Inborn Metabolic Diseases Research Articles

Argininosuccinic aciduria: A developmental and biochemical case study

An infant with argininosuccinic aciduria was detected through the routine newborn screening program for inborn metabolic diseases and has been followed for over 7 years. Treatment consisting of restricted protein intake and arginine base supplementation was initiated at the age of 8 months and was continued intermittently. She maintained normal psychomotor development to the age of 3 years and currently at the age of 7.3 years, she has measured intelligence in the borderline range. She has had mild symptoms of cerebellar ataxia. Her physical growth has been below normal. Biochemical abnormalities are described. Special metabolic investigations and the effects of treatment are discussed.

Quantitative two-dimensional protein electrophoresis for studies of inborn errors of metabolism.

High-resolution electrophoretic methods and sensitive protein-detection techniques permit new approaches to understanding and diagnosis of the inborn errors of metabolism. These approaches encompass: the search for protein alterations that represent primary mutations effects; observation of alterations in protein patterns due to secondary effects, as might occur in major metabolic pathway abnormalities; and identification of protein polymorphisms that are genetically linked to an inborn metabolic disease. With the aid of computer analysis of the electrophoretograms, all three approaches are being developed. Protein density and position are evaluated with an interactive computer program that requires that gel polypeptides be indexed by the investigator. Proteins on the gels are made visible with an inexpensive, rapid silver stain, which can be used quantitatively. The Lesch-Nyhan syndrome, one of a few neuropsychiatric diseases for which the molecular defect is known, was chosen for study with these techniques. Four hundred proteins were analyzed for positional or quantitative variation. Eleven significant (2p less than 0.01) quantitative differences were found in autoradiograms from gels of phytohemagglutinin-stimulated lymphocytes. Specific patterns of polypeptide variation are now being sought in an expanded clinical study primarily focusing on Huntington's disease. Large studies are required to establish the specificity of observed alterations. As the number and variety of analyses increase, a correlative catalog of molecular variation and polymorphism will be generated.

Detection of genetic defects by amniocentesis in early pregnancy (author's transl)

In the view of the obstetrician the development of prenatal diagnosis of genetic diseases is the consequent continuation of preventive measures for mother and child during prenatal care. In vitro cultivation of fetal cells after amniocentesis in the beginning second trimester enabled the use of those cells for cytogenetic and biochemical analyses. In doing so, chromosomal anomalies, an increasing number of inborn metabolic diseases and open neural tube defects can be detected or excluded in early pregnancy. We are today in a position to encourage carrier families suffering from hereditary defects to have children in cases which have so far been dissuaded from pregnancy. Due to the fact that in approximately 95% of the cases an inborn anomaly can be excluded prenatal diagnosis of congenital defects has got a positive effect on the ongoing pregnancy and over all family planning. Based on our studies of 1000 amniocenteses indications, risks and results are being presented. The diagnostic possibilities of the fetoscopy are being discussed in the light of the first own experiences.

Macular Cherry-Red Spots and β-Galactosidase Deficiency in an Adult

An adult patient with macular cherry-red spots, a gargoyle-like physical appearance, cerebellar ataxia, myoclonus, convulsive seizures, and pyramidal tract signs showed a profound deficiency of beta-galactosidase in liver and brain. Thrombocytopathy of undetermined etiology was evident since childhood, and the patient died of intracranial bleeding at age 22. Cerebral ganglioside pattern was normal. Hepatic mucopolysaccharides were not increased. GM1-gangliosidosis and mucopolysaccharidosis were ruled out by those analytical data. However, a large amount of amylopectin-like polysaccharide was found to be accumulated in liver. Hepatocyte contained numerous inclusion bodies with granulofibrillary structure similar to Lafora bodies, corpora amylacea, and inclusion bodies in glycogenosis type IV. This case seems to represent a new inborn metabolic disease closely related to GM1-gangliosidosis and mucopolysaccharidosis. The primary metabolic defect is not known at present.

Alpha1-Fetoprotein measurement in blood spotted on paper: discriminating test for hereditary tyrosinemia in neonatal mass screening.

