Very Long Chain Acyl-CoA Dehydrogenase Deficiency

Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD)

Background
Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) is a disorder of β-oxidation of fatty acids. The enzymatic deficiency is one of four mitochondrial acyl-CoA dehydrogenases that carries out the initial dehydrogenation step in the β-oxidation of fatty acids. VLCAD deficiency impairs oxidation of dietary and endogenous fatty acids of long chain length (16 carbons and longer). The buildup of the long chain fatty acid acyl-CoA intermediates results in toxic effects to normal metabolism. The gene is on chromosome 17 and encodes a protein that functions on the inner mitochondrial membrane.

Clinical
Two general presentations have been reported with VLCAD deficiency, although both can vary considerably. Infants can present with severe, sepsis-like symptoms resembling a Reye-like syndrome, which is often lethal. The patient may be hypoglycemic with fasting and have metabolic acidosis, elevated liver enzymes with hepatomegaly (due to steatosis), cholestasis, hypertrophic cardiomyopathy, proteinuria, and hematuria. A second presentation has later onset and exhibits lethargy and coma with fasting. These patients have hypoketotic hypoglycemia, hepatomegaly, recurrent “infections”, and easy fatigue resulting in recurrent sore muscles. Some present with exercise-induced rhabdomyolysis.

Testing

Newborn screening using tandem mass spectrometry detects increased levels of C14:1, C16, and C12 acylcarnitines indicating a probable case of VLCAD deficiency. Clinical testing may reveal hypoglycemia with elevations of lactate, pyruvate, ammonia, and CK. Elevated dicarboxylic acids, both saturated and unsaturated, are often seen on urine organic acid analysis when the patient is ill. Enzyme studies performed on cultured fibroblasts can also be used to indirectly detect VLCAD activity using a labeled probe for β-oxidation.

Treatment
VLCAD deficiency patients are treated with carnitine supplementation and strict avoidance of fasting. Maintaining glucose homeostasis is accomplished with frequent feedings, restricting dietary fat and increasing carbohydrates, using medium-chain triglycerides (MCT) oil supplementation and possibly cornstarch if necessary to prevent hypoglycemia. Workup of a suspected VLCAD deficient patient should rule out Medium Chain Acyl-CoA Dehydrogenase deficiency (MCAD) or Glutaric Aciduria Type II (GA-II), because MCT oil supplementation is contra-indicated for these disorders. For individuals with VLCAD, it is imperative that the lethargic patient receives parenteral glucose to avoid hypoglycemia.

Because the diagnosis and therapy of VLCAD Deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

Inheritance
This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

References
Cox, G.F., Souri, M., Aoyama, T., et al. Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in a very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatrics 133:247, 1998.

Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg. 2297 - 2326.

Yamaguchi, S., Indo, Y., Coates, P.M., et al. Identification of very-long-chain acyl-coenzyme A dehydrogenase deficiency in three patients previously diagnosed with long-chain acyl-CoA dehydrogenase deficiency. Pediatric Research 34:111-113, 1993.

Web Sites

SaveBabies.org
Site established and maintained by parents of newborns affected with a rare genetic defect, with information for parents and professionals and links to other informative sites.

National Newborn Screening and Genetics Resource Center
Provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

Disclaimers
The analyses conducted by PerkinElmer Genetics produce results that can be used by qualified physicians in the diagnosis of disorders described herein. Evidence of these conditions will be detected in the vast majority of affected individuals; however, due to genetic variability, age of the patient at the time of specimen collection, quality of the specimen, health status of the patient, and other variables, such conditions may not be detected in all affected patients. PerkinElmer Genetics makes no warranty whatsoever, express or implied, including any warranty as to accuracy, completeness or timeliness, concerning the information contained herein, and you should not assume that such information is complete or the most up-to-date information available. PerkinElmer Genetics shall not be liable for any loss, claim or damages caused in whole or in part by our provision of, or your use of, any of the information contained herein. As a general statement, this information was drawn from published literature and is not drawn from our patient population or screening experience. The information contained herein is not intended to be a substitute for professional medical advice and should not be used for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions.

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