Home / Deep Research / Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency

Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency

Disease Pathophysiology Research Template

2026-02-23
Falcon MONDO:0012173 Model: Edison Scientific Literature 40 citations

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Comprehensive research report: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD)

Target disease and identifiers • Disease: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a subset of mitochondrial trifunctional protein (MTP/TFP)–related long-chain fatty acid oxidation disorders. (baydakova2023newacylcarnitineratio pages 1-2, mutze2024neurologicaloutcomein pages 1-2) • MONDO ID: Not retrieved in the current evidence set.

1) Key concepts and definitions (current understanding)

1.1 Definition and biochemical locus of defect LCHADD is an autosomal recessive mitochondrial long-chain fatty-acid β-oxidation (LC-FAO) disorder caused most commonly by a recurrent HADHA variant (NM_000182.5:c.1528G>C; p.Glu510Gln / p.E510Q) that selectively reduces the LCHAD catalytic activity within the mitochondrial trifunctional protein (TFP/MTP). (baydakova2023newacylcarnitineratio pages 1-2, mutze2024neurologicaloutcomein pages 1-2, gaston2023ag1528chadha pages 1-2) The mitochondrial trifunctional protein is an inner-mitochondrial-membrane–associated multienzyme complex. Baydakova et al. define that “LCHAD, long-chain enoyl-CoA hydratase (LCEH) and long-chain 3-ketoacyl-CoA thiolase (LCKAT) together constitute mitochondrial trifunctional protein (MTP) … [which] … plays an essential role in the catalysis of the last three steps of long-chain FAO.” (baydakova2023newacylcarnitineratio pages 1-2) MTP (TFP) deficiency (MTPD; due to other HADHA/HADHB variants) can reduce multiple MTP enzyme activities; LCHADD (E510Q) often retains the other two functions relatively intact while impairing the LCHAD step. (mutze2024neurologicaloutcomein pages 1-2, gaston2023ag1528chadha pages 1-2)

1.2 Hallmark biochemical signature Selective LCHAD impairment produces a characteristic accumulation of long-chain 3-hydroxyacylcarnitines (e.g., C16OH, C18OH, C18:1OH). Baydakova et al. propose a newborn screening biomarker ratio: “HADHA ratio” = (C16OH + C18OH + C18:1OH)/C0, reported as “significantly elevated in all 54 affected individuals” and not elevated in VLCAD deficiency. (baydakova2023newacylcarnitineratio pages 1-2)

1.3 Core pathophysiologic principle: energy failure + toxicity Because LC-FAO supplies acetyl-CoA and reducing equivalents (NADH, FADH2) to support ketogenesis and oxidative phosphorylation, LC-FAO block yields both: • Inadequate energy availability (especially under fasting/illness/exertion), and • Accumulation of partially oxidized long-chain intermediates that can be lipotoxic and pro-oxidant. (baydakova2023newacylcarnitineratio pages 1-2, vockley2020longchainfattyacid pages 2-4) Baydakova et al. state: “Disrupted FAO in LCHAD-deficient individuals leads to a decrease in the production of ketone bodies and ATP … inadequate energy supply … [and] … accumulation of toxic FAO intermediates, thereby inducing oxidative stress, lipotoxicity and altering cell homeostasis.” (baydakova2023newacylcarnitineratio pages 1-2)

2) Core pathophysiology (molecular/cellular mechanisms)

2.1 Dysregulated pathways Primary dysregulated pathway: mitochondrial long-chain fatty-acid β-oxidation (LC-FAO) and downstream ketogenesis/TCA/oxidative phosphorylation coupling. (baydakova2023newacylcarnitineratio pages 1-2, mutze2024neurologicaloutcomein pages 1-2, vockley2020longchainfattyacid pages 2-4) Secondary/linked pathway: mitochondrial membrane phospholipid homeostasis—especially cardiolipin (CL) remodeling—because the TFP α-subunit (HADHA) has monolysocardiolipin acyl-transferase activity linking FAO to CL remodeling and respiratory-chain supercomplex organization. (neto2024mitochondrialbioenergeticsand pages 1-2, neto2024mitochondrialbioenergeticsand pages 7-10)

2.2 Cellular energy deficit and hypoketotic hypoglycemia In LC-FAO defects, acetyl-CoA supply for ketone bodies is reduced and energy supply during fasting is impaired, predisposing to hypoketotic hypoglycemia. (penaquintana2024nutritionalmanagementof pages 1-3, baydakova2023newacylcarnitineratio pages 1-2) Peña-Quintana & Correcher-Medina describe a general FAOD mechanism: “Due to the enzyme deficit, acetyl-CoA is not produced; gluconeogenesis, ureagenesis and ketone body formation are not activated, resulting in energy deficit, which can lead to hypoglycaemia without ketone body formation …” (penaquintana2024nutritionalmanagementof pages 1-3)

