# Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
**Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)** is a rare autosomal recessive disorder of fatty acid oxidation in which the body cannot convert long-chain fatty acids into energy, particularly during fasting, because the dehydrogenase component of the mitochondrial trifunctional protein is not working.[1](https://medlineplus.gov/genetics/condition/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency/) Signs typically begin in infancy or early childhood with hypoketotic hypoglycemia (low blood sugar without ketones, hallmark of fat-burning failure), liver dysfunction, cardiomyopathy, and muscle problems, and the condition is distinguished from other fatty acid oxidation defects by progressive retinopathy and peripheral neuropathy.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/)
| Key fact | Detail |
|---|---|
| Inheritance | Autosomal recessive; caused by biallelic pathogenic variants in the HADHA gene[1](https://medlineplus.gov/genetics/condition/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency/) • [2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) |
| Enzyme defect | Isolated loss of the long-chain 3-hydroxyacyl-CoA dehydrogenase activity of mitochondrial trifunctional protein; loss of all three activities defines TFP deficiency[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) |
| Common variant | The missense variant c.1528G>C (p.E510Q) in HADHA accounts for approximately 87%–90% of LCHAD-deficient alleles[3](https://www.sciencedirect.com/topics/medicine-and-dentistry/mitochondrial-trifunctional-protein-deficiency) • [4](https://www.ncbi.nlm.nih.gov/clinvar/RCV000009266.19/) |
| Frequency | One estimate, from a Finnish population, is 1 in 62,000 affected pregnancies; the incidence in the United States is probably much lower[1](https://medlineplus.gov/genetics/condition/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency/) |
| Presentation | In a 50-patient cohort, mean age at presentation was 5.8 months (range 1 day to 26 months); 78% presented with hypoketotic hypoglycemia[5](https://publications.aap.org/pediatrics/article/109/1/99/79785/Long-Chain-3-Hydroxyacyl-CoA-Dehydrogenase) |
| Distinctive complications | Retinopathy in about 80% and peripheral neuropathy in about 67% of LCHAD-deficient individuals in pre-newborn-screening data[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) |
| Maternal risk | HELLP syndrome or acute fatty liver of pregnancy occurs in an estimated 15%–25% of pregnancies carrying an affected fetus[6](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/pdf/Bookshelf_NBK583531.pdf) |
| Mainstay treatment | Frequent feeding to avoid fasting, a diet low in long-chain fat supplemented with medium-chain triglycerides or triheptanoin, and DHA supplementation[3](https://www.sciencedirect.com/topics/medicine-and-dentistry/mitochondrial-trifunctional-protein-deficiency) • [2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) |
## Role of the trifunctional protein
Mitochondrial trifunctional protein (MTP) is a multi-enzyme complex anchored in the inner mitochondrial membrane that catalyzes the last three steps of long-chain fatty acid beta-oxidation: long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), and long-chain 3-ketoacyl-CoA thiolase. The complex contains four alpha subunits, which carry the hydratase and dehydrogenase activities and are encoded by the [HADHA](https://www.edgepedia.org/hadha) gene, and four beta subunits, which carry the thiolase activity and are encoded by HADHB.[3](https://www.sciencedirect.com/topics/medicine-and-dentistry/mitochondrial-trifunctional-protein-deficiency) • [7](https://pmc.ncbi.nlm.nih.gov/articles/PMC9546250/)
In isolated LCHAD deficiency, only the dehydrogenase activity is impaired, so the pathway is blocked after the hydratase reaction and before the dehydrogenase reaction, causing accumulation of medium- and long-chain 3-hydroxy fatty acids and their metabolites. In complete MTP (TFP) deficiency, all three activities are deficient. LCHAD deficiency was first described in 1989 and MTP deficiency in 1992; in 1992 two independent groups showed that LCHAD is part of the MTP complex.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC2848452/) [Fatty acids](https://www.edgepedia.org/fatty-acids) are a major energy source for the heart and muscles, and during fasting they are important for the liver and other tissues, which explains why symptoms concentrate in these organs.[1](https://medlineplus.gov/genetics/condition/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency/)
## Clinical presentation
The clinical spectrum runs from severe neonatal disease to mild late-onset neuromyopathic disease. LCHAD deficiency typically presents with a severe-to-intermediate phenotype, while TFP deficiency spans severe-to-mild.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/)
