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Isovaleric Acidemia

Last updated Oct. 17, 2018

Approved by: Maulik P. Purohit MD MPH

Isovaleric Acidemia (IVA) is a rare genetic disorder in which the affected individuals have difficulty breaking down the amino acid leucine from the food that they ingest (consume). This leads to the buildup of isovaleric acid in blood.

What are the other Names for this Condition? (Also known as/Synonyms)

  • Isovaleryl CoA Dehydrogenase Deficiency
  • IVA (Isovaleric Acidemia)
  • IVD (Isovaleric Acid CoA Dehydrogenase) Deficiency

What is Isovaleric Acidemia? (Definition/Background Information)

  • Isovaleric Acidemia (IVA) is a rare genetic disorder in which the affected individuals have difficulty breaking down the amino acid leucine from the food that they ingest (consume). This leads to the buildup of isovaleric acid in blood
  • An excess buildup of isovaleric acid can lead to damage of the brain and nervous system, which can eventually lead to seizures, coma, and even death
  • Usually, Isovaleric Acidemia is inherited in an autosomal recessive pattern. This requires that both parents pass on the abnormal gene to their child
  • IVA is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene. Normally, this gene provides instructions for making the isovaleryl-CoA dehydrogenase enzyme, which processes the amino acid leucine
  • When there are mutations in the IVD gene, the isovaleryl-CoA dehydrogenase enzyme does not function properly and isovaleric acid builds up to harmful levels in the body
  • Isovaleric Acidemia exists in two forms:
    • Acute IVA, where the symptoms are persistent
    • Chronic intermittent IVA, where symptoms are not always present
  • A prompt and proper treatment from a very early age is necessary to prevent severe signs and symptoms or adverse complications from developing. The treatment measures include dietary changes, such as having a low-leucine diet, avoidance of certain high-protein foods, and prescription medications
  • The prognosis of Isovaleric Acidemia is improved with early and effective treatment. In the absence of proper treatment, the prognosis is guarded. Children with chronic forms of IVA do better than those with acute forms of IVA

Who gets Isovaleric Acidemia? (Age and Sex Distribution)

  • The worldwide incidence of Isovaleric Acidemia is unknown. But, it affects at least 1 in 250,000 Americans
  • The disorder can onset within a couple of weeks after birth, if the child has acute IVA
  • If the child has chronic intermittent IVA, the onset may be around (or after) the time the child is a year old
  • Both males and females are equally affected

What are the Risk Factors for Isovaleric Acidemia? (Predisposing Factors)

  • Isovaleric Acidemia is a genetic disorder that is passed on in an autosomal recessive pattern. If each parent passes on the mutated isovaleryl-CoA dehydrogenase (IVD) gene, then the child will develop IVA, because the child has two sets of mutated IVD genes
  • If the child only inherits one copy of the mutated IVD gene, then the child becomes a carrier of the condition and will not develop IVA, or show any symptoms

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Isovaleric Acidemia? (Etiology)

  • Isovaleric Acidemia is caused by a mutation to the isovaleryl-CoA dehydrogenase (IVD) gene. This mutation is generally inherited in an autosomal recessive manner
  • When this gene malfunctions, the body is not able to break leucine, an amino acid that makes up many of the proteins found in foods, which one consumes
  • With the inability to break down leucine, isovaleric acid begins to build up in the body. Once isovaleric acid buildup reaches harmful levels, the symptoms of IVA are manifested, which may even become deadly

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Isovaleric Acidemia?

Acute Isovaleric Acidemia begins right after birth of the baby, between 1-15 days. The signs and symptoms of acute IVA include:

  • Metabolic crises
  • Poor appetite
  • Lack of energy, extreme sleepiness
  • Vomiting
  • Odor similar to “sweaty feet”
  • High levels of ammonia in blood
  • Ketones in urine
  • Seizures
  • Swelling of brain
  • Bleeding in brain
  • Coma

Signs of chronic intermittent IVA arise in the child, at or after the child is a year old; although, they may start later, during one’s childhood as well. The signs and symptoms include:

  • Metabolic crises
  • Trouble gaining weight
  • Delayed growth
  • Muscle weakness
  • Learning problems
  • Vomiting
  • Poor appetite
  • Seizures
  • Coma

Children with chronic intermittent Isovaleric Acidemia do not have constant symptoms. Rather, symptoms are intermittently seen - they come and go over time. However, they become worse during times of illnesses, consumption of foods containing high proteins, or during long periods without food (starvation).

How is Isovaleric Acidemia Diagnosed?

Isovaleric Acidemia can be diagnosed using a variety of tests and exams. These include:

  • Physical examination with medical and family history evaluation
  • Isovaleric Acidemia can be diagnosed through genetic testing: Using a blood sample, genetic tests can be conducted to look for mutations on the IVD gene
  • Prenatal diagnosis is also possible by measuring the amount of isovalerylglycine in amniotic fluid, or by measuring isovaleryl-CoA dehydrogenase enzyme activity in chorionic villi or cultured amniocytes

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Isovaleric Acidemia?

The complications of Isovaleric Acidemia include:

  • Metabolic crises often occur in individuals with Isovaleric Acidemia. When too much toxic isovaleric acid builds up in the body, metabolic crisis that is characterized by poor appetite, nausea, vomiting, diarrhea, and behavior changes, occurs
  • Often, metabolic crisis is triggered by illness, infection, long periods of fasting, and even heavy exercising. If the symptoms become severe, then seizures, coma, and even death may occur

How is Isovaleric Acidemia Treated?

If prompt and efficient treatment is provided, children with Isovaleric Acidemia can lead healthy lives with normal growth and development. While most children do see significant improvement and are able to live normal lives, other children continue to experience metabolic crises that may lead to life-long learning problems, mental retardation, or even death by coma or seizure.

  • In order to prevent metabolic crisis, prompt treatment of Isovaleric Acidemia is essential. Although, there is no cure to eliminate IVA, changes in diet have been shown to improve the symptoms
  • A low-leucine diet will help eliminate isovaleric acid buildup in the body
  • It is suggested that milk and dairy products, meat, fish, eggs, dried beans, legumes, nuts, and peanut butter, which are all high in protein (and leucine), be avoided
  • There are also specialized medical foods and formulas that are made for those with such organic acid metabolic disorders. Taking or consuming these products can help reduce the symptoms
  • Medications containing the amino acid glycine, are also often prescribed to individuals with IVA, because glycine helps the body get rid of isovaleric acid, thus helping prevent any metabolic crises
  • Similarly, L-carnitine is often used to get rid of excess isovaleric acid as well
  • If the symptoms of metabolic crisis have already begun, bicarbonate and glucose are often used to help reduce the amount of isovaleric acid in the body

How can Isovaleric Acidemia be Prevented?

  • Currently, there are no specific methods or guidelines to prevent Isovaleric Acidemia genetic condition
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of Isovaleric Acidemia? (Outcomes/Resolutions)

  • If the presence of Isovaleric Acidemia is promptly recognized and treatment started immediately, the outcome of the disorder is better
  • With proper treatment, many individuals are able to lead relatively normal lives, with few episodes of metabolic crisis
  • However, if the symptoms are not treated properly, those with IVA will continue to experience episodes of metabolic crisis, eventually developing mental disabilities, learning problems, which progress to seizures or coma that may ultimately lead to death
  • A high mortality rate is associated with the acute, neonatal form of IVA, when the signs and symptoms are observed within the first few weeks

Additional and Relevant Useful Information for Isovaleric Acidemia:

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Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: Nov. 1, 2014
Last updated: Oct. 17, 2018