Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency

Mendelian MONDO:0012173 Pathograph 32 Fatty Acid Oxidation Disorder Inborn Error of Metabolism

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an autosomal recessive disorder of mitochondrial long-chain fatty acid beta-oxidation caused by biallelic pathogenic variants in HADHA, most commonly the c.1528G>C (p.Glu510Gln) founder mutation. LCHADD selectively impairs the LCHAD catalytic activity within the mitochondrial trifunctional protein (MTP/TFP), leading to energy failure during fasting or physiologic stress and accumulation of toxic long-chain 3-hydroxyacyl intermediates. Clinical manifestations include hypoketotic hypoglycemia, cardiomyopathy, rhabdomyolysis, hepatopathy, peripheral neuropathy, and a distinctive progressive chorioretinopathy not seen in other fatty acid oxidation disorders. Despite improved neonatal survival through newborn screening, long-term morbidity remains substantial, with myopathy in 82%, metabolic decompensations in 80%, and cardiomyopathy in 28% of screened individuals.

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Pathophysiology

HADHA molecular function deficiency within mitochondrial trifunctional protein

Biallelic pathogenic variants in HADHA reduce long-chain 3-hydroxyacyl-CoA dehydrogenase catalytic activity within mitochondrial trifunctional protein.

HADHA link

long-chain 3-hydroxyacyl-CoA dehydrogenase activity link ↓ DECREASED

mitochondrion link

Downstream

Impaired mitochondrial long-chain fatty acid beta-oxidation Reduced HADHA catalytic activity blocks the LCHAD step of long-chain FAO.

Show evidence (1 reference)

PMID:32840329 SUPPORT Other

"LC-FAODs are caused by mutations in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids (LCFAs) into energy during times of fasting and physiologic stress."

Supports molecular dysfunction of mitochondrial FAO enzymes including HADHA in LCHADD.

Impaired mitochondrial long-chain fatty acid beta-oxidation

Deficiency of LCHAD catalytic activity blocks the third step of long-chain fatty acid beta-oxidation, reducing acetyl-CoA and reducing equivalent supply for ketogenesis and oxidative phosphorylation. This causes energy failure during fasting, illness, or prolonged exercise when tissues depend on fatty acid oxidation for fuel.

hepatocyte link cardiac muscle cell link skeletal muscle fiber link

fatty acid beta-oxidation link ↓ DECREASED ketone body biosynthetic process link ↓ DECREASED

mitochondrion link

Downstream

Toxic intermediate accumulation and oxidative stress

Cardiolipin remodeling defect

Catabolic stress-triggered energy failure During fasting, illness, or exertion, impaired long-chain FAO limits energy production and ketogenesis.

Long-chain 3-hydroxyacylcarnitines (C16OH, C18OH, C18:1OH) The LCHAD enzymatic block produces elevated long-chain 3-hydroxyacylcarnitines used for diagnosis.

HADHA ratio (C16OH + C18OH + C18:1OH)/C0 The diagnostic HADHA ratio aggregates the elevated C16OH, C18OH, and C18:1OH species normalized to free carnitine.

Ketone bodies Impaired hepatic long-chain FAO limits ketogenesis during fasting or physiologic stress.

Show evidence (1 reference)

PMID:32840329 SUPPORT Other

Supports impaired long-chain FAO and stress-related energy failure downstream of HADHA dysfunction.

Catabolic stress-triggered energy failure

Fasting, febrile illness, exercise, and other physiologic stressors increase dependence on long-chain fatty acid oxidation. Because LCHADD cannot efficiently use long-chain fatty acids for energy, catabolic stress produces acute energy crises with hypoketotic hypoglycemia, hepatic dysfunction, cardiomyopathy, exercise intolerance, and rhabdomyolysis.

hepatocyte link cardiac muscle cell link skeletal muscle fiber link

fatty acid beta-oxidation link ↓ DECREASED ketone body biosynthetic process link ↓ DECREASED

Downstream

Hypoketotic hypoglycemia Impaired fatty acid oxidation and ketogenesis during fasting leads to severe hypoglycemia with inadequate ketone production.

Metabolic decompensation Acute crises of energy production occur during fasting, illness, or other catabolic stress.

Lethargy Severe hypoglycemic crises can progress to reduced alertness or coma.

Hepatopathy Catabolic energy failure causes hepatic dysfunction and steatosis during decompensation.

Cardiomyopathy Cardiac muscle reliance on long-chain FAO links energy crises to cardiomyopathy.

Myopathy Skeletal muscle energy shortage during sustained demand contributes to chronic myopathy.

Rhabdomyolysis Exercise, fasting, and illness trigger skeletal muscle breakdown when fatty acid oxidation cannot meet energy demand.

Exercise intolerance Limited fatty acid-derived energy during exertion reduces exercise capacity.

Show evidence (1 reference)

PMID:32840329 SUPPORT Other

"Patients may present with rhabdomyolysis induced by exercise; fasting or illness; hepatic dysfunction, including severe hypoglycemia and hyperammonemia; and cardiomyopathy."

Identifies the stress-triggered clinical manifestations of long-chain FAO defects including LCHADD.

Toxic intermediate accumulation and oxidative stress

Impaired LCHAD activity leads to accumulation of long-chain 3-hydroxyacyl-CoA intermediates and their corresponding acylcarnitines (C16OH, C18OH, C18:1OH). These toxic intermediates induce oxidative stress, lipid peroxidation, and altered cell homeostasis, contributing to tissue damage in heart, skeletal muscle, liver, and retina.

retinal pigment epithelial cell link

response to oxidative stress link lipid oxidation link

mitochondrial inner membrane link

Downstream

RPE-specific lipid peroxidation

Free carnitine (C0) Accumulated acyl-CoA intermediates are conjugated to carnitine, contributing to secondary depletion of free carnitine.

Hypocarnitinemia Increased acylcarnitine formation and excretion contributes to the hypocarnitinemia observed in LCHADD.

Peripheral neuropathy LCHADD-specific toxic intermediate burden is linked clinically to peripheral neuropathy.

Show evidence (1 reference)

PMID:39283617 SUPPORT In Vitro

"When LCHADD-RPE are exposed to docosahexaenoic acid (DHA), they have increased oxidative stress, lipid peroxidation, decreased viability, and are rescued by antioxidant agents potentially explaining the pathologic mechanism of RPE loss in LCHADD."

Demonstrates oxidative stress and lipid peroxidation from toxic intermediate accumulation in LCHADD RPE cells.

Cardiolipin remodeling defect

The TFP alpha-subunit (HADHA) possesses monolysocardiolipin acyltransferase activity linking fatty acid oxidation to cardiolipin remodeling. HADHA/TFP mutations disrupt cardiolipin content and composition, creating a mitochondrial inner-membrane lipid abnormality distinct from the primary beta-oxidation block.

cardiolipin metabolic process link ↓ DECREASED oxidative phosphorylation link ⚠ ABNORMAL

mitochondrial inner membrane link

Downstream

Cardiolipin Abnormal TFP/HADHA function reduces cardiolipin abundance in mitochondrial membranes.

Mitochondrial bioenergetic abnormalities Cardiolipin composition changes are linked to altered mitochondrial bioenergetic parameters in TFP-deficient fibroblasts.

Show evidence (2 references)

PMID:39088276 SUPPORT In Vitro

"Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model."

Demonstrates cardiolipin remodeling defect in TFP/LCHAD-deficient fibroblasts and mouse liver mitochondria.

PMID:39088276 SUPPORT In Vitro

"TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function."

Establishes TFP role in cardiolipin remodeling beyond fatty acid oxidation.

Mitochondrial bioenergetic abnormalities

TFP-deficient patient fibroblasts show altered mitochondrial bioenergetic parameters downstream of cardiolipin and phospholipid remodeling abnormalities. This separates the respiratory/bioenergetic consequence from the upstream cardiolipin remodeling defect.

oxidative phosphorylation link ⚠ ABNORMAL

mitochondrial inner membrane link

Show evidence (1 reference)

PMID:39088276 SUPPORT In Vitro

"Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls."

Patient-derived fibroblast data support abnormal mitochondrial bioenergetic parameters in TFP deficiency.

RPE-specific lipid peroxidation

The retinal pigment epithelium (RPE) relies on fatty acid oxidation for energy. In LCHADD, RPE cells accumulate 3-hydroxyacylcarnitines and are susceptible to DHA-triggered lipid peroxidation, leading to RPE degeneration and vision loss. Exogenous HADHA gene addition rescues the biochemical and oxidative stress phenotypes.

retinal pigment epithelial cell link

fatty acid beta-oxidation link ↓ DECREASED response to oxidative stress link ↑ INCREASED

retina link

Downstream

Chorioretinopathy RPE lipid peroxidation and degeneration produce progressive LCHADD-associated chorioretinopathy.

Myopia Myopia is part of the ophthalmic phenotype observed alongside choroidal atrophy and outer retinal disruption.

