RARE DISEASE
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Synonyms: LCHAD deficiency, LCHADD, Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
Synonyms: LCHAD deficiency, LCHADD, Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
Synonyms: LCHAD deficiency, LCHADD, Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
Drug discovery
3
drugs
With orphan designations
Overview
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid oxidation caused by HADHA gene mutations, impairing long-chain fatty acid breakdown. It presents in infancy/childhood with hypoketotic hypoglycemia, cardiomyopathy, hepatopathy, retinopathy, and peripheral neuropathy. Metabolic crises, triggered by fasting or illness, risk sudden death. Diagnosis involves newborn screening (elevated hydroxyacylcarnitines) and genetic confirmation. Management prioritizes fasting avoidance, medium-chain triglyceride (MCT) supplementation, and emergency glucose during catabolic states [1][3][6][15][17].
Categories: rare cardiac diseases, rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
108 drug discovery papers about Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
108 drug discovery papers about Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-25 | LCHAD Deficiency as a Model of Carnitine-Mediated Lipotoxicity: A Clinical Case with Therapeutic Carnitine Reduction
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a severe inherited disorder of mitochondrial β-oxidation. The transport of toxic long-chain fatty acids (LCFA) into mitochondria is mediated by the carnitine shuttle, making free carnitine a potential therapeutic target. We present a clinical case of a female child (age at study onset: 1.5 years) with a homozygous c.1528G>C mutation in the HADHA gene, managed with meldonium (a carnitine synthesis inhibitor) to achieve therapeutic carnitine reduction. Over 15 months of monitoring, hydroxyacylcarnitines decreased from 0.78 to 0.03 µmol/L (C16-OH) when free carnitine was maintained at 7–8 µmol/L. A critical threshold was identified: free carnitine levels above 8–9 µmol/L were associated with an increase in toxic hydroxyacylcarnitines. The patient remained clinically stable, including during severe influenza with fever up to 39.4°C. A persistent predominance of sebacic acid (C10) with a ratio C10 >> C8 > C6 was observed in urinary dicarboxylic acids, consistent with dominant peroxisomal β-oxidation. A riboflavin supplementation trial (24 mg/day for one month) did not alter the dicarboxylic acid profile, indicating that the peroxisomal pathway operates at kinetic maximum rather than cofactor limitation. Following these findings, we revised our earlier thesis of complete TFP non-functionality, demonstrating minimal but clinically insignificant residual activity. We propose that LCHAD represents a model of carnitine-mediated lipotoxicity with implications extending to metabolic syndrome and type 2 diabetes.
2026-09-10 | Naloxone as mitochondrial phenotype rescuer in a 3D bioprinted LCHADD/VLCADD model
Abstract For patients diagnosed with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) or very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), fasting episodes or high-energy demands remain life threatening. Due to the low incidence, clinical trials for novel LCHADD/VLCADD therapies are limited, and current mouse models recapitulate human symptoms only partially. Here, we report the use of mitochondrial morphology and 3D bioprinted, vascularized tissue models to establish a robust testing platform for dietary-based and experimental treatment approaches. Using this platform, we demonstrated that mitochondrial morphology is strictly regulated by NOX2-driven ROS formation. Treatment of LCHADD/VLCADD-derived fibroblasts with the NOX2-inhibitor naloxone led to the reassembly of mitochondrial structures controlled by DNM1L/MFN2. Using RNA transcriptomics, we identified a pro-fibrotic phenotype in LCHADD and VLCADD patient cells, which impaired vessel formation in fully 3D bioprinted human tissue equivalents. Metabolic supplementation with dietary approaches, which are used in standard therapy, partially improved vascularization. Naloxone induced the strongest improvement, restoring vessel length and network complexity to those of healthy controls, suggesting increased oxidative stress as main driver. Interestingly, naloxone had no effect on healthy fibroblasts, underscoring its safety. Taken together, these findings suggest the opioid antagonist naloxone as a potential rescue medication during LCHADD/VLCADD-driven metabolic crises.
2026-04-28 | Bezafibrate-MCT Oil Combination Therapy for Enhanced Alternative Energy Metabolism
Bezafibrate activates PPARα to upregulate medium-chain acyl-CoA dehydrogenase (MCAD) and short-chain acyl-CoA dehydrogenase (SCAD) expression. Combined with medium-chain triglyceride oil, this bypasses the LCHAD deficiency by providing readily oxidizable medium-chain fatty acids while enhancing the enzymatic capacity for their metabolism through peroxisome proliferator response elements.
