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 2 first-in-class and 2 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 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2024-09-16 | 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.
2024-09-10 | 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.
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.
2024-09-16 | 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.
2024-09-10 | 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.
Access all drug discovery articles and probability of success in trials forecasts:
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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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