**Severe neonatal form.** Newborns present within a few days of birth with hypoketotic hypoglycemia, hepatomegaly, encephalopathy, and often cardiomyopathy, a Reye-like picture that is rapidly progressive and often lethal when associated with dilated cardiomyopathy. This presentation is more common in TFP deficiency (about 39% of cases) than in LCHAD deficiency (about 15%).[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/)
**Intermediate (hepatic) form.** This is the most common presentation in LCHAD deficiency: acute metabolic decompensation with hypoketotic hypoglycemia, lactic acidosis, elevated liver enzymes, and high creatine kinase, precipitated by fasting or infection, often with vomiting, lethargy, poor feeding, and hepatomegaly.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) In the 50-patient Dutch cohort, 39 patients (78%) presented with hypoketotic hypoglycemia, the classical feature of a fatty acid oxidation disorder, while 11 (22%) presented with chronic problems such as failure to thrive, feeding difficulties, cholestatic liver disease, or hypotonia; most of those with acute crises had also had nonspecific chronic symptoms beforehand.[5](https://publications.aap.org/pediatrics/article/109/1/99/79785/Long-Chain-3-Hydroxyacyl-CoA-Dehydrogenase)
**Late-onset (neuromyopathic) form.** Presenting after infancy, this form features episodic rhabdomyolysis triggered by prolonged exercise, cold exposure, fasting, or infection, with muscle pain, weakness, and myoglobinuria, plus progressive peripheral neuropathy.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/)
**Triggers and mimics.** Metabolic crises can be triggered by fasting, illnesses such as viral infections, or weather extremes. The disorder is sometimes mistaken for [Reye syndrome](https://www.edgepedia.org/reye-syndrome), a severe disorder that can develop in children recovering from viral infections such as chicken pox or flu, most cases of which are associated with aspirin use.[1](https://medlineplus.gov/genetics/condition/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency/)
## Long-term complications
Two complications distinguish LCHAD/TFP deficiency from every other fatty acid oxidation defect: progressive pigmentary retinopathy and peripheral neuropathy.[3](https://www.sciencedirect.com/topics/medicine-and-dentistry/mitochondrial-trifunctional-protein-deficiency) • [2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) In pre-newborn-screening data, retinopathy affected about 80% of individuals with LCHAD deficiency (versus 12% with TFP deficiency) and peripheral neuropathy about 67%; approximately half of individuals with LCHAD deficiency have evidence of retinopathy by age two years.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) • [6](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/pdf/Bookshelf_NBK583531.pdf) The retinal changes are described as a progressive rod-cone dystrophy, and vision problems such as myopia and night blindness worsen over time.[9](https://onlinelibrary.wiley.com/doi/10.1002/jimd.70251) • [1](https://medlineplus.gov/genetics/condition/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency/) Neuropathy onset ranges from infancy to adulthood with a median around age 7 years, begins earlier in TFP deficiency, and early treatment can delay but may not prevent it.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/)
## Pregnancy complications
Pregnancies carrying a fetus affected with LCHAD/TFP deficiency are associated with maternal liver disease: [HELLP syndrome](https://www.edgepedia.org/hellp-syndrome) (hemolysis, elevated liver enzymes, and low platelets) and acute fatty liver of pregnancy occur in an estimated 15%–25% of such pregnancies.[6](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/pdf/Bookshelf_NBK583531.pdf) Guidelines accordingly recommend monitoring for these conditions in pregnant women who are heterozygous carriers of an HADHA or HADHB pathogenic variant, and a history of acute fatty liver of pregnancy or HELLP is a reason to screen the baby specifically for LCHAD deficiency.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) • [10](https://newbornscreening.hrsa.gov/conditions/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency)
## Diagnosis
[Newborn screening](https://www.edgepedia.org/newborn-screening) uses tandem mass spectrometry of dried blood spots, primarily quantifying the acylcarnitines 3-hydroxypalmitoylcarnitine (C16-OH) and 3-hydroxyoleoylcarnitine (C18:1-OH); an out-of-range result requires follow-up plasma acylcarnitine and urine organic acid testing.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) The diagnosis is established by elevation of long-chain 3-hydroxyacylcarnitine species in plasma or increased urinary 3-hydroxy-dicarboxylic acids together with biallelic pathogenic variants in HADHA; distinguishing LCHAD deficiency from TFP deficiency requires enzyme assay in lymphocytes or skin fibroblasts showing isolated dehydrogenase deficiency versus deficiency of all three activities.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) No consensus clinical diagnostic criteria have been published.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) Molecular screening is feasible because the common c.1528G>C (p.E510Q) variant can be detected in approximately 90% of LCHAD-deficient alleles.[3](https://www.sciencedirect.com/topics/medicine-and-dentistry/mitochondrial-trifunctional-protein-deficiency)
