Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “AMINO ACIDURIA”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 919 records · Page 51Linked to original sources
PubMed1991

Organic acidurias: a review. Part 2.

Laboratory findings are an essential part of the diagnostic approach to organic acidemias. In most organic acidemias, metabolism of glucose, ketone bodies, and ammonia is deranged primarily or secondarily, in addition to derangement of the acid-base balance. Hypoglycemia, lactic and/or ketoacidosis, and hyperammonemia of varying severity accompany the overt or compensated acidosis. In most instances, a definite diagnosis will be achieved by gas chromatography/mass spectrometry (GC/MS) studies of the urine. We detail the pattern of excreted organic acids in the major disorders. When the diagnosis reached by clinical and laboratory assessments is not conclusive, it must be supported by loading tests. We list the available methods of demonstrating the putative enzyme deficiency in the patient's cells and tissues. The majority of organic acidemias may be treated by limiting the source of or removing the toxic intermediary metabolite. We provide lists of available diets, supplements, and medications. In some instances, residual defective enzyme activity may be stimulated. We describe symptomatic management of the disturbed acid-base and electrolyte balance.

Acidosis↗
PubMed2005

Gamma-hydroxybutyric aciduria: a biochemist's education from a heritable disorder of GABA metabolism.

In keeping with the theme of the 41st Annual Symposium (Metabolic Encephalopathies), the current report provides an overview of a quarter century of research investigating a rare inborn error of GABA metabolism, succinic semialdehyde dehydrogenase (SSADH) deficiency (also referred to as gamma-hydroxybutyric aciduria). The clinical phenotype, treatment challenges, pathomechanistic concepts, as well as metabolic, enzymatic and molecular characteristics, of the disorder are summarized. In addition, important features of a recently developed murine model are presented, with discussion of how this model has broadened thinking about, and treatment approaches to, the clinical disease. In addition, a brief scientific history of the author is provided, and an account of how serendipitous circumstances brought him together with other colleagues to begin delineating the aetiological mechanisms in SSADH deficiency. The evolution of research on SSADH deficiency re-establishes the classical approach beginning at clinical characterization, evolving to enzyme and metabolite identification as well as molecular characterization, and eventually to model development and preclinical treatment approaches. This scientific evolution admirably supports the life and ideals of Dr George Komrower, in whose honour this lecture is named.

3-Hydroxybutyric Acid↗
PubMed1991

Phenotypic heterogeneity in the syndromes of 3-methylglutaconic aciduria.

Combined 3-methylglutaconic and 3-methylglutaric aciduria, one of the more common urinary organic acid abnormalities, has been observed in at least three clinical syndromes. We studied an additional seven patients with 3-methylglutaconic aciduria, four of whom were best categorized as having the type II syndrome, two as having an "unspecified" syndrome, and one who may have had a primary urea cycle defect. In cultured cells and autopsy tissues derived from patients with the type II and unspecified syndromes, we were unsuccessful in identifying a defect in the leucine degradative pathway distal to 3-methylcrotonyl-coenzyme A carboxylase and in the cholesterol biosynthetic pathway between 3-hydroxy-3-methylglutaryl-coenzyme A reductase and diphosphomevalonate decarboxylase. Further assessment of the cholesterol biosynthetic pathway in several patients with one of the two types of disease also provided no defined abnormality. The primary metabolic defects in the type II and unspecified syndromes remain undefined.

Amino Acid Metabolism, Inborn Errors↗
PubMed1984

Homocystinuria and megaloblastic anemia responsive to vitamin B12 therapy. An inborn error of metabolism due to a defect in cobalamin metabolism.

