![]() ![]() ![]() Generous administration of IV fluids helps eliminate organic acids through renal loss. Hemodialysis, if available, can lower the levels of the branched-chain amino acids and organic acids in the plasma. Treatment often begins with aggressive intervention in an acute metabolic crisis. Prenatal diagnosis can be accomplished by measuring enzyme activity in chorionic villi cells or cultured amniocytes. Deficiency of the branched-chain a-ketoacid dehydrogenase enzyme complex activity can be measured in cultured fibroblasts. The diagnosis of MSUD is based on measuring elevated plasma branched-chain amino acids along with alloisoleucine, and the abnormal urine organic acids. During a crisis, patients are acidotic from elevated organic acids and lactate, and are typically ketotic. Oxidative decarboxylation is the second step in the degradative metabolic pathway, which is blocked in MSUD and results in the build up 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. In MSUD, these amino acids are not metabolized (decarboxylated) and accumulate to very high levels, the highest being leucine. Leucine, isoleucine, and valine are nutritionally required amino acids. Newborn screening of a dried blood spot specimen using tandem mass spectrometry measures valine and the sum of leucine, isoleucine, and alloisoleucine, the branchedchain amino acids. Variable phenotypes arise from different mutations in the branched-chain a-ketoacid dehydrogenase complex and the residual metabolic capacity of a given patient. With all forms of MSUD, neurologic symptoms are typically evident by two years of age. 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. If the patient survives this period, any infection or metabolic stress is life threatening. Cerebral edema results in encephalopathy exhibited as alternating hyper- and hypotonia, scissoring of the legs, opisthotonos, abnormal respirations, coma, and death. Neurologic deterioration is progressive and rapid. Metabolic acidosis with increased anion-gap is typically present, and plasma branch-chain amino acids (leucine, isoleucine, and valine) are seen. The infant may have a high-pitched cry and the odour of maple syrup may emanate from the diaper. Patients appear normal at birth, but begin to have feeding difficulties with vomiting, progressing to lethargy and coma. ![]() The most common form of MSUD presents with overwhelming symptoms in the first days of life. MSUD is estimated to occur in less than 1 in 100,000 live births but is as common as 1 to 176 in Old Order Mennonites. This enzyme activity resides in the branched-chain a-ketoacid dehydrogenase complex in the mitochondrial membrane. MSUD is caused by a deficiency in the ability to decarboxylate branched-chain amino acids. Each died with a progressive neurologic disease in the first weeks of life. Lysosomal transport diseases (e.g.Maple syrup urine disease (MSUD) was first described in 1954 in a family with four successive affected newborns.Sphingolipidoses (e.g., Niemann-Pick type A and B, Gaucher disease, Krabbe disease, Fabry disease, GM1 and GM2 gangliosidoses, metachromatic leukodystrophy, Farber disease).Lipidoses (e.g., Niemann-Pick types C and D, neuronal ceroid lipofuscinoses, lysosomal acid lipase deficiency).Oligosaccharidoses (e.g., alpha- and beta-mannosidoses, Schindler disease).Mucopolysaccharidoses (e.g., Hurler syndrome, Hunter syndrome, Sanfilippo syndrome Morquio syndrome, Maroteax-Lamy syndrome, Sly syndrome).Glycogen storage diseases (e.g., Pompe disease).Organic Acid Disorders (Organic Acidemias).Lecithin Cholesterol Acyltransferase (LCAT) Deficiency.Urea cycle disorders (e.g., citrullinemia, argininosuccinic aciduria, ornithine transcarbamylase deficiency).DRDMG also regulates Investigational New Drug Applications (INDs), New Drug Applications (NDAs), and Biologics License Applications (BLAs) for drugs and biologics intended for the prevention and treatment of rare inborn errors of metabolism including: ![]() The Division of Rare Diseases and Medical Genetics (DRDMG) serves as a hub for rare disease drug development across the Office of New Drugs by coordinating rare disease education, policy, research and stakeholder engagement. ![]()
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