Isovaleric Acidaemia and Leucin Metabolism

What is Isovaleric Acidaemia and Disorders of Leucin Metabolism?

Isovaleric acidaemia is an inherited condition in which abnormal metabolism of the amino acid leucine causes the fatty acid isovaleric acid to build up in the blood and urine.

Amino acids are the building blocks of proteins. After eating proteins, the body ‘metabolises’ or breaks them down into amino acids. Animal proteins include dairy products, meat, eggs and fish. Proteins are also found in plants including soy, legumes, grains and nuts. The body uses the amino acids to make its own proteins essential for life – for example enzymes; structural proteins in muscles, hair, skin, cells and cartilage; proteins that generate movement in muscles; or those involved in cell functioning or immune responses. In periods of fasting or illness, proteins in the body can be broken down to generate energy. Leucine is an essential amino acid meaning that it is not made by the body. Therefore, this amino acid comes from ingested protein or from the breakdown of previously ingested and stored proteins. Foods with a high-leucine content include beef, fish, chicken, soy beans, lentils and nuts.

Similarly, fatty acids are the building blocks of fats used by our bodies for energy.

Isovaleric acidaemia (-aemia meaning ‘in the blood’) is also known as isovaleric aciduria (-uria meaning ‘in the urine’) or isovaleric acid CoA dehydrogenase (IVD) deficiency, which describes the enzyme deficiency at its root.

Accumulation of isovaleric acid damages the brain and nervous system, leading to learning problems, seizures and loss of movement or ‘motor’ ability. The condition is closely related to maple syrup urine disease.

How common is isovaleric acidaemia?

This rare condition is seen in up to 1 in 50,000 children. The condition affects males and females and different races equally.

What causes isovaleric acidaemia?

The cause of isovaleric acidaemia is a mutation in the gene that codes for the enzyme isovaleryl CoA dehydrogenase. This enzyme is needed to metabolise leucine correctly. In individuals with isovaleric acidaemia, the enzyme is missing or functions poorly so the multi-step processing stops after the production of isovaleric acid. This fatty acid cannot be further processed so levels increase progressively.

Isovaleric acidaemia is a recessively inherited genetic disorder, meaning that a child would only have the condition if both parents ‘carry’ the genetic mutation. Genes are arranged in structures called chromosomes that contain two strings or ‘alleles’. Offspring inherit one allele from their father and one from their mother. Carrying one copy of the mutated gene does not affect health, but when two mutated copies come together, the linked enzyme is deficient either in quantity or effect and the disease is expressed. For each and every pregnancy, there is a 1 in 4 chance of two carriers of the genetic mutation having a child with isovaleric acidaemia. 

What are the symptoms and signs of isovaleric acidaemia?

There are two distinct patterns of symptoms in isovaleric acidaemia – either serious and typically life-threatening (acute), or long-standing and less severe (chronic).

Acute isovaleric acidaemia manifests in the first days of life, with pronounced accumulation of acidic metabolic products (metabolic acidosis). Infants may shake and tremble and their body temperature may be lower than normal. Severe symptoms of poor feeding, vomiting and tiredness progress to seizures and sometimes coma. Many infants do not survive such acute episodes. 

In the chronic form, repeated attacks of metabolic acidosis are seen throughout life, in which acidic metabolites known as ketones accumulate in blood, tissues and urine. The events are triggered by infections, periods without food or through eating too much protein, and are due to the body breaking down stored proteins. During attacks, individuals experience vomiting, lack of appetite and extreme tiredness. They also emit an odour similar to that of sweaty feet.

This is a distinctive feature of isovaleric acidaemia and is a direct result of high levels of isovaleric acid. Between episodes, individuals are usually symptom free. Attacks may be common in infancy and early childhood but their frequency usually diminishes with increasing age. The severity of chronic isovaleric acidaemia varies between individuals. Some show no permanent signs while in others there may be delayed development and/or poor growth.

How is isovaleric acidaemia diagnosed?

The characteristic odour during periods of illness helps to guide the diagnosis of isovaleric acidaemia. Diagnosis is usually confirmed through blood and urine tests that detect high levels of isovaleric acid. Genetic testing may also be used to identify the genetic abnormality and enzyme assays can assess levels of enzyme activity.

In some countries, routine newborn screening identifies sufferers.

How is isovaleric acidaemia treated?

The mainstay of treatment is a leucine-restricted diet to reduce the levels of isovaleric acid in the body. This diet needs to be continued indefinitely and must be initiated only after consultation with a dietician. To avoid malnutrition of other amino acids, children should be given a leucine-free formula. These specially formulated powders contain a balanced mix of essential and non-essential amino acids, vitamins and minerals, with minimal carbohydrates. Products are available for children of all ages.

Oral carnitine and glycine supplements are useful as these molecules bind to isovaleric acid and nullify its toxic effects. However, aspirin must not be taken by children receiving these supplements since aspirin interferes with their action.

Infections and fevers are treated aggressively to prevent muscle breakdown and subsequent release of stored proteins. This is achieved by limiting dietary protein during periods of illness and increasing the intake of carbohydrates. A range of special low-protein food products is available. The dose of carnitine is also increased at these times. 

No cure exists for isovaleric acidaemia. However, early identification and intervention are effective, with many individuals showing normal development if the recommended treatment is maintained and acute attacks are well managed.