2.3 Toxic intermediate accumulation → oxidative stress and mitochondrial dysfunction Long-chain 3-hydroxyacyl intermediates and derived acylcarnitines accumulate and are implicated in oxidative stress and broad mitochondrial dysfunction. (baydakova2023newacylcarnitineratio pages 1-2) A key 2024 mechanistic advance is mitochondrial lipidomics and bioenergetics profiling in patient fibroblasts and a mouse model: • FAO flux defect: Neto et al. report, using radiolabeled oleate, that “The release of 3H2O was significantly decreased in all patient fibroblasts.” (neto2024mitochondrialbioenergeticsand pages 7-10) • Respiratory limitation: Neto et al. note “a clear reduction of maximal respiration and spare respiratory capacity” in TFP/LCHAD-deficient fibroblasts. (neto2024mitochondrialbioenergeticsand pages 7-10) • Oxidative lipid damage: increased oxidized phospholipids (e.g., oxidized PE/PC and in some lines oxidized cardiolipins) and increased lysophospholipids support a lipid-peroxidation/oxidative stress phenotype. (neto2024mitochondrialbioenergeticsand pages 7-10) • Cardiolipin remodeling defect: decreased CL content/species and increased MLCL/dilysocardiolipins were observed in βTFP mouse liver mitochondria and in patient fibroblasts. (neto2024mitochondrialbioenergeticsand pages 7-10, neto2024mitochondrialbioenergeticsand pages 1-2) These findings mechanistically connect FAO enzyme deficiency to inner mitochondrial membrane remodeling and reduced respiratory reserve, a plausible substrate for stress-induced decompensations.

2.4 Retina/RPE-specific mechanisms of chorioretinopathy (unique LCHADD complication) LCHADD is notable for progressive chorioretinopathy/retinopathy not typical of most other FAO disorders. (babcock2024thelchaddmouse pages 1-2, devine2024ipscderivedlchaddretinal pages 1-2) Two complementary 2024 experimental systems provide a mechanistic framework: A) In vivo RPE/sclera metabolite evidence (mouse model) Babcock et al. measured acylcarnitines directly in isolated RPE/sclera and found “a 5- to 7-fold increase in long-chain hydroxyacylcarnitines” in LCHADD vs WT, consistent with a block at the LCHAD step in RPE FAO. (babcock2024thelchaddmouse pages 1-2, babcock2024thelchaddmouse media 0d3f86e7) B) Human patient iPSC-derived RPE cell pathomechanism and rescue DeVine et al. show that LCHADD-RPE “accumulate 3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones than WT-RPE.” They further report that upon exposure to docosahexaenoic acid (DHA), LCHADD-RPE exhibit “increased oxidative stress, lipid peroxidation, decreased viability,” and that antioxidant agents rescue viability, supporting lipid-peroxidation mediated RPE cell death as a candidate mechanism. Exogenous HADHA gene addition delivered by rAAV reduced hydroxyacylcarnitine accumulation and increased resistance to oxidative stress, indicating a causal link to HADHA loss-of-function and supporting a gene-addition therapeutic strategy for vision loss. (devine2024ipscderivedlchaddretinal pages 1-2) Clinical observations align with RPE-first progression: early retinal pigment epithelium/choroidal changes (e.g., pigment dispersion, choroidal atrophy) are described as early signs, and progression is associated with metabolic decompensation episodes. (lange2024ophthalmicsymptomsof pages 1-2)

2.5 Heart and skeletal muscle vulnerability High-energy-demand tissues (heart, skeletal muscle, liver) are particularly FAO-dependent; defects predispose to cardiomyopathy and rhabdomyolysis, often triggered by stressors such as fasting and illness. (penaquintana2024nutritionalmanagementof pages 1-3, vockley2020longchainfattyacid pages 2-4) In a Hadha G1528C knock-in model, Gaston et al. reported reduced fat oxidation, plasma 3-hydroxyacylcarnitine accumulation, lower ketones with fasting, treadmill exhaustion, and dilated cardiomyopathy, supporting causal linkage from the canonical human mutation to systemic energy failure and organ phenotypes. (gaston2023ag1528chadha pages 1-2)

