Aciduria

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency has been recorded in only a few patients and these show wide variation in clinical presentation. The defect has been seen in infants with a syndrome of psychomotor retardation and failure to thrive. These infants showed abnormal organic aciduria, and drastically decreased SCAD activity was demonstrable in cultured fibroblasts. Muscle symptoms were only part of a wider syndrome in all infants and children so far reported to have SCAD deficiency, but were the sole presenting feature in two adult patients, in whom lipid storage was demonstrable in skeletal muscle. The gene encoding for human SCAD has been mapped to chromosome 12. 

This complex contains 11 polypeptide subunits of which only one is encoded by mtDNA. Defects of complex III are relatively uncommon and clinical presentations vary. Fatal infantile encephalomyopathies have been described in which severe neonatal lactic acidosis and hypotonia are present along with generalized amino aciduria, a Fanconi syndrome of renal insufficiency and eventual coma and death. Muscle biopsy findings may be uninformative since abnormal mitochondrial distribution is not seen, i.e., there are no ragged-red fibers. Other patients present with pure myopathy in later life and the existence of tissue-specific subunits in complex III has been suggested since one of these patients was shown to have normal complex 111 activity in lymphocytes and fibroblasts. 

Mortensen PB. C6-C10-dicarboxyUc aciduria in starved, fat-fed and diabetic rats receiving decanoic acid or medium-cbain triacylglycerol. An in vivo measure of the rate of beta-oxidation of fatty acids. Biochim BiophysActa, 1981, 664(2), 349-355. 

The catabolism of leucine, valine, and isoleucine presents many analogies to fatty acid catabolism. Metabolic disorders of branched-chain amino acid catabolism include hypervalinemia, maple syrup urine disease, intermittent branched-chain ketonuria, isovaleric acidemia, and methylmalonic aciduria. 

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

The orotic aciduria that accompanies Reye s syndrome probably is a consequence of the inabifity of severely damaged mitochondria to utifize carbamoyl phosphate, which then becomes available for cytosofic overproduction of orotic acid. Type I orotic aciduria reflects a deficiency of both orotate phosphoribosyltransferase and orotidylate decarboxylase (reactions 5 and 6, Figure 34—7) the rarer type II orotic aciduria is due to a deficiency only of orotidylate decarboxylase (reaction 6, Figure 34-7). 

Excess carbamoyl phosphate exits to the cytosol, where it stimulates pyrimidine nucleotide biosynthesis. The resulting mild orotic aciduria is increased by high-nitrogen foods. 

The water-soluble vitamins comprise the B complex and vitamin C and function as enzyme cofactors. Fofic acid acts as a carrier of one-carbon units. Deficiency of a single vitamin of the B complex is rare, since poor diets are most often associated with multiple deficiency states. Nevertheless, specific syndromes are characteristic of deficiencies of individual vitamins, eg, beriberi (thiamin) cheilosis, glossitis, seborrhea (riboflavin) pellagra (niacin) peripheral neuritis (pyridoxine) megaloblastic anemia, methyhnalonic aciduria, and pernicious anemia (vitamin Bjj) and megaloblastic anemia (folic acid). Vitamin C deficiency leads to scurvy. 

Arglnlnos ucclnlc aciduria Cystlnosls Fabry disease... 

Methylmalonic aciduria (Bi2-reslstant) Mucolipidosis II (I-cell disease) Nlemann-Plck disease Sandhoff disease... 

Figure 32, Chromatograms of plasma and urine samples with various abnormalities, A, Phenylalaninemia B, tyrosinemia C, elevated plasma methionine seen in homocystinuria D, glycinemia E, normal urine F, argininosuccinic aciduria G, homocystinuria H, hyperglycinuria I, hyperlysinuria.

Canavan s disease (spongy degeneration) AR Aspartoacylase Widespread white matter edema with diminished myelin AT-acetylaspartic aciduria see text 1,25, Ch. 40... 

The major metabolic fate of amino acids is conversion into organic acids absent an enzyme to oxidize an organic acid, an organic aciduria results 668... 

Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria 677 Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12 677 Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration 678... 

The major metabolic fate of amino acids is conversion into organic acids absent an enzyme to oxidize an organic acid, an organic aciduria results. Three features characterize the metabolism of essentially all amino acids (1) incorporation into protein (2) conversion into messenger compounds such as hormones and neurotransmitters ... 

Glutaric acidurias Type I Primary defect of glutarate oxidation Type II Defect of electron transfer flavoprotein Type I Severe basal ganglia/cerebellar disease with macrocephaly. Onset 1-2 years Type II Fulminant neurological syndrome of the neonate. Often with renal/hepatic cysts. Usually fatal Diet low in lysine and tryptophan Supplementation with coenzyme Q, riboflavin, carnitine... 

Many organic acidurias originate in the breakdown of the three branched-chain amino acids, leucine, isoleucine and valine (Fig. 40-1). Metabolism of the organic acids requires the presence of specific enzymes, congenital... 

On rare occasions an organic aciduria occurs not because of an enzyme deficiency but from a failure to transport or activate a water-soluble vitamin that serves as a cofactor for the reaction in question. Thus, congenital deficiencies in the metabolism of vitamin B12 commonly give rise to methylmalonic aciduria (Fig. 40-1, Table 40-2). Similarly, deficiencies of biotin metabolism can cause a severe organic aciduria (Table 40-2). It is very important to be aware of the defects of vitamin metabolism because the administration of large doses of these cofactors may completely prevent brain damage. 

TABLE 40-2 The organic acidurias Organic aciduria Enzyme deficiency... 

Patients typically present by 6-12 months with severe developmental retardation, convulsions, microcephaly and homocysteinemia (=50pmol/l) with hypomethioninemia (<20 pmol/1). A few individuals have had psychiatric disturbances. The blood concentration of vitamin B12 is normal, and, unlike individuals with defects of cobalamin metabolism, these patients manifest neither anemia nor methylmalonic aciduria. The blood folic acid level is usually low. 

In cobalamin-E (cblE) disease there is a failure of methyl-B12 to bind to methionine synthase. It is not known if this reflects a primary defect of methionine synthase or the absence of a separate enzyme activity. Patients manifest megaloblastic changes with a pancytopenia, homocystinuria and hypomethioninemia. There is no methylmalonic aciduria. Patients usually become clinically manifest during infancy with vomiting, developmental retardation and lethargy. They respond well to injections of hydroxocobalamin. 

The fibroblasts do not convert cyanocobalamin or hydroxocobalamin to methylcobalamin or adenosyl-cobalamin, resulting in diminished activity of both N5-methyltetrahydrofolate homocysteine methyltransferase and methylmalonyl-CoA mutase. Supplementation with hydroxocobalamin rectifies the aberrant biochemistry. The precise nature of the underlying defect remains obscure. Diagnosis should be suspected in a child with homocystinuria, methylmalonic aciduria, megaloblastic anemia, hypomethioninemia and normal blood levels of folate and vitamin B12. A definitive diagnosis requires demonstration of these abnormalities in fibroblasts. Prenatal diagnosis is possible. 

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