Jerry Vockley, M.D., Ph.D.

Regina Ensenauer, M.D.

Background:

Isovaleric acidemia (IVA) is an inborn error of the branched-chain amino acid leucine caused by a deficiency of the enzyme isovaleryl-CoA dehydrogenase (IVD). It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. It can present as a severe, potentially life-threatening disorder manifesting with acute neonatal coma in about half of affected individuals (“acute form”), and recurrent episodes of vomiting, lethargy, and varying degrees of developmental delay in the other half of patients (“chronic form”). Affected patients are at risk of episodes of acute acidosis and metabolic decompensation, usually due to intercurrent illnesses or other physiologic stress including fasting. During times of poor metabolic control the patient may present with the typical odor of isovaleric acid, also called “sweaty feet odor”. More recently, a third group of individuals with mild metabolite abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. DNA studies of the IVD gene from patients with IVA have allowed characterization of different types of mutations in this gene. One gene mutation, 932C>T (substituting the amino acid valine for alanine at position 282 in the IVD protein), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. However, the consequences of this mutation regarding clinical outcome and the necessity of therapy are still unknown.

Treatment: 

The majority of patients with IVA today are diagnosed pre-symptomatically through newborn screening by use of MS/MS which reveals elevations of the marker metabolite C5 acylcarnitine in dried blood spots. Isovalerylcarnitine in plasma and isovalerylglycine in urine are the hallmarks of this disorder, and are elevated regardless of a patient’s metabolic condition. There are three aspects of therapy of IVA: 1) prevention of metabolic crisis; 2) dietary restriction of protein; 3) medication with carnitine (with or without glycine). 

Prevention of metabolic crisis: Careful clinical observation of the patient regardless of the severity of IVA is required during times of metabolic stress (including illness and fasting).  Sick day precautions for patients with IVA should include increased caloric intake in addition to decreased leucine intake. This is accomplished with oral solutions containing simple sugars and leucine free metabolic formulae or powders. Acute episodes of metabolic decompensation can present with vomiting, lethargy and signs of acidosis. Under these circumstances, immediate hospitalization is required so that IV access can be established and glucose administered. IV insulin may become necessary to maintain normal glucose levels in the blood. Reintroduction of oral intake including protein (0.5 gm/kg per day) with leucine should occur as soon as it can be tolerated, otherwise parenteral amino acids should be provided.

Dietary restriction of protein: If a child with IVA is on a protein-restricted diet, total protein and caloric intake must be adequate to support normal growth, and thus monitoring of weight, length and head circumference is essential at follow up. In many cases, it may be sufficient to moderately reduce protein intake with natural foods to approximately 1.5 gm/kg per day. In patients with severe and recurrent clinical symptoms, leucine restriction in excess of total natural protein may also be necessary. The protein necessary to reach the recommended age-appropriate daily requirement must then be provided with leucine-free amino acids. Because leucine is important for protein build-up in the body, leucine restriction should not be too stringent to avoid potential side effects including muscle wasting.    

Medication: The third aspect of therapy in patients with IVA is medication with carnitine with or without glycine in order to prevent toxic metabolites from accumulating in the body. Recognition of isovalerylglycine in urine in the initial patients with IVA first led to the use of glycine as a mediation for this disorder. Isovaleryl-CoA is linked to glycine in a reaction that can be enhanced with extra glycine. Such supplementation prevents or lowers the accumulation of isovaleric acid in blood and reduces the length and severity of symptoms during febrile illnesses, but the optimum dose has not been determined. Patients show a dose sensitive increase in excretion of isovaleryglycine, but at least in one report an increase in the glycine dose from 300 to 600 mg/kg of body weight led to a decrease in the excretion of isovalerylglycine. Therefore, initial dosing in the range of 150 to 250 mg/kg per day is reasonable in patients with severe IVA. No reports of glycine toxicity have been published.

The identification of isovalerylcarnitine in blood and urine along with the frequent observation of a reduction in free carnitine levels in patients with IVA has prompted treatment with carnitine. A dose of 100 mg/kg body weight per day has generally been suggested and has been shown to increase the excretion of isovalerylcarnitine in urine. Combined therapy with carnitine and glycine has been shown to maximize the total excretion of isovaleryl-CoA conjugates, but the relative merits of the two therapies either singly or together in patients with more severe presentations including recurrent crises remains a matter of debate.

The optimal treatment for individuals diagnosed by newborn screening and carrying the common 932C>T (A282V) mutation is unclear at this point in time. Specifically, the potential for metabolic decompensation remains to be elucidated. It is important to observe affected individuals clinically, particularly when exposed to metabolic stressors such as febrile illnesses or fasting (e.g. when undergoing surgery). Additionally, low-dose carnitine supplementation (approximately 50 mg/kg body weight per day) is recommended if the plasma free carnitine concentration is reduced.

A better understanding of the variability of IVA and the clinical management of patients are among the challenges remaining in the study of this disorder in the upcoming years.

References:

Vockley J and Ensenauer R. Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity. Am J Med Genet (in press, 2006). 

Ensenauer R, Vockley J, Willard JM, Huey JC, Sass JO, Edland SD, Burton BK, Berry SA, Santer R, Grünert S, Koch HG, Marquardt I, Rinaldo P, Hahn S, Matern D (2004). A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. Am J Hum Genet 75:1136-1142.