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Acute metabolic decompensation in an adult patient with isovaleric acidemia. (Case Report).

Abstract: Isovaleric acidemia is a rare autosomal recessive inborn error of leucine catabolism caused by deficiency of isovaleryl coenzyme A dehydrogenase. This enzymatic deficiency leads to severe metabolic derangement, manifested clinically as vomiting, dehydration, and acidosis progressing to seizures, coma, and death. The two phenotypic expressions are the acute severe and the chronic intermittent form. The acute severe phenotype typically results in death during early infancy, whereas patients with the chronic intermittent form are asymptomatic at baseline but have episodes of acute metabolic decompensation, usually in the setting of infection, physical exertion, or ingestion of protein-rich food. This case illustrates how inborn errors of metabolism resulting in organic acidemia can be manifested in adults and why the internist needs to be aware of them.


Key Points

* Isovaleric acidemia is a rare autosomal recessive disorder of leucine catabolism.

* Diagnosis of isovaleric acidemia requires a high degree of clinical suspicion.

* If left untreated, isovaleric acidemia leads to acidemia, seizures, coma, and death.

* Administration of carnitine and glycine is effective as an abortive and preventive therapy.

* Isovaleric acidemia is a diagnosis that is no longer applicable only to pediatric patients.

Isovaleric acidemia (IVA) is a rare inborn error of L-leucine catabolism, caused by deficiency of isovaleryl coenzyme A dehydrogenase. The natural history of IVA is characterized by severe metabolic derangement leading to coma, seizure, and death. With prompt diagnosis and institution of effective therapy, children with IVA can have normal growth and development. (1,2) Thus, internists must be able to recognize and treat these patients. The Online Mendelian Inheritance of Man (OMIM) number for IVA is 243500. OMIM is an invaluable tool in medical genetics and can be found at Although a review of the literature reveals only two cases of isovaleric acidemia in adults, these two cases illustrate how IVA can cause morbidity in adults. (3,4) We present the case of an 18-year-old man with severe nausea, vomiting, and obtundation due to metabolic decompensation of IVA.


In 1966, Tanaka et al (6) reported the first two cases of isovaleric acidemia. In this landmark publication, they described two siblings who had an unusual syndrome characterized by periodic episodes of acidosis and coma, with a prominent and offensive body odor. These children were referred to the Food and Flavor Laboratory, where two chemists (Sjostrim and Kendall) recognized the children's scent as being typical of short-chain fatty acids. With this olfactory clue, they developed gas chromatographic techniques to measure short-chain fatty acids in serum. This led to the discovery of a new inborn error in amino acid metabolism, isovaleric acidemia. (7) Gas chromatography-mass spectrometry (GC-MS) remains the assay of choice for the evaluation of known organic acidemias, as well as the discovery of new ones.

Isovaleric acidemia is an autosomal recessive disorder with an incidence of approximately 1 in 230,000. It occurs in all racial and socioeconomic groups. It is caused by a deficiency of isovaleryl coenzyme A dehydrogenase. The gene for this enzyme is located on the short arm of chromosome 15. Isovaleryl CoA dehydrogenase, which is located in the mitochondria, is important for metabolism of L-leucine. Deficiency of this enzyme results in accumulation of leucine catabolism byproducts, particularly isovaleryl carnitine, isovalerylglycine, 3-hydroxyisovaleric acid, and isovaleric acid itself. The accumulation of the last two metabolites above a toxic threshold, as well as the secondary carnitine deficiency that develops, produces the clinical syndrome of isovaleric acidemia (Fig. 1). Carnitine stores are depleted rapidly in an effort to decrease the accumulation of the aforementioned toxic metabolites. The resulting carnitine deficiency can lead to heart failure, conduction disturbances, or sensitivity to other potentially cardiotoxic medications.