Show evidence (2 references)

PMID:39283617 SUPPORT In Vitro

"LCHADD-RPE express TFP subunits and accumulate 3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones than WT-RPE."

Demonstrates impaired fatty acid oxidation and metabolite accumulation in LCHADD RPE cells.

PMID:38904639 SUPPORT Model Organism

"LCHADD RPE/sclera samples had a 5- to 7-fold increase in long-chain hydroxyacylcarnitines compared to WT, suggesting an impaired LCHAD step in long-chain FAO."

Demonstrates tissue-specific accumulation of toxic intermediates in RPE in vivo.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 1

Cardiomyopathy OCCASIONAL Cardiomyopathy (HP:0001638)

Show evidence (2 references)

PMID:38263760 SUPPORT Human Clinical

"neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%)"

Quantifies cardiomyopathy at 28% in the German NBS cohort, supporting OCCASIONAL frequency.

PMID:37644104 SUPPORT Model Organism

"LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice."

Recapitulates dilated cardiomyopathy in the knock-in mouse model.

Digestive 1

Hepatopathy FREQUENT Hepatic steatosis (HP:0001397)

Show evidence (1 reference)

PMID:10229030 SUPPORT Human Clinical

"Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia."

Confirms hepatic steatosis as a presenting feature.

Eye 2

Chorioretinopathy OCCASIONAL Chorioretinal dystrophy (HP:0001135)

Show evidence (2 references)

PMID:38595698 SUPPORT Human Clinical

"The main ophthalmic symptoms of LCHAD deficiency were choroidal atrophy, disorganization of the outer retinal layer, and myopia."

Details the specific ophthalmic features of LCHADD chorioretinopathy including choroidal atrophy.

PMID:38904639 SUPPORT Model Organism

"LCHADD mice have progressively decreased visual performance and increased RPE degeneration starting at 6 months."

Recapitulates progressive chorioretinopathy in the LCHADD mouse model.

Myopia OCCASIONAL Myopia (HP:0000545)

Show evidence (1 reference)

PMID:38595698 SUPPORT Human Clinical

"The main ophthalmic symptoms of LCHAD deficiency were choroidal atrophy, disorganization of the outer retinal layer, and myopia."

Confirms myopia as part of the ophthalmic phenotype in LCHADD.

Metabolism 1

Hypoketotic hypoglycemia VERY_FREQUENT Hypoketotic hypoglycemia (HP:0001985)

Show evidence (2 references)

PMID:10229030 SUPPORT Human Clinical

"Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia."

Directly supports hypoketotic hypoglycemia as a presenting feature of LCHADD.

PMID:37644104 SUPPORT Model Organism

"LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice."

Confirms hypoketotic state during fasting in the LCHADD mouse model.

Musculoskeletal 2

Myopathy VERY_FREQUENT Myopathy (HP:0003198)

Show evidence (1 reference)

PMID:38263760 SUPPORT Human Clinical

"neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%)"

Quantifies myopathy at 82% in the German NBS cohort, the most frequent complication.

Rhabdomyolysis FREQUENT Rhabdomyolysis (HP:0003201)

Show evidence (2 references)

PMID:10229030 SUPPORT Human Clinical

"Other manifestations are cardiomyopathy and rhabdomyolysis, which are frequent in defects of long-chain fatty acid oxidation."

Confirms rhabdomyolysis as a frequent manifestation in long-chain FAO defects.

PMID:32840329 SUPPORT Other

"Patients may present with rhabdomyolysis induced by exercise; fasting or illness"

Supports rhabdomyolysis triggered by exercise, fasting, or illness.

Nervous System 2

Peripheral neuropathy OCCASIONAL Peripheral neuropathy (HP:0009830)

Show evidence (1 reference)

PMID:10229030 SUPPORT Human Clinical

"In addition, LCHAD deficiency has specific features, namely peripheral neuropathy and chorioretinopathy."

Confirms peripheral neuropathy as a specific feature of LCHADD.

Lethargy FREQUENT Lethargy (HP:0001254)

Show evidence (1 reference)

PMID:10229030 PARTIAL Human Clinical

"Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia."

Hypoglycemic coma presentation is consistent with severe lethargy during decompensation.

Cellular 1

Hypocarnitinemia FREQUENT Decreased circulating carnitine concentration (HP:0003234)

Show evidence (1 reference)

PMID:10229030 SUPPORT Human Clinical

"Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia."

Directly supports hypocarnitinemia as a presenting feature of LCHADD.

Constitutional 1

Exercise intolerance VERY_FREQUENT Exercise intolerance (HP:0003546)

Show evidence (2 references)

PMID:32840329 PARTIAL Other

"Patients may present with rhabdomyolysis induced by exercise; fasting or illness"

Supports exercise as a trigger for muscle complications in LC-FAODs including LCHADD, consistent with exercise intolerance.

PMID:37644104 SUPPORT Model Organism

"LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice."

Demonstrates exercise intolerance in the LCHADD knock-in mouse model.

Other 1

Metabolic decompensation VERY_FREQUENT

Show evidence (1 reference)

PMID:32840329 SUPPORT Other

"Despite newborn screening, current management options leave many patients continuing to experience major clinical events, and mortality rates remain elevated."

Supports persistence of metabolic decompensation episodes despite NBS and treatment.

🧬

Genetic Associations

HADHA pathogenic variants causing LCHADD

Autosomal recessive

Show evidence (3 references)

PMID:38263760 SUPPORT Human Clinical

"Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447)."

Distinguishes LCHADD from MTPD clinical course.

PMID:39088276 SUPPORT In Vitro

"A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency."

Distinguishes isolated LCHAD from combined TFP deficiency at the genetic level.

CGGV:assertion_c8a5e15b-21f7-49cc-987c-5f3585742bbe-2018-02-12T170000.000Z SUPPORT Other

ClinGen classifies the HADHA-long chain 3-hydroxyacyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

Dietary fat restriction with MCT supplementation

Action: dietary intervention MAXO:0000088

Core dietary management involves restriction of long-chain triglycerides (LCT) to approximately 10% of total energy with supplementation of medium-chain triglycerides (MCT) at 10-25% of total energy. Essential fatty acid intake (linoleic and linolenic acid) must be maintained. Avoidance of prolonged fasting is critical.

Mechanism Target:

BYPASSES Impaired mitochondrial long-chain fatty acid beta-oxidation — Medium-chain triglycerides provide medium-chain fatty-acid substrate that bypasses reliance on the impaired long-chain beta-oxidation pathway.

Show evidence (1 reference)

PMID:39203843 SUPPORT Other

"In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 ratio), with medium-chain triglyceride supplementation at 10-25% of total energy"

Nutritional guidance supports long-chain fat restriction with MCT supplementation as bypass dietary therapy for long-chain FAO defects.

MODULATES Catabolic stress-triggered energy failure — Continuous caloric intake and long-chain fat restriction reduce lipolysis and reliance on the impaired long-chain FAO pathway.

Show evidence (1 reference)

PMID:39203843 SUPPORT Other

"Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible."

Supports dietary management as a way to reduce catabolic reliance on fatty acids.

Target Phenotypes: Hypoketotic hypoglycemia ↗ Rhabdomyolysis ↗

Show evidence (2 references)

PMID:39203843 SUPPORT Other

Specifies LCT restriction and MCT supplementation targets for long-chain FAO defects.

PMID:39203843 SUPPORT Other

Supports dietary management as the foundation of FAOD treatment.

Emergency glucose infusion for acute decompensation

Action: supportive care MAXO:0000950

Acute metabolic decompensation requires emergency IV glucose administration (10% dextrose at approximately 8 mg/kg/min) to suppress lipolysis and catabolism. Cessation of protein and fat intake and monitoring of electrolytes and creatine kinase are essential.

Mechanism Target:

BYPASSES Catabolic stress-triggered energy failure — Intravenous glucose supplies immediate carbohydrate energy and suppresses lipolysis during acute crises.

Show evidence (1 reference)

PMID:39203843 SUPPORT Other

"The main measure in emergency hospital treatment is the administration of IV glucose."

Directly supports IV glucose as emergency management for fatty acid oxidation decompensation.

Target Phenotypes: Hypoketotic hypoglycemia ↗ Lethargy ↗

Show evidence (2 references)

PMID:32840329 SUPPORT Other

"Long-chain fatty acid oxidation disorders (LC-FAODs) are rare, life-threatening, autosomal recessive genetic disorders characterized by acute crises of energy production and chronic energy deficiency."

Supports the need for emergency management of acute metabolic crises.

PMID:39203843 SUPPORT Other

"The main measure in emergency hospital treatment is the administration of IV glucose."

Directly supports IV glucose as the primary emergency intervention.

