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HADHA

hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha

The HADHA gene provides instructions for synthesising a component of the mitochondrial trifunctional protein, which plays a crucial role in breaking down long-chain fatty acids for energy. The HADHA gene produces the alpha subunit of the mitochondrial trifunctional protein, an enzyme complex vital for fatty acid oxidation within cells.

Chromosome 2p23.3 Autosomal recessive HGNC:4801 Tier C
HADHA 2p23.3 p arm q arm 2

HADHA is located on the short (p) arm of chromosome 2, at band 2p23.3. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 2 in the library →

Available at Jeen Health

Clinical tests that include this

Carrier Screening panel
HADHA is 1 of 1,008 genes on this panel
Expanded carrier screening for recessive and X-linked conditions
Newborn Genetic Screening panel
HADHA is 1 of 258 genes on this panel
Genomic newborn screening for actionable paediatric conditions

Overview

The HADHA gene, or hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha, is essential for metabolic processes within the human body. It provides the genetic blueprint for one of the subunits of the mitochondrial trifunctional protein, an enzyme complex located in the mitochondria, the cell's energy-producing organelles. This protein complex is critical for fatty acid oxidation, a multi-step process that metabolises fats into usable energy for various bodily functions.

The HADHA gene is classified under carrier screening, specifically for autosomal recessive conditions. Variations within this gene can lead to metabolic disorders, highlighting its importance in health. Jeen Health offers carrier screening and cancer screening tests via an accredited UK laboratory, with support from genetic counsellors, to help individuals understand their genetic profile.

What the gene does

The HADHA gene directs the production of the alpha subunit of the mitochondrial trifunctional protein (MTP). This large enzyme complex is composed of eight subunits: four alpha subunits, encoded by HADHA, and four beta subunits, encoded by the HADHB gene. The alpha subunits specifically contain two distinct enzymatic activities: long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 2-enoyl-CoA hydratase. The beta subunits contribute a third enzymatic activity.

Collectively, these three enzymes are indispensable for fatty acid oxidation, which is the process by which fats are broken down to generate energy. More precisely, the mitochondrial trifunctional protein is responsible for metabolising long-chain fatty acids, a type of fat found in many foods. These fatty acids are a primary energy source for vital organs such as the heart and muscles, and they become particularly important for the liver and other tissues during periods of fasting.

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Chromosome location

The HADHA gene is located on the short arm of chromosome 2, specifically at position 2p23.3. This chromosomal address indicates its precise position within the human genome. The gene contains instructions for synthesising a protein that is 763 amino acids in length.

Protein structure

Domain architecture has not been experimentally characterised in detail for this protein.

Key variants

Variants within the HADHA gene can alter the structure and function of the alpha subunit of the mitochondrial trifunctional protein, thereby affecting its enzymatic activities. These changes can impair the body's ability to metabolise long-chain fatty acids, leading to a spectrum of metabolic disorders. The clinical presentation and severity of these conditions depend on the specific variant and its impact on protein function.

The table below shows the top 10 pathogenic or likely-pathogenic variants currently classified in ClinVar for HADHA.
View all on ClinVar →

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.1029C>A
single nucleotide variant
 p.Tyr343Ter Pathogenic/Likely pathogenic ★★☆☆ Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
c.1059del
Deletion
 p.Lys353fs Pathogenic/Likely pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency
c.160del
Deletion
 p.Ile54fs Pathogenic/Likely pathogenic ★★☆☆ Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
c.315-2A>T
single nucleotide variant
 - Pathogenic ★★☆☆ Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
c.469C>T
single nucleotide variant
 p.Gln157Ter Pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency
c.556C>T
single nucleotide variant
 p.Gln186Ter Pathogenic/Likely pathogenic ★★☆☆ Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
c.68del
Deletion
 - Pathogenic/Likely pathogenic ★★☆☆ Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
c.761_764del
Deletion
 p.Lys254fs Pathogenic/Likely pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency
c.878dup
Duplication
 p.Thr294fs Pathogenic/Likely pathogenic ★★☆☆ Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
c.966_967del
Microsatellite
 p.Cys322_Glu323delinsTer Pathogenic/Likely pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Variants in the HADHA gene are primarily associated with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD deficiency), an autosomal recessive metabolic disorder. This condition arises when the long-chain 3-hydroxyacyl-CoA dehydrogenase activity of the mitochondrial trifunctional protein is reduced. In some cases, HADHA variants can also lead to mitochondrial trifunctional protein deficiency, where all three enzymatic activities of the protein complex are impaired.

Additionally, research suggests that certain HADHA variants may increase a pregnant woman's risk of developing severe liver disorders, such as acute fatty liver of pregnancy (AFLP) and HELLP syndrome, which involves haemolysis, elevated liver enzymes, and low platelet count.

