HADHA

The HADHA gene encodes the alpha subunit of the mitochondrial trifunctional protein (MTP), a key enzyme complex involved in the beta-oxidation of long-chain fatty acids—an essential energy pathway during fasting and metabolic stress. 

Mutations in HADHA can disrupt this process, leading to serious inherited disorders such as long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and mitochondrial trifunctional protein deficiency (TFPD), both of which require early diagnosis and targeted management.

What is HADHA (Hydroxyacyl-CoA Dehydrogenase Subunit Alpha)?

The HADHA gene encodes the alpha subunit of the mitochondrial trifunctional protein (MTP), a multi-enzyme complex located on the inner mitochondrial membrane. 

MTP catalyzes key steps in the beta-oxidation of long-chain fatty acids, which are essential energy sources during fasting, prolonged exercise, and metabolic stress.

HADHA: A Subunit of the Mitochondrial Trifunctional Protein (MTP)

HADHA produces a 763-amino acid protein responsible for two of MTP’s three core enzymatic activities:

• Long-chain enoyl-CoA hydratase
• Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)

These activities work alongside the beta subunit (HADHB), which provides 3-ketoacyl-CoA thiolase function, enabling complete degradation of long-chain fatty acids into acetyl-CoA for energy production.

MTP Function and Clinical Importance

MTP is essential in energy-demanding tissues (heart, liver, skeletal muscle). HADHA’s additional role in cardiolipin remodeling underscores its importance in mitochondrial membrane stability and apoptosis regulation.

Conditions Associated with HADHB Deficiency

The following conditions are associated with HADHA mutations:

Long-Chain Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency and Trifunctional Protein (TFP) Deficiency

Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are rare inherited disorders of long-chain fatty acid oxidation caused by mutations in the HADHA or HADHB genes. 

LCHAD affects one enzyme, while TFP affects all three enzymes of the mitochondrial trifunctional protein. Both are inherited in an autosomal recessive pattern.

Clinical Presentation

Symptoms range from severe illness in newborns to milder muscle issues in later life. Newborns may present with low blood sugar, liver problems, heart failure, and seizures. In infancy, metabolic crises triggered by fasting or illness are common. 

Milder forms may involve muscle weakness, exercise intolerance, and rhabdomyolysis. Long-term complications include progressive peripheral neuropathy and retinopathy, particularly in LCHAD.

Diagnosis

Diagnosis is based on elevated long-chain 3-hydroxyacylcarnitines in blood and specific organic acids in urine, confirmed by genetic testing. 

Enzyme analysis distinguishes LCHAD (single enzyme defect) from TFP (all enzymes affected). Newborn screening can identify at-risk infants early.

Management

Treatment focuses on preventing fasting, maintaining energy intake, and using a low-fat diet supplemented with MCT or triheptanoin. Emergency care includes IV glucose, fluids, and correcting metabolic acidosis. 

Regular monitoring is needed for nutrition, liver function, heart, nerves, and vision. Avoid high-fat diets, prolonged fasting, and certain anesthetics.

Genetic Counseling

Both conditions are autosomal recessive. Carriers are typically healthy but at risk for pregnancy complications if carrying an affected fetus. 

Family members, especially siblings, should be tested. Once mutations are known, prenatal and preimplantation testing are options.

When is HADHA Genetic or Biochemical Testing Relevant?

HADHA genetic testing may be considered in the following settings:

• Infants or children with unexplained hypoketotic hypoglycemia, cardiomyopathy, liver dysfunction, myopathy, or rhabdomyolysis
• Newborns flagged on metabolic screening for elevated long-chain hydroxyacylcarnitines
• Sudden infant death of unclear etiology
• Family history of LCHAD deficiency or mitochondrial trifunctional protein deficiency (TFPD)
• Mothers with acute fatty liver of pregnancy (AFLP) or HELLP syndrome, particularly when the fetus is affected

Diagnostic Tools

The following tests may be considered to understand if HADHA function is affected:

• Acylcarnitine profiling (e.g., elevated C16-OH, C18:1-OH)
• Molecular genetic testing of HADHA and/or HADHB
• Enzyme activity assays (in specialized labs)

HADHA Genetic Testing: Test Procedure and Interpretation

Testing for HADHA is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for HADHA genetic testing are considered to be without mutations that can alter the activity of the HADHA proteins.

What Do Specific HADHA Mutations Mean?

Pathogenic variants affecting the HADHA enzyme may be associated with:

• LCHAD deficiency: Commonly associated with the Glu510Gln (1528G>C) variant, impairing only dehydrogenase activity
• TFPD: Caused by mutations that impair all three MTP functions; often more severe

Clinical Consequences

Clinical consequences associated with HADHA mutations may include:

• Energy production failure during fasting or stress
• Accumulation of toxic fatty acid intermediates in liver, heart, retina, and muscle
• Risk of maternal liver complications during pregnancy (AFLP, HELLP) in HADHA carriers

Inheritance

Conditions associated with HADHA mutations are autosomal recessive; affected individuals inherit biallelic pathogenic variants.

What Does the Absence of Pathogenic HADHA Mutations Mean?

A negative HADHA test does not rule out TFPD, as mutations in HADHB can cause the same phenotype. If clinical suspicion remains, further testing is required (e.g., HADHB sequencing, broader exome testing).

Summary for Clinicians

HADHA is essential for long-chain fatty acid oxidation. Mutations cause LCHAD deficiency or TFPD, presenting in infancy with hypoglycemia, cardiomyopathy, liver disease, or sudden death.

HADHA testing is diagnostic and prognostic—critical in metabolic workups and prenatal counseling.

Early diagnosis enables dietary management, fasting avoidance, and monitoring for cardiac or hepatic complications.

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