Triheptanoin (Dojolvi)

Action: nutritional supplementation MAXO:0000106

Triheptanoin is an FDA-approved odd-chain triglyceride providing anaplerotic substrate (propionyl-CoA converted to succinyl-CoA) to support TCA cycle intermediate replenishment and energy generation in long-chain fatty acid oxidation disorders. Reported to reduce decompensation frequency and hospitalizations.

Mechanism Target:

BYPASSES Catabolic stress-triggered energy failure — Triheptanoin provides anaplerotic odd-chain substrate to support energy metabolism despite impaired long-chain FAO.

Show evidence (1 reference)

PMID:32840329 SUPPORT Other

"In recent years, the use of medium, odd-chain fatty acids, such as triheptanoin, have been studied as a treatment of LC-FAODs due to its anaplerotic properties."

Supports triheptanoin as an anaplerotic bypass strategy in LC-FAODs.

Show evidence (2 references)

PMID:32840329 SUPPORT Other

"In recent years, the use of medium, odd-chain fatty acids, such as triheptanoin, have been studied as a treatment of LC-FAODs due to its anaplerotic properties."

Supports triheptanoin as an anaplerotic therapy for LC-FAODs.

PMID:39203843 SUPPORT Other

"Trihepatnoin is a new therapeutic option with a good safety and efficacy profile."

Confirms triheptanoin as a therapeutic option with favorable profile. Note "Trihepatnoin" is a typo in the original publication abstract.

Newborn screening

Action: disease screening MAXO:0000124

Expanded newborn screening using tandem mass spectrometry acylcarnitine profiling identifies affected infants presymptomatically. Screening detects elevated C16OH, C18OH, and C18:1OH. While NBS improves neonatal survival, it does not reliably prevent long-term morbidity.

Show evidence (2 references)

PMID:38263760 SUPPORT Human Clinical

"Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived"

Demonstrates improved survival with NBS but persistent morbidity.

PMID:37754774 SUPPORT Human Clinical

"The established "HADHA ratio" = (C16OH + C18OH + C18:1OH)/C0 was significantly elevated in all 54 affected individuals in comparison to the control group."

Supports acylcarnitine-based NBS biomarkers for LCHADD detection.

Carnitine supplementation

Action: carnitine supplementation MAXO:0010006

L-carnitine supplementation to address secondary carnitine deficiency and support excretion of toxic acyl-CoA intermediates as acylcarnitines. Use remains somewhat controversial but commonly employed.

Target Phenotypes: Hypocarnitinemia ↗

Show evidence (2 references)

PMID:39203843 PARTIAL Other

"The use of carnitine remains controversial and new therapeutic options are under investigation."

Acknowledges carnitine supplementation while noting it remains controversial.

PMID:10229030 SUPPORT Human Clinical

"Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia."

Supports the rationale for carnitine supplementation given hypocarnitinemia.

Ophthalmologic monitoring

Action: eye examination MAXO:0001155

Regular retinal screening for chorioretinopathy is essential for all LCHADD patients, as choroidal atrophy and pigment dispersion are early signs of retinal degeneration. European metabolic centers concur on the importance of retinopathy screening as part of long-term monitoring.

Target Phenotypes: Chorioretinopathy ↗ Myopia ↗

Show evidence (2 references)

PMID:38245779 SUPPORT Human Clinical

"The centres concurred in many aspects of long-term monitoring of LCFAOD including the frequency of clinical visits, determination of laboratory parameters, cardiac monitoring and retinopathy screening."

Confirms retinopathy screening as a consensus monitoring practice.

PMID:38595698 SUPPORT Human Clinical

"Choroidal atrophy and pigment dispersion were consistently the earliest signs of LCHAD-associated chorioretinopathy."

Supports the importance of regular ophthalmologic monitoring to detect early signs.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for affected families including discussion of autosomal recessive inheritance, recurrence risk (25% for carrier parents), carrier testing, and prenatal diagnostic opportunities.

Show evidence (1 reference)

PMID:10229030 SUPPORT Human Clinical

"Because of therapeutic and prenatal diagnostic opportunities in LCHAD deficiency, it is important to recognize this severe disorder early in its course."

Supports the importance of early diagnosis and prenatal counseling for LCHADD.

Cardiac monitoring and management

Action: supportive care MAXO:0000950

Regular cardiac monitoring with echocardiography is recommended given the 28% prevalence of cardiomyopathy. European metabolic centers include cardiac monitoring as a consensus practice in long-term follow-up of LCFAOD patients.

Target Phenotypes: Cardiomyopathy ↗

Show evidence (1 reference)

PMID:38245779 SUPPORT Human Clinical

Confirms cardiac monitoring as consensus practice in European metabolic centers.

🔬

Biochemical Markers

Long-chain 3-hydroxyacylcarnitines (C16OH, C18OH, C18:1OH) (INCREASED)

Context: Elevated long-chain 3-hydroxyacylcarnitines are the hallmark diagnostic biomarkers for LCHADD, detectable on newborn screening by tandem mass spectrometry. These reflect the enzymatic block at the LCHAD step and accumulate in blood, tissues, and RPE.

Pathograph Readouts

Readout Of Impaired mitochondrial long-chain fatty acid beta-oxidation Positive Diagnostic

Elevated C16OH, C18OH, and C18:1OH report the blocked long-chain LCHAD-dependent beta-oxidation step.

Readout Of Toxic intermediate accumulation and oxidative stress Positive Diagnostic

Elevated long-chain 3-hydroxyacylcarnitines report the accumulated toxic intermediary pool.

Show evidence (2 references)

PMID:37754774 SUPPORT Human Clinical

"The established "HADHA ratio" = (C16OH + C18OH + C18:1OH)/C0 was significantly elevated in all 54 affected individuals in comparison to the control group."

Quantifies elevation of diagnostic hydroxyacylcarnitines in all affected patients.

PMID:10229030 SUPPORT Human Clinical

"Diagnosis is suggested by 3-hydroxylated acylcarnitine species in blood and the definitive diagnosis can be made by measuring intermediates of fatty acid beta-oxidation in fibroblasts or by detecting disease causing mutations."

Supports 3-hydroxyacylcarnitines as diagnostic biomarkers.

HADHA ratio (C16OH + C18OH + C18:1OH)/C0 (INCREASED)

Context: A novel composite biomarker ratio proposed by Baydakova et al. (2023) that shows high sensitivity and specificity for LCHADD/MTP deficiency. The ratio was elevated in all 54 affected individuals tested and was not elevated in VLCAD deficiency, providing good differential diagnostic utility.

Pathograph Readouts

Readout Of Impaired mitochondrial long-chain fatty acid beta-oxidation Positive Diagnostic

The composite HADHA ratio reports elevation of LCHADD-associated 3-hydroxyacylcarnitines relative to free carnitine.

Show evidence (1 reference)

PMID:37754774 SUPPORT Human Clinical

"As VLCAD-deficient patients did not show increased "HADHA ratio", the results emphasized the high specificity of this new ratio."

Demonstrates specificity of the HADHA ratio for LCHADD vs VLCAD.

Free carnitine (C0) (DECREASED)

Context: Secondary carnitine depletion due to increased conjugation and urinary excretion of long-chain acylcarnitines.

Pathograph Readouts

Readout Of Toxic intermediate accumulation and oxidative stress Negative Diagnostic

Lower free carnitine reflects secondary carnitine depletion as accumulated long-chain intermediates are converted to acylcarnitines.

Readout Of Hypocarnitinemia Negative Monitoring

Lower C0 directly tracks the clinical biochemical phenotype of hypocarnitinemia.

Show evidence (1 reference)

PMID:10229030 SUPPORT Human Clinical

"Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia."

Directly supports reduced free carnitine in LCHADD.

Ketone bodies (DECREASED)

Context: Inappropriately low ketone body production during fasting, reflecting impaired hepatic ketogenesis from blocked fatty acid oxidation. Also demonstrated in LCHADD RPE cells in vitro.

Pathograph Readouts

Readout Of Impaired mitochondrial long-chain fatty acid beta-oxidation Negative Diagnostic

Lower ketone production during fasting reports impaired fatty acid oxidation-driven ketogenesis.

Readout Of Catabolic stress-triggered energy failure Negative Monitoring

Lower ketones during fasting or illness track inadequate alternative-fuel generation during catabolic stress.

Show evidence (2 references)

PMID:39283617 SUPPORT In Vitro

"LCHADD-RPE express TFP subunits and accumulate 3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones than WT-RPE."

Demonstrates reduced ketone production in LCHADD cells.

PMID:37644104 SUPPORT Model Organism

"LCHADD mice exhibit lower ketones with fasting"

Confirms hypoketotic phenotype in the LCHADD mouse model.

Cardiolipin (DECREASED)

Context: Cardiolipin reduction in mitochondrial membranes, with concurrent increase in monolysocardiolipins, reflecting impaired cardiolipin remodeling by the TFP alpha-subunit.