2.6 Peripheral neuropathy mechanisms (current evidence) Clinical neuropathy is a recognized long-term complication and appears earlier in MTPD than isolated LCHADD in a German cohort (median 3.9 vs 11.4 years). (mutze2024neurologicaloutcomein pages 1-2) Mechanistically, current retrieved sources support plausible contributors rather than a single established mechanism: • Lipotoxicity/oxidative stress from toxic intermediates. (baydakova2023newacylcarnitineratio pages 1-2) • Mitochondrial membrane remodeling/bioenergetic limitation (cardiolipin remodeling defects; reduced respiratory reserve). (neto2024mitochondrialbioenergeticsand pages 7-10, neto2024mitochondrialbioenergeticsand pages 1-2) • Altered lipid classes associated with neurodegeneration are referenced in recent ophthalmology literature (altered sphingolipid profile as a risk factor, cited within a 2024 case series), but primary mechanistic evidence for myelin/demyelination was not retrieved in the current full-text set. (lange2024ophthalmicsymptomsof pages 10-10)

2.7 Maternal acute fatty liver of pregnancy (AFLP)/HELLP association A distinctive translational feature is the association of fetal LCHAD/MTP deficiency with maternal AFLP/HELLP. Baydakova et al. state that “the release of toxic 3-hydroxy intermediate metabolites from the LCHAD/MTP-deficient placenta and fetus into the maternal circulation is likely to be a culprit” in inducing maternal disease. (baydakova2023newacylcarnitineratio pages 1-2) An obstetric-medicine abstract compilation also discusses reported associations of the recurrent HADHA c.1528G>C variant with AFLP/HELLP in subsets of cases, but indicates heterogeneity across cohorts. (mahmood2023isomnasom2022abstracts pages 24-25)

3) Disease progression model (sequence of events)

Trigger → metabolic inflection 1) Baseline partial FAO limitation exists due to reduced LCHAD (or broader MTP) activity. (gaston2023ag1528chadha pages 1-2, mutze2024neurologicaloutcomein pages 1-2) 2) Catabolic stress (fasting, febrile illness, prolonged exercise) increases reliance on LC-FAO; the pathway bottleneck causes: a) insufficient acetyl-CoA/ketone availability and reduced reducing-equivalent supply, causing energy deficit and hypoketotic hypoglycemia, and b) accumulation of hydroxyacyl intermediates (hydroxyacylcarnitines/hydroxy-fatty acids) contributing to oxidative stress/lipotoxicity. (baydakova2023newacylcarnitineratio pages 1-2, vockley2020longchainfattyacid pages 2-4)

Organ dysfunction and chronic complications 3) Acute decompensations manifest as hypoketotic hypoglycemia, hepatic dysfunction, cardiomyopathy/arrhythmia risk, and rhabdomyolysis/myopathy. (baydakova2023newacylcarnitineratio pages 1-2, vockley2020longchainfattyacid pages 2-4) 4) Recurrent crises and/or chronic mitochondrial lipid/bioenergetic remodeling contribute to long-term complications, including peripheral neuropathy and progressive chorioretinopathy. Retina/RPE injury may reflect a tissue-specific susceptibility to lipid peroxidation and FAO-dependent homeostasis. (devine2024ipscderivedlchaddretinal pages 1-2, babcock2024thelchaddmouse pages 1-2, neto2024mitochondrialbioenergeticsand pages 7-10)

4) Phenotypic manifestations (with mechanistic links)

Key clinical features (representative) • Hypoketotic hypoglycemia: reduced ketogenesis and impaired fasting adaptation. (baydakova2023newacylcarnitineratio pages 1-2, penaquintana2024nutritionalmanagementof pages 1-3) • Cardiomyopathy: cardiac FAO dependency and energy deficit; observed in cohort and mouse model. (mutze2024neurologicaloutcomein pages 1-2, gaston2023ag1528chadha pages 1-2) • Rhabdomyolysis/myopathy: stress-induced muscle energy failure and toxic metabolite effects. (baydakova2023newacylcarnitineratio pages 1-2, mutze2024neurologicaloutcomein pages 1-2) • Hepatopathy: metabolic decompensation-associated hepatic dysfunction/steatosis. (mutze2024neurologicaloutcomein pages 1-2, baydakova2023newacylcarnitineratio pages 1-2) • Peripheral neuropathy: chronic complication, earlier in MTPD; mechanism likely multifactorial (lipotoxicity, mitochondrial dysfunction, lipid remodeling). (mutze2024neurologicaloutcomein pages 1-2, baydakova2023newacylcarnitineratio pages 1-2, neto2024mitochondrialbioenergeticsand pages 7-10) • Chorioretinopathy/retinopathy: LCHADD-specific; linked to RPE dysfunction, hydroxyacyl accumulation and lipid peroxidation, with gene-addition rescue in vitro. (devine2024ipscderivedlchaddretinal pages 1-2, babcock2024thelchaddmouse pages 1-2)

