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Metabolism of propionate in human subjects was studied using bolus administration of 1-13C-propionate i.v. or orally. The study population consisted of five patients with propionic acidemia (PA), eight with methylmalonic acidemia (MMA; four responsive to vitamin B12), one each with multiple carboxylase deficiency and transcobalamin-II deficiency, and five healthy volunteers. Concentrations of 1-13C-propionate were measured in blood in three patients with PA, two with MMA, and two controls. Breath samples were obtained at intervals during 3 h after the dose, isotopic enrichment of 13CO2 was measured, and the cumulative percentage of recovery of 13C was calculated from the individual's predicted resting energy expenditure. Recovery of 13CO2 and half-time of 1-13C-propionate in PA were significantly less than normal. The same parameters in MMA were below normal, but significantly greater than in PA. Recovery of 13CO2 was well correlated with clinical severity in PA, but did not correlate in MMA. Differences between MMA and PA may indicate different distribution of propionate pools, differences in inducibility of residual enzyme activities, or an alternate pathway for decarboxylation of propionate available in MMA but not PA. Only one patient with PA demonstrated increased 13CO2 production during biotin treatment. In a B12-responsive MMA patient, no differences were noted within 2 d of initiating treatment with B12, but there was an increase in 13CO2 production after 4 mo. Recovery of 13CO2 was normal in the patient with transcobalamin-II deficiency before and after treatment with vitamin B12.(ABSTRACT TRUNCATED AT 250 WORDS)

The expression of full-length dystrophin and various dystrophin deletion mutants was monitored in mdx mouse muscle after intramuscular injection of dystrophin-encoding plasmid DNAs. Recombinant dystrophin proteins, including those lacking either the amino terminus, carboxyl terminus, or most of the central rod domain, showed localization to the plasma membrane. This suggests that there are multiple attachment sites for dystrophin to the plasma membrane. Only those constructs containing the carboxyl terminus were able to stabilize dystrophin-associated proteins (DAP) at the membrane, consistent with other studies that suggest that this domain is critical to DAP binding. Colocalization with DAP was not necessary for membrane localization of the various dystrophin molecules. However, stabilization and co-localization of the DAP did seem to be a prerequisite for expression and/or stabilization of mutant dystrophins beyond 1 wk and these same criteria seemed important for mitigating the histopathological consequences of dystrophin deficiency.

The mdx mouse has been used for the development of cellular and gene therapies for Duchenne muscular dystrophy. The relatively frequent occurrence of dystrophin-positive muscle cells called revertants has hampered these efforts by interfering with data interpretation. The mdx4cv and mdx5cv dystrophin mouse mutants have approximately 10-fold fewer revertants than the mdx mutant at both 2 and 6 mo. The mdx3cv dystrophin mouse mutant may be a useful model for some types of human dystrophin deficiencies in which the levels of dystrophin are low but not completely absent.

We report clinical and biochemical studies in patients with multiple acyl-CoA dehydrogenation disorders (MAD) and their parents. A severely affected (MAD:S) patient presented with neonatal acidosis leading to death and excreted a wide range of straight- and branched-chain acyl CoA derivatives. Two patients with mild variants of the same disorder (MAD:M) presented with neurologic abnormalities, acidotic coma, and/or poor growth; they primarily excreted ethylmalonate and variable amounts of adipate. Fibroblasts from the MAD:S patient demonstrated severely defective radiolabeled substrate oxidation, while the MAD:M cells had milder oxidative defects. Fibroblasts from two other MAD:M and six other MAD:S patients demonstrated analogous defects in substrate oxidation. As a group, MAD:S cells deficient in electron transfer flavoprotein:ubiquinone oxidoreductase had significantly lower residual oxidative activities than did MAD:S cells deficient in electron transfer flavoprotein. Fibroblasts from the parents of four MAD:S patients oxidized radiolabeled substrates significantly less effectively than did normal infant controls but were indistinguishable from normal adult cells. We found relatively higher residual oxidative activities in maternal than in paternal cells. Amniocytes from a fetus at risk for MAD:S catabolized labeled substrates normally; the infant has been clinically and biochemically normal up to 30 months of age.

The effects of ascorbic acid on the excretion of homogentisic acid and its derivative benzoquinone acetic acid were studied in two adults and three infants. The administration of relatively large amounts of ascorbic acid to the adults was followed by a disappearance of benzoquinone acetic acid from the urine, whereas the level of excretion of homogentisic acid did not change. This could have relevance to the pathogenesis of ochronotic arthritis. In the 4-mo-old infant and the 5-mo-old infant ascorbic acid in the urine may have doubled the amount of homogentisic acid, presumably through an effect on the immature p-hydroxyphenylpyruvic acid oxidase. Dietary reduction of the intake of tyrosine and phenylalanine substantially reduced the excretion of homogentisic acid.

Plasma and red cell fatty acids were measured in 44 children with third degree malnutrition: 22 children with marasmus, 11 children with kwashiorkor, and 11 with marasmic kwashiorkor (MK). The presence of edema, dermatosis, hair changes, and hypoalbuminemia were positively correlated with the red cell percentage linoleic acid and negatively correlated with red cell percentage arachidonic acid. Red cell percentage linoleic acid in kwashiorkor was decreased from the control value of 15.3% to 10.9%. In marasmus and MK, there were significantly greater decreases, to 7.7% and 8.0%, respectively. Red cell arachidonic acid in kwashiorkor was significantly (P less than 0.001) decreased to 9.8% (control value of 13.1%) whereas in marasmus there was no significant change. Only one sample, plasma from an infant with marasmus, had any detectable eicosatrienoic acid (20:3,omega 9). Similar changes in fatty acid composition have been reported in infants with acrodermatitis enteropathica, in an infant with biotin deficiency, and in biotin-deficient rats.