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Isovaleric acidemia, also called isovaleric aciduria or isovaleric acid CoA dehydrogenase deficiency, is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.
In about half of cases, the signs and symptoms of this disorder become apparent within a few days after birth and include poor feeding, vomiting, seizures, and lack of energy that can progress to coma. These medical problems are typically severe and can be life-threatening. In the other half of cases, the signs and symptoms of the disorder appear during childhood and may come and go over time. They are often triggered by an infection or by eating an increased amount of protein-rich foods.
The urine of newborns can be screened for isovaleric acidemia using mass spectrometry, allowing for early diagnosis. Elevations of isovalerylglycine in urine and of isovalerylcarnitine in plasma are found.
The disorder has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene - one from each parent - must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.
Mutations in both copies of the IVD gene result in isovaleric acidemia.
The enzyme encoded by IVD, isovaleric acid-CoA dehydrogenase (EC 184.108.40.206), plays an essential role in breaking down proteins from the diet. Specifically, the enzyme is responsible for the third step in processing leucine, an essential amino acid. If a mutation in the IVD gene reduces or eliminates the activity of this enzyme, the body is unable to break down leucine properly. As a result, isovaleric acid and related compounds build up to toxic levels, damaging the brain and nervous system.
Treatment consists of dietary protein restriction, particularly leucine. During acute episodes, glycine is sometimes given, which conjugates with isovalerate forming isovalerylglycine, or carnitine which has a similar effect.
Elevated hydroxyisovalerate is a clinical marker of biotin deficiency. Without biotin, leucine and isoleucine cannot be fully metabolized. This leads to the formation of hydroxyisovalerate instead of the normal useful byproducts of leucine and isoleucine catabolism. Elevated hydroxyisovalerate can be caused by genetic conditions or dietary deficiency of biotin, and many patients with organic acidemias related to incomplete leucine catabolism can benefit from supplemental biotin. Biotin deficiency on its own can have severe physiological and cognitive consequences  that closely resemble symptoms of organic acidemias.
- Online 'Mendelian Inheritance in Man' (OMIM) 243500
- Lee, Yw; Lee, Dh; Vockley, J; Kim, Nd; Lee, Yk; Ki, Cs (September 2007). "Different spectrum of mutations of isovaleryl-CoA dehydrogenase (IVD) gene in Korean patients with isovaleric acidemia". Molecular genetics and metabolism 92 (1–2): 71–7. doi:10.1016/j.ymgme.2007.05.003. PMID 17576084.
- Dionisi-Vici C, Deodato F, Raschinger W, Rhead W, Wilcken B (2006). "Classical organic acidurias, propionic aciduria, methylmalonic aciduria, and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry". J Inherit Metab Dis. 29 (2–3): 383–389. doi:10.1007/s10545-006-0278-z. PMID 16763906.
- Tokatli A, Oskun T, Ozalp I (1998). "Isovaleric acidemia. Clinical presentation of 6 cases". Turk J Pediatr. 40 (1): 111–119. PMID 9673537.
- Organic Acidemia Association
- Isovaleric acidemia at NLM Genetics Home Reference
- -187695062 at GPnotebook
- GeneReviews: The Organic Acidemias