Background Mitochondrial Trifunctional Protein (TFP) Deficiency is a defect in mitochondrial fatty acid β-oxidation. Three enzyme activities that act sequentially in the oxidation of fatty acids reside together on the TFP enzyme complex located on the inner mitochondrial membrane. The enzymes are Long-Chain-2-Enoyl-CoA Hydratase, Long-Chain HydroxyAcyl-CoA Dehydrogenase (LCHAD), and β-KetoAcyl-CoA Thiolase. The TFP complex consists of two different protein subunits (α and β) coded for by two nuclear genes. The TFP complex has specificity toward fatty acids of ten carbons (C10) or longer. Clinical Diverse clinical presentations have been reported in patients having TFP Deficiency. The usual presentation is in infancy and follows a period of fasting associated with a minor illness. Patients develop non-ketotic hypoglycemia, hypotonia, and lactic acidemia. Areflexia and cardiomyopathy is often found on physical exam, and sudden death can occur. Patients may have elevated CK levels and even rhabdomyolysis, and a few have had hyperammonemia. Low carnitine levels have been measured in serum and muscle. Hepatic steatosis is found at biopsy. Many of these patients succumb to severe muscular hypotonia with respiratory distress. Testing Newborn screening of a dried blood spot using tandem mass spectrometry detects elevations of several long-chain and hydroxy acylcarnitines (i.e. C16-OH, C16:1-OH, C16, C18-OH, C18:1-OH, and C18). These findings are characteristic but not definitive of TFP Deficiency, because isolated LCHAD deficiency shows similar findings. Quantitative urine organic acid determination is usually not helpful, as elevation of C6 to C14 dicarboxylic and 3-hydroxy-dicarboxylic acids may or may not be present. Plasma acylcarnitine profile can demonstrate elevations of the above acylcarnitines noted in a dried blood spot. Definitive testing is performed by direct enzyme testing using leukocytes or fibroblasts or by probing cultured fibroblasts for the TFP activities using labeled fatty acid substrate. TFP deficiency can be caused by mutations in either the α -subunit or β-subunit genes for TFP. No common mutation in TFP deficiency has been reported, but prenatal diagnosis is theoretically possible if both mutations are known. Treatment Supportive care for the acutely ill child involves treating hypoglycemia, lactic acidosis, and hyperammonemia with IV fluids containing glucose and bicarbonate. Administration of L-Carnitine should be considered. Avoidance of fasting is important to prevent symptomatic episodes. Because the diagnosis and therapy of TFP 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 Dionisi-Vici, C., Garavaglia, B., Burlina, A.B., et al. Hypoparathyroidism in mitochondrial Trifunctional protein deficiency. J Pediatrics 129:159-162, 1996. Ibdah, J.A., Tein, I., Dionisi-Vici, C., et al. Mild Trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation. J Clinical Investigation 102:1193, 1998. Jackson, S., Singh Kler, R., Bartlett, K., et al. Combined enzyme defect of mitochondrial fatty acid oxidation. J Clinical Investigation 90:1219, 1992. 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. Ushikubo, S., Aoyama, T., Kamijo, T., et al. Molecular characterization of mitochondrial Trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both alpha- and beta-subunits. Amer J Human Genetics 58:979-988, 1996. Wanders, R.J.A., Ijlst, L., Poggi, F., et al. Human Trifunctional protein deficiency: A new disorder of mitochondrial fatty acid β-oxidation. Biochem Biophys Res Communications 188:1139, 1992.
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.
(c) 2008 PerkinElmer Genetics, Inc. All Rights Reserved
This information is copyrighted and is only for your personal, non-commercial use, provided that all copyright and other proprietary notices are retained on any copies made of it. The information may not be modified in any way or reproduced or distributed or used for any public or commercial purpose unless expressly permitted. Any use or display of the enclosed information for any purpose is prohibited.
|