Recent real-world morbidity statistics (NBS era) In a German national cohort of 67 individuals (54 NBS-identified), despite improved neonatal survival, long-term morbidity remained high: neonatal decompensations 28%; later metabolic decompensations 80%; cardiomyopathy 28%; myopathy 82%; hepatopathy 32%; retinopathy 17%; neuropathy 22%; mean hospitalizations up to 2.4/year; 14.8% mortality among screened MTPD. (mutze2024neurologicaloutcomein pages 1-2)

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 Improved biomarkers for screening/diagnosis (2023) Baydakova et al. (Aug 25, 2023) propose the “HADHA ratio” (C16OH + C18OH + C18:1OH)/C0 as a sensitive and specific MS/MS screening aid, elevated in all 54 affected individuals studied and not elevated in 19 VLCAD patients. URL: https://doi.org/10.3390/ijns9030048. (baydakova2023newacylcarnitineratio pages 1-2)

5.2 Disease-modifying mechanistic understanding in mitochondria (2024) Neto et al. (Sep 2024) provide lipidomics and Seahorse functional evidence linking TFP/LCHAD deficiency to (i) reduced FAO flux, (ii) reduced maximal respiration/spare respiratory capacity, and (iii) cardiolipin remodeling defects and oxidized phospholipids. URL: https://doi.org/10.1172/jci.insight.176887. (neto2024mitochondrialbioenergeticsand pages 7-10)

5.3 Retina pathogenesis and gene-therapy direction (2024) DeVine et al. (Sep 16, 2024) report that patient iPSC-derived RPE cells are “susceptible to lipid peroxidation” with DHA exposure, and that AAV-mediated wildtype HADHA expression rescues biochemical and oxidative-stress phenotypes, providing a preclinical rationale for retinal gene-addition therapy in LCHADD. URL: https://doi.org/10.1167/iovs.65.11.22. (devine2024ipscderivedlchaddretinal pages 1-2) Babcock et al. (Jun 21, 2024) demonstrate a direct tissue metabolite signature in RPE/sclera (5–7× hydroxyacylcarnitines), supporting local FAO block in the retina and suggesting toxicity/inflammation (two-fold subretinal macrophage increase). URL: https://doi.org/10.1167/iovs.65.6.33. (babcock2024thelchaddmouse pages 1-2, babcock2024thelchaddmouse media 0d3f86e7)

5.4 Natural history/outcomes in the newborn screening era (2024) Mütze et al. (Jan 2024) quantify persistent morbidity despite NBS, underscoring unmet need for disease-modifying therapies and the importance of adherence support. URL: https://doi.org/10.1002/acn3.52002. (mutze2024neurologicaloutcomein pages 1-2)

6) Current applications and real-world implementations

6.1 Newborn screening (NBS) Expanded NBS using tandem MS acylcarnitine profiling is widely implemented for LC-FAODs and identifies affected infants presymptomatically; it reduces mortality but not morbidity. (vockley2020longchainfattyacid pages 2-4, mutze2024neurologicaloutcomein pages 1-2)

6.2 Dietary management and emergency care Core principles emphasize prevention of catabolism (avoid prolonged fasting) and dietary fat manipulation. • Long-chain defects: LCT restriction and MCT supplementation targets are summarized in a 2024 review (e.g., LCT ~10% of energy; MCT 10–25%; essential fatty acids specified). (penaquintana2024nutritionalmanagementof pages 1-3) • Acute decompensation: prompt IV glucose is central; an emergency regimen from a 2020 managed-care review specifies 10% dextrose at 1.5× maintenance (~8 mg/kg/min glucose) to suppress catabolism with monitoring of electrolytes/creatinine/CPK until improvement. (vockley2020longchainfattyacid pages 2-4)

6.3 Triheptanoin (Dojolvi) and anaplerosis Triheptanoin is an odd-chain triglyceride intended to provide anaplerotic substrate (propionyl-CoA → succinyl-CoA) to support TCA cycle intermediates and energy generation in LC-FAODs, and is FDA approved (June 2020) for LC-FAOD. (vockley2020longchainfattyacid pages 2-4, vockley2020longchainfattyacid pages 4-6) In the German cohort analyzed by Mütze et al., triheptanoin was not used (not available/approved during study period), but is discussed as reported to “significantly reduce decompensation and hospitalization frequency” in other reports. (mutze2024neurologicaloutcomein pages 12-13)

6.4 Monitoring practices A 2024 MetabERN survey reports that European metabolic centers largely concur on key monitoring components including visit frequency, laboratory parameters, cardiac monitoring, and retinopathy screening, but vary in hepatic imaging, glucose monitoring, and electrophysiologic testing, reflecting uncertainty in NBS-era natural history. URL: https://doi.org/10.1186/s13023-024-03024-0. (schwantje2024longtermmonitoringof pages 1-2)

