Information on the following diseases can be found in the Related Disorders section of this report:

• Reye syndrome
• Fatty acid oxidation disorders
• MCAD deficiency

Three types of CPT1A deficiency have been recognized: The hepatic encephalopathy type usually occurs in children and is associated with a low level of ketones in the blood, low blood sugar (hypoglycemia), enlarged liver, muscle weakness and elevated carnitine in the blood. The adult-onset myopathy type is characterized by a sudden onset of muscle cramping associated with exercise without low blood sugar or liver dysfunction. The third type is acute fatty liver of pregnancy that occurs when a pregnant woman with one abnormal CPT1A gene carries a fetus with two abnormal CPT1A genes and is associated with liver failure in the mother.

CPT1A deficiency is caused by a mistake in the code for the CPT1A gene (mutation) resulting in decreased carnitine palmitoyltransferase 1 enzyme activity preventing normal metabolism of long-chain fatty acids from food and stored fat and decreased energy production.

CPT1A deficiency is inherited as an autosomal recessive genetic disorder with a 25% recurrence risk for future children to be affected. Autosomal recessive genetic diseases occur when each parent carries a mutation on the same gene (carrier) and each parent passes the mutated gene on to the child, giving the child no normal gene to compensate for the mutations.

If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry nearly 30 gene mutations. Usually, the parents do not match on the genes mutated and the children cannot be affected. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to be carrying the same abnormal gene, increasing their risk to have children with a recessive genetic disorder.

CPT1A deficiency has been reported in approximately 30-40 individuals. The incidence of this condition may be higher in the Hutterite populations in the northern United States and Canada and the Inuit populations in northern Canada, Alaska and Greenland. This condition occurs with equal frequency in males and females.

Symptoms of the following disorders are similar to those of CPT1A deficiency. Comparisons may be useful for a differential diagnosis:

Reye syndrome is a rare childhood disorder characterized by low blood sugar (hypoglycemia), liver dysfunction, and/or brain damage (encephalopathy). Symptoms of Reye syndrome usually occur after a viral illness, such as upper respiratory infection, chickenpox, or influenza. Additional symptoms of Reye syndrome may include vomiting, lack of energy (lethargy), diarrhea, and/or an abnormally high rate of breathing. Affected infants eventually exhibit profound lethargy, confusion, irritability, and/or other behavioral changes. Severe cases may lead to seizures and, eventually, coma. In addition, infants with Reye syndrome may develop an accumulation of fluid around the brain (cerebral edema), liver dysfunction, and/or an abnormally large liver (hepatomegaly) due to the buildup of certain fats. The exact cause of Reye syndrome is not known. (For more information on this disorder, choose "Reye" as your search term in the Rare Disease Database.)

Fatty acid oxidation disorders (FODs) are a group of genetic metabolic disorders that are characterized by the abnormal breakdown of fatty acids to energy in the body. This process requires fat and oxygen, and is known as fatty acid oxidation. It is similar to burning fuel in a fireplace and, instead of heat, the body produces chemical energy by this process of fat burning. As a result of the inherited mutation or FOD, affected individuals cannot use fats effectively for energy production. Stored fat is the secondary energy source for the body (the first is glucose). When glucose runs out, the body converts stored fat for energy. The inability to metabolize fatty acids completely due to an inherited block in the energy generation pathway results in the accumulation of the unburned fat by products that can be toxic. Thus, the symptoms of FODs relate to the poor energy production and the effects of the toxic buildup of waste products and, depending on the clinical needs for energy, can vary widely even among members of the same family. The FODs encompass many different disorders including medium chain acyl-CoA dehydrogenase (MCAD) deficiency, very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, short chain acyl-CoA dehydrogenase (SCAD) deficiency, and the primary carnitine deficiency syndromes. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a genetic metabolic disorder characterized by a deficiency of the enzyme medium chain acyl-CoA dehydrogenase. In infants with MCAD deficiency, symptoms may include recurrent episodes of unusually low levels of a certain sugar (glucose) in the blood (hypoglycemia), lack of energy (lethargy), vomiting, and/or liver malfunction. These symptoms are most frequently triggered when an affected infant does not eat for an extended period of time and has an intervening illness requiring increased energy production. MCAD deficiency is the most common disease in a group of disorders that involve abnormalities of fatty acid metabolism. MCAD deficiency is inherited as an autosomal recessive trait. (For more information on this disorder, choose "MCAD" as your search term in the Rare Disease Database.)