## Treatment and outcomes
The mainstay of therapy is avoidance of fasting through frequent feeds, a high-carbohydrate, low-long-chain-fat diet, and medium-chain triglyceride (MCT) oil or triheptanoin supplementation; DHA deficiency has been documented in these patients, and supplementation with cod liver oil extract high in DHA has shown encouraging response for the eye disease.[3](https://www.sciencedirect.com/topics/medicine-and-dentistry/mitochondrial-trifunctional-protein-deficiency) Acute decompensation is treated with hospitalization and intravenous fluid containing at least 10% dextrose.[2](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/) Anesthetics containing high doses of long-chain fatty acids, such as propofol and etomidate, are avoided.[6](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/pdf/Bookshelf_NBK583531.pdf)
Earlier diagnosis changes survival. In Finland, 16 patients diagnosed from 1997 to 2010 under strict dietary treatment had a therapeutic delay of 0 to 30 days and a survival rate of 62.5% at the end of the study, compared with a 10-year survival of 14.3% in an earlier cohort diagnosed from 1976 to 1996; survivors were in good overall condition, though some had developed mild retinopathy or neuropathy.[11](https://pubmed.ncbi.nlm.nih.gov/26676313/) A systematic review found some evidence that dietary management after screen-detection is associated with fewer heart and liver problems, though the evidence base is limited by small study sizes and confounding.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC6858661/)
Newborn screening improves neonatal survival but does not eliminate morbidity. In a German national multicenter study of 67 individuals with LCHAD/MTP deficiency identified between 1999 and 2020, all screened individuals with LCHAD deficiency survived, yet a symptomatic disease course occurred in 94%, later metabolic decompensations in 80%, myopathy in 82%, and retinopathy in 17%; the authors concluded that screening and early treatment cannot reliably prevent long-term morbidity.[13](https://pubmed.ncbi.nlm.nih.gov/38263760/) Even with early detection, chorioretinopathy and resulting vision loss still occur.[14](https://www.ohsu.edu/sites/default/files/2026-01/gillingham-newsletter-fallwinter-2025-v3.0_final.pdf)
## References
1. [Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency/)
2. [Prasun P, LoPiccolo MK, Ginevic I. Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency. GeneReviews, 2022](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/)
3. [Mitochondrial Trifunctional Protein Deficiency, ScienceDirect Topics overview](https://www.sciencedirect.com/topics/medicine-and-dentistry/mitochondrial-trifunctional-protein-deficiency)
4. [ClinVar: NM_000182.5(HADHA):c.1528G>C (p.Glu510Gln) and mitochondrial trifunctional protein deficiency](https://www.ncbi.nlm.nih.gov/clinvar/RCV000009266.19/)
5. [den Boer MEJ et al. Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: Clinical Presentation and Follow-Up of 50 Patients. Pediatrics 2002;109(1):99-104](https://publications.aap.org/pediatrics/article/109/1/99/79785/Long-Chain-3-Hydroxyacyl-CoA-Dehydrogenase)
6. [GeneReviews PDF: LCHAD/TFP Deficiency](https://www.ncbi.nlm.nih.gov/sites/books/NBK583531/pdf/Bookshelf_NBK583531.pdf)
7. [Genetic, biochemical, and clinical spectrum of MTP deficiency after introduction of newborn screening in the Netherlands](https://pmc.ncbi.nlm.nih.gov/articles/PMC9546250/)
8. [Mitochondrial Trifunctional Protein Defects: Clinical Implications and Therapeutic Approaches](https://pmc.ncbi.nlm.nih.gov/articles/PMC2848452/)
9. [Grünert SC. International Guideline on the Diagnosis, Treatment, and Monitoring of Long-Chain Fatty Acid Oxidation Disorders. Journal of Inherited Metabolic Disease, 2026](https://onlinelibrary.wiley.com/doi/10.1002/jimd.70251)
10. [Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency, Newborn Screening (HRSA)](https://newbornscreening.hrsa.gov/conditions/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency)
11. [Immonen T et al. Earlier diagnosis and strict diets improve the survival rate and clinical course of LCHAD deficiency. Acta Paediatrica 2016;105(5):549-554](https://pubmed.ncbi.nlm.nih.gov/26676313/)
12. [Evaluation of earlier versus later dietary management in LCHAD or MTP deficiency: a systematic review](https://pmc.ncbi.nlm.nih.gov/articles/PMC6858661/)
13. [Neurological outcome in long-chain hydroxy fatty acid oxidation disorders (German multicenter NBS study), Annals of Clinical and Translational Neurology 2024](https://pubmed.ncbi.nlm.nih.gov/38263760/)
14. [Gillingham Newsletter Fall/Winter 2025, Oregon Health & Science University](https://www.ohsu.edu/sites/default/files/2026-01/gillingham-newsletter-fallwinter-2025-v3.0_final.pdf)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Metabolism and metabolic pathways › Inborn errors of metabolism (biochemical scope) › Fatty acid oxidation and acyl-CoA defects › Distal beta-oxidation enzyme defects*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 11, 2026; Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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