Aminoaciduria

Deficiency of GC-S is extremely rare only five cases from four unrelated families have been reported so far (B18, HI7, K23). This enzyme deficiency appears to be inherited as an autosomal recessive and has been clearly associated with a moderate chronic hemolytic anemia and a marked decrement of red blood cell GSH. Spinocerebellar degeneration and aminoaciduria were present in both homozygous siblings in the first family, whereas no neurologic deficit was noted in the other three families. 

NS (acute) (general population) Renal Aminoaciduria Fanconi syndrome >80 (children) Chisolm 1962 Pueschel et al. 1972... 

Renal Effects. The characteristics of early or acute lead-induced nephropathy in humans include nuclear inclusion bodies, mitochondrial changes, and cytomegaly of the proximal tubular epithelial cells dysfunction of the proximal tubules (Fanconi s syndrome) manifested as aminoaciduria, glucosuria, and phosphaturia with hypophosphatemia and increased sodium and decreased uric acid excretion. These effects appear to be reversible. Characteristics of chronic lead nephropathy include progressive interstitial fibrosis, dilation of tubules and atrophy or hyperplasia of the tubular epithelial cells, and few or no nuclear inclusion bodies, reduction in glomerular filtration rate, and azotemia. These effects are irreversible. The acute form is reported in lead-intoxicated children, whose primary exposure is via the oral route, and sometimes in lead workers. The chronic form is reported mainly in lead workers, whose primary exposure is via inhalation. Animal studies provide evidence of nephropathy similar to that which occurs in humans, particularly the acute form (see Section 2.2.3.2). 

Full Fanconi syndrome has been reported to be present in some children with lead encephalopathy (Chisolm 1968 Chisolm et al. 1955). According to the National Academy of Sciences (NAS 1972), the Fanconi syndrome is estimated to occur in approximately one out of three children with encephalopathy and PbB levels of approximately 150 pg/dL. Aminoaciduria occurs at PbB levels >80 pg/dL in children with acute symptomatic lead poisoning (Chisolm 1962). The aminoaciduria and symptoms of lead toxicity disappeared after treatment with chelating agents (Chisolm 1962). 

Information is available on the renal toxicity of ingested lead in several species, including rats, dogs, monkeys, and rabbits. The results indicate that histopathological changes in the kidneys of lead-treated animals are similar to those in humans (see Section 2.2.1.2). Reduced glomerular filtration rates and aminoaciduria were reported in some of the animal studies. Key animal studies on lead-induced renal toxicity will be discussed below. 

Chisolm JJ Jr. 1962. Aminoaciduria as a manifestation of renal tubular injury in lead intoxication and a comparison with patterns of aminoaciduria seen in other diseases. J Pediatr 60 1-17. 

Chisolm JJ Jr, Harrison HC, Eberlein WR, et al. 1955. Aminoaciduria, hypophosphatemia, and rickets in lead poisoning Study of a case. Am J Dis Child 89 159-168. 

An aminoaciduria usually results from the congenital absence of an enzyme needed for metabolism of an amino acid 668... 

Untreated aminoacidurias can cause brain damage in many ways, often through impairing brain energy metabolism 670... 

Treatment of aminoacidurias with a low-protein diet may influence brain chemistry 671... 

In many aminoacidurias, there may occur deficits in neurotransmitters and receptors, particularly the, V methyl i> aspartate receptor 671... 

Brain edema, often associated with increased intracranial pressure, may accompany the acute phase of metabolic decompensation in the aminoacidurias 671... 

Treatment for nonketotic hyperglycinemia is less effective than that available for other aminoacidurias 674... 

An aminoaciduria usually results from the congenital absence of an enzyme needed for metabolism of an amino acid. Aminoacidopathies typically involve an inherited deficiency of an enzyme that is important for the metabolism of a particular amino acid (Table 40-1). The concentration of that amino acid and its metabolites consequently rise sharply in blood, urine and body tissues, including the brain. When the enzymatic deficiency is nearly complete, the onset of disease tends to occur in infancy, even in the neonatal period. Partial enzyme deficiencies may not become apparent until later in life [1,2]. 