The autosomal recessive deficiency of isovaleryl CoA dehydrogenase can result in one of two phenotypic expressions. The first is the acute severe neonatal form, which leads to death in the first year of life. The second is the chronic intermittent form, which is more likely to be encountered by physicians who care for adults. The first episode usually occurs in the first year of life. Episodes typically follow infection or ingestion of protein-rich food. The frequency of episodes is highest during infancy and then subsequently declines. These episodes resolve with protein restriction and infusion of glucose. Table 1 lists clinical features associated with isovaleric acidemia.

The diagnosis of isovaleric acidemia requires a high clinical suspicion. Analysis of the patient's plasma for short-chain fatty acids will reveal elevated isovaleric acid, isovalerylglycine, isovaleryl carnitine, and 3-hydroxyisovaleric acid. Other short-chain fatty acids will not be elevated. This test is difficult to perform and is often not readily available. However, several biochemical genetics laboratories are able to do such analysis. (A list of relevant laboratories can be found at The urine can be analyzed for nonvolatile organic acids. One will find dramatic elevation of isovalerylglycine and 3-hydroxyisovaleric acid levels during an attack. Urinary isovalerylglycine will remain elevated even during remission and is the only biochemical abnormality detectable when the patient is well. The standard is an assay of fibroblasts or leukocytes for deficiency of isovaleryl CoA dehydrogenase by tritium release. (8,9)

Effective therapy is available. During remission the goal of therapy is to prevent acute attacks of isovaleric acidemia by minimizing the accumulation of isovaleric acid and 3-hydroxyisovaleric acid, as well as to prevent the depletion of carnitine stores. This is accomplished by restriction of natural dietary protein to age-adjusted leucine requirements and supplementation with a leucine-free medical food as a source of other amino acids. (10-12) Avoidance of infection and activity that will increase endogenous protein catabolism are important as well. Long-term maintenance therapy with glycine and carnitine has been shown to be effective in case series. (1,2) The administration of carnitine is particularly important, since it prevents the accumulation of toxic metabolites, as well as the development of carnitine deficiency and its association morbidity. During an acute episode, management consists of nonspecific and specific measures directed at reducing levels of toxic metabolites. Stopping oral intake of protein and administering intravenous glucose to provide a calorie source, thereby decreasing endogenous protein catabolism, are nonspecific ways to decrease leucine catabolism. Oral administration of glycine, up to 600 mg/kg/d, and/or carnitine, 25 mg/kg every 6 hours, has proved effective in reversing the biochemical abnormalities associated with acute isovaleric acidemia. (13-19) The Figure shows the mechanism by which glycine and carnitine administration functions. Finally, as this case so poignantly illustrates, thorough medical and genetic counseling is necessary to educate patients on disease prevention.


Isovaleric acidemia is a rare autosomal recessive disorder of L-leucine catabolism manifested as either the acute severe form or the chronic intermittent form. Affected individuals who survive infancy tend to develop an innate aversion to protein-rich foods and self-impose a protein-restricted diet. This can result in their presentation later in life. Clinical scenarios that impede the patient's ability to maintain a low-protein diet or increase protein catabolism, such as infection or physical training, lead to elevated L-leucine catabolism and clinically apparent isovaleric acidemia. When patients present with acidosis, mental status changes, and peculiar odors, clinicians must consider inborn errors in metabolism that result in organic acidemia. When evaluating anion gap metabolic acidosis, the "I" in the mnemonic "MUDPILES" should also represent inborn errors of metabolism. (20)
Table 1

Clinical features of chronic intermittent isovaleric acidemia

Lethargy progressing to coma
Elevated ammonium level
Characteristic odor of sweaty feet
Psychomotor development ranging from
 normal to severe retardation

Accepted February 14, 2002.


(1.) Mayatepek E, Kurczynski TW, Hoppel CL. Long-term L-carnitine treatment in isovaleric acidemia. Pediatr Neural 1991;7:137-140.