Pathograph Readouts

Readout Of Cardiolipin remodeling defect Negative Diagnostic

Reduced cardiolipin reports the TFP/HADHA-associated mitochondrial inner-membrane remodeling defect.

Correlates With Mitochondrial bioenergetic abnormalities Negative Diagnostic

Lower cardiolipin is associated with abnormal mitochondrial bioenergetic parameters in TFP-deficient cells.

Show evidence (1 reference)

PMID:39088276 SUPPORT In Vitro

Demonstrates universal cardiolipin reduction in TFP-deficient cells and mouse liver.

{ }

Source YAML

click to show

name: Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency
category: Mendelian
creation_date: '2025-06-12T20:16:27Z'
updated_date: '2026-05-20T08:02:14Z'
synonyms:
- LCHADD
- LCHAD deficiency
- Isolated LCHAD deficiency
- Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
description: 'Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an autosomal recessive disorder of mitochondrial long-chain fatty acid beta-oxidation caused by biallelic pathogenic variants in HADHA, most commonly the c.1528G>C (p.Glu510Gln) founder mutation. LCHADD selectively impairs the LCHAD catalytic activity within the mitochondrial trifunctional protein (MTP/TFP), leading to energy failure during fasting or physiologic stress and accumulation of toxic long-chain 3-hydroxyacyl intermediates. Clinical manifestations include hypoketotic hypoglycemia, cardiomyopathy, rhabdomyolysis, hepatopathy, peripheral neuropathy, and a distinctive progressive chorioretinopathy not seen in other fatty acid oxidation disorders. Despite improved neonatal survival through newborn screening, long-term morbidity remains substantial, with myopathy in 82%, metabolic decompensations in 80%, and cardiomyopathy in 28% of screened individuals.

  '
disease_term:
  preferred_term: long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
  term:
    id: MONDO:0012173
    label: long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
parents:
- Fatty Acid Oxidation Disorder
- Inborn Error of Metabolism
prevalence:
- population: Central and Northern European
  percentage: 1 in 118,336 live births (Poland); carrier frequency 1:240 (Finland)
  notes: 'LCHADD is rare with birth prevalence varying by population. Predominantly observed in Central and Northern European populations due to the founder c.1528G>C mutation.

    '
  evidence:
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the frequency of the G1528C mutation in Finland revealed carrier \nfrequency of 1:240."
    explanation: Provides carrier frequency data in Finland.
  - reference: PMID:38595698
    reference_title: "Ophthalmic Symptoms of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: A Report of Three Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, \ntypically inherited as a recessive trait, is a genetic condition predominantly \nobserved in Central and Eastern Europe, with birth prevalence in Poland \namounting to 1/118,336."
    explanation: Provides birth prevalence estimate for Poland.
progression:
- phase: Neonatal/Infantile onset
  notes: 'Presents in infancy with acute metabolic decompensation including hypoketotic hypoglycemia, hepatic steatosis, and hypocarnitinemia. Neonatal decompensations occur in 28% of screened individuals.

    '
  evidence:
  - reference: PMID:38263760
    reference_title: "Neurological outcome in long-chain hydroxy fatty acid oxidation disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neonatal decompensations (28%), \nsymptomatic disease course (94%)"
    explanation: Quantifies early disease onset despite newborn screening.
- phase: Chronic progressive course
  notes: 'Despite improved neonatal survival through NBS, 94% of screened individuals develop symptomatic disease. Long-term complications include myopathy (82%), metabolic decompensations (80%), cardiomyopathy (28%), hepatopathy (32%), retinopathy (17%), and neuropathy (22%). Hospitalization rates up to 2.4 per year. Dietary adherence decreases with age (75% in year 1 to 12% by age 10).

    '
  evidence:
  - reference: PMID:38263760
    reference_title: "Neurological outcome in long-chain hydroxy fatty acid oxidation disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While NBS and early treatment result in improved (neonatal) \nsurvival, they cannot reliably prevent long-term morbidity in screened \nindividuals with LCHAD/MTP deficiency, highlighting the urgent need of better \ntherapeutic strategies and the development of disease course-altering treatment."
    explanation: Confirms persistent long-term morbidity despite NBS.
pathophysiology:
- name: HADHA molecular function deficiency within mitochondrial trifunctional protein
  description: 'Biallelic pathogenic variants in HADHA reduce long-chain 3-hydroxyacyl-CoA dehydrogenase catalytic activity within mitochondrial trifunctional protein.

    '
  genes:
  - preferred_term: HADHA
    term:
      id: hgnc:4801
      label: HADHA
  molecular_functions:
  - preferred_term: long-chain 3-hydroxyacyl-CoA dehydrogenase activity
    term:
      id: GO:0003857
      label: (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:32840329
    reference_title: "Long-chain fatty acid oxidation disorders and current management strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LC-FAODs are caused by mutations in nuclear genes encoding mitochondrial \nenzymes involved in the conversion of dietary long-chain fatty acids (LCFAs) \ninto energy during times of fasting and physiologic stress."
    explanation: Supports molecular dysfunction of mitochondrial FAO enzymes including HADHA in LCHADD.
  downstream:
  - target: Impaired mitochondrial long-chain fatty acid beta-oxidation
    description: Reduced HADHA catalytic activity blocks the LCHAD step of long-chain FAO.
- name: Impaired mitochondrial long-chain fatty acid beta-oxidation
  description: 'Deficiency of LCHAD catalytic activity blocks the third step of long-chain fatty acid beta-oxidation, reducing acetyl-CoA and reducing equivalent supply for ketogenesis and oxidative phosphorylation. This causes energy failure during fasting, illness, or prolonged exercise when tissues depend on fatty acid oxidation for fuel.

    '
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  - preferred_term: ketone body biosynthetic process
    term:
      id: GO:0046951
      label: ketone body biosynthetic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: ketone body
    term:
      id: CHEBI:73693
      label: ketone body
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:32840329
    reference_title: "Long-chain fatty acid oxidation disorders and current management strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LC-FAODs are caused by mutations in nuclear genes encoding mitochondrial \nenzymes involved in the conversion of dietary long-chain fatty acids (LCFAs) \ninto energy during times of fasting and physiologic stress."
    explanation: Supports impaired long-chain FAO and stress-related energy failure downstream of HADHA dysfunction.
  downstream:
  - target: Toxic intermediate accumulation and oxidative stress
  - target: Cardiolipin remodeling defect
  - target: Catabolic stress-triggered energy failure
    description: During fasting, illness, or exertion, impaired long-chain FAO limits energy production and ketogenesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32840329
      reference_title: "Long-chain fatty acid oxidation disorders and current management strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "LC-FAODs are caused by mutations in nuclear genes encoding mitochondrial \nenzymes involved in the conversion of dietary long-chain fatty acids (LCFAs) \ninto energy during times of fasting and physiologic stress."
      explanation: Clinical review evidence links long-chain FAO enzyme defects to energy failure during fasting and physiologic stress.
  - target: Long-chain 3-hydroxyacylcarnitines (C16OH, C18OH, C18:1OH)
    description: The LCHAD enzymatic block produces elevated long-chain 3-hydroxyacylcarnitines used for diagnosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10229030
      reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diagnosis is suggested by 3-hydroxylated acylcarnitine species in blood and the \ndefinitive diagnosis can be made by measuring intermediates of fatty acid \nbeta-oxidation in fibroblasts or by detecting disease causing mutations."
      explanation: Directly supports 3-hydroxylated acylcarnitines as the biochemical consequence of the beta-oxidation defect.
  - target: HADHA ratio (C16OH + C18OH + C18:1OH)/C0
    description: The diagnostic HADHA ratio aggregates the elevated C16OH, C18OH, and C18:1OH species normalized to free carnitine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37754774
      reference_title: "New Acylcarnitine Ratio as a Reliable Indicator of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The established \"HADHA ratio\" = (C16OH + \nC18OH + C18:1OH)/C0 was significantly elevated in all 54 affected individuals in \ncomparison to the control group."
      explanation: Patient biomarker data support the HADHA ratio as a downstream biochemical readout.
  - target: Ketone bodies
    description: Impaired hepatic long-chain FAO limits ketogenesis during fasting or physiologic stress.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37644104
      reference_title: "A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: LCHADD mice exhibit lower ketones with fasting
      explanation: Knock-in mouse data support reduced ketogenesis downstream of LCHAD deficiency during fasting.
- name: Catabolic stress-triggered energy failure
  description: 'Fasting, febrile illness, exercise, and other physiologic stressors increase dependence on long-chain fatty acid oxidation. Because LCHADD cannot efficiently use long-chain fatty acids for energy, catabolic stress produces acute energy crises with hypoketotic hypoglycemia, hepatic dysfunction, cardiomyopathy, exercise intolerance, and rhabdomyolysis.