7) Expert opinions/interpretation from authoritative sources

• Persisting morbidity despite NBS: Both the 2024 national cohort and the 2020 management review emphasize that screening improves survival but “most continue to experience substantial morbidity due to episodes of metabolic decompensation despite treatment,” motivating need for improved therapies. (vockley2020longchainfattyacid pages 2-4, mutze2024neurologicaloutcomein pages 1-2) • Emerging mechanistic convergence: 2024 mechanistic work suggests that beyond metabolite accumulation, mitochondrial inner membrane remodeling (cardiolipin depletion/MLCL changes) and reduced respiratory reserve may be key determinants of stress intolerance and tissue-specific vulnerability. (neto2024mitochondrialbioenergeticsand pages 7-10, neto2024mitochondrialbioenergeticsand pages 1-2) • Retina as a therapeutic entry point: 2024 iPSC-RPE data provide a plausible causal mechanism (DHA-driven lipid peroxidation susceptibility) and a targeted intervention (AAV-HADHA rescue), supporting a precision approach to the LCHADD-unique phenotype. (devine2024ipscderivedlchaddretinal pages 1-2)

8) Structured knowledge-base style annotations

8.1 Genes and proteins (HGNC) • HADHA (TFPα; contains LCEH and LCHAD activities; also linked to cardiolipin remodeling). Evidence: role in last three steps of LC-FAO and common c.1528G>C variant reducing LCHAD activity. (baydakova2023newacylcarnitineratio pages 1-2, gaston2023ag1528chadha pages 1-2, neto2024mitochondrialbioenergeticsand pages 1-2) • HADHB (TFPβ; contains long-chain 3-ketoacyl-CoA thiolase). Evidence: MTP hetero-oligomer; biallelic variants cause MTPD affecting multiple activities. (mutze2024neurologicaloutcomein pages 1-2, neto2024mitochondrialbioenergeticsand pages 1-2)

8.2 Disrupted biological processes (GO-like terms; label suggestions) • Mitochondrial long-chain fatty acid beta-oxidation (defect at LCHAD step / MTP complex). (baydakova2023newacylcarnitineratio pages 1-2, mutze2024neurologicaloutcomein pages 1-2) • Ketone body biosynthetic process / ketogenesis (reduced ketone production). (baydakova2023newacylcarnitineratio pages 1-2, devine2024ipscderivedlchaddretinal pages 1-2) • Mitochondrial electron transport / oxidative phosphorylation capacity (reduced maximal respiration/spare respiratory capacity). (neto2024mitochondrialbioenergeticsand pages 7-10) • Cardiolipin metabolic process / cardiolipin remodeling (decreased CL, increased MLCL/dilysocardiolipins). (neto2024mitochondrialbioenergeticsand pages 7-10, neto2024mitochondrialbioenergeticsand pages 1-2) • Response to oxidative stress / lipid peroxidation (increased oxidized phospholipids; DHA-triggered lipid peroxidation in RPE). (neto2024mitochondrialbioenergeticsand pages 7-10, devine2024ipscderivedlchaddretinal pages 1-2)

8.3 Cellular components • Mitochondrial inner membrane (MTP bound to inner membrane; cardiolipin localized to inner membrane and ETC supercomplex organization). (baydakova2023newacylcarnitineratio pages 1-2, neto2024mitochondrialbioenergeticsand pages 1-2) • Mitochondrion (site of FAO, ketone generation in some cells, respiratory chain). (neto2024mitochondrialbioenergeticsand pages 7-10, devine2024ipscderivedlchaddretinal pages 1-2)

8.4 Primary cell types (CL-like; label suggestions) • Retinal pigment epithelial cell (RPE): FAO-dependent; shows hydroxyacylcarnitine accumulation, oxidative stress and lipid peroxidation susceptibility, and gene-addition rescue. (devine2024ipscderivedlchaddretinal pages 1-2, babcock2024thelchaddmouse pages 1-2) • Hepatocytes/liver cells: key site of FAO for gluconeogenesis/ketogenesis; hepatopathy during decompensation. (penaquintana2024nutritionalmanagementof pages 1-3, mutze2024neurologicaloutcomein pages 1-2) • Cardiomyocytes: high FAO dependence; cardiomyopathy common. (penaquintana2024nutritionalmanagementof pages 1-3, mutze2024neurologicaloutcomein pages 1-2) • Skeletal muscle cells: myopathy/rhabdomyolysis. (mutze2024neurologicaloutcomein pages 1-2, vockley2020longchainfattyacid pages 2-4) • Peripheral neurons/Schwann cells (inferred from neuropathy phenotype; direct cell-type mechanistic evidence not retrieved). (mutze2024neurologicaloutcomein pages 1-2) • Macrophages (subretinal macrophage increase in mouse model). (babcock2024thelchaddmouse pages 1-2)

