In vitro confirmation of biochemical diagnoses of the following

FAO disorders:

-Short-chain acyl-CoA dehydrogenase (SCAD) deficiency

-Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

-Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

-Trifunctional protein deficiency

-Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency

-Carnitine palmitoyl transferase deficiency type II (CPT-II)

-Carnitine-acylcarnitine translocase (CACT) deficiency

-Multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia

 type II)

In addition, the following organic acid disorders can be confirmed

by this assay:

-2-Methylbutyryl-CoA dehydrogenase (SBCAD) deficiency

-Isobutyryl-CoA dehydrogenase (IBD) deficiency

Work is in progress to evaluate the applicability of this assay

to the remaining disorders of fatty acid transport and mitochondrial

oxidation.

Mitochondrial fatty acid beta-oxidation plays an important role in

energy production, particularly in skeletal and heart muscle, and

in hepatic ketone body formation. Disorders of fatty acid oxidation

(FAO) are characterized by hypoglycemia, hepatic dysfunction,

encephalopathy, skeletal myopathy, and cardiomyopathy. Most

FAO disorders have a rather similar presentation and their

biochemical diagnosis can, at times, be difficult. Commonly used

metabolite screens such as urine organic acids, plasma

acylcarnitines, and fatty acids are influenced by dietary factors

and the clinical status of the patient. This often leads to incomplete

diagnostic information or even false-negative results. Enzyme

assays are limited to 1 enzyme per assay, and molecular assays

for common mutations are limited by the frequent occurrence of

compound heterozygous patients with uncommon, private

mutations that must be distinguished from unaffected carriers.

Furthermore, neither specific enzyme assays nor molecular

genetic testing is available for each of the known defects. The

purpose of the in vitro probe assay is to offer screening for several

defects of FAO and organic acid metabolism under controlled

laboratory conditions using fibroblast cultures.

An interpretive report will be provided.

Abnormal results will include a description of the abnormal profile, in

comparison to normal and abnormal co-run controls. In addition, the

concentration of those acylcarnitine species that abnormally

accumulated in the cell medium are provided and compared to the

continuously updated reference range based on analysis of normal

controls. Interpretations of abnormal acylcarnitine profiles also

include information about the results' significance, a correlation to

available clinical information, possible differential diagnoses,

recommendations for additional biochemical testing and confirmatory

studies if indicated, name and phone number of contacts who may

provide these studies at the Mayo Clinic or elsewhere, and a phone

number to reach one of the laboratory directors in case the referring

physician has additional questions.

This assay is not informative if the deficient enzyme is physiologically

not expressed in skin fibroblasts.

Sometimes, an abnormal acylcarnitine profile cannot differentiate

between 2 disorders. In such instances, independent biochemical

(e.g., specific enzyme assay) or molecular genetic analyses are

required.

1.   Ensenauer R, Vockley J, Willard JM, et al:  A common mutation

      is associated with a mild, potentially asymptomatic phenotype in

      patients with isovaleric acidemia diagnosed by newborn screening.

      Am J Hum Genet 2004;75(6):1136-1142

2.  Rinaldo P, Matern D, Bennet MJ:  Fatty acid oxidation disorders. Ann

     Rev Physiol 2002;64:477-502

3.  Naylor EW, Chace DH:  Automated tandem mass spectrometry for

     mass newborn screening for disorders in fatty acid, organic acid

     and amino acid metabolism. J Child Neurol 1999;14:S4-S8

4.  Shen JJ, Matern D, Millington DS, et al:  Acylcarnitines in fibroblasts

     of patients with long-chain 3-hydroxyacyl-CoA dehydrogenase

     deficiency and other fatty aid oxidation disorders. J Inherit Metab Dis

     2000;23:27-44

5.  Matern D, Huey JC, Gregersen N, et al:  In vitro diagnosis of

     short-chain acyl-CoA dehydrogenase (SCAD) deficiency. J Inherit

     Metab Dis 2001;24(Suppl.1):66