Isovaleric acidemia (IVA) is an inherited metabolic disorder that affects the body’s ability to process a specific protein building block, an amino acid. It is an organic acid disorder where the body accumulates certain acids. These abnormal levels can become harmful, leading to various health complications.
Understanding Isovaleric Acidemia
Isovaleric acidemia stems from the body’s inability to properly break down leucine, an amino acid found in many proteins. Normally, leucine is processed to provide energy. In individuals with IVA, there is a deficiency or absence of the enzyme isovaleryl-CoA dehydrogenase (IVD), which is responsible for the third step in the leucine degradation pathway.
This enzyme converts isovaleryl-CoA, a metabolic intermediate, into 3-methylcrotonyl-CoA. When the IVD enzyme is not functioning correctly, isovaleryl-CoA and its derivatives, including isovaleric acid, accumulate in the blood and tissues. This buildup of toxic substances can damage the brain and nervous system, leading to serious health problems.
Recognizing the Signs
The signs and symptoms of isovaleric acidemia vary significantly in severity, from mild to life-threatening. In about half of cases, symptoms appear within a few days after birth, representing an acute or neonatal onset. These initial symptoms often include poor feeding, vomiting, lethargy, and seizures, which can progress to coma. A distinctive “sweaty feet” odor is a characteristic sign during acute illness, caused by isovaleric acid buildup.
For other individuals, signs and symptoms may appear later in childhood and fluctuate over time, indicating a chronic or intermittent form. These children might experience failure to gain weight and grow, along with developmental delays. Episodes of more severe health problems, known as metabolic crises, can be triggered by prolonged periods without food, infections, or increased protein intake.
Genetic Basis and Inheritance
Isovaleric acidemia is an inherited condition in an autosomal recessive pattern. This means a child must inherit two copies of the non-working gene—one from each parent—to be affected. The specific gene involved is the IVD gene, which provides instructions for making the isovaleryl-CoA dehydrogenase enzyme.
Parents who carry one working copy and one non-working copy of the IVD gene are unaffected themselves. If both parents are carriers, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two non-working genes and develop isovaleric acidemia. Many families have no prior history of the condition before the birth of an affected child.
Diagnosis and Management
Diagnosis of isovaleric acidemia often begins with newborn screening, typically performed using a heel prick test shortly after birth. This screening measures elevated isovalerylcarnitine (C5 acylcarnitine) levels, which can indicate the condition. An out-of-range screening result necessitates further follow-up testing.
Confirmatory tests include urine organic acid analysis, which often shows elevated isovalerylglycine, and plasma acylcarnitine analysis. Genetic testing of the IVD gene provides a definitive diagnosis by identifying specific mutations. Early diagnosis is important for prompt treatment to prevent serious health problems.
Management of isovaleric acidemia involves several key approaches. A primary strategy is dietary restriction of leucine, a low-protein diet tailored to individual needs to prevent toxic metabolite buildup. Specialized leucine-free formulas may also be used. Supplementation with L-carnitine and glycine helps the body excrete excess isovaleric acid by converting it into non-toxic forms like isovalerylcarnitine and isovalerylglycine, which are then eliminated in urine.
During metabolic crises, emergency protocols involve stopping all protein intake, providing high-calorie hydration, and sometimes administering intravenous glucose and L-carnitine. Lifelong management and regular monitoring are important for individuals with isovaleric acidemia.