8.5 Anatomical locations (UBERON-like; label suggestions) • Liver, heart, skeletal muscle, retina (macula/RPE/choroid), peripheral nerve. (penaquintana2024nutritionalmanagementof pages 1-3, mutze2024neurologicaloutcomein pages 1-2, babcock2024thelchaddmouse pages 1-2) • Placenta/fetus (maternal AFLP mechanism via metabolite release). (baydakova2023newacylcarnitineratio pages 1-2)

8.6 Chemical entities (ChEBI-like; label suggestions) • Long-chain 3-hydroxyacylcarnitines: C16OH, C18OH, C18:1OH (diagnostic markers/toxic intermediates). (baydakova2023newacylcarnitineratio pages 1-2, neto2024mitochondrialbioenergeticsand pages 7-10) • Palmitate (substrate used to demonstrate inability to oxidize fatty acid in LCHADD-RPE). (devine2024ipscderivedlchaddretinal pages 1-2) • Ketone bodies (reduced release in LCHADD-RPE; hypoketotic states). (devine2024ipscderivedlchaddretinal pages 1-2, baydakova2023newacylcarnitineratio pages 1-2) • Docosahexaenoic acid (DHA): triggers oxidative stress/lipid peroxidation in LCHADD-RPE experimental model; also referenced clinically for supplementation/visual function. (devine2024ipscderivedlchaddretinal pages 1-2) • Triheptanoin (odd-chain triglyceride; anaplerotic therapy for LC-FAOD). (vockley2020longchainfattyacid pages 4-6)

8.7 Phenotype associations (HPO-like; label suggestions) • Hypoketotic hypoglycemia; cardiomyopathy; rhabdomyolysis; myopathy; hepatopathy; peripheral neuropathy; chorioretinopathy/retinopathy; metabolic decompensation triggered by fasting/illness/exercise. (baydakova2023newacylcarnitineratio pages 1-2, mutze2024neurologicaloutcomein pages 1-2, vockley2020longchainfattyacid pages 2-4) • Maternal AFLP/HELLP association (maternal phenotype linked to fetal disease). (baydakova2023newacylcarnitineratio pages 1-2, mahmood2023isomnasom2022abstracts pages 24-25)

9) Evidence items (PMIDs and limitations) PMIDs were not available in the retrieved excerpts/metadata for the key 2023–2024 papers; therefore, PubMed IDs cannot be reliably provided from the current tool outputs. Primary evidence is provided via DOI and URL with publication dates.

Key sources (publication date; URL) • Baydakova GV et al. Aug 25, 2023. https://doi.org/10.3390/ijns9030048 (baydakova2023newacylcarnitineratio pages 1-2) • Gaston G et al. Aug 2023. https://doi.org/10.1038/s42003-023-05268-1 (gaston2023ag1528chadha pages 1-2) • Mütze U et al. Jan 2024. https://doi.org/10.1002/acn3.52002 (mutze2024neurologicaloutcomein pages 1-2) • Babcock SJ et al. Jun 21, 2024. https://doi.org/10.1167/iovs.65.6.33 (babcock2024thelchaddmouse pages 1-2, babcock2024thelchaddmouse media 0d3f86e7) • DeVine T et al. Sep 16, 2024. https://doi.org/10.1167/iovs.65.11.22 (devine2024ipscderivedlchaddretinal pages 1-2) • Neto EV et al. Sep 2024. https://doi.org/10.1172/jci.insight.176887 (neto2024mitochondrialbioenergeticsand pages 7-10) • Peña-Quintana L, Correcher-Medina P. Aug 14, 2024. https://doi.org/10.3390/nu16162707 (penaquintana2024nutritionalmanagementof pages 1-3) • Schwantje M et al. Jan 2024. https://doi.org/10.1186/s13023-024-03024-0 (schwantje2024longtermmonitoringof pages 1-2)

References

  1. (baydakova2023newacylcarnitineratio pages 1-2): Galina V. Baydakova, Polina G. Tsygankova, Natalia L. Pechatnikova, Olga A. Bazhanova, Yana D. Nazarenko, and Ekaterina Y. Zakharova. New acylcarnitine ratio as a reliable indicator of long-chain 3-hydroxyacyl-coa dehydrogenase deficiency. International Journal of Neonatal Screening, 9:48, Aug 2023. URL: https://doi.org/10.3390/ijns9030048, doi:10.3390/ijns9030048. This article has 5 citations.

