What is Isovaleric Acidemia?

Cause and symptoms
Forms of IVA
Case report
Diagnosis and treatment
Further reading

Tanaka and colleagues first described isovaleric acidemia (IVA), a rare genetic condition of leucine metabolism, in 1966.

A hereditary deficit of the enzyme isovaleryl-CoA dehydrogenase (IVD), which catalyzes the third stage in leucine catabolism, causes IVA. Isovaleric acidemia can cause various health concerns, ranging from minor to life-threatening. 

Poor eating, tremors, and vomiting are some of the symptoms. IVA occurs in acute and chronic forms following the autosomal recessive inheritance pattern. Diagnosis is based on clinical presentation and laboratory analysis of blood and urine.

​​​​​​​Image Credit: H_Ko/Shutterstock.com​​​​​​​Image Credit: H_Ko/Shutterstock.com

Cause and symptoms

Isovaleric acidemia is caused by IVD (isovaleryl-CoA dehydrogenase) gene mutations. Till now, more than 35 mutations have been reported in the literature. The IVD gene gives instructions for producing an enzyme that aids the digestion of proteins in the diet.

This enzyme aids in processing the amino acid leucine, which is found in many proteins. The body cannot adequately break down leucine if a mutation in the IVD gene decreases or eliminates the activity of this enzyme.

As a result, hazardous levels of an organic acid called isovaleric acid and related chemicals build up in the body.

The brain and nerve system are damaged due to this buildup, resulting in major health issues. Isovaleric acidemia has an autosomal recessive inheritance pattern.

IVA appears to have a wide range of clinical manifestations, ranging from severely impacted to asymptomatic individuals. Symptoms like vomiting, low muscle tone, tremors, lack of energy, poor feeding, and odor of sweaty feet are common.

A majority of patients also experience global developmental delay and metabolic acidosis. Seizure and cerebellar hemorrhage has also been observed.

Isovaleric Acidemia (IVA)

Forms of IVA

There are two types of IVA: acute and chronic intermittent. An acute episode, like an infection, can occur in any pattern during a catabolic state. Infections of the upper respiratory tract or a high-protein diet can set off the episodes.

If not treated effectively, an acute form causes vomiting and severe acidosis in the early stages of life, followed by lethargy, convulsions, coma, and death. The stink of sweaty feet or rancid cheese may be prevalent.

The first clinical presentation in the milder chronic intermittent pattern may not appear until the child is a few months or a year old. In other situations, the signs and symptoms of isovaleric acidemia first present in childhood and then fade away.

Children with this disorder may struggle to gain weight and grow normally, and their development is generally delayed.

Prolonged periods without food, fasting, infections, or eating more protein-rich foods can cause serious health problems in these youngsters.


Isovaleric acidemia is estimated to have a prevalence of around one in 100,000 persons.

The prevalence varies in different parts of the world, ranging from 1 in 67,000 in Germany to 1 in 775,000 in Australia.

Case report

The case of a six-month-old child was reported by Khan et al. in 2020. When admitted, she had a seven-day history of cough, fever, stridor, vomiting, and respiratory distress.

On initial examination, the patient appeared lethargic and dehydrated, with Kussmaul breathing. Metabolic acidosis was discovered through blood gas analysis. She had previously been hospitalized on several occasions and required acute care on two occasions.

It's worth noting that the patient was healthy and asymptomatic when she wasn't ill. Although her birth history was uneventful, one of her siblings died from the same illness.

The parents were found to be second-degree consanguineous. Urine organic acid analysis using gas chromatography-mass spectrometry revealed that 3-hydroxybutyric acid was excreted in large amounts, whereas 3-hydroxy-isovaleric acid was evacuated moderately.

The diagnosis of isovaleric acidemia was made based on the patient's medical history, physical examination, and test results. Fluid resuscitation, metabolic acidosis correction, antibiotics, and supportive care were used to treat the patient.

When individuals arrive with periodic vomiting, lethargy, and respiratory distress (and are products of a consanguineous marriage), organic acidemia should be included in the differential diagnosis, even if the patient appears normal in between episodes.

Diagnosis and treatment

The characteristic symptoms, clinical exam, and blood and urine testing are used to diagnose isovaleric acidemia. Genetic testing results may aid in the confirmation of the diagnosis.

IVA can be detected through newborn screening (NBS) as well. However, some persons who test positive for IVA as newborns may never have symptoms. IVA is an attractive candidate for NBS programs due to the possibility of pre-symptomatic identification by NBS and the apparent benefit established for patients detected and treated early.

More people will be detected when IVA becomes a target disorder of NBS programs in many nations worldwide.

IVA treatment focuses on symptom management and avoiding a metabolic crisis. A better outcome is linked to early diagnosis and treatment. A particular protein-restricted diet and drugs are used to minimize the amount of isovaleric acid in the body.

High-protein foods like fish, eggs, meat, nuts, and dairy products must be limited. Fasting and infections, which can create a metabolic crisis in children with the chronic, intermittent form of IVA, should be avoided.


Further reading

Last Updated: Sep 12, 2023


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