2026-04-28 | Coenzyme Q10 and Idebenone Combination for Mitochondrial Electron Transport Chain Enhancement
Coenzyme Q10 enhances electron transport chain efficiency at Complex III, while idebenone acts as an alternative electron acceptor bypassing Complex I dysfunction secondary to LCHAD deficiency. This combination improves ATP synthesis efficiency and reduces accumulation of toxic long-chain 3-hydroxyacyl-CoA intermediates through enhanced mitochondrial respiratory capacity.
2026-04-28 | Ashwagandha Withanolide A for Mitochondrial Stress Response in LCHAD Deficiency
Withanolide A activates the mitochondrial unfolded protein response (UPRmt) through ATF5 and CHOP transcription factors, enhancing mitochondrial protein quality control. It stabilizes remaining LCHAD enzyme through heat shock protein 60 (HSP60) upregulation and reduces oxidative stress via Nrf2-mediated antioxidant response.
gene therapies
2026-08-25 | Hormonal Responses to a Short Daytime Fast in Children With Beta-Oxidation Disorders.
Fasting-induced cellular energy deficiency and hypoglycemia are well-known complications of beta-oxidation disorders. The changes in energy homeostasis during fasting are under hormonal regulation. This aspect of fasting metabolism in beta-oxidation disorders is not fully characterized. This clinical study investigates hormonal and substrate profiles during fasting and after a standardized meal in patients with beta-oxidation disorders compared with age-matched healthy controls. Children with beta-oxidation disorders (4 LCHADD, 5 VLCADD, 6 MCADD, median age 8.5, 3-13 years) and healthy age-matched controls (n = 12, median age 9.5, 5-13 years) were subjected to a 4-h daytime fast. Blood samples for glucose, ketones, amino acids, nonesterified fatty acids (NEFA), acylcarnitines, and a panel of metabolically active hormones were analyzed after a 4-h fast and 60 min after intake of the standardized meal. Patients with a beta-oxidation disorder displayed a normal glycemic response to fasting. Most hormonal changes were similar to the changes observed in controls. However, children with LCHADD had higher insulin levels and BMI but, interestingly, relatively low HbA1c compared to children with VLCADD and MCADD. Our findings regarding a possible increased risk of insulin resistance in patients with LCHADD need to be verified in larger cohorts.
2026-03-11 | Single-nuclei transcriptomic profiling of human myocardium in long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
Single-nuclei transcriptomic profiling of human myocardium in long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency Hanna J. Tadros MBBCh1, Diwakar Turaga MD, PhD2,3, Yi Zhao PhD6, Chang-Ru Tsai, PhD9, Lalita Wadhwa PhD4, Debra L. Kearney MD7, Iki Adachi MD4,5, Xiao Li PhD6,8, James F. Martin MD, PhD6,9,10* 1. Department of Pediatrics, Section of Pediatric Cardiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. 2. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA 3. Division of Critical Care Medicine, Texas Children's Hospital, Houston TX, USA 4. Department of Surgery, Baylor College of Medicine, Houston, TX, USA 5. Division of Congenital Heart Surgery, Texas Children's Hospital, Houston, TX, USA 6. The Texas Heart Institute at Baylor College of Medicine, Houston, TX, USA 7. Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA 8. Department of Medicine, Baylor College of Medicine, Houston, TX, USA 9. Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA 10. Center for Organ Repair and Renewal, Baylor College of Medicine, Houston, TX, USA *Corresponding author. Email: jfmartin@bcm.edu
2026-02-01 | Acute Fatty Liver of Pregnancy and Fetal Fatty Acid Oxidation Disorders: A Systematic Review
