Carnitine/Acylcarnitine Translocase Deficiency

Background
Carnitine/Acylcarnitine Translocase (CACT) Deficiency is a disorder of fatty acid oxidation. Fatty acid oxidation generates ATP in the mitochondria and provides acetyl-CoA for gluconeogenesis. CACT normally acts to transport long-chain acylcarnitine across the inner mitochondrial membrane into the mitochondrial matrix where β-oxidation occurs. CACT also facilitates the export of free carnitine out of the mitochondria where it can be utilized for formation of acylcarnitines. Deficiency of this transport protein results in impaired long-chain fatty acid oxidation and causes the accumulation of long-chain acylcarnitines outside the mitochondria and in plasma. Short- and medium-chain (C8 and less) fatty acids do not require CACT for entry into the mitochondria and are therefore available for energy metabolism.

Clinical
There are two clinical presentations of CACT Deficiency. The severe form has neonatal onset of acute cardiorespiratory symptoms in the first days of life. If the patients survive the initial illness, they suffer from chronic muscle weakness, cardiac hypertrophy, hypoglycemia and hyperammonemia. Plasma carnitine is low. Death may occur due to cardiomyopathy complications. These patients have no measurable CACT activity.

A second phenotype may have milder symptoms because they possess some residual CACT activity. These patients exhibit hypoglycemia, which may result in early death, but lack cardiac symptoms. Severe steatosis has been reported in liver, heart and kidneys at autopsy.

Testing
Newborn screening of a dried blood spot using tandem mass spectrometry reveals elevations of several long-chain acylcarnitines (i.e. C16, C18, C18:1 and C18:2). These findings are characteristic but not definitive of CACT Deficiency, because Carnitine Palmitoyl Transferase II Deficiency has similar results. Quantitative urine organic acid determination is usually not helpful, as elevations of long chain fatty acids, including dicarboxylic and 3-hydroxy-dicarboxylic acids are inconsistently present. Plasma acylcarnitine profile testing can confirm elevations of the above acylcarnitines. Definitive diagnosis of CACT Deficiency requires testing cultured fibroblasts or performing DNA mutation analysis of the gene. Prenatal diagnosis can be accomplished using DNA analysis if mutations are identified in the parents.

Treatment
This rare disorder is treated by preventing hypoglycemia and suppressing the need for long-chain fatty acid oxidation. Dietary medium-chain triglyceride oil bypasses the CACT step in fatty acid oxidation and provides safe calories. Aggressive supportive treatment in the newborn period and during intercurrent illnesses is important, since any infection is potentially life threatening.

Because the diagnosis and therapy of CACT 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
Chalmers, R.A., Stanley, C.A., English, N. and Wigglesworth, J.S. Mitochondrial carnitine-acylcarnitine translocase deficiency presenting as sudden neonatal death. J Pediatrics 131:220, 1997.

Morris, A.A.M., Olpin, S.E., Brivet, M., et al. A patient with carnitine-acylcarnitine translocase deficiency with a mild phenotype. J Pediatrics 132:514, 1998.

Ogier de Baulney, H., Slama, A., Touati, G., et al. Neonatal hyperammonemia caused by a defect of carnitine-acylcarnitine translocase. J Pediatrics 127:723, 1995

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

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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