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
104 drug discovery papers about Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
104 drug discovery papers about Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
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.
2026-01-28 | Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD)-Associated Ocular Pathology-A Narrative Review.
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an extremely rare autosomal recessive disorder, with only a few hundred affected individuals worldwide. Since its initial recognition in the 1980s, only a limited number of studies have described its ocular manifestations. The aim of this review was to summarize and organize the available published evidence regarding ocular findings in LCHADD and their classification. A PubMed search was conducted for studies describing ocular findings associated with LCHADD, using combinations of the following keywords: LCHADD, chorioretinopathy, ocular findings, vision, therapy, and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. The review included studies published within the past 20 years that reported at least six cases. The search identified 11 eligible studies. Findings were grouped into three categories: LCHADD-associated chorioretinopathy, macular neovascularization (MNV), and the effects of dietary therapy on visual function. Chorioretinopathy emerged as the major pathognomonic ocular feature of LCHADD. MNV was reported in approximately 20% of eyes, often bilaterally but not simultaneously. Progressive myopia was observed in most patients. Newborn screening and early initiation of dietary therapy appear critical and may slow the progression of chorioretinopathy. A strong correlation between patient age and chorioretinopathy severity was consistently demonstrated, and visual deterioration occurred even in individuals with good metabolic control. LCHADD is a life- and vision-threatening disorder characterized by a distinctive chorioretinopathy present in nearly all patients. Early detection through newborn screening and regular ophthalmic follow-up is essential for the optimal management of affected individuals.
2025-11-12 | Long-Chain Fatty Acid Beta-Oxidation Defects: A Case Series and Literature Review.
Fatty acid beta-oxidation defects (FAOD) are a subgroup of lipid myopathies with heterogeneous presentations. Clinical presentation may manifest as muscular weakness, cramps, postexercise myalgias, and episodic rhabdomyolysis in children or adults. Our objective was to describe the clinical manifestations, biochemical, anatomopathological, and molecular results in a series of adult patients diagnosed with FAOD during adolescence or adulthood at five centers in Argentina. A total of seven patients with carnitine palmitoyltransferase-2 (CPT II), very-long-chain acyl-CoA dehydrogenase (VLCAD), and long-chain 3-hydroxyacyl-CoA dehydrogenase LCHAD deficiency were reported. The definite diagnosis of metabolic myopathies due to FAOD requires an understanding of clinical, biochemical, neurophysiological, and muscular imaging/biopsy patterns. All patients in this series consulted pediatricians, general practitioners, rheumatologists, and orthopedists for years, underscoring the need to disseminate these presentation patterns across various medical specialties. Early diagnosis and treatment using traditional diets and new pharmacological strategies not only enhance the quality of life, but also improve survival in these patients.
gene therapies
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.
2026-01-01 | Acute Arrhythmias in a Long-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) Mouse Model
10-06-25American Journal of Physiology - Heart and Circulatory PhysiologySupplemental Material for:Acute Arrhythmias in a Long-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) Mouse ModelGabriela Elizondo, MD, MS1, Arianna Scalco, PhD2, Ayah Asal3, Hak Chung, PhD1, Garen Gaston, MS1, Beth A. Habecker, PhD2, Melanie B. Gillingham, PhD RD1
Files:Supplemental Material 12-15-25.pdfSup Table 4 - Differentially expressed genes.pdf
2025-10-01 | S5567 An Atypical Case of Acute Fatty Liver of Pregnancy: A Case Report
Introduction: Acute fatty liver in pregnancy (AFLP) typically occurs in the third trimester and is caused by microvesicular fatty infiltration of hepatocytes. It can be diagnosed using the Swansea criteria which includes clinical presentation (e.g., vomiting and abdominal pain) and laboratory findings (e.g., hyperbilirubinemia and hypoglycemia). We present an atypical case of AFLP in a patient who did not meet the Swansea criteria but improved rapidly after giving birth. Case Description/Methods: A 27-year-old woman presents at 35 weeks’ gestation with abdominal pain, nausea, vomiting, and worsening liver enzymes. She denied pruritus. During her first trimester, she had normal liver enzymes; however, they started to rise around her third trimester with aspartate aminotransferase (AST) 190 U/L and alanine aminotransferase (ALT) 349 U/L. She denied recent travel, sick contacts, or use of antibiotics. Viral hepatitis