OBJECTIVE: To evaluate the association between maternal acute fatty liver of pregnancy (AFLP) and fetal fatty acid oxidation (FAO) disorders and to define the clinical and genetic characteristics of mothers with AFLP and their fetuses affected by FAO disorders, we performed a systematic literature review of all reported cases of AFLP that underwent genetic testing for FAO disorders. DATA SOURCES: We searched PubMed, Ovid MEDLINE, Cochrane Library, CINAHL (EBSCO), Scopus, and ClinicalTrials.gov. Terms included were related to AFLP and FAO testing. METHODS OF STUDY SELECTION: We conducted a systematic literature review from inception through May 18, 2025, to evaluate the relationship between AFLP and fetal FAO disorders. Studies were eligible for inclusion if they evaluated the relationship between AFLP and fetal FAO disorders and provided both detailed pregnancy characteristics for AFLP and the workup of maternal and/or fetal FAO disorder. TABULATION, INTEGRATION, AND RESULTS: Twenty-seven studies with 77 AFLP cases that underwent genetic or biochemical testing for maternal or fetal FAO disorders were included. Of these 77 pregnancies, 27 (35.1%) were associated with confirmed fetal FAO disorders. The 27 neonates with FAO disorders included 22 fetuses (81.5%) with LCHAD deficiency, three (11.1%) with medium-chain acyl-CoA dehydrogenase deficiency, one (3.7%) with short-chain acyl-CoA dehydrogenase deficiency, and one (3.7%) with carnitine palmitoyl transferase-I deficiency. Stillbirth and infant mortality was reported in 14 of 22 cases (63.6%) with LCHAD deficiency, and there were no recorded fetal or neonatal deaths with other FAO disorders or those with negative genetic testing. One maternal death was reported in a pregnancy with negative genetic testing for FAO disorders and one patient in a coma at the time of publication with an LCHAD-deficient pregnancy. Presentation of AFLP with gastrointestinal manifestations occurred in 87.8% of patients. CONCLUSION: Acute fatty liver of pregnancy is associated with fetal FAO disorders in about a third of cases, with the most common FAO disorder being LCHAD deficiency. Both AFLP and LCHAD deficiency are associated with high morbidity and mortality in mothers and neonates. Evaluation for fetal and maternal LCHAD deficiency should be part of the diagnostic evaluation in AFLP. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021247166.
2026-01-19 | Pregnancies in Women With Long-Chain Fatty Acid Oxidation Disorders: Results of a European and North American Survey.
Long-chain fatty acid oxidation disorders (lcFAODs) are genetic disorders of energy metabolism that are associated with a risk of metabolic decompensation, especially during catabolic episodes. With improvement in diagnostics and treatment, more women with lcFAODs now reach child-bearing age. So far, little is known about the risk and outcome of pregnancies, particularly in women with more severe forms of lcFAODs. We performed an international web-based survey among health care professionals involved in the care of individuals with lcFAODs and collected data on 89 pregnancies in 39 women (mild VLCAD deficiency n = 8, severe VLCAD deficiency n = 10, LCHAD deficiency n = 4, CPT2 deficiency n = 14, CPT1 deficiency n = 3). There were 72 live births, 12 spontaneous miscarriages, and one stillbirth at 41 weeks of gestation. Four women were still pregnant at the time of the survey. In 25 women, the diagnosis was known before the first pregnancy, whereas 14 had at least one pregnancy before diagnosis. Most women remained metabolically stable during pregnancy, although 19% of women had at least one metabolic decompensation during pregnancy. Forty-one percent of babies were delivered by spontaneous vaginal delivery, 33% after induced labor, and 19% by an elective Caesarean section. Most deliveries were uncomplicated, with preventive i.v. glucose infusions given in 50%. However, 21% of mothers developed a metabolic decompensation in the postpartum period. No maternal deaths were reported. In conclusion, our data show that the outcome of pregnancies in lcFAOD patients is generally favorable, despite a significant risk of metabolic decompensation during the postpartum period.