We describe an inborn error of vitamin B12 metabolism in an infant who had severe developmental delay, megaloblastic anemia, and homocystinuria. There was no evidence of methylmalonic aciduria or deficiency of folate or vitamin B12. Treatment with hydroxocobalamin, but not with cyanocobalamin and folic acid, resulted in rapid clinical and biochemical improvement. Cultured fibroblasts showed an absolute growth requirement for methionine, defective incorporation of radioactivity from [14C]5-methyltetrahydrofolate into protein, and normal incorporation of radioactivity from [14C]propionate, thus assigning the intracellular defect to methionine synthesis. The proportion of intracellular methylcobalamin in the fibroblasts was decreased, but that of 5'-deoxyadenosylcobalamin was normal. Methionine synthetase activity in cell extracts was normal, as was cobalamin incorporation into cultured cells. This defect differs from those described previously in being limited to methylcobalamin accumulation and defective use of 5-methyltetrahydrofolate by intact cells with normal activity of methylmalonyl CoA mutase.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMedDate not supplied

Propionic acidemia revisited: a workshop report.

Propionic acidemia (PA) is one of the most frequent organic acidurias, but information on the outcome of individuals with PA is rather limited. We present data of 49 patients with PA, which were gathered from 18 metabolic centers throughout Central Europe on the occasion of an international workshop. All patients were identified by selective metabolic screening, and 86% of them were classified as having early-onset PA owing to their presentation with clinical symptoms within the first 90 days of life. Mortality rate was one third, and details of symptoms and treatment of the surviving patients are discussed. The great variation of phenotypic expression of the disease and different therapeutic strategies (especially in regard to the degree of protein restriction) used at the various institutions involved in this study imply the need for a registry of PA patients and for a multicenter prospective treatment study.

Amino Acid Metabolism, Inborn Errors↗
PubMed1988

[Argininosuccinic aciduria. Comparative studies and detection of carriers in 3 affected families].

Three patients with argininosuccinic aciduria are described. One of them is a neonatal form, with typical acute course and severe hyperammonemia who died on the sixth day of life. Postmortem analysis showed a marked plasmatic accumulation of argininosuccinic acid. Later on, red blood cell ASA-lyase levels demonstrated the heterozygosity of her parents and sisters. The two other patients are late onset forms and were diagnosed after detection of ASA and its anhydrides in plasma and urine. Levels of these metabolites did not correlate with levels of residual ASA-lyase in erythrocytes. Treatment with a hypoproteic diet supplemented with arginine has improved their clinical state. Carriers have been detected in both families. Importance of rapid diagnosis and treatment of hyperammonemic patients in order to prevent neurologic damage is emphasised.

Amino Acid Metabolism, Inborn Errors↗
PubMed2004

Glutaric aciduria type I and kynurenine pathway metabolites: a modified hypothesis.

Glutaric aciduria type I is an inborn error of organic acid metabolism that demonstrates a particular temporal vulnerability (acute encephalopathic episodes in infancy) and a spatial vulnerability (acute striatal necrosis, focused on the putamen). Excitotoxic mechanisms involving 3-hydroxyglutaric acid as the major neurotoxin have been suggested. This paper proposes a role for metabolites of the kynurenine pathway in the pathogenic process and modifies the hypothesis of Heyes. Deficiency of glutaryl-CoA dehydrogenase blocking the glutarate pathway and activation of indoleamine 2,3-dioxygenase in macrophages/monocytes by intercurrent inflammation may increase flux down the kynurenine pathway towards the production of quinolinic acid. Quinolinic acid is neurotoxic and is an endogenous agonist at N-methyl-D-aspartate receptors. Synergistic excitation of these receptors by quinolinic acid and 3-hydroxyglutaric acid, which alone does not have sufficient potency, may be involved in the pathogenesis of striatal necrosis.

Amino Acid Metabolism, Inborn Errors↗
PubMed1983

Ornithine carbamoyltransferase deficiency in an adult male patient: significance of hepatic ultrastructure in clinical diagnosis.