    '
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  - preferred_term: ketone body biosynthetic process
    term:
      id: GO:0046951
      label: ketone body biosynthetic process
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:32840329
    reference_title: "Long-chain fatty acid oxidation disorders and current management strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients may present with \nrhabdomyolysis induced by exercise; fasting or illness; hepatic dysfunction, \nincluding severe hypoglycemia and hyperammonemia; and cardiomyopathy."
    explanation: Identifies the stress-triggered clinical manifestations of long-chain FAO defects including LCHADD.
  downstream:
  - target: Hypoketotic hypoglycemia
    description: Impaired fatty acid oxidation and ketogenesis during fasting leads to severe hypoglycemia with inadequate ketone production.
    causal_link_type: DIRECT
  - target: Metabolic decompensation
    description: Acute crises of energy production occur during fasting, illness, or other catabolic stress.
    causal_link_type: DIRECT
  - target: Lethargy
    description: Severe hypoglycemic crises can progress to reduced alertness or coma.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hypoketotic hypoglycemia
  - target: Hepatopathy
    description: Catabolic energy failure causes hepatic dysfunction and steatosis during decompensation.
    causal_link_type: DIRECT
  - target: Cardiomyopathy
    description: Cardiac muscle reliance on long-chain FAO links energy crises to cardiomyopathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Myopathy
    description: Skeletal muscle energy shortage during sustained demand contributes to chronic myopathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Rhabdomyolysis
    description: Exercise, fasting, and illness trigger skeletal muscle breakdown when fatty acid oxidation cannot meet energy demand.
    causal_link_type: DIRECT
  - target: Exercise intolerance
    description: Limited fatty acid-derived energy during exertion reduces exercise capacity.
    causal_link_type: DIRECT
- name: Toxic intermediate accumulation and oxidative stress
  description: 'Impaired LCHAD activity leads to accumulation of long-chain 3-hydroxyacyl-CoA intermediates and their corresponding acylcarnitines (C16OH, C18OH, C18:1OH). These toxic intermediates induce oxidative stress, lipid peroxidation, and altered cell homeostasis, contributing to tissue damage in heart, skeletal muscle, liver, and retina.

    '
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: lipid oxidation
    term:
      id: GO:0034440
      label: lipid oxidation
  chemical_entities:
  - preferred_term: C16OH 3-hydroxyacylcarnitine
    term:
      id: CHEBI:73070
      label: 3-hydroxyhexadecanoylcarnitine
    modifier: INCREASED
  - preferred_term: C18OH 3-hydroxyacylcarnitine
    term:
      id: CHEBI:73077
      label: 3-hydroxyoctadecanoylcarnitine
    modifier: INCREASED
  - preferred_term: C18:1OH 3-hydroxyacylcarnitine
    term:
      id: CHEBI:73076
      label: (9Z)-3-hydroxyoctadecenoylcarnitine
    modifier: INCREASED
  - preferred_term: free carnitine
    term:
      id: CHEBI:17126
      label: carnitine
    modifier: DECREASED
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  locations:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  evidence:
  - reference: PMID:39283617
    reference_title: "iPSC-Derived LCHADD Retinal Pigment Epithelial Cells Are Susceptible to Lipid Peroxidation and Rescued by Transfection of a Wildtype AAV-HADHA Vector."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "When LCHADD-RPE are exposed to docosahexaenoic acid (DHA), they \nhave increased oxidative stress, lipid peroxidation, decreased viability, and \nare rescued by antioxidant agents potentially explaining the pathologic \nmechanism of RPE loss in LCHADD."
    explanation: Demonstrates oxidative stress and lipid peroxidation from toxic intermediate accumulation in LCHADD RPE cells.
  downstream:
  - target: RPE-specific lipid peroxidation
  - target: Free carnitine (C0)
    description: Accumulated acyl-CoA intermediates are conjugated to carnitine, contributing to secondary depletion of free carnitine.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Hypocarnitinemia
    description: Increased acylcarnitine formation and excretion contributes to the hypocarnitinemia observed in LCHADD.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Peripheral neuropathy
    description: LCHADD-specific toxic intermediate burden is linked clinically to peripheral neuropathy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10229030
      reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "In addition, LCHAD deficiency has specific features, \nnamely peripheral neuropathy and chorioretinopathy."
      explanation: The clinical association supports connecting peripheral neuropathy to the LCHADD-specific toxic-metabolite branch, while the exact intermediate mechanism remains unresolved.
- name: Cardiolipin remodeling defect
  description: 'The TFP alpha-subunit (HADHA) possesses monolysocardiolipin acyltransferase activity linking fatty acid oxidation to cardiolipin remodeling. HADHA/TFP mutations disrupt cardiolipin content and composition, creating a mitochondrial inner-membrane lipid abnormality distinct from the primary beta-oxidation block.

    '
  biological_processes:
  - preferred_term: cardiolipin metabolic process
    term:
      id: GO:0032048
      label: cardiolipin metabolic process
    modifier: DECREASED
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: ABNORMAL
  chemical_entities:
  - preferred_term: cardiolipin
    term:
      id: CHEBI:28494
      label: cardiolipin
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  evidence:
  - reference: PMID:39088276
    reference_title: "Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although CL reduction was \nuniversally identified, a simultaneous increase in monolysocardiolipins was \ndiscrepant among cells. A similar profile was seen in liver mitochondria \nisolates from a TFP-deficient mouse model."
    explanation: Demonstrates cardiolipin remodeling defect in TFP/LCHAD-deficient fibroblasts and mouse liver mitochondria.
  - reference: PMID:39088276
    reference_title: "Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TFP \nalso catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid \ncritical to mitochondrial membrane stability and function."
    explanation: Establishes TFP role in cardiolipin remodeling beyond fatty acid oxidation.
  downstream:
  - target: Cardiolipin
    description: Abnormal TFP/HADHA function reduces cardiolipin abundance in mitochondrial membranes.
    causal_link_type: DIRECT
  - target: Mitochondrial bioenergetic abnormalities
    description: Cardiolipin composition changes are linked to altered mitochondrial bioenergetic parameters in TFP-deficient fibroblasts.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Mitochondrial bioenergetic abnormalities
  description: 'TFP-deficient patient fibroblasts show altered mitochondrial bioenergetic parameters downstream of cardiolipin and phospholipid remodeling abnormalities. This separates the respiratory/bioenergetic consequence from the upstream cardiolipin remodeling defect.

    '
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: ABNORMAL
  locations:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  evidence:
  - reference: PMID:39088276
    reference_title: "Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Abnormalities in these parameters varied \nextensively among different fibroblasts, and some cells were able to maintain \nbasal oxygen consumption rates similar to controls."
    explanation: Patient-derived fibroblast data support abnormal mitochondrial bioenergetic parameters in TFP deficiency.
- name: RPE-specific lipid peroxidation
  description: 'The retinal pigment epithelium (RPE) relies on fatty acid oxidation for energy. In LCHADD, RPE cells accumulate 3-hydroxyacylcarnitines and are susceptible to DHA-triggered lipid peroxidation, leading to RPE degeneration and vision loss. Exogenous HADHA gene addition rescues the biochemical and oxidative stress phenotypes.

    '
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  chemical_entities:
  - preferred_term: C16OH 3-hydroxyacylcarnitine
    term:
      id: CHEBI:73070
      label: 3-hydroxyhexadecanoylcarnitine
    modifier: INCREASED
  - preferred_term: C18OH 3-hydroxyacylcarnitine
    term:
      id: CHEBI:73077
      label: 3-hydroxyoctadecanoylcarnitine
    modifier: INCREASED
  - preferred_term: C18:1OH 3-hydroxyacylcarnitine
    term:
      id: CHEBI:73076
      label: (9Z)-3-hydroxyoctadecenoylcarnitine
    modifier: INCREASED
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  evidence:
  - reference: PMID:39283617
    reference_title: "iPSC-Derived LCHADD Retinal Pigment Epithelial Cells Are Susceptible to Lipid Peroxidation and Rescued by Transfection of a Wildtype AAV-HADHA Vector."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "LCHADD-RPE express TFP subunits and accumulate \n3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones \nthan WT-RPE."
    explanation: Demonstrates impaired fatty acid oxidation and metabolite accumulation in LCHADD RPE cells.
  - reference: PMID:38904639
    reference_title: "The LCHADD Mouse Model Recapitulates Early-Stage Chorioretinopathy in LCHADD Patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LCHADD RPE/sclera samples had a 5- to 7-fold increase in long-chain \nhydroxyacylcarnitines compared to WT, suggesting an impaired LCHAD step in \nlong-chain FAO."
    explanation: Demonstrates tissue-specific accumulation of toxic intermediates in RPE in vivo.
  downstream:
  - target: Chorioretinopathy
    description: RPE lipid peroxidation and degeneration produce progressive LCHADD-associated chorioretinopathy.
    causal_link_type: DIRECT
  - target: Myopia
    description: Myopia is part of the ophthalmic phenotype observed alongside choroidal atrophy and outer retinal disruption.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Hypoketotic hypoglycemia
  frequency: VERY_FREQUENT
  description: 'Fasting intolerance with low ketone production and hypoglycemia, reflecting impaired fatty acid oxidation and ketogenesis during catabolic states.