2026-01-12 | Autism spectrum disorder in an adolescent with deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase of fatty acids caused by a mutation in the HADHA gene in a homozygous state (presentation of a clinical case)
Расстройство аутистического спектра у подростка с недостаточностью длинноцепочечной 3-гидроксиацил-КоА-дегидрогеназы жирных кислот, обусловленной мутацией в гене НАDНА в гомозиготном состоянии (презентация клинического случая) Шушпанова О.В., Бокша И.С., Зозуля С.А.ФГБНУ «Научный центр психического здоровья» Россия, 115522, Москва, Каширское шоссе, 34 РЕЗЮМЕ Дефицит длинноцепочечной 3-гидроксиацил-КоА-дегидрогеназы -это врожденное наследственное аутосомнорецессивное заболевание c нарушением метаболизма жирных кислот, характеризующееся ухудшением способности последовательно метаболизировать длинноцепочечные жирные кислоты до ацетил-КоА-молекул путем митохондриального бета-окисления.Гипофункция длинноцепочечной 3-гидроксиацил-КоА-дегидрогеназы вызывает нарушения различной степени тяжести в жизненно важных органах и системах на макро-и микроуровне, а также приводит к развитию психических расстройств с когнитивной недостаточностью, которые могут быть квалифицированы как расстройство аутистического спектра (РАС).В данной статье подробно рассмотрен клинический случай пациента с недостаточностью длинноцепочечной 3-гидроксиацил-КоА-дегидрогеназы жирных кислот, обусловленной мутацией в гене НАDНА в гомозиготном состоянии.Пациенту были проведены инструментальные (ЭЭГ) и лабораторные исследования (нейрохимические, биохимические и иммунологические маркеры) и консультирование/осмотр узких специалистов (педиатр, невролог, клинический психолог, психиатрическое обследование).По результатам комплексного обследования и клинического наблюдения возможно предположить наличие у больного коморбидного либо обусловленного наследственным нарушением митохондриального бета-окисления жирных кислот расстройства аутистического спектра или шизофрении с началом в детском возрасте.
antibodies
2025-08-27 | Macular Neovascularization in Pediatric Patients with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: A Retrospective Analysis of a Case Series
Background: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare autosomal recessive metabolic disorder affecting long-chain fatty acid β-oxidation. A hallmark feature of LCHADD is progressive chorioretinopathy, which may lead to severe visual complications, including macular neovascularization (MNV). The goal of the study was to analyze MNV in patients with genetically confirmed LCHADD. Methods: Data of 8 patients with LCHADD from the Kaszubia region in Poland followed in the clinic were retrospectively analyzed. The analyses included genetic confirmation, ophthalmologic examinations, spectral-domain optical coherence tomography (SD-OCT), and treatment responses. Results: Two patients with MNV in the course of LCHADD were identified. In Patient 1, a 9-year-old female, unilateral MNV at the fibrotic stage with a visual acuity of counting fingers was diagnosed in the right eye. No treatment was administered. The left eye remained stable, maintaining a best corrected visual acuity (BCVA) of 0.9 on the decimal Snellen chart. Patient 2, male, was followed from age 8 to 16 and during that time developed bilateral MNV. The right eye presented with inactive MNV at the age of 9, resulting in BCVA reduction to 0.3 without active fluid, and remained stable without intervention. The left eye developed active MNV at age 15 with subretinal fluid and retinal edema. Treatment with five intravitreal injections of ranibizumab led to complete resolution and recovery of BCVA to 1.0. Conclusions: MNV, although rare, can develop in pediatric LCHADD patients silently and bilaterally. Early detection through regular ophthalmologic screening is crucial, as timely anti-VEGF treatment can preserve or restore vision. Delayed diagnosis may result in irreversible damage and limited therapeutic benefit.
2015-08-28 | Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza
In response to infection, patients with inborn errors of metabolism may develop a functional deterioration termed metabolic decompensation. The biochemical hallmarks of this disruption of metabolic homeostasis are disease specific and may include acidosis, hyperammonemia or hypoglycemia. In a model system previously published by our group, we noted that during influenza infection, mice displayed a depression in hepatic mitochondrial enzymes involved in nitrogen metabolism. Based on these findings, we hypothesized that this normal adaptation may extend to other metabolic pathways, and as such, may impact various inborn errors of metabolism. Since the liver is a critical organ in inborn errors of metabolism, we carried out untargeted metabolomic profiling of livers using mass spectrometry in C57Bl/6 mice infected with influenza to characterize metabolic adaptation. Pathway analysis of metabolomic data revealed reductions in CoA synthesis, and long chain fatty acyl CoA and carnitine species. These metabolic adaptations coincided with a depression in hepatic long chain β-oxidation mRNA and protein. To our surprise, the metabolic changes observed occurred in conjunction with a hepatic innate immune response, as demonstrated by transcriptional profiling and flow cytometry. By employing an immunomodulation strategy to deplete Kupffer cells, we were able to improve the expression of multiple genes involved in β-oxidation. Based on these findings, we are the first to suggest that the role of the liver as an immunologic organ is central in the pathophysiology of hepatic metabolic decompensation in inborn errors of metabolism due to respiratory viral infection.