Ornithine carbamoyltransferase (OCT) activity was deficient (8% of control) in the liver of a 21-year-old man who died after suddenly becoming comatose. Activities of other enzymes of the urea cycle in the liver were normal. There was no known prior illness or injury; the patient, however, had been taking liquid protein supplements to his diet. Hyperammonemia and orotic aciduria were present, and the concentration of lysine in the plasma was elevated. Survey of earlier reports indicates that neither the specific deficiency of hepatic OCT nor the urine and plasma findings provide a basis for definitive diagnosis of the patient's illness as primary OCT deficiency or as Reye's syndrome. Indeed, the age of the patient at onset of symptoms and the absence of any prodromal infection argue against the OCT deficiency being either primary or a sequel to Reye's syndrome. We suggest that it was secondary to mitochondrial injury caused by an unknown agent. Electron microscopic study of hepatocyte ultrastructure lends support to this view; abnormalities of the patient's mitochondria (bizarre, elongated shapes) do not resemble those seen in Reye's syndrome, nor have abnormalities been found in primary OCT deficiency.

Adult↗
PubMed1999

Liver transplantation in urea cycle disorders.

We report here our experience in the long-term management of 28 patients with citrullinaemia, 13 patients with carbamoyl phosphate synthase deficiency and 15 patients with argininosuccinic aciduria. In addition, we report a national French survey of 119 patients with ornithine transcarbamylase (OTC) deficiency enzymatically characterized in our laboratory. We also include in this report four personal patients (two with OTC and two with citrullinaemia) who were liver transplanted, and one OTC patient from the National French survey. Although this retrospective series is not really representative of the modern treatment combining low protein diet and arginine, sodium benzoate and sodium phenylbutyrate, it is obvious that the long-term outcome of all urea cycle disorders remains very guarded. We highlight the severity of the neonatal forms of such disorders, and mostly for OTC-deficient males. According to this evidence, our policy is not to treat such severely affected patients in the neonatal period who die anyway spontaneously within 2 to 3 days. At the present time, we only have three patients with neonatal citrullinaemia, aged 1, 6 and 10 years respectively, who are still doing well. One of them has been successfully liver transplanted at 5 years. Another transplanted patient died in the post-surgical phase. We emphasize the unexpected severity of argininosuccinic aciduria in which there is no one patient doing well. This is a rather surprising finding as this disorder is easy to manage and rarely presents with recurrent attacks of hyperammonaemia when it is treated by arginine supplementation. This consideration would suggest to extend the indication of orthotopic liver transplantation in this disorder. Finally, the most difficult indication is in the late onset symptomatic female OTC group. In this last group, despite a significant residual activity due to heterozygote status, even with a variable lyonisation, only seven girls are still mentally and neurologically normal. Interestingly, three of these seven were liver-transplanted before the constitution of irreversible neurological damage. These three girls and their family declare their well-being, their feeling to be cured and enjoy their normal life.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

Glutaric aciduria type 1: an underdiagnosed cause of encephalopathy and dystonia-dyskinesia syndrome in children.

Two cases of glutaric aciduria type 1 (GA 1) are presented. GA 1 is probably underdiagnosed and misdiagnosed, and may explain a proportion of cases of extrapyramidal and 'postencephalitic' cerebral palsy. Most cases of GA 1 present with a severe dystonic-dyskinetic syndrome following an acute encephalopathy. Asymptomatic cases have also been described, complicating genetic counselling and prenatal diagnosis. We raise awareness of GA 1 and stress that if clinically suspected, immediate institution of therapy may reduce late morbidity. Moreover, if recognised in the presymptomatic stage, early institution of treatment may prevent the onset of neurological symptoms. GA 1 is an inborn error of lysine and tryptophan catabolism, caused by deficiency of the enzyme, glutaryl coenzyme-A dehydrogenase. Urine organic acid analyses may be negative. Blood acylcarnitine profile has recently been employed as a more sensitive test but was negative in both our patients. Enzyme assay remains the definitive diagnostic test.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Glutaric aciduria type 1 an atypical presentation together with some observations upon treatment and the possible cause of cerebral damage.