    '
  phenotype_term:
    preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  evidence:
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Like \nseveral beta-oxidation defects, it presents during infancy with hypoglycemic \ncoma, hepatic steatosis, and hypocarnitinemia."
    explanation: Directly supports hypoketotic hypoglycemia as a presenting feature of LCHADD.
  - reference: PMID:37644104
    reference_title: "A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LCHADD mice exhibit lower ketones with fasting, exhaust earlier during \ntreadmill exercise and develop a dilated cardiomyopathy compared to WT mice."
    explanation: Confirms hypoketotic state during fasting in the LCHADD mouse model.
- name: Cardiomyopathy
  frequency: OCCASIONAL
  description: 'Cardiac involvement with cardiomyopathy, particularly dilated cardiomyopathy, occurring in approximately 28% of screened individuals. Reflects cardiac dependence on fatty acid oxidation for energy.

    '
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:38263760
    reference_title: "Neurological outcome in long-chain hydroxy fatty acid oxidation disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neonatal decompensations (28%), \nsymptomatic disease course (94%), later metabolic decompensations (80%), \ncardiomyopathy (28%), myopathy (82%)"
    explanation: Quantifies cardiomyopathy at 28% in the German NBS cohort, supporting OCCASIONAL frequency.
  - reference: PMID:37644104
    reference_title: "A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LCHADD mice exhibit lower ketones with fasting, exhaust earlier during \ntreadmill exercise and develop a dilated cardiomyopathy compared to WT mice."
    explanation: Recapitulates dilated cardiomyopathy in the knock-in mouse model.
- name: Myopathy
  frequency: VERY_FREQUENT
  description: 'Skeletal myopathy is the most common long-term complication, occurring in 82% of screened individuals. Manifests as exercise intolerance and recurrent rhabdomyolysis triggered by fasting, illness, or exertion.

    '
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:38263760
    reference_title: "Neurological outcome in long-chain hydroxy fatty acid oxidation disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neonatal decompensations (28%), \nsymptomatic disease course (94%), later metabolic decompensations (80%), \ncardiomyopathy (28%), myopathy (82%)"
    explanation: Quantifies myopathy at 82% in the German NBS cohort, the most frequent complication.
- name: Rhabdomyolysis
  frequency: FREQUENT
  description: 'Stress-induced skeletal muscle breakdown with elevated creatine kinase, triggered by fasting, febrile illness, or prolonged exercise.

    '
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other manifestations are \ncardiomyopathy and rhabdomyolysis, which are frequent in defects of long-chain \nfatty acid oxidation."
    explanation: Confirms rhabdomyolysis as a frequent manifestation in long-chain FAO defects.
  - reference: PMID:32840329
    reference_title: "Long-chain fatty acid oxidation disorders and current management strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients may present with \nrhabdomyolysis induced by exercise; fasting or illness"
    explanation: Supports rhabdomyolysis triggered by exercise, fasting, or illness.
- name: Hepatopathy
  frequency: FREQUENT
  description: 'Hepatic dysfunction including hepatic steatosis during metabolic decompensation, occurring in approximately 32% of screened individuals.

    '
  phenotype_term:
    preferred_term: Hepatic steatosis
    term:
      id: HP:0001397
      label: Hepatic steatosis
  evidence:
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Like \nseveral beta-oxidation defects, it presents during infancy with hypoglycemic \ncoma, hepatic steatosis, and hypocarnitinemia."
    explanation: Confirms hepatic steatosis as a presenting feature.
- name: Chorioretinopathy
  frequency: OCCASIONAL
  description: 'Progressive chorioretinopathy unique to LCHADD and not observed in other fatty acid oxidation disorders. Involves choroidal atrophy, outer retinal layer disruption, and pigment dispersion. Observed in 17% of screened individuals and linked to RPE dysfunction and lipid peroxidation.

    '
  phenotype_term:
    preferred_term: Chorioretinal dystrophy
    term:
      id: HP:0001135
      label: Chorioretinal dystrophy
  evidence:
  - reference: PMID:38595698
    reference_title: "Ophthalmic Symptoms of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: A Report of Three Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main ophthalmic symptoms of LCHAD deficiency were choroidal \natrophy, disorganization of the outer retinal layer, and myopia."
    explanation: Details the specific ophthalmic features of LCHADD chorioretinopathy including choroidal atrophy.
  - reference: PMID:38904639
    reference_title: "The LCHADD Mouse Model Recapitulates Early-Stage Chorioretinopathy in LCHADD Patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LCHADD mice have progressively decreased visual performance and \nincreased RPE degeneration starting at 6 months."
    explanation: Recapitulates progressive chorioretinopathy in the LCHADD mouse model.
- name: Peripheral neuropathy
  frequency: OCCASIONAL
  description: 'Chronic peripheral neuropathy is a recognized long-term complication, occurring in 22% of screened individuals. Onset is later in isolated LCHADD (median 11.4 years) compared to combined MTP deficiency (median 3.9 years).

    '
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, LCHAD deficiency has specific features, \nnamely peripheral neuropathy and chorioretinopathy."
    explanation: Confirms peripheral neuropathy as a specific feature of LCHADD.
- name: Metabolic decompensation
  frequency: VERY_FREQUENT
  description: 'Recurrent episodes of metabolic decompensation triggered by fasting, febrile illness, or physiologic stress, occurring in 80% of screened individuals. Presents with lethargy, vomiting, and hypoglycemia.

    '
  evidence:
  - reference: PMID:32840329
    reference_title: "Long-chain fatty acid oxidation disorders and current management strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Despite newborn \nscreening, current management options leave many patients continuing to \nexperience major clinical events, and mortality rates remain elevated."
    explanation: Supports persistence of metabolic decompensation episodes despite NBS and treatment.
- name: Lethargy
  frequency: FREQUENT
  description: 'Decreased alertness and lethargy during episodes of acute metabolic decompensation.

    '
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Like \nseveral beta-oxidation defects, it presents during infancy with hypoglycemic \ncoma, hepatic steatosis, and hypocarnitinemia."
    explanation: Hypoglycemic coma presentation is consistent with severe lethargy during decompensation.
- name: Hypocarnitinemia
  frequency: FREQUENT
  description: 'Secondary carnitine deficiency due to increased carnitine conjugation and excretion of accumulated long-chain intermediates.

    '
  phenotype_term:
    preferred_term: Decreased circulating carnitine concentration
    term:
      id: HP:0003234
      label: Decreased circulating carnitine concentration
  evidence:
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Like \nseveral beta-oxidation defects, it presents during infancy with hypoglycemic \ncoma, hepatic steatosis, and hypocarnitinemia."
    explanation: Directly supports hypocarnitinemia as a presenting feature of LCHADD.
- name: Exercise intolerance
  frequency: VERY_FREQUENT
  description: 'Reduced exercise capacity due to impaired muscle fatty acid oxidation and energy generation.

    '
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:32840329
    reference_title: "Long-chain fatty acid oxidation disorders and current management strategies."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Patients may present with \nrhabdomyolysis induced by exercise; fasting or illness"
    explanation: Supports exercise as a trigger for muscle complications in LC-FAODs including LCHADD, consistent with exercise intolerance.
  - reference: PMID:37644104
    reference_title: "A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LCHADD mice exhibit lower ketones with fasting, exhaust earlier during \ntreadmill exercise and develop a dilated cardiomyopathy compared to WT mice."
    explanation: Demonstrates exercise intolerance in the LCHADD knock-in mouse model.
- name: Myopia
  frequency: OCCASIONAL
  description: 'Progressive shortsightedness observed in LCHADD patients as part of the ophthalmic spectrum.

    '
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:38595698
    reference_title: "Ophthalmic Symptoms of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: A Report of Three Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main ophthalmic symptoms of LCHAD deficiency were choroidal \natrophy, disorganization of the outer retinal layer, and myopia."
    explanation: Confirms myopia as part of the ophthalmic phenotype in LCHADD.
biochemical:
- name: Long-chain 3-hydroxyacylcarnitines (C16OH, C18OH, C18:1OH)
  presence: INCREASED
  context: 'Elevated long-chain 3-hydroxyacylcarnitines are the hallmark diagnostic biomarkers for LCHADD, detectable on newborn screening by tandem mass spectrometry. These reflect the enzymatic block at the LCHAD step and accumulate in blood, tissues, and RPE.