small molecules
2026-09-25 | LCHAD Deficiency as a Model of Carnitine-Mediated Lipotoxicity: A Clinical Case with Therapeutic Carnitine Reduction
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a severe inherited disorder of mitochondrial β-oxidation. The transport of toxic long-chain fatty acids (LCFA) into mitochondria is mediated by the carnitine shuttle, making free carnitine a potential therapeutic target. We present a clinical case of a female child (age at study onset: 1.5 years) with a homozygous c.1528G>C mutation in the HADHA gene, managed with meldonium (a carnitine synthesis inhibitor) to achieve therapeutic carnitine reduction. Over 15 months of monitoring, hydroxyacylcarnitines decreased from 0.78 to 0.03 µmol/L (C16-OH) when free carnitine was maintained at 7–8 µmol/L. A critical threshold was identified: free carnitine levels above 8–9 µmol/L were associated with an increase in toxic hydroxyacylcarnitines. The patient remained clinically stable, including during severe influenza with fever up to 39.4°C. A persistent predominance of sebacic acid (C10) with a ratio C10 >> C8 > C6 was observed in urinary dicarboxylic acids, consistent with dominant peroxisomal β-oxidation. A riboflavin supplementation trial (24 mg/day for one month) did not alter the dicarboxylic acid profile, indicating that the peroxisomal pathway operates at kinetic maximum rather than cofactor limitation. Following these findings, we revised our earlier thesis of complete TFP non-functionality, demonstrating minimal but clinically insignificant residual activity. We propose that LCHAD represents a model of carnitine-mediated lipotoxicity with implications extending to metabolic syndrome and type 2 diabetes.
2026-09-10 | Naloxone as mitochondrial phenotype rescuer in a 3D bioprinted LCHADD/VLCADD model
Abstract For patients diagnosed with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) or very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), fasting episodes or high-energy demands remain life threatening. Due to the low incidence, clinical trials for novel LCHADD/VLCADD therapies are limited, and current mouse models recapitulate human symptoms only partially. Here, we report the use of mitochondrial morphology and 3D bioprinted, vascularized tissue models to establish a robust testing platform for dietary-based and experimental treatment approaches. Using this platform, we demonstrated that mitochondrial morphology is strictly regulated by NOX2-driven ROS formation. Treatment of LCHADD/VLCADD-derived fibroblasts with the NOX2-inhibitor naloxone led to the reassembly of mitochondrial structures controlled by DNM1L/MFN2. Using RNA transcriptomics, we identified a pro-fibrotic phenotype in LCHADD and VLCADD patient cells, which impaired vessel formation in fully 3D bioprinted human tissue equivalents. Metabolic supplementation with dietary approaches, which are used in standard therapy, partially improved vascularization. Naloxone induced the strongest improvement, restoring vessel length and network complexity to those of healthy controls, suggesting increased oxidative stress as main driver. Interestingly, naloxone had no effect on healthy fibroblasts, underscoring its safety. Taken together, these findings suggest the opioid antagonist naloxone as a potential rescue medication during LCHADD/VLCADD-driven metabolic crises.
2026-04-28 | Bezafibrate-MCT Oil Combination Therapy for Enhanced Alternative Energy Metabolism
Bezafibrate activates PPARα to upregulate medium-chain acyl-CoA dehydrogenase (MCAD) and short-chain acyl-CoA dehydrogenase (SCAD) expression. Combined with medium-chain triglyceride oil, this bypasses the LCHAD deficiency by providing readily oxidizable medium-chain fatty acids while enhancing the enzymatic capacity for their metabolism through peroxisome proliferator response elements.
2026-04-28 | Coenzyme Q10 and Idebenone Combination for Mitochondrial Electron Transport Chain Enhancement
Coenzyme Q10 enhances electron transport chain efficiency at Complex III, while idebenone acts as an alternative electron acceptor bypassing Complex I dysfunction secondary to LCHAD deficiency. This combination improves ATP synthesis efficiency and reduces accumulation of toxic long-chain 3-hydroxyacyl-CoA intermediates through enhanced mitochondrial respiratory capacity.