  2. (mutze2024neurologicaloutcomein pages 1-2): Ulrike Mütze, Alina Ottenberger, Florian Gleich, Esther M. Maier, Martin Lindner, Ralf A. Husain, Katja Palm, Skadi Beblo, Peter Freisinger, René Santer, Eva Thimm, Stephan vom Dahl, Natalie Weinhold, Karina Grohmann‐Held, Claudia Haase, Julia B. Hennermann, Alexandra Hörbe‐Blindt, Clemens Kamrath, Iris Marquardt, Thorsten Marquardt, Robert Behne, Dorothea Haas, Ute Spiekerkoetter, Georg F. Hoffmann, Sven F. Garbade, Sarah C. Grünert, and Stefan Kölker. Neurological outcome in long‐chain hydroxy fatty acid oxidation disorders. Annals of Clinical and Translational Neurology, 11:883-898, Jan 2024. URL: https://doi.org/10.1002/acn3.52002, doi:10.1002/acn3.52002. This article has 8 citations and is from a peer-reviewed journal.

  3. (gaston2023ag1528chadha pages 1-2): Garen Gaston, Shannon Babcock, Renee Ryals, Gabriela Elizondo, Tiffany DeVine, Dahlia Wafai, William Packwood, Sarah Holden, Jacob Raber, Jonathan R. Lindner, Mark E. Pennesi, Cary O. Harding, and Melanie B. Gillingham. A g1528c hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-coa dehydrogenase deficiency. Communications Biology, Aug 2023. URL: https://doi.org/10.1038/s42003-023-05268-1, doi:10.1038/s42003-023-05268-1. This article has 12 citations and is from a peer-reviewed journal.

  4. (vockley2020longchainfattyacid pages 2-4): J. Vockley. Long-chain fatty acid oxidation disorders and current management strategies. The American journal of managed care, 26 7 Suppl:S147-S154, Aug 2020. URL: https://doi.org/10.37765/ajmc.2020.88480, doi:10.37765/ajmc.2020.88480. This article has 78 citations.

  5. (neto2024mitochondrialbioenergeticsand pages 1-2): Eduardo Vieira Neto, Meicheng Wang, Austin J. Szuminsky, Lethicia Ferraro, Erik Koppes, Yudong Wang, Clinton Van’t Land, Al-Walid Mohsen, Geancarlo Zanatta, Areeg H. El-Gharbawy, Tamil S. Anthonymuthu, Yulia Y. Tyurina, Vladimir A. Tyurin, Valerian Kagan, Hülya Bayır, and Jerry Vockley. Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency. JCI Insight, Sep 2024. URL: https://doi.org/10.1172/jci.insight.176887, doi:10.1172/jci.insight.176887. This article has 12 citations and is from a domain leading peer-reviewed journal.

  6. (neto2024mitochondrialbioenergeticsand pages 7-10): Eduardo Vieira Neto, Meicheng Wang, Austin J. Szuminsky, Lethicia Ferraro, Erik Koppes, Yudong Wang, Clinton Van’t Land, Al-Walid Mohsen, Geancarlo Zanatta, Areeg H. El-Gharbawy, Tamil S. Anthonymuthu, Yulia Y. Tyurina, Vladimir A. Tyurin, Valerian Kagan, Hülya Bayır, and Jerry Vockley. Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency. JCI Insight, Sep 2024. URL: https://doi.org/10.1172/jci.insight.176887, doi:10.1172/jci.insight.176887. This article has 12 citations and is from a domain leading peer-reviewed journal.

  7. (penaquintana2024nutritionalmanagementof pages 1-3): Luis Peña-Quintana and Patricia Correcher-Medina. Nutritional management of patients with fatty acid oxidation disorders. Nutrients, 16:2707, Aug 2024. URL: https://doi.org/10.3390/nu16162707, doi:10.3390/nu16162707. This article has 7 citations.

  8. (babcock2024thelchaddmouse pages 1-2): Shannon J. Babcock, Allison G. Curtis, Garen Gaston, Gabriela Elizondo, Melanie B. Gillingham, and Renee C. Ryals. The lchadd mouse model recapitulates early-stage chorioretinopathy in lchadd patients. Investigative Ophthalmology & Visual Science, 65:33, Jun 2024. URL: https://doi.org/10.1167/iovs.65.6.33, doi:10.1167/iovs.65.6.33. This article has 6 citations and is from a domain leading peer-reviewed journal.