    '
  readouts:
  - target: Impaired mitochondrial long-chain fatty acid beta-oxidation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated C16OH, C18OH, and C18:1OH report the blocked long-chain LCHAD-dependent beta-oxidation step.
  - target: Toxic intermediate accumulation and oxidative stress
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated long-chain 3-hydroxyacylcarnitines report the accumulated toxic intermediary pool.
  evidence:
  - reference: PMID:37754774
    reference_title: "New Acylcarnitine Ratio as a Reliable Indicator of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The established \"HADHA ratio\" = (C16OH + \nC18OH + C18:1OH)/C0 was significantly elevated in all 54 affected individuals in \ncomparison to the control group."
    explanation: Quantifies elevation of diagnostic hydroxyacylcarnitines in all affected patients.
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is suggested by 3-hydroxylated acylcarnitine species in blood and the \ndefinitive diagnosis can be made by measuring intermediates of fatty acid \nbeta-oxidation in fibroblasts or by detecting disease causing mutations."
    explanation: Supports 3-hydroxyacylcarnitines as diagnostic biomarkers.
- name: HADHA ratio (C16OH + C18OH + C18:1OH)/C0
  presence: INCREASED
  context: 'A novel composite biomarker ratio proposed by Baydakova et al. (2023) that shows high sensitivity and specificity for LCHADD/MTP deficiency. The ratio was elevated in all 54 affected individuals tested and was not elevated in VLCAD deficiency, providing good differential diagnostic utility.

    '
  readouts:
  - target: Impaired mitochondrial long-chain fatty acid beta-oxidation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: The composite HADHA ratio reports elevation of LCHADD-associated 3-hydroxyacylcarnitines relative to free carnitine.
  evidence:
  - reference: PMID:37754774
    reference_title: "New Acylcarnitine Ratio as a Reliable Indicator of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As VLCAD-deficient patients did not show \nincreased \"HADHA ratio\", the results emphasized the high specificity of this new \nratio."
    explanation: Demonstrates specificity of the HADHA ratio for LCHADD vs VLCAD.
- name: Free carnitine (C0)
  presence: DECREASED
  context: 'Secondary carnitine depletion due to increased conjugation and urinary excretion of long-chain acylcarnitines.

    '
  biomarker_term:
    preferred_term: carnitine
    term:
      id: CHEBI:17126
      label: carnitine
  readouts:
  - target: Toxic intermediate accumulation and oxidative stress
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower free carnitine reflects secondary carnitine depletion as accumulated long-chain intermediates are converted to acylcarnitines.
  - target: Hypocarnitinemia
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: MONITORING
    interpretation: Lower C0 directly tracks the clinical biochemical phenotype of hypocarnitinemia.
  evidence:
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Like \nseveral beta-oxidation defects, it presents during infancy with hypoglycemic \ncoma, hepatic steatosis, and hypocarnitinemia."
    explanation: Directly supports reduced free carnitine in LCHADD.
- name: Ketone bodies
  presence: DECREASED
  context: 'Inappropriately low ketone body production during fasting, reflecting impaired hepatic ketogenesis from blocked fatty acid oxidation. Also demonstrated in LCHADD RPE cells in vitro.

    '
  biomarker_term:
    preferred_term: ketone body
    term:
      id: CHEBI:73693
      label: ketone body
  readouts:
  - target: Impaired mitochondrial long-chain fatty acid beta-oxidation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower ketone production during fasting reports impaired fatty acid oxidation-driven ketogenesis.
  - target: Catabolic stress-triggered energy failure
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: MONITORING
    interpretation: Lower ketones during fasting or illness track inadequate alternative-fuel generation during catabolic stress.
  evidence:
  - reference: PMID:39283617
    reference_title: "iPSC-Derived LCHADD Retinal Pigment Epithelial Cells Are Susceptible to Lipid Peroxidation and Rescued by Transfection of a Wildtype AAV-HADHA Vector."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "LCHADD-RPE express TFP subunits and accumulate \n3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones \nthan WT-RPE."
    explanation: Demonstrates reduced ketone production in LCHADD cells.
  - reference: PMID:37644104
    reference_title: "A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: LCHADD mice exhibit lower ketones with fasting
    explanation: Confirms hypoketotic phenotype in the LCHADD mouse model.
- name: Cardiolipin
  presence: DECREASED
  context: 'Cardiolipin reduction in mitochondrial membranes, with concurrent increase in monolysocardiolipins, reflecting impaired cardiolipin remodeling by the TFP alpha-subunit.

    '
  biomarker_term:
    preferred_term: cardiolipin
    term:
      id: CHEBI:28494
      label: cardiolipin
  readouts:
  - target: Cardiolipin remodeling defect
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced cardiolipin reports the TFP/HADHA-associated mitochondrial inner-membrane remodeling defect.
  - target: Mitochondrial bioenergetic abnormalities
    relationship: CORRELATES_WITH
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower cardiolipin is associated with abnormal mitochondrial bioenergetic parameters in TFP-deficient cells.
  evidence:
  - reference: PMID:39088276
    reference_title: "Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although CL reduction was \nuniversally identified, a simultaneous increase in monolysocardiolipins was \ndiscrepant among cells. A similar profile was seen in liver mitochondria \nisolates from a TFP-deficient mouse model."
    explanation: Demonstrates universal cardiolipin reduction in TFP-deficient cells and mouse liver.
genetic:
- name: HADHA pathogenic variants causing LCHADD
  gene_term:
    preferred_term: HADHA
    term:
      id: hgnc:4801
      label: HADHA
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:10229030
      reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the vast majority of patients, LCHAD \ndeficiency is caused by a common autosomal recessive mutation G1528C."
      explanation: Directly supports autosomal recessive inheritance pattern.
  variants:
  - name: HADHA c.1528G>C (p.Glu510Gln)
    description: 'The most common pathogenic variant in LCHADD, a founder mutation affecting the LCHAD catalytic site. This variant selectively impairs LCHAD activity while relatively preserving the other two TFP enzymatic functions (enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase). Carrier frequency in Finland is 1:240.

      '
    evidence:
    - reference: PMID:10229030
      reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the vast majority of patients, LCHAD \ndeficiency is caused by a common autosomal recessive mutation G1528C."
      explanation: Confirms c.1528G>C as the predominant mutation.
    - reference: PMID:10229030
      reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Analysis of the frequency of the G1528C mutation in Finland revealed carrier \nfrequency of 1:240."
      explanation: Quantifies carrier frequency in the Finnish population.
  features: 'LCHADD is caused by biallelic pathogenic variants in HADHA, which encodes the alpha-subunit of the mitochondrial trifunctional protein. The common c.1528G>C (p.Glu510Gln) founder mutation selectively reduces LCHAD catalytic activity. Other HADHA or HADHB variants that reduce multiple TFP enzyme activities cause the broader phenotype of mitochondrial trifunctional protein deficiency (MTPD), which has a similar but often more severe clinical course including earlier neuropathy onset.