Inheritance pattern

Conditions caused by pathogenic HADHA variants typically follow autosomal recessive inheritance.

♀ Carrier parent 1 altered copy ♂ Carrier parent 1 altered copy Affected Carrier Carrier Unaffected Affected Carrier Unaffected Circles = females · Squares = males

When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.

Carrier frequency by population How common is heterozygous HADHA carrier status across ancestry groups?

UK clinical status

The HADHA gene is included in several NHS England Genomic Medicine Service national test directories, indicating its clinical relevance for various conditions. It is part of panels for acute rhabdomyolysis, cholestasis (including neonatal cholestasis), foetal anomalies, hereditary neuropathy or pain disorder, hyperammonaemia, intellectual disability, likely inborn error of metabolism, paediatric or syndromic cardiomyopathy, rhabdomyolysis and metabolic muscle disorders, and undiagnosed metabolic disorders.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Acute rhabdomyolysis · R419 NHS GMS → Cholestasis · R171 NHS GMS → Fetal anomalies · R21 NHS GMS → Hereditary neuropathy or pain disorder · R78 NHS GMS → Likely inborn error of metabolism · R98 NHS GMS → Paediatric or syndromic cardiomyopathy · R135 NHS GMS → DDG2P NHS GMS → Intellectual disability NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Frequently asked questions

What is the primary function of the HADHA gene?

The HADHA gene provides instructions for making the alpha subunit of the mitochondrial trifunctional protein, an enzyme complex crucial for breaking down long-chain fatty acids into energy within the body's cells.

What conditions are associated with variants in the HADHA gene?

Variants in the HADHA gene are primarily linked to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD deficiency) and mitochondrial trifunctional protein deficiency. Some variants may also increase a woman's risk for acute fatty liver of pregnancy (AFLP) and HELLP syndrome during pregnancy.

How is HADHA gene deficiency inherited?

Deficiencies related to the HADHA gene are typically inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the gene, one from each parent, to develop the condition.

References

  1. Gutiérrez Junquera C, Balmaseda E, Gil E. Acute fatty liver of pregnancy and neonatal long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency. European journal of pediatrics. 2009. PMID: 18408953
  2. Spiekerkoetter U, Mueller M, Cloppenburg E. Intrauterine cardiomyopathy and cardiac mitochondrial proliferation in mitochondrial trifunctional protein (TFP) deficiency. Molecular genetics and metabolism. 2008. PMID: 18485779
  3. Choi JH, Yoon HR, Kim GH. Identification of novel mutations of the HADHA and HADHB genes in patients with mitochondrial trifunctional protein deficiency. International journal of molecular medicine. 2007. PMID: 17143551
  4. Blish KR, Ibdah JA. Maternal heterozygosity for a mitochondrial trifunctional protein mutation as a cause for liver disease in pregnancy. Medical hypotheses. 2005. PMID: 15533621
  5. Angdisen J, Moore VD, Cline JM. Mitochondrial trifunctional protein defects: molecular basis and novel therapeutic approaches. Current drug targets. Immune, endocrine and metabolic disorders. 2005. PMID: 15777202
  6. Shekhawat PS, Matern D, Strauss AW. Fetal fatty acid oxidation disorders, their effect on maternal health and neonatal outcome: impact of expanded newborn screening on their diagnosis and management. Pediatric research. 2005. PMID: 15817498
  7. Oey NA, den Boer ME, Wijburg FA. Long-chain fatty acid oxidation during early human development. Pediatric research. 2005. PMID: 15845636
  8. Spiekerkoetter U, Khuchua Z, Yue Z. General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover. Pediatric research. 2004. PMID: 14630990
  9. den Boer ME, Wanders RJ, Morris AA. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics. 2002. PMID: 11773547
  10. Yang Z, Zhao Y, Bennett MJ. Fetal genotypes and pregnancy outcomes in 35 families with mitochondrial trifunctional protein mutations. American journal of obstetrics and gynecology. 2002. PMID: 12237653
  11. Yang Z, Yamada J, Zhao Y. Prospective screening for pediatric mitochondrial trifunctional protein defects in pregnancies complicated by liver disease. JAMA. 2002. PMID: 12413376
  12. Ibdah JA, Yang Z, Bennett MJ. Liver disease in pregnancy and fetal fatty acid oxidation defects. Molecular genetics and metabolism. 2000. PMID: 11001809
  13. Tyni T, Pihko H. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Acta paediatrica (Oslo, Norway : 1992). 1999. PMID: 10229030
  14. Ibdah JA, Bennett MJ, Rinaldo P. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. The New England journal of medicine. 1999. PMID: 10352164
  15. Sims HF, Brackett JC, Powell CK. The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. Proceedings of the National Academy of Sciences of the United States of America. 1995. PMID: 7846063
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 11 October 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .