Isovaleric acidemia (IVA) is a rare genetic disorder that affects the ability of the body to use the amino acid leucine, a natural building block of protein. It is caused by a deficiency of the enzyme isovaleryl-CoA dehydrogenase (IVD). When IVD does not function properly it leads to an accumulation of high levels of the chemical isovaleric acid in the blood. This chemical, a breakdown product of leucine, is toxic to the brain and other parts of the nervous system and body.
IVA is extremely variable. Some children develop symptoms as newborns while others remain well for many years. A high level of isovaleric acid in the blood leads to severe symptoms with nausea, vomiting, drowsiness, and coma. This most frequently happens with ingestion of a high protein meal or when an individual has an otherwise minor illness such as a cold or the flu. It is especially common in the newborn periods when affected babies start to feed. Often, however, affected children show a milder, more chronic picture with learning problems, muscular weakness, and poor growth. These children are at risk to have more severe episodes during times of stress such as illness. Patients who first show the more severe form of IVA can later evolve to the chronic form of the disease.
A diagnosis of IVA may first be considered because of the presence of the characteristic smell of IVA in sweat or ear wax of an affected baby or child (described to be similar to sweaty socks), however, definitive identification of the disease requires specialized genetic testing. The abnormal compounds characteristic of the disorder are identified in blood or urine. Then the diagnosis must then be confirmed by measurement of IVD in skin or blood cells. Finally, it is sometimes possible to directly identify the genetic changes in the IVD gene responsible for the IVD deficiency. IVA can be identified by specialized prenatal testing and by expanded newborn screening with mass spectrometry.
Early recognition and treatment of the disorder can be lifesaving. In an acutely ill child, giving glucose (a simple sugar) though IV fluids will help restore the metabolic balance and reverse symptoms. Long term, affected persons must be maintained on a diet that is reduced in leucine-containing natural protein. To provide enough of the other amino acids in protein that are necessary for normal growth and development, children usually require supplementation of their diet with a special medical formula that does not contain leucine.
IVA is inherited in an autosomal recessive fashion. We all have two copies of each of our genes. In a recessive disorder, both copies of the genes must be defective before a disease arises. When both parents carry one copy of the IVD gene that does not function properly, they are carriers of IVA. If both parents pass on the copy of the IVD gene that does not function, the baby has no copies that work and has IVA.