PerkinElmer Genetics

Background
Maple Syrup Urine Disease (MSUD) was first described in 1954 in a family with four successive affected newborns. Each died with a progressive neurologic disease in the first weeks of life. MSUD is caused by a deficiency in the ability to decarboxylate branched-chain amino acids. This enzyme activity resides in the branched-chain a-ketoacid dehydrogenase complex in the mitochondrial membrane.

Clinical
The most common form of MSUD presents with overwhelming symptoms in the first days of life. Patients appear normal at birth, but begin to have feeding difficulties with vomiting, progressing to lethargy and coma. The infant may have a high-pitched cry and the odor of maple syrup may emanate from the diaper. Metabolic acidosis with increased anion-gap is typically present, and plasma branch-chain amino acids (leucine, isoleucine, and valine) are seen. Hypoglycemia may occur. Neurologic deterioration is progressive and rapid. Cerebral edema results in encephalopathy exhibited as alternating hyper- and hypotonia, scissoring of the legs, opisthotonos, abnormal respirations, coma, and death. If the patient survives this period, any infection or metabolic stress is life threatening. Other less acute presentations have been reported, including an intermittent form associated with episodic ataxia and acidosis, and a milder, more chronic intermediate form with less severe acidosis. With all forms of MSUD, neurologic symptoms are typically evident by two years of age. Variable phenotypes arise from different mutations in the branched-chain a-ketoacid dehydrogenase complex and the residual metabolic capacity of a given patient.

Testing
Newborn Screening of a dried blood spot specimen using tandem mass spectrometry measures valine and the sum of leucine, isoleucine, and alloisoleucine, the branched-chain amino acids. Leucine, isoleucine, and valine are nutritionally required amino acids. In MSUD, these amino acids are not metabolized (decarboxylated) and accumulate to very high levels, the highest being leucine. Oxidative decarboxylation is the second step in the degradative metabolic pathway, which is blocked in MSUD and results in the buildup of three organic acids - 2-oxoisocaproic acid from leucine, 2-oxo-3-methylvaleric acid from isoleucine, and 2-oxoisovaleric acid from valine - which are detected in high levels in the urine of affected patients. During a crisis, patients are acidotic from elevated organic acids and lactate, and are typically ketotic. The diagnosis of MSUD is based on measuring elevated plasma branched-chain amino acids along with alloisoleucine, and the abnormal urine organic acids. Deficiency of the branched-chain a-ketoacid dehydrogenase enzyme complex activity can be measured in cultured fibroblasts. Prenatal diagnosis can be accomplished by measuring enzyme activity in chorionic villi cells or cultured amniocytes.

Treatment
Treatment often begins with aggressive intervention in an acute metabolic crisis. Hemodialysis, if available, can lower the levels of the branched-chain amino acids and organic acids in the plasma. Generous administration of IV fluids helps eliminate organic acids through renal loss. IV glucose provides an alternate energy source that reduces protein catabolism, which is a major source of branch-chain amino acids in acutely ill infants. Restriction of protein intake is usually a life-long requirement and commercial formulas that are depleted in branched-chain amino acids are available. Carnitine supplementation is useful in removing organic acids and repleting carnitine stores. Some patients respond to high-dose thiamine supplementation, a cofactor of the enzyme complex, and all newly diagnosed critically ill infants should be treated with this vitamin. Close monitoring of patients who survive the newborn period or who have a later presentation is required to reduce morbidity and mortality.

Because the diagnosis and therapy of MSUD 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.

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.