIRT3 overexpression in islets markedly decreased palmitate-potentiated insulin secretion, whereas islets from SIRT3 knockout mice secreted more insulin, with an opposite action on FAO.ECHA overexpression partially reversed SIRT3 deficiency-elicited insulin hypersecretion.Our study highlights the potential role of protein acetylation in insulin secretion.
2019-08-19 | Regulation of mitochondrial trifunctional protein modulates nonalcoholic fatty liver disease in mice.
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.
small molecules
2025-11-19 | The Hidden Metabolic Threat: A Case of Fatty Acid Oxidation Disorder Masquerading as Viral Myocarditis.
Fatty acid oxidation disorders (FAODs) are rare inherited metabolic diseases that can present with various features including cardiomyopathy, arrhythmias, hypoketotic hypoglycemia, and liver dysfunction. Their clinical and radiological manifestations may at times overlap with acquired conditions such as viral myocarditis and multisystem inflammatory syndrome in children (MIS-C), making timely diagnosis challenging. We describe a 10-month-old infant boy with undiagnosed long-chain FAOD (LC-FAOD) who presented with sudden cardiac arrest following a viral illness. The patient's family history was significant for cardiac disease and sudden death. The infant displayed early symptoms of cardiac dysfunction at three months and was misdiagnosed with COVID-19-related myocarditis at the age of six months. Despite initial cardiac recovery and metabolic stabilisation, the child remained comatose and succumbed to refractory respiratory distress syndrome. The initial workup identified metabolites suggestive of LC-FAOD and whole-exome sequencing (WES) identified a homozygous variant in HADHA gene, ultimately confirming the diagnosis of mitochondrial trifunctional protein deficiency (TFPD). Early recognition through newborn screening and genetic testing, coupled with timely initiation of targeted metabolic management, remains crucial to improving outcomes and preventing fatal consequences.
2024-09-10 | Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency.
Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting CL metabolism might be dependent on patient genotype.
2023-07-10 | Molecular targets of spermidine: implications for cancer suppression
Spermidine is a ubiquitous, natural polyamine with geroprotective features. Supplementation of spermidine extends the lifespan of yeast, worms, flies, and mice, and dietary spermidine intake correlates with reduced human mortality. However, the crucial role of polyamines in cell proliferation has also implicated polyamine metabolism in neoplastic diseases, such as cancer. While depleting intracellular polyamine biosynthesis halts tumor growth in mouse models, lifelong external spermidine administration in mice does not increase cancer incidence. In contrast, a series of recent findings points to anti-neoplastic properties of spermidine administration in the context of immunotherapy. Various molecular mechanisms for the anti-aging and anti-cancer properties have been proposed, including the promotion of autophagy, enhanced translational control, and augmented mitochondrial function. For instance, spermidine allosterically activates mitochondrial trifunctional protein (MTP), a bipartite protein complex that mediates three of the four steps of mitochondrial fatty acid (β-oxidation. Through this action, spermidine supplementation is able to restore MTP-mediated mitochondrial respiratory capacity in naïve CD8+ T cells to juvenile levels and thereby improves T cell activation in aged mice. Here, we put this finding into the context of the previously described molecular target space of spermidine.
2023-06-13 | Case report: Mitochondrial trifunctional protein deficiency caused by HADHB gene mutation (c.1175C>T) characterized by higher brain dysfunction followed by neuropathy, presented gadolinium enhancement on brain imaging in an adult patient
Mitochondrial trifunctional protein (MTP) deficiency is an autosomal recessive disorder caused by impaired metabolism of long-chain fatty acids (LCFAs). Childhood and late-onset MTP deficiency is characterized by myopathy/rhabdomyolysis and peripheral neuropathy; however, the features are unclear. A 44-year-old woman was clinically diagnosed with Charcot-Marie-Tooth disease at 3 years of age due to gait disturbance. Her activity and voluntary speech gradually decreased in her 40s. Cognitive function was evaluated and brain imaging tests were performed. The Mini-Mental State Examination and frontal assessment battery scores were 25/30 and 10/18, respectively, suggesting higher brain dysfunction. Peripheral nerve conduction studies revealed axonal impairments. Brain computed tomography showed significant calcification. Magnetic resonance imaging revealed an increased gadolinium contrast-enhanced signal in the white matter, suggesting demyelination of the central nervous system (CNS) due to LCFAs. The diagnosis of MTP deficiency was confirmed through genetic examination. Administration of L-carnitine and a medium-chain fatty triglyceride diet was initiated, and the progression of higher brain dysfunction was retarded within 1 year. This patient's presentation was suggestive of CNS demyelination. The presence of brain calcification, higher brain dysfunction, or gadolinium enhancement in the white matter in patients with peripheral neuropathy may be suggestive of MTP deficiency.
2022-06-25 | Recurrent metabolic alkalosis following ketone body treatment of adult mitochondrial trifunctional protein deficiency: A case report
Recent studies have reported the potential for the therapeutic use of ketones in the form of ketone salts (KSs) in pediatric patients with fatty acid oxidation disorders (FAODs). We report a case of ketone salt administration in an adult patient with mitochondrial trifunctional protein deficiency (MTPD), an ultra-rare inborn error of the fatty acid metabolism. This patient was treated with oral KSs during an episode of sepsis of unknown origin. Before KS supplementation was initiated, he had developed severe rhabdomyolysis as well as a respiratory insufficiency that did not respond to emergency treatment aimed at stabilizing the metabolic decompensation by promoting anabolism. Therefore, KS supplementation was attempted twice to support his energy production and help regain metabolic stability. In both instances, KS supplementation led to a considerable metabolic alkalosis, which prompted its discontinuation. This adverse event could have been caused by an increase in extracellular sodium load due to KS administration. Therefore, the clinical applicability of KSs in adults may be limited. Alternative chemical forms of beta-hydroxybutyrate (βHB), such as ketone esters, might provide a more acceptable safety profile for future research into the therapeutic benefits of ketone body supplementation in adult patients with FAODs.
gene therapies
2024-09-16 | iPSC-Derived LCHADD Retinal Pigment Epithelial Cells Are Susceptible to Lipid Peroxidation and Rescued by Transfection of a Wildtype AAV-HADHA Vector.
