Dicarboxylic aciduria

The genetically determined defect of membrane carnitine transport is the only known condition that fulfills the criteria for primary carnitine deficiency [4, 9]. This condition, like the other conditions involving the carnitine cycle, is not associated with dicarboxylic aciduria. It is... 

A few patients have been described with a defect involving the carnitine-acylcarnitine translocase system, which facilitates the movement of long-chain acylcarnitine esters across the inner membrane of the mitochondrion (Fig. 42-2). These patients have extremely low carnitine concentrations and minimal dicarboxylic aciduria [4]. 

Nevertheless, malonyl-CoA is a major metabolite. It is an intermediate in fatty acid synthesis (see Fig. 17-12) and is formed in the peroxisomal P oxidation of odd chain-length dicarboxylic acids.703 Excess malonyl-CoA is decarboxylated in peroxisomes, and lack of the decarboxylase enzyme in mammals causes the lethal malonic aciduria.703 Some propionyl-CoA may also be metabolized by this pathway. The modified P oxidation sequence indicated on the left side of Fig. 17-3 is used in green plants and in many microorganisms. 3-Hydroxypropionyl-CoA is hydrolyzed to free P-hydroxypropionate, which is then oxidized to malonic semialdehyde and converted to acetyl-CoA by reactions that have not been completely described. Another possible pathway of propionate metabolism is the direct conversion to pyruvate via a oxidation into lactate, a mechanism that may be employed by some bacteria. Another route to lactate is through addition of water to acrylyl-CoA, the product of step a of Fig. 17-3. Tire water molecule adds in the "wrong way," the OH ion going to the a carbon instead of the P (Eq. 17-8). An enzyme with an active site similar to that of histidine ammonia-lyase (Eq. 14-48) could... 

Tsemg KY, Jin SJ, Kerr DS, Hoppel CL. Urinary 3-hydroxydicarboxylic acids in pathophysiology of metabolic disorders with dicarboxylic aciduria. Metab Clin Exp. 1991 40(7) 676-82. 

Carnitine uptake defect (CUD, 14.1) is due to a defect in the high-affinity carnitine transporter [1]. Plasma free and total carnitine levels are extremely low. Clinically two forms exist an early childhood-onset cardiomyopathic form and a hepatic form with recurrent crises of Reye-like syndrome. In general the response to oral carnitine supplements is very good. Plasma acylcarnitines are normal, there are scattered reports on moderate dicarboxylic aciduria. 

CPTl deficiency (14.2) has only hepatic involvement cardiomyopathy is absent. The clinical presentation is rather homogenous with recurrent episodes of hepatic dysfunction, often accompanied by hypoglycemia. Many patients develop renal tubular acidosis (unexplained) [2]. This is one of the defects in which the mother of a patient may experience acute fatty liver of pregnancy [3]. Plasma-free carnitine is reportedly increased, but normal values have been observed. Dicarboxylic aciduria is a rarity. 

Carnitine acylcarnitine carrier deficiency (CAC, 14.3) has two forms, i.e. a severe form with a high incidence of sudden childhood death and a mild form. Both cardiomyopathic acid hepatopathic features occur. All patients have a very low plasma free carnitine and increased Cig-Cis acylcarnitines [4]. A subtle dicarboxylic aciduria may be present. A number of patients initially presented with coma and marked hyperammonemia. 

Three forms of VLCAD deficiency (14.5) are known, i.e. a (lethal) neonatal cardiomyopathic form, a childhood form with recurrent Reye-like episodes, and an adolescent/adult muscular form [6]. The latter may be accompanied by severe rhabdomyolysis and sometimes renal failure. Diagnostic criteria are the abnormal plasma acylcarnitine and organic acid profile (Ci4 i, Ci4 2 and Ci6 i) and the Cg-Cio dicarboxylic aciduria, especially in young patients. 

Carnitine and its esters (see [1]) cannot be introduced to the mass spectrometer by gas chromatography, as they incorporate quaternary amine functions and will decompose in the attempt. Fast atom bombardment (FAB) and electrospray ionization (ESI) can use the formal charge on the quaternary amine function to advantage, as carnitine and its esters are very easily desorbed from glycerol on the FAB probe and from aerosol sprays in ESI. Eigure 7A illustrates the use of EAB in the quantitation of carnitine and its esters excreted in the urine of a patient presenting with a severe dicarboxylic aciduria associated with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. 

Yoshida, H. Araki, J. Sonoda, J. Nobta, H. Ishida, J. Hirose, S. Yamaguchi, M. Screening method for organic aciduria by spectrofluorometric measurement of total dicarboxylic acids in human urine based on intramolecular excimer-forming fluorescence derivatization. Anal. Chim. Acta 2005,534,177-183. 

Genetically normal human subjects have not yet been shown to accumulate these abnormal urinary products but, in contrast, humans who bear an abnormal gene resulting in dicarboxylic aciduria do quite frequently respond to riboflavin supplements, showing a reduction in their excretion of abnormal fatty acid... 

Gregersen, N., Lauritzen, R. and Rasmussen, K. (1976), Suberylglycine excretion in the urine from a patient with dicarboxylic aciduria. Clin. Chim. Acta, 70,417. 

Gregersen, N., K0lvraa, S., Rasmussen, K. and Gr0n, I. (1977b), Demonstration of A-dicarboxyl-mono-glycines in dicarboxylic acidurias by mass fragmentography. Clin. Chim. Acta, 78,173. 

Dicarboxylic aciduria (congenital medium-chain-length dicarboxylic aciduria) ... 

The dissimilarity of these patients from those with apparent multiple acyl-CoA dehydrogenase deficiency (Section 14.2.1) and other dicarboxylic acidurias is noticeable and the primary defect remains unknown. 

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