2026-04-28 | Ashwagandha Withanolide A for Mitochondrial Stress Response in LCHAD Deficiency
Withanolide A activates the mitochondrial unfolded protein response (UPRmt) through ATF5 and CHOP transcription factors, enhancing mitochondrial protein quality control. It stabilizes remaining LCHAD enzyme through heat shock protein 60 (HSP60) upregulation and reduces oxidative stress via Nrf2-mediated antioxidant response.
gene therapies
2026-08-25 | Hormonal Responses to a Short Daytime Fast in Children With Beta-Oxidation Disorders.
Fasting-induced cellular energy deficiency and hypoglycemia are well-known complications of beta-oxidation disorders. The changes in energy homeostasis during fasting are under hormonal regulation. This aspect of fasting metabolism in beta-oxidation disorders is not fully characterized. This clinical study investigates hormonal and substrate profiles during fasting and after a standardized meal in patients with beta-oxidation disorders compared with age-matched healthy controls. Children with beta-oxidation disorders (4 LCHADD, 5 VLCADD, 6 MCADD, median age 8.5, 3-13 years) and healthy age-matched controls (n = 12, median age 9.5, 5-13 years) were subjected to a 4-h daytime fast. Blood samples for glucose, ketones, amino acids, nonesterified fatty acids (NEFA), acylcarnitines, and a panel of metabolically active hormones were analyzed after a 4-h fast and 60 min after intake of the standardized meal. Patients with a beta-oxidation disorder displayed a normal glycemic response to fasting. Most hormonal changes were similar to the changes observed in controls. However, children with LCHADD had higher insulin levels and BMI but, interestingly, relatively low HbA1c compared to children with VLCADD and MCADD. Our findings regarding a possible increased risk of insulin resistance in patients with LCHADD need to be verified in larger cohorts.
2026-03-11 | Single-nuclei transcriptomic profiling of human myocardium in long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
Single-nuclei transcriptomic profiling of human myocardium in long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency Hanna J. Tadros MBBCh1, Diwakar Turaga MD, PhD2,3, Yi Zhao PhD6, Chang-Ru Tsai, PhD9, Lalita Wadhwa PhD4, Debra L. Kearney MD7, Iki Adachi MD4,5, Xiao Li PhD6,8, James F. Martin MD, PhD6,9,10* 1. Department of Pediatrics, Section of Pediatric Cardiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. 2. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA 3. Division of Critical Care Medicine, Texas Children's Hospital, Houston TX, USA 4. Department of Surgery, Baylor College of Medicine, Houston, TX, USA 5. Division of Congenital Heart Surgery, Texas Children's Hospital, Houston, TX, USA 6. The Texas Heart Institute at Baylor College of Medicine, Houston, TX, USA 7. Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA 8. Department of Medicine, Baylor College of Medicine, Houston, TX, USA 9. Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA 10. Center for Organ Repair and Renewal, Baylor College of Medicine, Houston, TX, USA *Corresponding author. Email: jfmartin@bcm.edu
2026-02-01 | Acute Fatty Liver of Pregnancy and Fetal Fatty Acid Oxidation Disorders: A Systematic Review
OBJECTIVE: To evaluate the association between maternal acute fatty liver of pregnancy (AFLP) and fetal fatty acid oxidation (FAO) disorders and to define the clinical and genetic characteristics of mothers with AFLP and their fetuses affected by FAO disorders, we performed a systematic literature review of all reported cases of AFLP that underwent genetic testing for FAO disorders. DATA SOURCES: We searched PubMed, Ovid MEDLINE, Cochrane Library, CINAHL (EBSCO), Scopus, and ClinicalTrials.gov. Terms included were related to AFLP and FAO testing. METHODS OF STUDY SELECTION: We conducted a systematic literature review from inception through May 18, 2025, to evaluate the relationship between AFLP and fetal FAO disorders. Studies were eligible for inclusion if they evaluated the relationship between AFLP and fetal FAO disorders and provided both detailed pregnancy characteristics for AFLP and the workup of maternal and/or fetal FAO disorder. TABULATION, INTEGRATION, AND RESULTS: Twenty-seven studies with 77 AFLP cases that underwent genetic or biochemical testing for maternal or fetal FAO disorders were included. Of these 77 pregnancies, 27 (35.1%) were associated with confirmed fetal FAO disorders. The 27 neonates with FAO disorders included 22 fetuses (81.5%) with LCHAD deficiency, three (11.1%) with medium-chain acyl-CoA dehydrogenase deficiency, one (3.7%) with short-chain acyl-CoA dehydrogenase deficiency, and one (3.7%) with carnitine palmitoyl transferase-I deficiency. Stillbirth