HADHA-related disorders

What are HADHA-Related Disorders?

HADHA-related disorders result from the body lacking an enzyme called mitochondrial trifunctional protein. Without this enzyme, the body has trouble turning a specific type of fat from foods, known as long-chain fatty acids, into energy. This process, called fatty acid oxidation, normally breaks down long-chain fatty acids stepwise until they can be turned into usable energy. When mitochondrial trifunctional protein is missing, fatty acids build up in the body and cause damage to organs and tissues. HADHA-related disorders are caused by mutations in the HADHA gene.

Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency

Individuals with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) have trouble converting long-chain fatty acids into energy, especially when they are not eating for a period of time (fasting), when they are ill, or when they do strenuous exercise. Symptoms can begin in infancy and include poor feeding, muscle weakness (hypotonia), low blood sugar (hypoglycemia), and low energy (lethargy). There can also be liver problems, vision loss due to damage to the retina, muscle breakdown, seizures, and sensory problems in the arms and legs (peripheral neuropathy). In more severe situations, individuals with LCHADD can have problems breathing and trouble with their heart muscle (cardiomyopathy) or rhythm (arrhythmia), which can lead to coma or death.

Mitochondrial Trifunctional Protein Deficiency (MTPD)

Individuals with MTPD tend to have similar symptoms to those with LCHADD, though the symptoms may be more severe. Most babies with the neonatal form of MTPD die in infancy. Children with a less-severe form of MTPD may not show symptoms until times of fasting, when they are ill, or when they do strenuous exercise. Some children may not have symptoms between these episodes, but repeated crisis events can lead to brain damage and intellectual and developmental disabilities.

How Common Are HADHA-Related Disorders?

The incidence of HADHA-related disorders in the United States is estimated at approximately 1 in 90,000 individuals. A similar carrier frequency and incidence (1 in 91,700) is seen in Estonia while the incidence in Germany and Poland ranges from 1 in 250,000 to 1 in 109,090 births with certain regions of Poland seeing a higher incidence of up to 1 in 16,900 births.

How Are HADHA-Related Disorders Treated?

The main method of management for LCHADD and MTPD is a special diet and avoidance of fasting. A physician or nutritionist will recommend a diet low in fats and high in carbohydrates, which are easier for an affected individual to break down, and a feeding schedule with frequent meals. Often it is necessary to have an additional dietary protocol in place for illness or other stressful times. A physician may also prescribe medium-chain triglyceride oil, L-carnitine, or other supplements for additional energy.

What Is the Prognosis for an Individual with a HADHA-Related Disorder?

Untreated, LCHADD and MTPD are often fatal in infancy or childhood. When symptoms appear in infancy, treatment is often not effective because the disease causes irreparable damage to the heart and leads to cognitive impairments.

For some cases of LCHADD and less-severe forms of MTPD, early detection and early treatment can prevent many of the severe complications and allow affected individuals to have typical growth and development. Even with careful treatment, there may still be some episodes of low blood sugar and damage to the heart, liver, and muscle. Recurrent acute episodes of low blood sugar can lead to cognitive impairments over time. With treatment, some individuals with LCHADD or MTPD may live into adulthood.

Individuals with later-onset disease and symptoms limited to muscle weakness and pain are typically healthy and do not have problems with the heart, liver, or changes in cognitive ability or intellect.

Additional Considerations for Carriers

Carriers of HADHA-related disorders do not typically show symptoms of the disease. However, female carriers of a HADHA-related disorder may be at risk for pregnancy complications involving the liver and blood. Carriers who are planning a pregnancy or who are pregnant should speak with their physician for recommendations.