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PubMed1978

Argininosuccinic aciduria: assignment of the argininosuccinate lyase gene to the pter to q22 region of human chromosome 7 by bioautography.

Argininosuccinic aciduria, an autosomal recessive disorder of the urea cycle in humans, is associated with a deficiency of argininosuccinate lyase (ASL; L-argininosuccinate arginine-lyase, EC 4.3.2.1). ASL activity was visualized on gels after electrophoresis by a new method, termed bioautography. Bioautography involves the use of mutant bacteria to visualize the location of mammalian enzymes after zone electrophoresis. By this technique, human ASL migrated to a position different from mouse ASL, while a survey of mouse strains, tissues, and tissue culture cell extracts demonstrated the same electrophoretic form and no genetic variants of mouse ASL. Identifying human ASL, by bioautography in human-mouse somatic cell hybrids has made it possible to regionally locate the ASL gene on human chromosome 7. The human ASL phenotype segregated concordantly with the human enzyme beta-glucoronidase (GUS; beta-D-glucoronide glucuronosohydrolase, EC 3.2.1.31) in cell hybrids, but showed discordant segregation with 32 other enzyme markers representing 23 linkage groups. The gene for GUS has been assigned to chromosome 7 in humans, and cosegregation (synteny) of ASL and GUS demonstrates the assignment of ASL to chromosome 7. Regional location of ASL and GUS to the pter to q22 region of chromosome 7 was achieved in hybrids segregating a 7/9 translocation.

Amino Acid Metabolism, Inborn Errors↗
PubMed2000

Intragenic complementation and the structure and function of argininosuccinate lyase.

Argininosuccinate lyase (ASL) catalyzes the reversible hydrolysis of argininosuccinate to arginine and fumarate, a reaction important for the detoxification of ammonia via the urea cycle and for arginine biosynthesis. ASL belongs to a superfamily of structurally related enzymes, all of which function as tetramers and catalyze similar reactions in which fumarate is one of the products. Genetic defects in the ASL gene result in the autosomal recessive disorder argininosuccinic aciduria. This disorder has considerable clinical and genetic heterogeneity and also exhibits extensive intragenic complementation. Intragenic complementation is a phenomenon that occurs when a multimeric protein is formed from subunits produced by different mutant alleles of a gene. The resulting hybrid protein exhibits greater enzymatic activity than is found in either of the homomeric mutant proteins. This review describes the structure and function of ASL and its homologue delta crystallin, the genetic defects associated with argininosuccinic aciduria and current theories regarding complementation in this protein.

Amino Acid Metabolism, Inborn Errors↗
PubMed2003

Glutaric aciduria type 1 and neonatal screening: time to proceed--with caution.

The new technology of tandem mass spectrometry is having a significant impact on the diagnostics of inborn metabolic errors. One of the most important aspects of this new technology is the possibility of recognising a whole class of disorders within a single analytical step. Shall this powerful technology be applied to the screening of newborn babies? Careful evaluation of every single disorder that could potentially be identified is needed. In the following, I will present some considerations that concern glutaric aciduria type 1 (MIM 231670; glutaryl-CoA dehydrogenase deficiency).

Amino Acid Metabolism, Inborn Errors↗
PubMed2003

D-2-Hydroxyglutaric aciduria with absence of corpus callosum and neonatal intracranial haemorrhage.

We report D-2-hydroxyglutaric aciduria in a neonate with intracranial haemorrhage and absence of the corpus callosum. D-2-hydroxyglutaric acid was confirmed by specific chiral derivatization gas chromatography-mass spectrometry. Absence of the corpus callosum and spontaneous neonatal intracranial haemorrhage should raise the suspicion for metabolic disease, and especially organic acidurias.

Abnormalities, Multiple↗
PubMed1994

A study of urinary metabolites in patients with dicarboxylic aciduria for differential diagnosis.

Dicarboxylic aciduria (DCA-uria) is a relatively common finding in the screening of organic acidemias by gas chromatography/mass spectrometry (GC/MS). A considerable number of patients with DCA-uria are involved in disturbances of mitochondrial and peroxisomal fatty acid beta-oxidation. The differential diagnosis of DCA-uria was investigated using a combination of organic acid analysis by GC/MS, carnitine determination, acylcarnitines by fast atom bombardment/mass spectrometry (FAB/MS) and acylglycines by stable-isotope dilution analysis. The relative distribution of urinary metabolites was examined in 46 patients with DCA-uria of different origins, including physiological ketosis of childhood, disorders of propionic acid metabolism, glutaric aciduria type II, Zellweger syndrome and patients who were clinically diagnosed as having Reye syndrome. Zellweger syndrome seemed to be distinguishable from other disorders by the high sebacic acid/adipic acid ratio of DCA-uria and increased excretion of 4-hydroxyphenyllactic acid and 2-hydroxysebacic acid. The mild form of glutaric aciduria type II was often missed by current organic acid analysis alone, but was readily diagnosed by acylcarnitine and acylglycine determination. The ratio of free/total carnitine was low in most of the DCA-uria patients except for two of five cases of Zellweger syndrome and one of three cases of Reye syndrome. The acylcarnitine analysis by FAB/MS showed adipyl-, suberyl-, sebacyl- or dodecanedioylcarnitine as major peaks in most of these patients, although these were not specific. Disease-specific peaks were detectable only in congenital organic acidemias such as glutaric aciduria type II, methylmalonic acidemia and propionic acidemia.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

[Hereditary metabolic causes of stroke and pseudo-stroke in adulthood].

