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.
Al-Arrayed (Personal communication, Dubai, 2006) indicated that isovaleric acidemia occurs in Bahrain at an approximate incidence of 2/10,000 births.
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.
Joshi et al. (2002) carried out a retrospective analysis of all patients born with inborn errors of metabolism in Oman between June 1998 and December 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]. Few years later, 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 using Tandem Mass Spectrometry (TMS). Out of a total of 38 neonates with positive TMS results, three babies, all with consanguineous parents, were diagnosed with Isovaleric Acidemia. Their ages ranged from one to eight days, two were males, and one was a female. In addition, two of these patients had a family history of the condition. One baby with positive family history presented with unexplained biochemical abnormalities while the other one presented with unusual smell and oculocutaneous albinism. All three of these patients presented with acute neonatal encephalopathy with or without seizures.
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). MS/MS was used to analyze blood samples from heel pricks. A total of 119 of these neonates were found to test positive for an IEM. Isovaleric Acidemia was detected in 10 neonates (seven females, three males), belonging to seven families. Seven of the patients had a family history of the condition, while six had consanguineous parents.
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. Patients were mainly Saudi; however, 10-25% were from neighboring countries in the Arabian Peninsula. Hypoglycemia was rare and mild among neonates with classic MSUD, ethylmalonic aciduria, and isovaleric acidemia.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Organic acidopathies were diagnosed in 48 out of 248 cases (19%). Among them, six cases from three families were found to have isovaleric aciduria. The estimated incidence of this condition is 4 in 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
Kaya et al. (2013) reported the first Saudi IVA patients from a consanguineous family with a novel transversion (p.G362V) in IVD gene.
Hertecant et al (2012) studied IVA patients from five unrelated families. Four novel mutations in the IVD gene were uncovered, three of these were missense (p.R392H, p.R395Q and p.E408K) and one was a frameshift (p.F382fs). The mutation p.R395Q was detected in 2 families. Intriguingly, it was found that a 17 year-old girl was homozygous for p.R392H with no clinical symptoms.