and infant mortality was reported in 14 of 22 cases (63.6%) with LCHAD deficiency, and there were no recorded fetal or neonatal deaths with other FAO disorders or those with negative genetic testing. One maternal death was reported in a pregnancy with negative genetic testing for FAO disorders and one patient in a coma at the time of publication with an LCHAD-deficient pregnancy. Presentation of AFLP with gastrointestinal manifestations occurred in 87.8% of patients. CONCLUSION: Acute fatty liver of pregnancy is associated with fetal FAO disorders in about a third of cases, with the most common FAO disorder being LCHAD deficiency. Both AFLP and LCHAD deficiency are associated with high morbidity and mortality in mothers and neonates. Evaluation for fetal and maternal LCHAD deficiency should be part of the diagnostic evaluation in AFLP. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021247166.
2026-01-19 | Pregnancies in Women With Long-Chain Fatty Acid Oxidation Disorders: Results of a European and North American Survey.
Long-chain fatty acid oxidation disorders (lcFAODs) are genetic disorders of energy metabolism that are associated with a risk of metabolic decompensation, especially during catabolic episodes. With improvement in diagnostics and treatment, more women with lcFAODs now reach child-bearing age. So far, little is known about the risk and outcome of pregnancies, particularly in women with more severe forms of lcFAODs. We performed an international web-based survey among health care professionals involved in the care of individuals with lcFAODs and collected data on 89 pregnancies in 39 women (mild VLCAD deficiency n = 8, severe VLCAD deficiency n = 10, LCHAD deficiency n = 4, CPT2 deficiency n = 14, CPT1 deficiency n = 3). There were 72 live births, 12 spontaneous miscarriages, and one stillbirth at 41 weeks of gestation. Four women were still pregnant at the time of the survey. In 25 women, the diagnosis was known before the first pregnancy, whereas 14 had at least one pregnancy before diagnosis. Most women remained metabolically stable during pregnancy, although 19% of women had at least one metabolic decompensation during pregnancy. Forty-one percent of babies were delivered by spontaneous vaginal delivery, 33% after induced labor, and 19% by an elective Caesarean section. Most deliveries were uncomplicated, with preventive i.v. glucose infusions given in 50%. However, 21% of mothers developed a metabolic decompensation in the postpartum period. No maternal deaths were reported. In conclusion, our data show that the outcome of pregnancies in lcFAOD patients is generally favorable, despite a significant risk of metabolic decompensation during the postpartum period.
2026-01-12 | Autism spectrum disorder in an adolescent with deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase of fatty acids caused by a mutation in the HADHA gene in a homozygous state (presentation of a clinical case)
Расстройство аутистического спектра у подростка с недостаточностью длинноцепочечной 3-гидроксиацил-КоА-дегидрогеназы жирных кислот, обусловленной мутацией в гене НАDНА в гомозиготном состоянии (презентация клинического случая) Шушпанова О.В., Бокша И.С., Зозуля С.А.ФГБНУ «Научный центр психического здоровья» Россия, 115522, Москва, Каширское шоссе, 34 РЕЗЮМЕ Дефицит длинноцепочечной 3-гидроксиацил-КоА-дегидрогеназы -это врожденное наследственное аутосомнорецессивное заболевание c нарушением метаболизма жирных кислот, характеризующееся ухудшением способности последовательно метаболизировать длинноцепочечные жирные кислоты до ацетил-КоА-молекул путем митохондриального бета-окисления.Гипофункция длинноцепочечной 3-гидроксиацил-КоА-дегидрогеназы вызывает нарушения различной степени тяжести в жизненно важных органах и системах на макро-и микроуровне, а также приводит к развитию психических расстройств с когнитивной недостаточностью, которые могут быть квалифицированы как расстройство аутистического спектра (РАС).В данной статье подробно рассмотрен клинический случай пациента с недостаточностью длинноцепочечной 3-гидроксиацил-КоА-дегидрогеназы жирных кислот, обусловленной мутацией в гене НАDНА в гомозиготном состоянии.Пациенту были проведены инструментальные (ЭЭГ) и лабораторные исследования (нейрохимические, биохимические и иммунологические маркеры) и консультирование/осмотр узких специалистов (педиатр, невролог, клинический психолог, психиатрическое обследование).По результатам комплексного обследования и клинического наблюдения возможно предположить наличие у больного коморбидного либо обусловленного наследственным нарушением митохондриального бета-окисления жирных кислот расстройства аутистического спектра или шизофрении с началом в детском возрасте.