Metabolic diseases are a rare cause of strokes. However, prevention and treatment are available for some of them. This work describes some metabolic diseases generating strokes by disturbing directly vascular function (homocysteine disorders, Fabry disease, congenital defects of glycosylation) and those for which clinical presentation is similar to a stroke (urea cycle disorders, branched-chain organic acidurias, mitochondrial diseases).

Adult↗
PubMed1995

Vitamin B12 in health and disease: part I--inherited disorders of function, absorption, and transport.

All of vitamin B12 in nature is of microbial origin. Cobalamin, as vitamin B12 should correctly be termed, is a large polar molecule that must be bound to specialized transport proteins to gain entry into cells. Entry from the lumen of the intestine under physiological conditions occurs only in the ileum and only when bound to intrinsic factor. It is transported into all other cells only when bound to another transport protein, transcobalamin II. Congenital absence or defective synthesis of intrinsic factor or transcobalamin II result in megaloblastic anemia. The Immerslund-Graesbeck syndrome, a congenital defect in the transcellular transport of cobalamin through the ileal cell during absorption, also presents with megaloblastic anemia, but with accompanying albuminuria. In most bacteria and in all mammals, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, the conversion of N5-methyltetrahydrofolate to tetrahydrofolate, which in turn is linked to the conversion of homocysteine to methionine. This reaction occurs in the cytoplasm, and it is catalyzed by methionine synthase, which requires methyl cobalamin (MeCbl), one of the two coenzyme forms of the vitamin, as a cofactor. Defects in the generation of MeCbl (cobalamin E and G diseases) result in homocystinuria; affected infants present with megaloblastic anemia, retardation, and neurological and ocular defects. 5'-Deoxyadenosyl cobalamin (AdoCbl), the other coenzyme form of cobalamin, is present within mitochondria, and it is an essential cofactor for the enzyme Methylmalonyl-CoA mutase, which converts L-methylmalonyl CoA to succinyl CoA. This reaction is in the pathway for the metabolism of odd chain fatty acids via propionic acid, as well as that of the amino acids isoleucine, methionine, threonine, and valine. Impaired synthesis of AdoCbl (cobalamin A or B disease) results in infants with methylmalonic aciduria who are mentally retarded, hypotonic, and who present with metabolic acidosis, hypoglycemia, ketonemia, hyperglycinemia, and hyperammonemia. Megaloblastic anemia does not develop in these children because adequate amounts of MeCbl are present, but the effect of methylmalonic acid on marrow stem cells may give rise to pancytopenia. Congenital absence of reductases in the cytoplasm, which normally reduce the cobalt atom in cobalamin from its oxidized to its reduced state (cobalamin C and D diseases), results in impaired synthesis of both MeCbl and AdoCbl. Both methylmalonic aciduria and homocystinuria therefore develop in these children, and they present with megaloblastosis, mental retardation, a host of neurological and ocular disorders, and failure to thrive; however, they do not have hyperglycinemia or hyperammonemia. A similar biochemical profile and clinical presentation is also seen in cobalamin F disease, which results from a defect in the release of cobalamin from lysosomes, following receptor-mediated endocytosis of the transcobalamin II-cobalamin complex into cells. It is important to recognize these inborn errors of cobalamin absorption, transport, or function as soon after birth as possible, because most respond (in some patients more fully than others) to parenteral administration of cobalamin. Delays in diagnosis can lead to grave clinical consequences.

Biological Transport↗
PubMed1999

Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism.

Development of acylcarnitine and amino acid profiling using tandem mass spectrometry, and its application for use with dried blood specimens collected on filter-paper cards, has introduced an innovative new technology for detecting inborn errors of fatty acid, organic acid, and amino acid metabolism. From November 1, 1992 through June 30, 1999 we screened more than 700,000 newborns in Pennsylvania, Ohio, North Carolina, and Louisiana. We have prospectively detected 163 inborn errors of metabolism. Eighty-six patients have amino acid metabolism errors. Among them are phenylketonuria, hyperphenylalaninemia, maple syrup urine disease, and several urea cycle disorders. Thirty-two have organic acid metabolism errors, including glutaric aciduria type 1; 3-methylcrotonyl coenzyme A (CoA) carboxylase deficiency, propionic acidemia, methylmalonic acidemia, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency; and 45 have fatty acid oxidation errors, including 36 with medium-chain acyl-CoA dehydrogenase deficiency. Details of the methodology are presented and the potential of this screening technology is discussed.

Amino Acids↗