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Interpretive Handbook

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Test 83644 :
Isovaleryl-CoA Dehydrogenase (IVD) Mutation Analysis (A282V)

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism associated with germline mutations of the isovaleryl-CoA dehydrogenase gene. Mutations in this gene cause isovaleryl-CoA dehydrogenase (IVD) deficiency. This enzyme defect results in the accumulation of derivatives of isovaleryl-CoA, including free isovaleric acid, 3-OH valeric acid, N-isovalerylglycine, and isovalerylcarnitine. Diagnosis relies primarily on the identification of these metabolites in urine by organic acid and acylglycine analyses, and in plasma by acylcarnitine analysis.

 

Patients with IVA may present with various phenotypes, from the acute, neonatal phenotype to the chronic intermittent phenotype. Typically patients present with fairly non-specific features including poor feeding and vomiting. During these episodes, a characteristic smell of "dirty socks" may be present. In the past, many patients with neonatal onset died during the first episode, while survivors of acute manifestations often suffered neurological sequelae due to incurred central nervous system damage. Therefore, early diagnosis and treatment is of the utmost importance. Newborn screening for IVA was established to allow for early detection by acylcarnitine analysis and presymptomatic initiation of treatment. This early detection has led to improved prognosis for IVA patients.

 

Molecular follow up testing for patient's with positive newborn screening for IVA has led to the identification of specific mutant alleles. One such mutant allele, A282V, has been found to be over represented in patients detected by newborn screening. Clinical evaluation of patients with the A282V mutant allele suggests that this specific mutant allele may confer a milder clinical phenotype. Accordingly, determination of the patient's genotype with respect to the A282V mutation has implications for patient management and genetic counseling.

Useful For Suggests clinical disorders or settings where the test may be helpful

Confirmation of clinical and/or biochemical diagnosis of isovaleric acidemia

 

Providing prognostic information

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

This assay will not detect all of the mutations that cause Isovaleric acidemia (IVA). Therefore, the absence of a detectable mutation(s) does not rule out the possibility that an individual is a carrier of or affected with this disease.

 

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

 

Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

 

In rare cases, DNA alterations of undetermined significance may be identified.

 

A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

 

Many disorders may present with symptoms similar to those present in IVA. Therefore, biochemical assays (OAU / Organic Acids Screen, Urine or ACYLG / Acylglycines, Quantitative, Urine) are recommended to establish the diagnosis of IVA prior to DNA analysis.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Ensenauer R, Vockley J, Grunert S, et al: A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric academia diagnosed by newborn screening. Am J Hum Genet 2004 Dec 75(6):1136-1142

2. Vockley J, Ensenauer R: Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity. Am J Med Genet 2006;42C:95-103

3. Sweetman L, Williams JC: Branched chain organic acidurias. In The Metabolic and Molecular Bases of Inherited Disease. Vol. 2. Eighth edition. Edited by CR Scriver, AL Beaudet, WS Sly, et al. New York, McGraw-Hill Book Company, 2001, pp 2125-2163


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