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2025-08-27 | Macular Neovascularization in Pediatric Patients with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: A Retrospective Analysis of a Case Series
Background: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare autosomal recessive metabolic disorder affecting long-chain fatty acid β-oxidation. A hallmark feature of LCHADD is progressive chorioretinopathy, which may lead to severe visual complications, including macular neovascularization (MNV). The goal of the study was to analyze MNV in patients with genetically confirmed LCHADD. Methods: Data of 8 patients with LCHADD from the Kaszubia region in Poland followed in the clinic were retrospectively analyzed. The analyses included genetic confirmation, ophthalmologic examinations, spectral-domain optical coherence tomography (SD-OCT), and treatment responses. Results: Two patients with MNV in the course of LCHADD were identified. In Patient 1, a 9-year-old female, unilateral MNV at the fibrotic stage with a visual acuity of counting fingers was diagnosed in the right eye. No treatment was administered. The left eye remained stable, maintaining a best corrected visual acuity (BCVA) of 0.9 on the decimal Snellen chart. Patient 2, male, was followed from age 8 to 16 and during that time developed bilateral MNV. The right eye presented with inactive MNV at the age of 9, resulting in BCVA reduction to 0.3 without active fluid, and remained stable without intervention. The left eye developed active MNV at age 15 with subretinal fluid and retinal edema. Treatment with five intravitreal injections of ranibizumab led to complete resolution and recovery of BCVA to 1.0. Conclusions: MNV, although rare, can develop in pediatric LCHADD patients silently and bilaterally. Early detection through regular ophthalmologic screening is crucial, as timely anti-VEGF treatment can preserve or restore vision. Delayed diagnosis may result in irreversible damage and limited therapeutic benefit.
2015-08-28 | Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza
In response to infection, patients with inborn errors of metabolism may develop a functional deterioration termed metabolic decompensation. The biochemical hallmarks of this disruption of metabolic homeostasis are disease specific and may include acidosis, hyperammonemia or hypoglycemia. In a model system previously published by our group, we noted that during influenza infection, mice displayed a depression in hepatic mitochondrial enzymes involved in nitrogen metabolism. Based on these findings, we hypothesized that this normal adaptation may extend to other metabolic pathways, and as such, may impact various inborn errors of metabolism. Since the liver is a critical organ in inborn errors of metabolism, we carried out untargeted metabolomic profiling of livers using mass spectrometry in C57Bl/6 mice infected with influenza to characterize metabolic adaptation. Pathway analysis of metabolomic data revealed reductions in CoA synthesis, and long chain fatty acyl CoA and carnitine species. These metabolic adaptations coincided with a depression in hepatic long chain β-oxidation mRNA and protein. To our surprise, the metabolic changes observed occurred in conjunction with a hepatic innate immune response, as demonstrated by transcriptional profiling and flow cytometry. By employing an immunomodulation strategy to deplete Kupffer cells, we were able to improve the expression of multiple genes involved in β-oxidation. Based on these findings, we are the first to suggest that the role of the liver as an immunologic organ is central in the pathophysiology of hepatic metabolic decompensation in inborn errors of metabolism due to respiratory viral infection.
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Drug Discovery Landscape
3 orphan drug designations for Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency.
3 orphan drug designations for Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Mavodelpar sodium | small molecules | EMA | — | Scendea (NL) B.V. |
Triheptanoin | small molecules | EMA | Ultragenyx Netherlands B.V. | |
Triheptanoin [Triheptanoin] | small molecules | EMA | B. Braun Melsungen AG |
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