and autoimmune serologies were negative. Her serum bile acids were elevated at 33.8 µmol/L. Her liver enzymes continued to rise peaking at AST 626 U/L, ALT 972 U/L, and alkaline phosphatase 203 IU/L. Her platelet count, creatinine, PT/international normalized ratio, glucose, ammonia, leukocyte count, and total bilirubin remained normal. Due to the continued rise of her liver enzymes, a prompt decision for induction of labor was made. Maternal liver enzymes after birth significantly improved. Her infant was found to have rising AST/ALT and hypoglycemia prompting transfer to a higher level of care. MRI/MRCP in the mother was normal. Genetic testing for deficiency in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) was positive in the mother and infant. Discussion: AFLP is a rare but serious complication of pregnancy which can lead to both maternal and fetal mortality. It is traditionally diagnosed when meeting 6 or more of the Swansea criteria. Our case highlights a patient who only met 3 of the diagnostic criteria but who clinically worsened during her hospitalization. The differential for elevated liver enzymes in pregnancy includes AFLP, viral hepatitis, cholestasis of pregnancy, autoimmune hepatitis, and HELLP syndrome. Serologic workup was negative except for her serum bile acids. However, the absence of symptoms such as pruritus and the hepatocellular pattern of liver enzymes suggested an alternative process. The diagnosis of AFLP in this case is supported by the rapid improvement in liver enzymes after birth, infant hypoglycemia, and deficiency in LCHAD. Cognizance of atypical presentations of AFLP can expedite workup and prevent mortality of the mother and the fetus.
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
2026-04-28 | 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.
2026-01-28 | Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD)-Associated Ocular Pathology-A Narrative Review.
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an extremely rare autosomal recessive disorder, with only a few hundred affected individuals worldwide. Since its initial recognition in the 1980s, only a limited number of studies have described its ocular manifestations. The aim of this review was to summarize and organize the available published evidence regarding ocular findings in LCHADD and their classification. A PubMed search was conducted for studies describing ocular findings associated with LCHADD, using combinations of the following keywords: LCHADD, chorioretinopathy, ocular findings, vision, therapy, and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. The review included studies published within the past 20 years that reported at least six cases. The search identified 11 eligible studies. Findings were grouped into three categories: LCHADD-associated chorioretinopathy, macular neovascularization (MNV), and the effects of dietary therapy on visual function. Chorioretinopathy emerged as the major pathognomonic ocular feature of LCHADD. MNV was reported in approximately 20% of eyes, often bilaterally but not simultaneously. Progressive myopia was observed in most patients. Newborn screening and early initiation of dietary therapy appear critical and may slow the progression of chorioretinopathy. A strong correlation between patient age and chorioretinopathy severity was consistently demonstrated, and visual deterioration occurred even in individuals with good metabolic control. LCHADD is a life- and vision-threatening disorder characterized by a distinctive chorioretinopathy present in nearly all patients. Early detection through newborn screening and regular ophthalmic follow-up is essential for the optimal management of affected individuals.
2025-11-12 | Long-Chain Fatty Acid Beta-Oxidation Defects: A Case Series and Literature Review.
Fatty acid beta-oxidation defects (FAOD) are a subgroup of lipid myopathies with heterogeneous presentations. Clinical presentation may manifest as muscular weakness, cramps, postexercise myalgias, and episodic rhabdomyolysis in children or adults. Our objective was to describe the clinical manifestations, biochemical, anatomopathological, and molecular results in a series of adult patients diagnosed with FAOD during adolescence or adulthood at five centers in Argentina. A total of seven patients with carnitine palmitoyltransferase-2 (CPT II), very-long-chain acyl-CoA dehydrogenase (VLCAD), and long-chain 3-hydroxyacyl-CoA dehydrogenase LCHAD deficiency were reported. The definite diagnosis of metabolic myopathies due to FAOD requires an understanding of clinical, biochemical, neurophysiological, and muscular imaging/biopsy patterns. All patients in this series consulted pediatricians, general practitioners, rheumatologists, and orthopedists for years, underscoring the need to disseminate these presentation patterns across various medical specialties. Early diagnosis and treatment using traditional diets and new pharmacological strategies not only enhance the quality of life, but also improve survival in these patients.
gene therapies
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.