This report describes an infant diagnosed aged twenty-five months as having glutaric aciduria Type 1 (GA 1). Initial presentation was with isolated macrocephaly at four months of age. Severe hypertonia, and dystonia, within 24 hours of minor head injury occurred at nineteen months of age. Serial cranial imaging showed subdural fluid collections, and increasing underlying cerebral atrophy, mainly frontal and temporal. Confirmation of the clinical diagnosis required repeated blood and urine analysis by high performance liquid chromatography and gas chromatography/mass spectrometry; diagnosis was later confirmed enzymologically. Treatment with riboflavin, L-carnitine, vigabatrin and baclofen, produced some symptomatic relief; a low protein diet, nitrazepam and sodium valproate appeared of less obvious use. The rationale for these attempts at treatment is discussed. The possible role of quinolinic acid in the genesis of the fronto temporal and striatal atrophy is discussed and measurement of the quinolinate concentration in cerebrospinal fluid (CSF) of this case and age-related controls is presented.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

Long-term correction of urea cycle disorders.

Long-term correction of urea cycle disorders is achieved by correction of the enzymatic defect in hepatocytes. Currently, orthotopic liver transplantation is the primary means of achieving this correction. In the United States most liver transplantations for urea cycle disorders have been restricted to patients with ornithine transcarbamylase deficiency and argininosuccinic aciduria. However, patients with citrullinemia have also received transplants, but more so in Europe and Japan. Recent advances in organ procurement, surgical technique, and immunosuppression have significantly decreased morbidity and mortality. However, unique short-term complications associated with surgery and long-term complications associated with chronic immunosuppression have spurred continued efforts to develop gene replacement therapies for management of acute metabolic decompensations as intercurrent therapy until liver transplantation, and ultimately, for long-term correction. The pathophysiology of urea cycle disorders requires gene vector delivery systems that are highly efficient for liver transduction and transgene expression. To date, adenoviral vectors are unique in fulfilling these criteria, and significant data have been gained in both animal and human studies with early versions of adenoviral vectors. Ultimately, the development of helper-dependent adenoviral vectors may offer the long-term expression and increased margin of safety necessary for adjunctive therapies.

Adenoviridae↗
PubMed1993

Molecular studies of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in the two original families.

We describe mutations identified in stored skin fibroblast cell lines from two original probands (JB and JM), first reported with 2-methylacetoacetic aciduria, and shown later to have a deficiency of the K(+)-activated enzyme, mitochondrial acetoacetyl-coenzyme A thiolase (T2). JB is homozygous for a 4-base insertion (GCAG) which is derived mutation. The primary mutation is an AG/gt to AG/gc transition at the 5'-splice-junction site in intron 11. An alternative splice site 4 bp downstream (Ggcag/gt) is used which causes a frame shift and replaces 39 C-terminal residues by 70 nonfunctional residues. JM is homozygous for a mutation in the translation-initiation codon (ATG to AAG). By expression analyses the JB mutation (IVS11nt2) causes an unstable T2 polypeptide and the JM mutation (M1K) severely impairs T2 mRNA translation. The JB allele associates with Dutch ancestry (no consanguinity) and the JM allele with Chilean ancestry (distant consanguinity).

Acetyl-CoA C-Acetyltransferase↗
PubMed2004

3-methylglutaconic aciduria type I in a boy with fever-associated seizures.

3-Methylglutaconic-aciduria type I (MGA1, OMIM 250950) resulting from 3-Methylglutaconyl-coenzyme A hydratase deficiency is a rare inherited metabolic disorder of l-leucine catabolism. We diagnosed this condition in a 4-year-old German male with generalized fever-associated seizures from the age of 12 months and normal psychomotor development. First he was considered to suffer from uncomplicated febrile seizures. After his eighth seizure, laboratory investigations were performed to exclude inborn errors of metabolism. Analysis of organic acids in urine indicated highly elevated concentrations of 3-methylglutaconic and 3-hydroxyisovaleric acids. 3-Methylglutaconyl-coenzyme A hydratase activity was markedly decreased in skin fibroblasts. Mutation analysis in the AUH gene revealed homozygosity for a novel splice site mutation IVS9-2A>G. We conclude that MGA1 may be associated with fever-associated seizures even in children without delayed psychomotor development.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

[3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency as a cause of severe neurological damage].