(2.) Berry GT, Yudkoff M, Segal S. Isovaleric acidemia: Medical and neuro-developmental effects of long-term therapy. J Pediatr 1988;113:58-64.

(3.) Weinberg GL, Laurito CE, Geldner P, Pygon BH, Burton BK. Malignant ventricular dysrhythmias in a patient with isovaleric acidemia receiving general and local anesthesia for suction lipectomy. J Clin Anesth 1997;9:668-670.

(4.) Shih VE, Aubry RH, DeGrande G, Gursky SF, Tanaka K. Maternal isovaleric acidemia. J Pediatr 1984;105:77-78.

(5.) DeGowin RL. DeGowin and DeGowin's Diagnostic Examination. New York, McGraw-Hill, 1987, ed 6, p 197.

(6.) Tanaka K, Budd MA, Efron ML, Isselbacher KJ. Isovaleric acidemia: A new genetic defect of leucine metabolism. Proc Natl Acad Sci U S A 1966;56:236-242.

(7.) Budd MA, Tanaka K, Holmes LB, Efron ML, Crawford JD, Isselbacher KJ. Isovaleric acidemia: Clinical features of a new genetic defect of leucine metabolism. N Engl J Med 1967;277:321-327.

(8.) Scriver CR, Beaudet AL, Valle D, Sly WS, Childs B, Kinzler KW, et al (eds). The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 2001, vol 2, ed 8, pp 2130-2138.

(9.) Hyman DB, Tanaka K. Isovaleryl-CoA dehydrogenase activity in isovaleric acidemia fibroblasts using an improved tritium release assay. Pediatr Res 1986;20:59-61.

(10.) Lott IT, Erickson AM, Levy HL. Dietary treatment of an infant with isovaleric acidemia. Pediatrics 1972;49:616-618.

(11.) Levy HL, Erickson AM, Lott IT, Kurtz DJ. Isovaleric acidemia: Results of family study and dietary treatment. Pediatrics 1973;52:83-94.

(12.) Millington DS, Roe CR, Maltby DA, Inoue F. Endogenous catabolism is the major source of toxic metabolites in isovaleric acidemia. J Pediatr 1987;110:56-60.

(13.) Krieger I, Tanaka K. Therapeutic effects of glycine in isovaleric acidemia. Pediatr Res 1976;10:25-29.

(14.) Naglak M, Salvo R, Madsen K, Dembure P, Elsas L. The treatment of isovaleric acidemia with glycine supplement. Pediatr Res 1988;24:9-13.

(15.) Itoh T, Ito T, Ohba S, Sugiyama N, Mizuguchi K, Yamaguchi S, et al. Effect of carnitine administration on glycine metabolism in patients with isovaleric acidemia: Significance of acetylcarnitine determination to estimate the proper carnitine dose. Tohoku J Exp Med 1996;179:101-109.

(16.) Fries MH, Rinaldo P, Schmidt-Sommerfeld E, Jurecki E, Packman S. Isovaleric acidemia: Response to a leucine load after three weeks of supplementation with glycine, L-camitine, and combined glycine-earnitine therapy. J Pediatr 1996;129:449-452.

(17.) Roe CR, Millington DS, Maltby DA, Kahler SG, Bohan TP. L-carnitine therapy in isovaleric acidemia. J Chin Invest 1984;74:2290-2295.

(18.) Cohn RM, Yudkoff M, Rothman R, Segal S. Isovaleric acidemia: Use of glycine therapy in neonates. N Engl J Med 1978;299:996-999.

(19.) Yudkoff M, Cohn RM, Puschak R, Rothman R, Segal S. Glycine therapy in isovaleric acidemia. J Pediatr 1978;92:813-817.

(20.) Mehta KC, Zsolway K, Osterhoudt KC, Krantz I, Henretig FM, Kaplan P. Lessons from the late diagnosis of isovaleric acidemia in a five-year-old boy. J Pediatr 1996;129:309-310.

