3-Hydroxyacyl-CoA Dehydrogenase Deficiency

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3-Hydroxyacyl-CoA Dehydrogenase Deficiency is a rare metabolic disease that is often grouped with the mitochondrial fatty acid oxidation disorders, but is functionally different from them.

Fat or adipose tissue is the main energy store of our bodies. It is derived not only from the fat that we eat, but also made in the body from any excess calories obtained from our food and drink. When fat is broken down it releases fatty acids. When we eat regular carbohydrate-containing meals our body uses the sugar in the meals as an energy source and does not use much fat. However, if we fast for a long time, and particularly if we are not eating because we are unwell, our bodies will rely on fatty acids as a major energy source more and more with time.

This disorder is caused by defects in the HADH gene which provides instructions for making an enzyme called 3-hydroxyacyl-CoA dehydrogenase. The resulting deficiency of this impairs the final steps in the conversion of fatty acids to energy, but the resultant accumulation of fatty acid intermediates is probably of little or no clinical significance. Rather, the 3-hydroxyacyl-CoA dehydrogenase protein has second function, binding to a second enzyme (glutamate dehydrogenase) to inhibit its function. Mutations in HADH impair this binding and lead to activation of glutamate dehydrogenase, which in turn causes hypersensitivity to insulin and hypoglycemia.

The exact incidence is unknown. Only a small number of cases have been reported so far in the literature.

Patients usually present with atypical hypoglycaemia, especially after a very short period of fasting or a protein load. Deficiency usually presents in either infancy or early childhood and symptoms are related to hypoglycemia:

• Reduced level of consciousness
• Poor appetite
• Lethargy
• Irritability
• Vomiting
• Seizures

Complications include breathing problems, coma and sudden death.

This disorder can be diagnosed through specialist testing on skin samples and the blood. Genetic testing is available. Some countries screen for this disorder as part of newborn screening programmes. However, it is not currently routinely screened for in the UK.

Individuals should avoid long periods without food. The medication diazoxide may be helpful. Your metabolic consultant and dietitian will give you advice on a feeding plan and recommended meal/feed times and an emergency regimen to be followed during illness or refusal to feed. In some cases, a low fat, high carbohydrate diet may be recommended. Those with high insulin levels may require medication. Any new dietary changes, supplements or medications must be discussed with your specialist.

Humans have chromosomes composed of DNA. Genes are pieces of DNA that carry the genetic instruction. Each chromosome may have several thousand genes. We inherit particular chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents.

This is an inherited condition. There is nothing that could have been done to prevent it.

Everyone has a pair of genes that make the enzyme. In children with 3-hydroxyacyl-CoA dehydrogenase, neither of these genes works correctly. These children inherit one non-working gene from each parent. Parents of children with Farber Disease are carriers of the condition. Carriers do not have the disorder because the other gene of this pair is working correctly.

When both parents are carriers, in each pregnancy the risk to the baby is as follows:

• 25% chance (1 in 4) of inheriting the disorder
• 50% chance (1 in 2) for the baby to be a carrier
• 25% chance (1 in 4) for the baby to have two working genes and neither have the disorder or be a carrier

References are available on request. Please contact us by phoning 0845 241 2173 or emailing contact@metabolicsupportuk.org [Resource Library No: AFKB04].