Generalized defects of protein synthesis have not yet been described, presumably because they would be lethal early in development. Disturbances in the synthesis of messenger compounds such as thyroxine or neurotransmitters may occur but they do not result in an aminoaciduria because relatively little amino acid is so disposed. 

Distortion of the plasma aminogram in individuals with an aminoaciduria also may lead to a relative failure of brain protein synthesis. Thus, in mice with a deficiency of phenylalanine hydroxylase, the blood concentration of phenylalanine is more than 20 times greater than the control value, leading to partial saturation of the transport system and a diminution in the brain level of neutral amino acids other than phenylalanine. Rates of protein synthesis were concomitantly reduced [8]. 

Treatment of aminoacidurias with a low-protein diet may influence brain chemistry. It should be emphasized that the treatment of the patient with an aminoaciduria may affect brain chemistry, perhaps in an adverse manner. Nearly all patients receive a low-protein diet. Indeed, undiagnosed patients sometimes avoid consumption of protein, which they feel intuitively can cause lethargy, headache, nausea and mental confusion. As dietary protein declines, the intake of carbohydrate frequently increases. The concomitant rise of endogenous insulin secretion favors an increase in the ratio of the concentration of blood tryptophan to that of other amino acids, thereby promoting the entry of tryptophan to the brain. The latter amino acid is precursor to brain serotonin, which tends to increase. This physiology is known to be operative in patients with urea cycle defects. 

Phenylketonuria usually is caused by a congenital deficiency of phenylalanine hydroxylase. Phenylketonuria (PKU) is among the more common aminoacidurias (-1 20,000 live births). The usual cause is a nearly complete deficiency of phenylalanine hydroxylase, which converts phenylalanine into tyrosine (Fig. 40-2 reaction 1). 

Treatment for nonketotic hyperglycinemia is less effective than that available for other aminoacidurias. There is no specific therapy. Exchange transfusion and dialysis usually do not alter the progressive neurological deterioration. Sodium benzoate has been administered in the hope that glycine would react with it to form hippuric acid, but this approach is not helpful. It may be that a combination of benzoate and carnitine therapy is more effective [28]. Similarly, the restriction of dietary protein... 

Defects of complex III. Like defects of complex I, these can be due to nDNA mutations or to mtDNA mutations. The only nuclear defect described thus far does not affect a complex III subunit, but an ancillary protein needed for proper assembly, BCS1L. Mutations in BCS1L can cause a Leigh s-syndrome-like disorder or a fatal infantile disease called GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death). 

Defects of complex IV. These disorders, also termed COX deficiency, have clinical phenotypes that fall into two main groups one in which myopathy is the predominant or exclusive manifestation and another in which brain dysfunction predominates (Fig. 42-3). In the first group, the most common disorder is fatal infantile myopathy, causing generalized weakness, respiratory insufficiency and death before age 1 year. There is lactic acidosis and renal dysfunction, with glycosuria, phosphaturia and aminoaciduria, also termed DeToni-Fanconi-Debre syndrome. The association of myopathy and cardiopathy in the same patient and myopathy and liver disease in the same family has also been described [14]. 

The Editors have striven, as in previous years, to include in the present volume reviews on greatly diversified subjects, all of timely importance. The article on mellituria in Volume 4 has been supplemented by a survey of galactosemia, and we expect to follow in future volumes with reviews of other inborn errors of metabolism or, in modern parlance, of molecular diseases. Likewise, the article on peptiduria supplements that on aminoaciduria in Volume 2 and that on microbiological assay of vitamins extends previous summaries on the nucleogenic vitamins. The haptoglobins lie on the borderline of hematology. 