This paper describes the first Argentine case of 3-hydroxy-3-methylglutaric aciduria, a genetic defect of ketogenesis and leucine catabolism step. At the age of 4 months, the patient presented a life-threatening episode of hypoglucemia, metabolic acidosis and hyperammonemia resembling Reye syndrome. The lack of urinary ketone bodies, normal levels of plasma aminoacids and normal urinary excretion of p-hydroxyphenolic acids, led us to look for a ketogenic defect. An abnormal profile of urinary organic acids detected by thin layer chromatography and later characterized and quantified by gas chromatography-mass spectrometry (Figs. 1, 2; Table 1), showed a marked increase in the acidic metabolites typical of the 3-hydroxy-3-methylglutaric aciduria: 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids. The activity of 3-hydroxy-3-methylglutaryl coenzyme A lyase was absent in white cell pellets and between 2-5% of the control values in skin fibroblasts (Table 2). Treatment of the disorder, mainly restricted leucine or low-protein diet and addition of L-carnitine had no significant effect on the severe neurological injuries present since the first illness. MRI of the brain, at the age of 1 year and 8 months, showed images in T1 suggestive of marked cerebral atrophy and in T2 hyperintensive images predominating in the right frontal and posterior parietal areas and of the punctiform lesions in the basal ganglia, particularly in the heads of both caudate nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1993

[Glutaric aciduria type I].

We report three patients with glutaric aciduria type I. The biochemical diagnosis of two cases was revealed by determination of free glutaric acid in urine, by using the CG/EM method. In the third patient, however, these levels were only slightly increased and the diagnosis was attained by the determination of total glutaric acid and glutaryl-carnitine. Serum carnitine levels were decreased in two cases. Clinical symptoms of this type of organic acidemia are highlighted by an acute or subacute presentation with signs of dysfunction of the neostriatum, simulating a cerebral paralysis with extrapyramidal signs. Homozygous patients have been reported with the same biochemical and enzymatic activity findings, but these patients were neurologically asymptomatic throughout life. Other features suggestive of the disease are macrocephaly associated with a widening of the subarachnoid spaces. Riboflavin and carnitine administration to these patients seems to prevent new bouts of neurological dysfunction.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Glutaric aciduria type I in the Arab and Jewish communities in Israel.

Mutation analysis was performed in eight families (16 patients) with glutaric aciduria type I (GA-I), which were all the families diagnosed in Israel in the years 1987-1994. Six families were of Moslem origin and two were non-Ashkenazi Jews. The entire coding region of the cDNA of the glutaryl-CoA dehydrogenase gene was sequenced in one patient of each family. Seven new mutations were identified in 15 of 16 mutated alleles, including six point mutations: T416I (4 alleles), G390R (1 allele), and S305L, A293T, L283P, and G1O1R (2 alleles each). In addition, a 1-bp deletion at position 1173 was identified in two alleles. These findings do not provide a molecular basis for the clinical variability in GA-I families. The occurrence of multiple novel mutations in a small geographic area may be explained by their recent onset in isolated communities with a high consanguinity rate.

Adult↗
PubMed2006

D-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect.

D-2-Hydroxyglutaric aciduria (D-2-HGA) is a neurometabolic inherited disorder first described in 1980. In the following years, it became clear that the clinical phenotype of the disease varies widely from severe neonatal to asymptomatic. However, the sparse biochemical knowledge made D-2-HGA a poorly understood disease. Much progress has been made in the last five years in various studies, revealing two human enzymes that play a role in the metabolism of D-2-hydroxyglutarate (D-2-HG): hydroxyacid-oxoacid transhydrogenase (HOT) and D-2-HG dehydrogenase. HOT is expected to be responsible for the formation of D-2-HG, while D-2-HG dehydrogenase converts D-2-HG into 2-ketoglutarate. We demonstrated pathogenic mutations in the D2HGD gene in patients with D-2-HGA, helping to unravel the primary defect causing D-2-HGA. However, in approximately 50% of the patients with D-2-HGA examined, no pathogenic mutations have yet been found.

Alcohol Oxidoreductases↗