(21.) Amiel J, de Lonlay P, Francannet C, Picard A, Bruel H, Rabier D, et al. Facial anomalies in D-2-hydroxyglutaric aciduria. Am J Med Genet 1999;86:124-129.


An 18-year-old male U.S. Air Force recruit, in Day 3 of basic training, came to the emergency department with severe nausea, vomiting, and mental status changes. He reported that he had been in good health until the previous day. He denied fever, chills, sweats, abdominal pain, diarrhea, shortness of breath, cough, chest pain, or headaches. The nausea had begun 18 hours before presentation, with rapid progression to intractable vomiting. During the previous 6 hours, he had had more than 30 episodes of bilious, nonbloody emesis. He denied the use of alcohol, tobacco, or illicit drugs. He was not taking any medications. At the time, he reported no medical or surgical history. His mother, father, and younger sister were all healthy.

The patient was afebrile and normotensive, with a heart rate 93/mm, respiratory rate 22/mm, and oxygen saturation by pulse oximetry 95% on room air. Inspection revealed a young, fit appearing man with tachypnea, despite his depressed level of consciousness. A prominent and offensive body odor, similar to that of sweaty feet, filled the examining room. Inspection of the skin revealed cutis verticis gyrata. He was markedly somnolent, arousable only to painful stimulus. The remainder of the physical examination was unremarkable. Routine laboratory evaluation revealed an anion gap metabolic acidosis (anion gap of 23) and respiratory alkalosis, in the absence of a potential bicarbonate (pH, 7.31; [PCO.sub.2], 25 mm Hg; [PaO.sub.2], 114 mm Hg; [HCO.sub.3], 15 mmol/L). With the exception of an elevated NH4 (146 mg/dl), liver function studies were within normal limits. Despite a normal glucose value (86 mg/dl), the tests for serum and urine ketones were positive. Complete blood count was normal.

The patient was admitted to the hospital, was administered nothing by mouth, and was treated aggressively with hydration with intravenous normal saline. On hospital Day 2, his mental status improved slightly and further history was obtained. In early childhood, he was found to have isovaleric acidemia and was placed on a low-protein diet. He had had similar episodes, provoked by dietary indiscretion, approximately once per year until the age of 15. During the previous 3 years, he had had no further clinical manifestations and assumed he had "outgrown" the isovaleric acidemia. During the same period, however, he strictly adhered to his low-protein diet. It is likely that the rigors of basic training resulted in a catabolic demand that led to his acute presentation.

On the basis of the additional history, intravenous fluid therapy was changed to 5% dextrose in normal saline. To confirm the diagnosis, we measured the short-chain fatty acids in the urine. During the next 5 days, the clinical and metabolic derangement abated. In hope of preventing future decompensation, we counseled the patient regarding disease modifying diet and behavior patterns. He was given camitine and glycine supplementation and discharged from the hospital. Follow-up laboratory tests (Quest Diagnostics, Inc., San Juan Capistrano, CA) revealed dramatic elevations in the urinary levels of both isovalerylglycine (1,900 mmol/L/M Cr) and 3-hydroxyisovaleric acid (221 mmol/L/M Cr), with normal values being 0 to 5 and less than 58 mmol/L/M Cr, respectively. At the time of discharge, his chemistry, blood gas, and [NH.sub.4] values had returned to normal.

From the Department of Internal Medicine, Wilford Hall Medical Center, Lackland AFB, TX.

The views presented in this article represent those of the authors and not the U.S. Department of Defense or the U.S. Air Force.

Reprint requests to Jeffrey A. Feinstein, MD, Department of Rheumatology, 2200 Bergquist Drive, Suite 1, Lackland AFB, TX 78236.

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Title Annotation:medical research; includes symptoms table
Author:O'Brien, Kevin
Publication:Southern Medical Journal
Geographic Code:1U7TX
Date:May 1, 2003
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