The urine frequently contains casts and amorphous debris, but rarely any considerable number of red blood corpuscles. Proteinuria and aminoaciduria are found in nearly all untreated patients from a very early age. The proteinuria is usually reported as albuminuria in the literature, but in some cases the urinary protein has been shown by electrophoresis to consist largely of a-globulin and other relatively low-molecular-weight proteins (B21). A similar urinary pattern occurs in a number of diseases of the renal tubule. The proteinuria is often only moderate in degree, e.g., < 50 to 150 mg protein per 100 ml of urine, but is easily detected by the conventional tests for protein, such as salicylsulfonic acid. Excretion of protein can rise to nearly 1 g/100 ml in some cases (H8, L7). 

In some cases, the amino acid pattern on a paper chromatogram is very similar to that found in diseases of the renal tubules, such as cystinosis, where there is a failure to reabsorb all amino acids from the glomerular filtrate and, in consequence, the urinary amino acid pattern resembles that of plasma (W6, W9). In other cases the aminoaciduria is less marked and the amino acids found in greatest excess are glycine, alanine, serine, threonine, and glutamine. In some cases no aminoaciduria has been detected. 

The proteinuria and aminoaciduria, and acidosis and glucosuria where they occur, are probably caused by reversible inhibition of some functions of the renal tubule. There would appear to be no structural damage to the kidney. However, 2 children developed nephrolithiasis while being treated with a low-lactose diet (B7, C5), The time course of events, when galactose is withdrawn from and returned to the diet, suggests that some metabolite of galactose accumulates in the cells of the renal tubules and has an inhibitory effect on the reabsorption of a number of substances. 

Laboratory procedures specific to galactosemia are dealt with below, but a number of other tests are also of value. Liver function tests, though sometimes helpful, are not always informative (see above, Section 2.2). Protein is usually present in the urine in untreated cases, but this occurs in other diseases. Aminoaciduria is a very common finding in galactosemia, though Holzel (H3) states it is absent in some older children with a mild form of galactosemia aminoaciduria occurs in other diseases and is frequently accompanied by proteinuria and glucosuria. 

In those patients who survive more than a few weeks, the effects of renal tubular dysfunction become more severe. Acidosis and hypo-phosphatemic rickets are prominent features. The urine is alkaline and gives a strong Rothera reaction. However, the ability to concentrate the urine is never lost and there is neither polydipsia nor polyuria. Aminoaciduria, hydroxyphenyluria, glucosuria, fructosuria, and proteinuria continue. The liver remains large and cirrhotic. Death finally occurs in liver failure, sometimes after several years. There is evidence that some children recover with no residual signs other than a large firm liver. 

Stein et al. found in the course of experiments dealing with free and conjugated urinary amino acids in Wilson s disease (S9) that besides a marked aminoaciduria, almost a twofold increase in the excretion of all bound amino acids could be observed. As compared with normal urine (S8), unusual amounts of conjugated leucine, isoleucine, and valine are excreted in cases of Wilson s disease. Also the increase of glutamic acid, aspartic acid, and phenylalanine after urine hydrolysis is much more distinct in this disease than in normal conditions. Other bound amino acids are at or below normal levels. 

In the course of studies on aminoaciduria in Fanconi s syndrome, Dent (Dl) isolated from the urine of the subject investigated a simple peptide identified as serylglycylglycine. Carsten (Cl) found in normal urine several peptides containing in every case one of the dicarboxylic amino acids. He discovered also two tetrapeptides, one of them consisting of equimolar amounts of aspartic acid and glycine, and the second composed of glycine, alanine, and glutamic acid in the ratio 2 1 1. The first of these tetrapeptides was also found in the urine of a patient with rheumatoid arthritis. 

H3. Harris, H., Aminoaciduria in men. Proc. Intern. Congr. Biochem. 3rd Congr. Brussels 19SS pp. 467-474 (1956). 

Sarnecka-Keller, M., Joraszowa, E., and Noworytko, J., Aminoaciduria u pacjentow Ieczonych promieniami X. [Amino aciduria in patients treated with X-rays.] Polskie Arch. Med. Wewngtrznej 29, 1521-1528 (1959). 

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