Isovaleric Acidemia

Alternative Names

  • IVA
  • Isovaleric Acid CoA Dehydrogenase Deficiency
  • IVD Deficiency
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WHO-ICD-10 version:2010

Endocrine, nutritional and metabolic diseases

Metabolic disorders

OMIM Number

243500

Mode of Inheritance

Autosomal recessive

Gene Map Locus

15q14-q15

Description

Isovaleric acidemia (IVA) is a branched-chain amino acidemia characterized by a defect in the catabolism of leucine and the build-up of isovaleryl CoA in the body. A characteristic feature of the acute state of the condition is a distinctive odor of sweaty feet, caused by the accumulation of isovaleric acid. Other symptoms, such as loss of appetite, lethargy, vomiting, hypotonia, seizures, and cardiac abnormalities are similar to other organic acidemias. The condition is estimated to affect 1 in every 250,000 individuals.

Diagnosis, as in the case of other organic acidemias, relies on chromatography followed by mass spectrometric analysis. Tandem Mass Spectrometry of hell stick dried blood spots is one of the most widely used methods, in which presence of elevated levels of the compound acylcarnitine are looked out for. The result of TM is combined with that of urinalysis to make a confirmed diagnosis. The urinalysis is especially required to rule out 2-methylbutyryl CoA dehydrogenase deficiency. It is also possible to measure the level of isovalyrylglycine in the amniotic fluid, or IVD activity in chorionic villi samplings, as a prenatal diagnostic method. The first step in treatment is to reduce the dietary intake of leucine. Infections need to be handled carefully, since the leucine stored in proteins tends to be released during such states. It is important to monitor the growth, development, and biochemical parameters of affected children at frequent intervals. Early detection and proper management results in normal development.

Molecular Genetics

IVA results from mutations in the IVD gene, which codes for the IVD enzyme. The IVD enzyme plays an important role in the metabolism of lysine in the body. Mutations in this gene result in defective or no production of the enzyme, causing a build up of isovaleric acid in the body. This accumulation is harmful, especially in the brain and nervous system, and causes the signs and symptoms of this condition.

Mutations in the IVD gene can be point mutations or large deletions and insertions. About 60% of affected patients show loss of function of the enzyme, whereas the remaining 40% have absolutely no production of the enzyme at all.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
243500.1.1Saudi ArabiaMaleYesYes Acidosis; Episodic vomiting; LethargyNM_002225.5:c.1172G>THomozygousAutosomal, RecessiveKaya et al. 2013 Index patient
243500.1.2Saudi ArabiaYesYes Acidosis;NM_002225.5:c.1172G>THomozygousAutosomal, RecessiveKaya et al. 2013 Sibling of 243500.1....
243500.1.3Saudi ArabiaYesYes Acidosis;NM_002225.5:c.1172G>THomozygousAutosomal, RecessiveKaya et al. 2013 Sibling of 243500.1....
243500.2United Arab EmiratesFemaleNoYes Metabolic acidosis; Body odorNM_002225.4:c.1136_1138+4delHomozygousAutosomal, RecessiveHertecant et al. 2012
243500.3United Arab EmiratesMaleNoYes Metabolic acidosis; Body odor; Vomiti...NM_002225.5:c.1184G>AHomozygousAutosomal, RecessiveHertecant et al. 2012
243500.4United Arab EmiratesFemaleNoYes Metabolic acidosis; Body odor; Feedi...NM_002225.5:c.1184G>AHomozygousAutosomal, RecessiveHertecant et al. 2012 The patient has a yo...
243500.5.1United Arab EmiratesMaleNoYes Metabolic acidosis; Feeding difficult...NM_002225.5:c.1175G>AHomozygousAutosomal, RecessiveHertecant et al. 2012 Index patient
243500.5.2United Arab EmiratesFemaleNoYes Metabolic acidosis; VomitingNM_002225.5:c.1175G>AHomozygousAutosomal, RecessiveHertecant et al. 2012 Sister of 243500.5.1
243500.5.3United Arab EmiratesFemaleNoYes AsymptomaticNM_002225.5:c.1175G>AHomozygousAutosomal, RecessiveHertecant et al. 2012 Sister of 243500.5.1
243500.5.4United Arab EmiratesNoYes Aborted fetusNM_002225.5:c.1175G>AHomozygousAutosomal, RecessiveHertecant et al. 2012 Sibling of 243500.5....
243500.6EgyptMaleYesYes Metabolic acidosis; Body odor; Atten...NM_002225.5:c.1222G>AHomozygousAutosomal, RecessiveHertecant et al. 2012 The patient had an o...
243500.G.1United Arab Emirates Metabolic acidosisNM_002225.5:c.286+5G>THomozygousAutosomal, RecessiveAl-Shamsi et al. 2014 Group of unknown num...
243500.G.2United Arab Emirates Metabolic acidosisNM_002225.5:c.1175G>AHomozygousAutosomal, RecessiveAl-Shamsi et al. 2014 Group of unknown num...
243500.G.3United Arab Emirates Metabolic acidosisNM_002225.5:c.1184G>AHomozygousAutosomal, RecessiveAl-Shamsi et al. 2014 Group of unknown num...
243500.G.4United Arab Emirates Metabolic acidosisNM_002225.4:c.1136_1138+4delHomozygousAutosomal, RecessiveAl-Shamsi et al. 2014 Group of unknown num...

Other Reports

Bahrain

Al-Arrayed (Personal communication, Dubai, 2006) indicated that isovaleric acidemia occurs in Bahrain at an approximate incidence of 2/10,000 births.

Lebanon

In a retrospective analysis of IEMs diagnosed over a 12-year period (1998-2010) in a hospital in Lebanon, Karam et al. (2013) found 11 patients diagnosed with isovaleric acidemia. Four of these were through newborn screening. The mean age of diagnosis was 7.5-years.

Oman

Joshi et al. (2002) carried out a retrospective analysis of all patients born with inborn errors of metabolism in Oman between 1998 and 2000. Among the 82 patients, one was diagnosed with isovaleric academia [CTGA Database Editor's note: Computed annual incidence rate is 0.8/100,000].

Subsequently, Joshi and Venugopalan (2007) conducted a study over a seven year period (1998-2005) to evaluate the clinical profiles of 166 neonates at high risk of having inborn errors of metabolism. Three babies, all with consanguineous parents, were diagnosed with Isovaleric Acidemia. 

Al-Riyami et al (2012) reported on the types and patterns of IEMs encountered in a sample of 1100 high-risk neonates referred to SQU Hospital in Oman over a 10-year period (1998-2002). Isovaleric Acidemia was detected in 10 neonates (seven females, three males), belonging to seven families.

Saudi Arabia

Worthen et al. (1994) conducted a retrospective study for 144 patients who were followed for 1-5 years to study the severity and frequency of hypoglycemia. Hypoglycemia was rare and mild among neonates with classic MSUD, ethylmalonic aciduria, and isovaleric acidemia.

Moammar et al. (2010) reviewed 165530 Saudi infants born from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia for inborn errors of metabolism. Among them, six cases were found to have isovaleric aciduria. The estimated incidence of this condition is 4 in 100,000 live births.

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