Progressive choroid and retinal pigment epithelial (RPE) degeneration causing vision loss is a unique characteristic of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a fatty acid oxidation disorder caused by a common c.1528G>C pathogenic variant in HADHA, the α subunit of the mitochondrial trifunctional protein (TFP). We established and characterized an induced pluripotent stem cell (iPSC)-derived RPE cell model from cultured skin fibroblasts of patients with LCHADD and tested whether addition of wildtype (WT) HAHDA could rescue the phenotypes identified in LCHADD-RPE. We constructed an rAAV expression vector containing 3' 3xFLAG-tagged human HADHA cDNA under the transcriptional control of the cytomegalovirus (CMV) enhancer-chicken beta actin (CAG) promoter (CAG-HADHA-3XFLAG). LCHADD-RPE were cultured, matured, and transduced with either AAV-GFP (control) or AAV-HADHA-3XFLAG. LCHADD-RPE express TFP subunits and accumulate 3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones than WT-RPE. When LCHADD-RPE are exposed to docosahexaenoic acid (DHA), they have increased oxidative stress, lipid peroxidation, decreased viability, and are rescued by antioxidant agents potentially explaining the pathologic mechanism of RPE loss in LCHADD. Transduced LCHADD-RPE expressing a WT copy of TFPα incorporated TFPα-FLAG into the TFP complex in the mitochondria and accumulated significantly less 3-hydroxy-acylcarnitines, released more ketones in response to palmitate, and were more resistant to oxidative stress following DHA exposure than control. iPSC-derived LCHADD-RPE are susceptible to lipid peroxidation mediated cell death and are rescued by exogenous HADHA delivered with rAAV. These results are promising for AAV-HADHA gene addition therapy as a possible treatment for chorioretinopathy in patients with LCHADD.
2024-08-06 | Newborn screening for long-chain fatty acid oxidation disorders
Long-chain fatty acid oxidation disorders (lcFAOD) are a group of metabolic disorders where the body cannot properly use dietary long-chain fatty acids (LCFAs) for energy. LCFAs are crucial energy sources, particularly during fasting, fever, or exercise. Genetic variants in the proteins or enzymes involved in the long-chain fatty acid oxidation pathway can cause lcFAOD, leading to the accumulation of specific long-chain acyl-CoAs and their carnitine derivatives, known as long-chain acylcarnitines. Symptoms of lcFAOD include hypoglycemia, myopathy, rhabdomyolysis, exercise intolerance, cardiomyopathy, and arrhythmia, which typically manifest during metabolic stress. Mitochondrial trifunctional protein (MTP) disorders uniquely present with pigmentary retinopathy and peripheral neuropathy. Newborn screening (NBS) aims to promptly diagnose conditions that can cause irreversible harm early in life, preventing severe outcomes through early treatment. Mass spectrometry allows for the detection of multiple metabolites in dried blood spots, enabling the inclusion of numerous disorders in NBS programs worldwide. In 2007, the Netherlands included two lcFAOD, very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), in their NBS program, showing benefits in preventing severe hypoglycemia. Despite its benefits, NBS also presents several challenges. Utilizing a wide variety of methods, including in vitro experiments, innovative monitoring techniques, testing protocols, questionnaires, and retrospective chart research, the research described in this thesis aimed to identify and clarify some of the challenges introduced by NBS with a focus on lcFAOD. One of the discussed challenges is the risk of over- and underdiagnosis. Sensitive methods detect minor biochemical abnormalities, potentially identifying mildly affected or asymptomatic individuals, raising questions about the benefits of NBS for these cases. Conversely, some patients, particularly those with thermo-sensitive lcFAOD may be missed due to the absence of characteristic acylcarnitine abnormalities at normal temperatures. To enhance early recognition, genetic screening may be beneficial. Predicting prognosis after NBS diagnosis is crucial to balance early disease detection and avoiding unnecessary treatment, but remains difficult. Studies identified candidate biomarkers for disease severity, such as C18:2-carnitine for VLCADD, which can predict severe phenotypes, and lysophosphatidylcholine (LPC)(14:1), a potential severity marker for VLCADD. For LCHADD, a novel lipid class, S-(3-hydroxyacyl)cysteamines, was discovered as a specific biomarker. Understanding the natural history of NBS-diagnosed lcFAOD patients is vital for prognosis and personalized treatment. Research involving exercise tests and quantitative MRI (qMRI) in adolescent lcFAOD patients revealed variable exercise capacities and potential disease markers. These insights may help tailor monitoring and treatment strategies, though long-term monitoring remains necessary to understand the disease course and develop evidence-based guidelines. Current treatments, such as dietary management and preventing catabolism, do not completely prevent symptoms in all lcFAOD patients. Future approaches may involve gene therapy, aiming to correct the genetic root cause of the disorders. The ultimate goal is personalized treatment and early disease stratification to provide optimal care while minimizing unnecessary interventions and burden.
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Drug Discovery Landscape
1 orphan drug designation for Mitochondrial trifunctional protein deficiency.
1 orphan drug designation for Mitochondrial trifunctional protein deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Triheptanoin | small molecules | EMA | 2015-07-28 | — | Ultragenyx Netherlands B.V. |
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