Inborn metabolic errors

The second method for mixture analysis is the use of specialized software together with spectral databases. We have developed a mixture analysis program AMIX for one- and multidimensional spectra. The most important present applications are the field of combinatorial chemistry and toxicity screening of medical preparations in the pharmaceutical industry. An important medical application is screening of newborn infants for inborn metabolic errors. 

People can suffer from a variety of inborn metabolic errors that can result in various amino acids exhibiting toxic effects if ingested above certain threshold levels. Specialty products, intended to be absent these amino acids, must be rigorously tested for verification that threshold levels are not exceeded. Examples of this situation include phenylketoneuria (intolerance of phenylalanine) and maple syrup urine disease (intolerance for leucine, isoleucine, and valine). 

Uric acid is the chief end product of purine metabolism in primates, birds, lizards, and snakes. An inborn metabolic error in humans results in increased levels of uric acid and its deposition as painful crystals in the joints. This condition (gout) may be treated by the drug allopurinol which is also oxidized by xanthine oxidase to allo-xanthine (dashed line in Eq. 19.29). However, alloxanthine binds so tightly to the molybdenum that the enzyme is inactivated, the catalytic cycle broken, and uric acid formation is inhibited. The extra stability of the alloxanthine complex may be a result of strong N—H --N hydrogen bonding by the nitrogen in the 8-position ... 

There have been reports in the literature of hypouricemia coincident with specific inborn metabolic errors, but many of these cases are attributable to defects in the kidney leading to failure of renal tubular reabsorption. It was mentioned above that the excretion of uric acid by the Dalmatian coach hound can be attributed to such a mechanism (Fll). Similarly, the hypouricemia found in the Fanconi syndrome (L4) and Wilson s disease (B12) can be attributed to kidney malfunction. These are not true examples of underproduction of oxypurines, including uric acid, since the daily output of uric acid is normal. The large number of healthy people who have extremely low serum urate values, however, may indicate that there are individuals who underproduce oxypurines but suffer no ill effects because of this. The one well-documented inborn error that results in underproduction of uric acid is xanthinuria. It has been reported in relatively few cases, probably because individuals with this metabolic abnormality who suffer no ill effects would not come to the attention of a physician. 

Leuco-dystrophy as an inborn metabolic error , comparable to lipidosis. In Cerebral lipidoses. Oxford Blackwell 1957. 

Fatty infiltration of the liver (FFl) is a common asymptomatic condition reported to be present in as much as 10% of the adult population and is usually associated with a variety of clinical situations, of which alcoholism, diabetes and obesity are the most common in the developed countries (el-Hassan et al. 1992). There are many other reported causes that include inborn metabolic errors, drug toxicity, glucocorticoid therapy, and infections (Alpers et al. 1993). Kammen et al. (2001) described an overall incidence of focal fatty liver in as many as 9% of children and... 

It is somewhat difficult to be sure of the precise diagnostic criteria included in some published reports, but since some at least of the reported conditions are genetically determined, it is reasonable to assume that they may be the clinical expression of inborn metabolic errors, as in Refsum s disease. There have been at least two reports describing abnormalities of pyruvate metabolism in Dejerine-Sottas disease [143, 144]. The latter authors concluded that at least in some of their patients abnormal pyruvate tolerance was secondary to dietary thiamine deficiency. 

Council of Europe working party to study hereditary metabolic diseases. Report (1973), Collective results of mass screening for inborn metabolic errors in eight European countries. Acta Paediatr. Scand., 62,413. 

Many inborn metabolic disorders are associated with the absence of activity of one particular enzyme normally found in the body. Of the 1250 autosomal recessive human genetic diseases, over 200 involve errors in metabolism that result from specific known enzyme deficiencies. Table 44.1 lists some examples of inborn errors or disorders in metabolism due to enzyme deficiencies. 

However, encephalopathies with a metabohc basis tend to be the most problanatic for infants or children, with functional outcomes dependent upon timely and pradent interventions. Three varieties of metabolic encephalopathy in children are discussed here. The first two are closely related. Inborn (genetic) errors of metabolism can present in the newborn as severe encephalopathy from hyperammonemia alone. When a metabolic error presents months to years later, a degree of hepatic insufficiency may complicate the metabolic derangement. In acute or fulminant hepatic failure of any etiology (i.e., infections, drug-induced, toxin-related), the rise in serum ammonia may be only moderate but other factors contribute to the ensuing encephalopathy, which may be devastating within days. 

Epilepsy may be defined as a permanent, recurrent seizure disorder. Examples of the known causes of epilepsy include brain injury at birth, head injuries, and inborn errors of metabolism, hi some patients, the cause of epilepsy is never determined. 

Garrod AE Inborn errors of metabolism. (Croonian Lectures.) Lancet 1908 2 1,73, 142,214. 

Van den Berghe G Inborn errors of fructose metabolism. Annu Rev Nutr 1994 l4 4l. 

Hepatic urea synthesis takes place in part in the mitochondrial matrix and in part in the cytosol. Inborn errors of metabolism are associated with each reaction of the urea cycle. 

Understanding of the degradative pathways for GAGs, as in the case of glycoproteins (Chapter 47) and glycosphingohpids (Chapter 24), has been gready aided by elucidation of the specific enzyme deficiencies that occur in certain inborn errors of metabolism. When GAGs are involved, these inborn errors are called mucopolysaccharidoses (Table 48—7). 

Phenylketoniuia (PKU) is an inborn error of metabolism by which the body is unable to convert siuplus pherylalanine (PA) to tyrosine for use in the biosynthesis of, for... 

Other diseases Autoimmune diseases Amyloidosis Aplastic anemia Paroxysmal nocturnal hemoglobinuria Fanconi s anemia Thalassemia major Sickle cell anemia Severe combined immunodeficiency Inborn errors of metabolism... 

Sepsis syndrome Anorexia nervosa Complications during pregnancy Geriatric patients with multiple chronic disease Organ transplantation Inborn errors of metabolism Cystic fibrosis Extreme prematurity... 

Lead has been shown to decrease circulating levels of the active form of vitamin D (1,25-dihydroxy-vitamin D) in children. The conversion of vitamin D to this active hormonal form takes place via hydroxylation to 25-hydroxyvitamin D in the liver, followed by 1-hydroxylation in the mitochondria of the renal tubule by a complex cytochrome P-450 (heme-containing) system (Mahaffey et al. 1982 Rosen and Chesney 1983). Comparisons of the serum 1,25-dihydroxyvitamin D levels in children with blood lead levels of 33 g/dL with those in children with severe renal insufficiency (Rosen et al. 1980) and in children with an inborn error of vitamin D metabolism in which the 1-hydroxylase system or component... 

Nyhan, W. L. The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. /. Inherit. Metab. Dis. 20 171-178,1997. 

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