    '
  evidence:
  - reference: PMID:38263760
    reference_title: "Neurological outcome in long-chain hydroxy fatty acid oxidation disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease courses in screened individuals with LCHAD and MTP \ndeficiency were similar except for neuropathy, occurring earlier in individuals \nwith MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447)."
    explanation: Distinguishes LCHADD from MTPD clinical course.
  - reference: PMID:39088276
    reference_title: "Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A single common mutation, HADHA c.1528G>C \n(p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency."
    explanation: Distinguishes isolated LCHAD from combined TFP deficiency at the genetic level.
  - reference: CGGV:assertion_c8a5e15b-21f7-49cc-987c-5f3585742bbe-2018-02-12T170000.000Z
    reference_title: "HADHA / long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HADHA | HGNC:4801 | long chain 3-hydroxyacyl-CoA dehydrogenase deficiency | MONDO:0012173 | AR | Definitive"
    explanation: ClinGen classifies the HADHA-long chain 3-hydroxyacyl-CoA dehydrogenase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Dietary fat restriction with MCT supplementation
  description: 'Core dietary management involves restriction of long-chain triglycerides (LCT) to approximately 10% of total energy with supplementation of medium-chain triglycerides (MCT) at 10-25% of total energy. Essential fatty acid intake (linoleic and linolenic acid) must be maintained. Avoidance of prolonged fasting is critical.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_phenotypes:
  - preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  target_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid beta-oxidation
    treatment_effect: BYPASSES
    description: Medium-chain triglycerides provide medium-chain fatty-acid substrate that bypasses reliance on the impaired long-chain beta-oxidation pathway.
    evidence:
    - reference: PMID:39203843
      reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "In long-chain \ndeficits, long-chain triglyceride restriction should be 10% of total energy, \nwith linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 \nratio), with medium-chain triglyceride supplementation at 10-25% of total energy"
      explanation: Nutritional guidance supports long-chain fat restriction with MCT supplementation as bypass dietary therapy for long-chain FAO defects.
  - target: Catabolic stress-triggered energy failure
    treatment_effect: MODULATES
    description: Continuous caloric intake and long-chain fat restriction reduce lipolysis and reliance on the impaired long-chain FAO pathway.
    evidence:
    - reference: PMID:39203843
      reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Treatment of fatty acid oxidation disorders is based on dietary, pharmacological \nand metabolic decompensation measures. It is essential to provide the patient \nwith sufficient glucose to prevent lipolysis and to avoid the use of fatty acids \nas fuel as far as possible."
      explanation: Supports dietary management as a way to reduce catabolic reliance on fatty acids.
  evidence:
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In long-chain \ndeficits, long-chain triglyceride restriction should be 10% of total energy, \nwith linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 \nratio), with medium-chain triglyceride supplementation at 10-25% of total energy"
    explanation: Specifies LCT restriction and MCT supplementation targets for long-chain FAO defects.
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment of fatty acid oxidation disorders is based on dietary, pharmacological \nand metabolic decompensation measures. It is essential to provide the patient \nwith sufficient glucose to prevent lipolysis and to avoid the use of fatty acids \nas fuel as far as possible."
    explanation: Supports dietary management as the foundation of FAOD treatment.
- name: Emergency glucose infusion for acute decompensation
  description: 'Acute metabolic decompensation requires emergency IV glucose administration (10% dextrose at approximately 8 mg/kg/min) to suppress lipolysis and catabolism. Cessation of protein and fat intake and monitoring of electrolytes and creatine kinase are essential.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  - preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  target_mechanisms:
  - target: Catabolic stress-triggered energy failure
    treatment_effect: BYPASSES
    description: Intravenous glucose supplies immediate carbohydrate energy and suppresses lipolysis during acute crises.
    evidence:
    - reference: PMID:39203843
      reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The main measure in emergency hospital treatment is the \nadministration of IV glucose."
      explanation: Directly supports IV glucose as emergency management for fatty acid oxidation decompensation.
  evidence:
  - reference: PMID:32840329
    reference_title: "Long-chain fatty acid oxidation disorders and current management strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Long-chain fatty acid oxidation disorders (LC-FAODs) are rare, life-threatening, \nautosomal recessive genetic disorders characterized by acute crises of energy \nproduction and chronic energy deficiency."
    explanation: Supports the need for emergency management of acute metabolic crises.
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The main measure in emergency hospital treatment is the \nadministration of IV glucose."
    explanation: Directly supports IV glucose as the primary emergency intervention.
- name: Triheptanoin (Dojolvi)
  description: 'Triheptanoin is an FDA-approved odd-chain triglyceride providing anaplerotic substrate (propionyl-CoA converted to succinyl-CoA) to support TCA cycle intermediate replenishment and energy generation in long-chain fatty acid oxidation disorders. Reported to reduce decompensation frequency and hospitalizations.

    '
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
  target_mechanisms:
  - target: Catabolic stress-triggered energy failure
    treatment_effect: BYPASSES
    description: Triheptanoin provides anaplerotic odd-chain substrate to support energy metabolism despite impaired long-chain FAO.
    evidence:
    - reference: PMID:32840329
      reference_title: "Long-chain fatty acid oxidation disorders and current management strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "In recent years, the \nuse of medium, odd-chain fatty acids, such as triheptanoin, have been studied as \na treatment of LC-FAODs due to its anaplerotic properties."
      explanation: Supports triheptanoin as an anaplerotic bypass strategy in LC-FAODs.
  evidence:
  - reference: PMID:32840329
    reference_title: "Long-chain fatty acid oxidation disorders and current management strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In recent years, the \nuse of medium, odd-chain fatty acids, such as triheptanoin, have been studied as \na treatment of LC-FAODs due to its anaplerotic properties."
    explanation: Supports triheptanoin as an anaplerotic therapy for LC-FAODs.
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Trihepatnoin is a new therapeutic option with a \ngood safety and efficacy profile."
    explanation: Confirms triheptanoin as a therapeutic option with favorable profile. Note "Trihepatnoin" is a typo in the original publication abstract.
- name: Newborn screening
  description: 'Expanded newborn screening using tandem mass spectrometry acylcarnitine profiling identifies affected infants presymptomatically. Screening detects elevated C16OH, C18OH, and C18:1OH. While NBS improves neonatal survival, it does not reliably prevent long-term morbidity.

    '
  treatment_term:
    preferred_term: disease screening
    term:
      id: MAXO:0000124
      label: disease screening
  evidence:
  - reference: PMID:38263760
    reference_title: "Neurological outcome in long-chain hydroxy fatty acid oxidation disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixty-seven individuals with LCHAD/MTP deficiency were included in the \nstudy, thereof 54 identified by NBS. All screened individuals with LCHAD \ndeficiency survived"
    explanation: Demonstrates improved survival with NBS but persistent morbidity.
  - reference: PMID:37754774
    reference_title: "New Acylcarnitine Ratio as a Reliable Indicator of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The established \"HADHA ratio\" = (C16OH + \nC18OH + C18:1OH)/C0 was significantly elevated in all 54 affected individuals in \ncomparison to the control group."
    explanation: Supports acylcarnitine-based NBS biomarkers for LCHADD detection.
- name: Carnitine supplementation
  description: 'L-carnitine supplementation to address secondary carnitine deficiency and support excretion of toxic acyl-CoA intermediates as acylcarnitines. Use remains somewhat controversial but commonly employed.

    '
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: MAXO:0010006
      label: carnitine supplementation
  target_phenotypes:
  - preferred_term: Hypocarnitinemia
    term:
      id: HP:0003234
      label: Decreased circulating carnitine concentration
  evidence:
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "The use of carnitine remains controversial and new \ntherapeutic options are under investigation."
    explanation: Acknowledges carnitine supplementation while noting it remains controversial.
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Like \nseveral beta-oxidation defects, it presents during infancy with hypoglycemic \ncoma, hepatic steatosis, and hypocarnitinemia."
    explanation: Supports the rationale for carnitine supplementation given hypocarnitinemia.
- name: Ophthalmologic monitoring
  description: 'Regular retinal screening for chorioretinopathy is essential for all LCHADD patients, as choroidal atrophy and pigment dispersion are early signs of retinal degeneration. European metabolic centers concur on the importance of retinopathy screening as part of long-term monitoring.

    '
  treatment_term:
    preferred_term: eye examination
    term:
      id: MAXO:0001155
      label: eye examination
  target_phenotypes:
  - preferred_term: Chorioretinopathy
    term:
      id: HP:0001135
      label: Chorioretinal dystrophy
  - preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:38245779
    reference_title: "Long-term monitoring of fatty acid oxidation defects: results from a MetabERN survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The centres concurred in many aspects of \nlong-term monitoring of LCFAOD including the frequency of clinical visits, \ndetermination of laboratory parameters, cardiac monitoring and retinopathy \nscreening."
    explanation: Confirms retinopathy screening as a consensus monitoring practice.
  - reference: PMID:38595698
    reference_title: "Ophthalmic Symptoms of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: A Report of Three Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Choroidal \natrophy and pigment dispersion were consistently the earliest signs of \nLCHAD-associated chorioretinopathy."
    explanation: Supports the importance of regular ophthalmologic monitoring to detect early signs.
- name: Genetic counseling
  description: 'Genetic counseling for affected families including discussion of autosomal recessive inheritance, recurrence risk (25% for carrier parents), carrier testing, and prenatal diagnostic opportunities.

    '
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:10229030
    reference_title: "Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of therapeutic and prenatal diagnostic opportunities \nin LCHAD deficiency, it is important to recognize this severe disorder early in \nits course."
    explanation: Supports the importance of early diagnosis and prenatal counseling for LCHADD.
- name: Cardiac monitoring and management
  description: 'Regular cardiac monitoring with echocardiography is recommended given the 28% prevalence of cardiomyopathy. European metabolic centers include cardiac monitoring as a consensus practice in long-term follow-up of LCFAOD patients.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:38245779
    reference_title: "Long-term monitoring of fatty acid oxidation defects: results from a MetabERN survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The centres concurred in many aspects of \nlong-term monitoring of LCFAOD including the frequency of clinical visits, \ndetermination of laboratory parameters, cardiac monitoring and retinopathy \nscreening."
    explanation: Confirms cardiac monitoring as consensus practice in European metabolic centers.
notes: 'LCHADD is distinguished from the broader mitochondrial trifunctional protein deficiency (MTPD) by the selective impairment of LCHAD activity due to the common HADHA c.1528G>C variant. MTPD involves additional loss of enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase activities due to other HADHA or HADHB variants. An association between fetal LCHAD/MTP deficiency and maternal acute fatty liver of pregnancy (AFLP) or HELLP syndrome has been described, attributed to toxic 3-hydroxy intermediate metabolites released from the deficient placenta into maternal circulation. Emerging 2024 research demonstrates a gene therapy approach using AAV-HADHA to rescue RPE cell phenotypes, providing preclinical rationale for retinal gene-addition therapy.

  '

📚

References & Deep Research

Deep Research

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Disease Pathophysiology Research Template

Edison Scientific Literature 40 citations 2026-02-23T23:51:33.848869

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

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(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.

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