Background Long-chain-3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a disorder of mitochondrial fatty acid ß-oxidation. LCHAD is one of two enzymes that carry out the third step (of 4) in the ß-oxidation of fatty acids – the other enzyme being short-chain hydroxyacyl-CoA dehydrogenase (SCHAD), which acts on shorter-chain substrates. LCHAD activity resides on the Mitochondrial Trifunctional Protein, which acts to catalyze 3 sequential steps in ß-oxidation. LCHAD deficiency occurs as an isolated defect (described here) or together with deficiency of the other 2 enzymes in Mitochondrial Trifunctional Protein deficiency. LCHAD deficiency impairs oxidation of dietary and endogenous fatty acids of long-chain length (16 carbons and longer). Clinical LCHAD deficiency can present clinically from day one to 3 years of age. Two clinical scenarios have been described. One group of LCHAD deficiency patients presents with symptoms of cardiomyopathy, which may lead to death. Several cardiac problems have been described, including cardiomegaly, left ventricular hypertrophy, and poor contractility. Onset may be acute or chronic. A second group of patients presents, usually following fasting, with non-ketotic hypoglycemia, vomiting, hypotonia, and hepatomegaly. Rhabdomyolysis may occur. Both presentations are highly variable and may have overlapping features. Symptoms may be initiated by a seemingly innocuous illness (a cold or otitis media), leading to prolonged fasting. Symptoms often precede onset of hypoglycemia. Hypoglycemia occurs from an inability to meet gluconeogenic requirements during fasting despite activation of an alternate pathway of substrate production – proteolysis. Physical examination of the acutely ill child may find mild to moderate hepatomegaly and muscle weakness. Laboratory examination of blood may reveal hypoglycemia, elevated CK and abnormal transaminases. Unique among the fatty acid oxidation disorders, LCHAD patients may develop a sensorimotor peripheral neuropathy and pigmentary retinopathy over time. Fatty liver is noted at autopsy, often leading to a misdiagnosis of Reye’s syndrome or Sudden Infant Death Syndrome (SIDS) in an infant. HELLP Syndrome (hemolysis, elevated liver enzymes, and low platelets) may occur in pregnancies where a fetus is affected with LCHAD deficiency. A complication of pregnancy has been described in women carrying a fetus affected with LCHAD deficiency. HELLP Syndrome (hemolysis, elevated liver enzymes, and low platelets) may occur in pregnancy. Testing Newborn screening using tandem mass spectrometry of a dried blood spot identifies elevated levels of several long chain hydroxyacylcarnitines (C16-OH, C16:1-OH, C18-OH, C18:1-OH, C18:2-OH, and generalized C12 through C14 species). Biochemical testing of blood and urine for carnitine, acylcarnitines, acylglycines, and organic acids is diagnostic for this disorder. Dicarboxylic and hydroxydicarboxylic acids are usually found with urine organic acid analysis, but may be “normal” when the patient is not acutely ill. Analysis of LCHAD activity in fibroblasts can reveal affected individuals compared to heterozygous carrier and normal fibroblast lines. LCHAD activity should be assayed after antibody precipitation of SCHAD activity, due to the overlap in substrate recognition. LCHAD patients have a common mutation (1528G>C) in the a-subunit of mitochondrial trifunctional protein. Detection of mutations in the DNA of affected individuals allows for confirmation of biochemical test results and accurate detection of asymptomatic carriers among other family members. Prenatal diagnosis is possible by enzyme assay of cultured amniocytes or by in vitro probe of the ß-oxidation pathway. DNA analysis can also be used for prenatal diagnosis of affected fetuses in at-risk pregnancies when both parents carry a known mutation. Treatment Fundamental to the medical management of LCHAD is the avoidance of fasting, particularly during periods of high metabolic stress, such as illness. Overnight fasts should last no longer that twelve hours and infants should receive late evening feedings to reduce this period. The addition of food-grade uncooked cornstarch mixed in liquid at bedtime has helped some infants decrease the frequency of morning hypoglycemia. A diet high in natural fat should be avoided. Medium-chain triglyceride supplementation bypasses the metabolic block and provides safe calories. Supplementation with oral L-Carnitine has not been shown to be beneficial in avoiding or ameliorating clinical symptoms. High carbohydrate intake should be encouraged during illness, with initiation of intravenous glucose supplementation if the child is unsuccessful in keeping down fluids, or unable to take adequate oral feedings. For individuals with LCHAD deficiency, it is imperative that the lethargic patient receive parenteral dextrose to avoid hypoglycemia during evaluation. Because the diagnosis and therapy of LCHAD 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 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 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. Tyni, T., Palotie, A., Viinikka, L., et al. Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G1528C mutation: Clinical presentation of thirteen patients. J Pediatrics 130:67, 1997.
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. |