Diagnosis
CPT1A deficiency is diagnosed by a combination of physical symptoms and laboratory testing. The typical laboratory findings include low levels of ketones, elevated liver transaminases, elevated ammonia and elevated total serum carnitine. CPT1A enzyme activity on the cultured skin cells from affected individuals is 1-5% of normal. Molecular genetic testing is available to confirm the diagnosis if the enzyme test is abnormal. Some state newborn screening programs perform screening for CPT1A deficiency by measuring the ratio of free to total carnitine in blood plasma or serum. Carrier testing for relatives is available using CPT1A enzyme testing or molecular genetic testing.

Treatment
Prevention of hypoglycemia is recommended to reduce the risk of neurological effects. This can be accomplished with a high carbohydrate, low fat diet and frequent feeding. If acute hypoglycemia occurs, intravenous dextrose should be provided. Individuals with CPT1A deficiency should have regular liver function testing performed. Female carriers of an abnormal CPT1A gene should be informed about the possibility of obstetric complications.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

nformation on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Research on inborn errors of metabolism is ongoing. Scientists are studying the causes of these disorders and trying to design enzyme replacement therapies that will return a missing enzyme to the body.

Bennett, MJ and Narayan SB, (Posted 7/27/05). Carnitine Palmitoyltransferase 1A Deficiency. In GeneReviews at Genetests:Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2006. Available at http://genetests.org. Accessed 3/06.

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Carnitine Palmitoyltransferase I Deficiency. Number; 255120: Last Edit Date; 8/23/2004.

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Carnitine Palmitoyltransferase I, Muscle; CPT1B Entry Number; 601987: Last Edit Date; 8/6/2002.

TEXTBOOKS
Fauci AS, Braunwald E, Isselbacher KJ, et al. Eds. Harrison's Principles of Internal Medicine. 14th ed.McGraw-Hill Companies. New York, NY; 1998:2479.

Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:2305, 2317-18.

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REVIEW ARTICLES
McGarry JD. Travels between carnitine palmitoyltransferase I: from liver cell to germ cell with stops in between. Biochem Soc Trans. 2001;20 (Pt2):241-45.

Vockley J, Rinaldo P, Bennett MJ, et al. Synergistic heterozygosity: disease resulting from multi[ple partial defects in one or more metabolic pathways. Mol Genet Metab. 2000;71:10-18.

Bonnefont JP, Demaugre F, Prip-Buus C, et al. Carnitine palmitoyltransferase deficiencies. Mol Genet Metab. 1999;68:424-40.

Tein I. Neonatal metabolic myopathies. Semin Perinatol. 1999;23:125-51.

JOURNAL ARTICLES
Morillas M, Lopez-Vinas E, Valencia A, et al. Structural model of carnitine palmitoyltransferase I based on the carnitine-acetyltransferase crystal. Biochem J. 2004;379(Pt3):777-84.

Gobin S, Thuillier L, Jogl G, et al. Functional and structural basis of carnitine palmitoyltransferase 1A deficiency. J Biol Chem. 2003;278:50428-434.

Shigematsu Y, Hirano S, Hata I, et al. Selective screening for fatty acid oxidation disorders by tandem mass spectrometry: difficulties in practical discrimination. J Chromatogr B Analyt Technol Biomed Life Sci. 2003;15:63-72.

Gobin S, Bonnefont JP, Prip-Buus C, et al. Organization of the human liver carnitine palmitoyltransferase 1 gene (CPT1A) and identification of novel mutations in hypoketotic hypoglycaemia. Hum Genet. 2002;111:179-89.

Invernizzi F, Burlin AB, Donadio A, et al. Lethal neonatal presentation of carnitine palmitoyltransferase I deficiency. J Inherit Metab Dis. 2001;24:601-02.

FROM THE INTERNET
Vladutiu GD. Mind Over Matter: The Realities of a Common Muscle Disease. ©1999-2004 FOD Support Family Support Group. 4pp.
www.fodsupport.org/cpt2.htm

Vladutiu GD. Fundamental differences [between CPT-I and CPT-II]. ©1999-2000. The Spiral Notebook. 2pp.
www.spiralnotebook.org/fundamentaldifferences/

Roe CR. Diagnostic Approach to Disorders of Fat Oxidation/Information for Clinicians. ©1999-2004 FOD Support Family Support Group. 11pp.
www.fodsupport.org/dx_fod.htm

Bonnefort J-P, Thullier L. Carnitine palmitoyltransferase 1 deficiency. Orphanet. April 2002. 2pp.
www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=156