We describe an electroimmunodiffusion technique for measuring alpha1-fetoprotein in blood spotted on chromatography paper. The system is being used as a complementary test in a neonatal mass-screening program for detection of inborn metabolic diseases in the Province of Quebec. In a series of 102 cases of neonatal hypertyrosinemia, the test has proven to be highly discriminative for hereditary tyrosinemia. It has permitted early detection of eight cases of this disease, including two that would have been missed by the previously used screening procedure, tyrosine measurement only. The test not only virtually eliminates the risk of misdiagnosis or missed diagnosis, but also permits earlier diagnosis of hereditary tyrosinemia and considerably reduces the follow-up work required for newborns with transitory tyrosinemia. The AFP test is simple, fast, practical, and inexpensive. Combined with tyrosine determination, it constitutes an optimal device for mass screening of hereditary tyrosinemia.

Cytochemical Leukocyte Reactions in Normal Children

Five cytochemical reactions in current use (MPO, PAS, LAP, SB and EST) were operated on 180 children aged 1 month to 6 years, divided into three age groups (less than 12 months, 1-3 years and 3-6 years). No significant differences are apparent from one group to another, and the mean values are identical with those of adults. On the other hand, certain variations are evident in comparison with the scores of newborn children: important decrease in LAP, increase in SB, EST and PAS. These tests should be done in investigations of inborn metabolic errors, chromosome anomalies, blood diseases, and defects in defense mechanisms.

Effect of selenium compounds on selenium content, growth and 35S-cystine metabolism of skin fibroblasts from normal and cystinotic individuals

Kidney samples from children with the inborn metabolic disease cystinosis contain 4 times more selenium (Se) than do kidney samples from normal individuals (p = 0.1). However, when cultured skin fibroblasts from cystinotic patients and normal control individuals are incubated in Se-D,L-methionine, Se-D,L-cystine, Se-cystamine-HCl, Se-urea, selenite or in medium without added selenium, only the cystinotic fibroblasts grown in Se-urea or selenite (SeO 3 =) contain more selenium than do the corresponding normal cells (p < 0.05). In both types of cultured fibroblasts, the order of descending toxicity per ppm selenium is: Se-urea > Se-cystamine > Se-cystine > SeO 3 = ⪢ Se-methionine. High (apparently toxic) concentrations of Se-urea and Se-cystamine lower the elevated intracellular free (nonprotein) cystine content of cystinotic fibroblasts to less than 60% of control values; at lower concentrations, these compounds raise the cystine content of these cells to over 140% of control values. Appropriate concentrations of SeO 3 =, Se-cystine and Se-

Cystic fibrosis and liver β-galactosidase and β-glucosidase

The pH profiles of β-galactosidase and the isoenzyme patterns of β-galactosidase and β-glucosidase, separated by gel column chromatography, were compared for cystic fibrosis, inborn metabolic disease and control liver. The pH profile and specific activity of β-galactosidase of cystic fibrosis liver was similar to that for the controls. A marked variation in the level of the three isoenzymes of β-galactosidase and the two peaks of β-glucosidase was found for individual livers. It seems probable that these two enzymes in cystic fibrosis have isoenzyme patterns that conform to the control type.

The catabolism of ornithine after intravenous loading in normal subjects and two patients with hyperprolinaemia type II

The results of studies in which intravenous ornithine or proline loadings were administered to normal subjects suggest a rate-limiting function of ornithine-ketoacid aminotransferase in the conversion of ornithine to glutamate, and of proline oxidase in the conversion of proline to glutamate. The failure of Δ 1-pyrroline-5-carboxylic acid to appear in the plasma and urine during ornithine-proline loading indicates the high capacity of Δ 1-pyrroline-5-carboxylic acid dehydrogenase in the conversion of its substrate to glutamate. In two patients with hyperprolinaemia type II, the urinary excretion of Δ 1-pyrroline-5-carboxylic acid increased slightly during ornithine loading. This suggests that this inborn metabolic disease exhibits a defect in the conversion of Δ 1-pyrroline-5-carboxylic acid to glutamate and that ornithine may be converted to this substance.

DETECTION OF INBORN METABOLIC DISEASE IN THE YOUNG CHILD.

DETECTION OF INBORN METABOLIC DISEASE IN THE YOUNG CHILD.