Maple syrup urine disease treatment

Effective treatment of maple syrup urine disease involves the restriction of dietary branched-chain amino acids 672... 

Effective treatment of maple syrup urine disease involves the restriction of dietary branched-chain amino acids. Long-term treatment entails the dietary restriction of the BCAAs. This is accomplished by administration of a special formula from which these amino acids are removed. The outlook for intellectual development is favorable in youngsters in whom diagnosis is made early and who do not suffer recurrent, severe episodes of metabolic decompensation [17]. 

As discussed above, in the case of phenylketonuria, early intervention can make the difference between mental retardation and a near normal life course for a newborn. Congenital adrenal hyperplasia and maple syrup urine disease are two examples of neonatal hereditary disorders where early diagnosis and medical intervention can make the difference between life and death for the newborn. In addition, in a number of genetic diseases, early diagnosis and treatment can help ameliorate symptoms these include fragile X syndrome, homocystinuria, sickle cell anemia, cystic fibrosis, and many /1-thalassemias. 

T There is a relatively rare genetic disease in which the three branched-chain a-lceto acids (as well as their precursor amino acids, especially leucine) accumulate in the blood and spill over into the urine. This condition, called maple syrup urine disease because of the characteristic odor imparted to the urine by the a-lceto acids, results from a defective branched-chain a-lceto acid dehydrogenase complex. Untreated, the disease results in abnormal development of the brain, mental retardation, and death in early infancy. Treatment entails rigid control of the diet, limiting the intake of valine, isoleucine, and leucine to the minimum required to permit normal growth. ... 

Maple syrup urine disease (MSUD) is a recessive disorder in which there is a partial or complete deficiency in branched-chain a-ketoacid dehydrogenase—an enzyme that decarboxylates leucine, isoleucine, and valine. These amino acids and their corresponding a-keto acids accumulate in the blood, causing a toxic effect that interferes with brain func tion. Symptoms include feeding problems, vomiting, dehydration, severe metabolic acidosis, and a characteristic smell of the urine. If untreated, the disease leads to mental retardation, physical disabilities, and death. Diagnosis is based on a blood sample within 24 hours of birth. Treatment of MSUD involves a synthetic formula that contains limited amounts of leucine, isoleucine, and valine. 

Apeirt from children with thiamin-responsive maple syrup urine disease (Section 6.3.1.4) and thiamin-responsive megaloblastic anemia (Section 6.2), there are no established pharmacological uses of thieimin other than the treatment of deficiency. Because of the neurological involvement in thiamin deficiency, the vitamin has been used in nerve tonics, edthough there is no evidence that it has any effect except in cases of deficiency. 

Four inherited disorders responsive to treatment with pharmacological doses of thiamine are summarized in Table 38-1. However, at least for megaloblastic anemia and maple syrup urine disease, more nonresponsive than responsive cases are known. Since thiamine is promptly excreted in the urine, excessive intake is not associated with toxicity. 

In maple syrup urine disease, also called branched chain ketoaciduria, the a-keto acids derived from leucine, isoleucine, and valine accumulate in large quantities in blood. Their presence in urine imparts a characteristic odor that gives the malady its name. All three a-keto acids accumulate because of a deficient branched chain a-keto acid dehydrogenase complex. (This enzymatic activity is responsible for the conversion of the a-keto acids to their acyl-CoA derivatives.) If left untreated, affected individuals experience vomiting, convulsions, severe brain damage, and mental retardation. They often die before 1 year of age. As with phenylketonuria, treatment consists of rigid dietary control. 

The absence of sufficient branched-chain a-keto acid dehydrogenase causes maple-syrup urine disease, which leads to the excretion of branched-chain a-keto acids. There is a nutritional treatment for this disease. 

Fig. 3.22. GC separation of keto and hydroxy acids from the urine of a patient with maple syrup urine disease. Top chromatogram, the patient before dietary treatment middle chromatogram, the same patient after two days on a diet bottom chromatogram, a mixture of reference compounds. Peaks 1, lactic acid 2, 2-hydroxyisobutyric acid 3, 2-hydroxybutyric acid 4, pyruvic acid 5, 3-hydroxyisobutyric acid 6, 3-hydroxybutyric acid 7, 2-hydroxyisovaleric acid 8, 2-ketobutyric acid 9, malonic acid (internal standard) 10, 2-methyl-3-hydroxybutyric acid 11, 2-hydroxy-n-valeric acid 12. methylmalonic acid 13, 3-hydroxyisovaleric acid 14a and b, 2-ketoisovaleric acid IS, acetoacetic add 16, 2-hydroxyisocaproic acid 17, 2-hydroxy-3-methylvaleric acid 18a, L-2-keto-3-methylvaleric add 18b, D-2-keto-3-methyl-valeric acid 19, 2-ketoisocaproic acid. Reproduced from [386],...

Zinnanti WJ, et al. Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease. Brain. 2009 132(Pt 4) 903-18. 

Strauss KA, et al. Elective liver transplantation for the treatment of classictil maple syrup urine disease. Am J Transplant. 2006 6(3) 557-64. 

Because treatment is most effective if started in earliest infancy, it is necessary to make the diagnosis of phenylketonuria before any clinical signs appear, i.e. from the biochemical changes. Every newborn infant must be tested and, therefore, the test used must be inexpensive, simple and reliable [70, 71]. The available methods are determination of phenylalanine concentration in the blood, o-hydroxyphenyl-acetic acid in urine or phenylpyruvic acid in urine. The third method, once widely used, has now been largely abandoned the first and, to a lesser extent, the second are used on a very large scale in many countries. Sometimes tests for other conditions, such as homocystinuria, galactosaemia and maple syrup urine disease, are combined with the test for phenylketonuria. 

Gaull, G.E. (1969), Pathogenesis of maple syrup urine disease observations during dietary management and treatment of coma by peritoneal dialysis. Biomed. Med., 3, 130. 

Snyderman, S.E. (1975), Maple syrup urine disease. In The Treatment of Inherited Metabolic Disease (ed. D.N. Raine), Medical and Technical Publishing Co., Lancaster, Chapter 3, pp. 71-90. 

In a rare autosomal recessive condition (discovered in 1954) the urine and perspiration has a maple syrup odor/ High concentrations of the branched-chain 2-oxoacids formed by transamination of valine, leucine, and isoleucine are present, and the odor arises from decomposition products of these acids. The branched-chain amino acids as well as the related alcohols also accumulate in the blood and are found in the urine. The biochemical defect lies in the enzyme catalyzing oxidative decarboxylation of the oxoacids, as is indicated in Fig. 24-18. Insertions, deletions, and substitutions may be present in any of the subunits (Figs. 15-14,15-15). The disease which may affect one person in 200,000, is usually fatal in early childhood if untreated. Children suffer seizures, mental retardation, and coma. They may survive on a low-protein (gelatin) diet supplemented with essential amino acids, but treatment is difficult and a sudden relapse is apt to prove fatal. Some patients respond to administration of thiamin at 20 times the normal daily requirement. The branched-chain oxoacid dehydrogenase from some of these children shows a reduced affinity for the essential coenzyme thiamin diphosphate.d... 

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