2026-01-01 | Acute Arrhythmias in a Long-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) Mouse Model
10-06-25American Journal of Physiology - Heart and Circulatory PhysiologySupplemental Material for:Acute Arrhythmias in a Long-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) Mouse ModelGabriela Elizondo, MD, MS1, Arianna Scalco, PhD2, Ayah Asal3, Hak Chung, PhD1, Garen Gaston, MS1, Beth A. Habecker, PhD2, Melanie B. Gillingham, PhD RD1
Files:Supplemental Material 12-15-25.pdfSup Table 4 - Differentially expressed genes.pdf
2025-10-01 | S5567 An Atypical Case of Acute Fatty Liver of Pregnancy: A Case Report
Introduction: Acute fatty liver in pregnancy (AFLP) typically occurs in the third trimester and is caused by microvesicular fatty infiltration of hepatocytes. It can be diagnosed using the Swansea criteria which includes clinical presentation (e.g., vomiting and abdominal pain) and laboratory findings (e.g., hyperbilirubinemia and hypoglycemia). We present an atypical case of AFLP in a patient who did not meet the Swansea criteria but improved rapidly after giving birth. Case Description/Methods: A 27-year-old woman presents at 35 weeks’ gestation with abdominal pain, nausea, vomiting, and worsening liver enzymes. She denied pruritus. During her first trimester, she had normal liver enzymes; however, they started to rise around her third trimester with aspartate aminotransferase (AST) 190 U/L and alanine aminotransferase (ALT) 349 U/L. She denied recent travel, sick contacts, or use of antibiotics. Viral hepatitis and autoimmune serologies were negative. Her serum bile acids were elevated at 33.8 µmol/L. Her liver enzymes continued to rise peaking at AST 626 U/L, ALT 972 U/L, and alkaline phosphatase 203 IU/L. Her platelet count, creatinine, PT/international normalized ratio, glucose, ammonia, leukocyte count, and total bilirubin remained normal. Due to the continued rise of her liver enzymes, a prompt decision for induction of labor was made. Maternal liver enzymes after birth significantly improved. Her infant was found to have rising AST/ALT and hypoglycemia prompting transfer to a higher level of care. MRI/MRCP in the mother was normal. Genetic testing for deficiency in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) was positive in the mother and infant. Discussion: AFLP is a rare but serious complication of pregnancy which can lead to both maternal and fetal mortality. It is traditionally diagnosed when meeting 6 or more of the Swansea criteria. Our case highlights a patient who only met 3 of the diagnostic criteria but who clinically worsened during her hospitalization. The differential for elevated liver enzymes in pregnancy includes AFLP, viral hepatitis, cholestasis of pregnancy, autoimmune hepatitis, and HELLP syndrome. Serologic workup was negative except for her serum bile acids. However, the absence of symptoms such as pruritus and the hepatocellular pattern of liver enzymes suggested an alternative process. The diagnosis of AFLP in this case is supported by the rapid improvement in liver enzymes after birth, infant hypoglycemia, and deficiency in LCHAD. Cognizance of atypical presentations of AFLP can expedite workup and prevent mortality of the mother and the fetus.
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.
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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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Mavodelpar sodium | small molecules | EMA | 2020-08-21 | — | Scendea (NL) B.V. |
Triheptanoin | small molecules | EMA | 2015-07-28 | — | Ultragenyx Netherlands B.V. |
Triheptanoin [Triheptanoin] | small molecules | EMA | 2012-12-06 | — | B. Braun Melsungen AG |
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