  9. (devine2024ipscderivedlchaddretinal pages 1-2): Tiffany DeVine, Gabriela Elizondo, Garen Gaston, Shannon J. Babcock, Dietrich Matern, Mikhail S. Shchepinov, Mark E. Pennesi, Cary O. Harding, and Melanie B. Gillingham. Ipsc-derived lchadd retinal pigment epithelial cells are susceptible to lipid peroxidation and rescued by transfection of a wildtype aav-hadha vector. Investigative Ophthalmology & Visual Science, 65:22, Sep 2024. URL: https://doi.org/10.1167/iovs.65.11.22, doi:10.1167/iovs.65.11.22. This article has 2 citations and is from a domain leading peer-reviewed journal.

  10. (babcock2024thelchaddmouse media 0d3f86e7): Shannon J. Babcock, Allison G. Curtis, Garen Gaston, Gabriela Elizondo, Melanie B. Gillingham, and Renee C. Ryals. The lchadd mouse model recapitulates early-stage chorioretinopathy in lchadd patients. Investigative Ophthalmology & Visual Science, 65:33, Jun 2024. URL: https://doi.org/10.1167/iovs.65.6.33, doi:10.1167/iovs.65.6.33. This article has 6 citations and is from a domain leading peer-reviewed journal.

  11. (lange2024ophthalmicsymptomsof pages 1-2): Natalia Lange, Aleksandra Maria Bodetko, Renata Mozrzymas, and Agnieszka Kowal-Lange. Ophthalmic symptoms of long-chain 3-hydroxyacyl-coa dehydrogenase deficiency: a report of three cases. Case Reports in Ophthalmology, 15:310-319, Apr 2024. URL: https://doi.org/10.1159/000537895, doi:10.1159/000537895. This article has 1 citations and is from a peer-reviewed journal.

  12. (lange2024ophthalmicsymptomsof pages 10-10): Natalia Lange, Aleksandra Maria Bodetko, Renata Mozrzymas, and Agnieszka Kowal-Lange. Ophthalmic symptoms of long-chain 3-hydroxyacyl-coa dehydrogenase deficiency: a report of three cases. Case Reports in Ophthalmology, 15:310-319, Apr 2024. URL: https://doi.org/10.1159/000537895, doi:10.1159/000537895. This article has 1 citations and is from a peer-reviewed journal.

  13. (mahmood2023isomnasom2022abstracts pages 24-25): Hamza Mahmood, Cassie Fayowski, Susan Huang, Dongmei Sun, Ellen Miles, Amanda Huynh, Helen Zhao, T. Chaworth-Musters, S. Purkiss, and Wee-Shian Chan. Isom/nasom 2022 abstracts. Obstetric Medicine, 16:S3-S26, Feb 2023. URL: https://doi.org/10.1177/1753495x221149339, doi:10.1177/1753495x221149339. This article has 3 citations and is from a peer-reviewed journal.

  14. (vockley2020longchainfattyacid pages 4-6): J. Vockley. Long-chain fatty acid oxidation disorders and current management strategies. The American journal of managed care, 26 7 Suppl:S147-S154, Aug 2020. URL: https://doi.org/10.37765/ajmc.2020.88480, doi:10.37765/ajmc.2020.88480. This article has 78 citations.

  15. (mutze2024neurologicaloutcomein pages 12-13): Ulrike Mütze, Alina Ottenberger, Florian Gleich, Esther M. Maier, Martin Lindner, Ralf A. Husain, Katja Palm, Skadi Beblo, Peter Freisinger, René Santer, Eva Thimm, Stephan vom Dahl, Natalie Weinhold, Karina Grohmann‐Held, Claudia Haase, Julia B. Hennermann, Alexandra Hörbe‐Blindt, Clemens Kamrath, Iris Marquardt, Thorsten Marquardt, Robert Behne, Dorothea Haas, Ute Spiekerkoetter, Georg F. Hoffmann, Sven F. Garbade, Sarah C. Grünert, and Stefan Kölker. Neurological outcome in long‐chain hydroxy fatty acid oxidation disorders. Annals of Clinical and Translational Neurology, 11:883-898, Jan 2024. URL: https://doi.org/10.1002/acn3.52002, doi:10.1002/acn3.52002. This article has 8 citations and is from a peer-reviewed journal.

  16. (schwantje2024longtermmonitoringof pages 1-2): Marit Schwantje, Sarah C. Grünert, and Sabine A. Fuchs. Long-term monitoring of fatty acid oxidation defects: results from a metabern survey. Orphanet Journal of Rare Diseases, Jan 2024. URL: https://doi.org/10.1186/s13023-024-03024-0, doi:10.1186/s13023-024-03024-0. This article has 0 citations and is from a peer-reviewed journal.