October 02, 2020
Years published: 1988, 1989, 2002, 2007, 2020
NORD gratefully acknowledges Sukhdeep Jatana, MDCM Candidate, McGill University School of Medicine, and Jerry Vockley, MD, PhD, Cleveland Family Endowed Chair in Pediatric Research and Professor of Human Genetics, University of Pittsburgh; Chief of Medical Genetics and Director of the Center for Rare Disease Therapy, UPMC Children’s Hospital of Pittsburgh, for assistance in the preparation of this report.
Isovaleric acidemia is a hereditary metabolic disorder, caused by a change (mutation) in the gene encoding the enzyme isovaleryl-CoA dehydrogenase, resulting in deficient or absent activity. This enzyme is responsible for helping break down leucine, an amino acid, and its deficiency leads to a buildup of chemicals in the blood that cause symptoms. The disorder can present with acute intermittent attacks in infancy or later in childhood. The acute attacks are characterized by vomiting, refusal to eat, listlessness, abnormal lab values, and a sweaty foot odor. Chronic symptoms include failure to thrive and developmental delay. Management for this disease includes a low protein diet with leucine restriction, avoiding triggers of acute attacks, and supplementation with carnitine and/or glycine. Though there is no cure, but as patients age, acute attacks become less frequent.
Isovaleric acidemia is a rare metabolic disorder that ranges in severity from asymptomatic to mild or life-threatening symptoms depending on the mutation and factors predisposing acute attacks. Two major clinical scenarios are often described, an acute form and a chronic intermittent form, but in reality the disease is best thought of as a continuous spectrum from asymptomatic to life threatening. A characteristic ‘sweaty feet’ odor is often present in patient sweat or cerumen due to a buildup of isovaleric acid. Patients may develop aversion early to protein-rich foods.
Acute, early symptoms present soon after birth with increasing lethargy, poor feeding and vomiting, progressing to coma. These findings are related to chemical imbalances in the baby including an increase in acid, ammonia, and specific toxic compounds derived from isovaleric acid. Prolonged metabolic stress can lead to low levels of certain types of white blood cells (neutropenia) and other cell types (pancytopenia). Patients may also present with lowered body temperature (hypothermia). After resolution of this first attack, patients typically show the chronic intermittent form of the disease unless severe neurologic damage has occurred due to the original presentation.
After the newborn period chronic intermittent symptoms are usual. Patients can have slowed growth rates (failure to thrive), developmental delay, intellectual disability or symptoms affecting the nervous system such as seizures and spasticity, most commonly related to early acute damage. Patients can also experience acute attacks similar to the newborn period, typically triggered by other illnesses such as infections. Patients can exhibit a chronic picture even if a newborn acute attack has not occurred. Recognition of acute neonatal symptoms has led to newborn screening for isovaleric acidemia in the United States and many other developed studies. If identified prior to the development of symptoms, outcomes are generally better, with normal growth and development. About half of babies identified through newborn screening have a very mild deficiency that remains asymptomatic and requires no therapy.
Isovaleric acidemia is a genetic disorder inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
In patients with isovaleric acidemia, there is a mutation in the IVD gene that inactivates the enzyme isovaleryl-Co-enzyme A (CoA) dehydrogenase. This enzyme is needed for the breakdown of the amino acid leucine into energy.
Isovaleric acidemia is a rare disorder that presents either soon after birth or during infancy. It may present up to adolescence. It affects an equal number of males and females. The prevalence of this condition is 1 per 526,000 in Western populations and the incidence is 1 per 250,000 in the US.
In the United States and some developed countries, isovaleric acidemia is routinely identified by newborn screening through a blood test called tandem mass spectrometry, often designated as MS/MS. In other countries, the diagnosis must be suspected clinically before it can be diagnosed. Laboratory studies that can be useful in symptomatic patients include checking for high levels of acid and ketones (ketoacidosis) in blood, high levels of glycine in the blood or urine (hyperglycinemia and hyperglycinuria), high levels of ammonia (hyperammonemia), or low levels of certain white blood cells (neutropenia), platelets (thrombocytopenia) or all blood cell types (pancytopenia). The diagnosis is then confirmed by DNA testing. Less commonly, certain types of cells from the body (white blood cells, skin cells) may be sampled from the patient and tested to confirm decreased or deficient activity of the enzyme isovaleryl-CoA dehydrogenase.
In families in whom a previous child has been affected, isovaleric acidemia can be diagnosed before birth (prenatally) by measuring the concentration of abnormal metabolites in amniotic fluid, the activity of the isovaleryl-CoA dehydrogenase enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS], or testing of fetal tissue or amniocytes for a DNA changes (mutations) identified in the first child
While there is no cure of isovaleric acidemia, outcome is usually good if severe neonatal symptoms are avoided or treated rapidly. Patients should be followed regularly by a geneticist or metabolic physician familiar with management of organic acidemias. Frequency of follow-up is determined by the severity of the disease and the frequency of acute attacks. Patient should be monitored for growth, development, and dietary history. Additional testing should include blood acid levels, blood counts, and electrolytes. Additionally, physicians may monitor for complications and do examinations of the nervous system, liver, or other organs.
Supplementation with L-carnitine or glycine allows increased removal of acids form the blood by the kidney. Patients typically require a low protein diet to avoid overconsumption of the amino acid leucine. However, patients need enough protein in their diet to meet the body’s demands, which increase over time with growth. However, it may be impossible for patients with severe disease to eat enough natural protein to meet bodily requirements. In this case, use of medical foods that do not include leucine is necessary. A dietician should be available to also help families with creating a low-protein diet for the patient.
During acute attacks, protein should be reduced or withheld for 24 hours with a subsequent increase in low protein, high sugar foods to maintain calorie intake. If a patient cannot eat, hospitalization is required so that glucose can be provided by intravenous fluids. Other metabolic abnormalities such as high ammonia may need to be corrected depending on the individual patient’s clinical findings. A return to the patient’s standard diet can usually be achieved over the course of a few days.
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