Hyper-β-Alaninemia Associated with β-Aminoaciduria and γ-Aminobutyricaciduria, Somnolence and Seizures

Cr, Scriver; Pueschel, Siegfried M.; Davies, Eluned

doi:10.1056/nejm196603242741201

Cited by 111 publications

(22 citation statements)

References 28 publications

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“…They postulated that a defect in a selective mechanism for f-amino acid transport might account for the taurinuria in mutant mice. Others (6)(7)(8) have confirmed the pres-"Abbreviations used in this paper: AIB, aminoisobutyric acid; AOA, (aminooxy)acetic acid hemihydrochloride; ECF, extracellular water; ICF, intracellular water; i.p., intraperitoneal; PAH, para-aminohippuric acid; taut+, normal in net tubular reabsorption of taurine; taut-, hypertaurinuric; TTW, total tissue water.…”

Section: Introductionmentioning

confidence: 73%

Localization of the membrane defect in transepithelial transport of taurine by parallel studies in vivo and in vitro in hypertaurinuric mice.

Chesney¹,

Scriver²,

Mohyuddin³

1976

J. Clin. Invest.

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A B S T R A C T We investigated the mechanism of taurinuria in three inbred strains of mice: A/J, a normal taurine excretor (taut+) ; and two hypertaurinuric (taut) strains, C57BL/6J and PRO/Re. Plasma taurine is comparable in the three strains (-0.5 mM), but taurinuria is 10-fold greater in tau'-animals. Fractional reabsorption of taurine is 0.967±0.013 (mean±SD) in A/J); and 0.839±0.08 and 0.787+0.05 in C57BL/6J and PRO/Re, respectively. Taurine concentration in renal cortex intracellular fluid (free of urine contamination) is similar in the three strains. Taurine reabsorption is inhibited by fi-alanine, in taut`and taut' strains. These in vivo findings reveal residual taurine transport activity in the taut' phenotype and no evidence for impaired efflux at basilar membranes as the cause of impaired taurine reabsorption.Cortex slices provide information about uptake of amino acids at the antiluminal membrane. Taurine behaves as an inert metabolite in mouse kidney cortex slices. Taurine uptake by slices is active and, at < 1 mM, is greater than normal in taut' slices. Concentration-dependent uptake studies reveal more than one taurine carrier in taut+ and taut' strains. The apparent K. values for uptake below 1 mM are different in taut' and taut`slices (-0.2 mM and 0.7 mM, respectively); the apparent K. values above 1 mM taurine are similar in taut and taut' slices. Efflux from slices in all strains is the same (0.0105-0.0113 Amol min-lfg-1 wet wt), but taut' tissue retains about 10% more radioactivity over the period of efflux. P-Alanine is actively metabolized in mouse kidney.

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Section: Introductionmentioning

confidence: 73%

Localization of the membrane defect in transepithelial transport of taurine by parallel studies in vivo and in vitro in hypertaurinuric mice.

Chesney¹,

Scriver²,

Mohyuddin³

1976

J. Clin. Invest.

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“…Epileptic or convulsive attacks were reported in more than half of the cases with a near complete deficiency of DPD (Van Gennip et al 1981a, 1987aBakkeren et al 1984;Berger et al 1984;Wilcken et al 1985;Braakhekke et al 1987;Brockstedt et al 1990); in three out of the four patients with DHP deficiency (Duran et al 1990;Henderson et al 1993;Ohba et al 1994;Van Gennip et al 1997); in the one patient with presumed BAKAT deficiency (Scriver et al 1966); and in the patient with a proven partial deficiency (±30% of normal activity) of BAKAT in fibroblasts (Higgins et al 1994). Both of these last two patients also had a striking lethargy.…”

Section: Clinical Aspects Of Pyrimidine Degradation Defects Symptomatmentioning

confidence: 99%

“…Treatment of patients with DPD or DHP deficiency has not been described. Treatment for hyper-β-alaninaemia may be effective: in the first patient the metabolic, but not the clinical, phenotype improved with treatment with 10mg/day of pyridoxine (Scriver et al 1966); in the second patient both the metabolic as well as clinical phenotype improved dramatically on 100mg/day of pyridoxine (Higgins et al 1994). …”

Section: Treatmentmentioning

confidence: 99%

“…The patient with BAKAT deficiency (Scriver et al 1966) and the patient with proven partial BAKAT deficiency (Higgins et al 1994) both presented with persistently elevated concentrations of β-alanine in plasma (patients, range 20 -51 µmol/L; normal < 14), CSF (patient 1, 45 µmol/L; patient 2, elevated; normal < 0.06) and urine (patient 1, 100 times normal; patient 2, 28 µmol/24h; normal, trace). GABA was also reported to be elevated in the urine of both patients, and in plasma and CSF of patient 1.…”

Section: Detection and Diagnosismentioning

confidence: 99%

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Inborn errors of pyrimidine degradation: Clinical, biochemical and molecular aspects

Gennip

Abeling

Vreken

et al. 1997

J of Inher Metab Disea

103

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The pyrimidines, uracil and thymine, are degraded in four steps. The first three steps of pyrimidine catabolism, controlled by enzymes shared by both pathways, result in the production of the neurotransmitter amino acid β‐alanine from uracil and the nonfunctional (R)‐(‐)‐β‐aminoisobutyrate from thymine. The fourth step is controlled by several aminotransferases, which have different affinities for β‐alanine, β‐aminoisobutyrate and GABA. Defects concerning the first three steps all lead to a reduced production of β‐alanine; defects of the transaminases involving the metabolism of β‐alanine and GABA lead to accumulation of these neurotransmitter substances. In addition, other metabolites will accumulate or be reduced depending on the specific enzyme defect. Analysis of the abnormal concentrations of these metabolites in the body fluids is essential for the detection of patients with pyrimidine degradation defects. Clinically these disorders are often overlooked because symptomatology is highly aspecific. The growth in our knowledge concerning inborn errors of pyrimidine degradation has emphasized the importance of the clinical awareness of these defects as a possible cause of neurological disease and a contraindication for treatment of cancer patients with certain pyrimidine analogues. The various defects are discussed and attention is paid to clinical, genetic and diagnostic aspects.

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“…in brain, liver, kidney and pancreas [ l -31. The function of the enzyme in liver appears to be simply that of facilitating the entry into the general metabolic pool of 4-aminobutyrate and /3-alanine produced by bacterial decarboxylation of glutamate and aspartate in the intestine [4]. However, in brain and pancreas, where 4-aminobutyrate fulfils an important role as an inhibitory neurotransmitter, the presence of the enzyme is likcly to be linked to the parallel existence in these tissues of glutamale decarboxylase which synthesiscs 4-aminobutyrate from glutamate.…”

mentioning

confidence: 99%

Protein structure of pig liver 4‐aminobutyrate aminotransferase and comparison with a cDNA‐deduced sequence

Biase¹,

Maras²,

Bossa³

et al. 1992

European Journal of Biochemistry

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The amino acid sequence of pig liver 4‐aminobutyrate aminotransferase has been determined by gas‐phase sequencing of proteolytically derived peptide fragments. The sequence differs substantially from that predicted for the same enzyme on the basis of the sequence of cDNA derived from pig brain in recently published work [Kwon, O., Park, J. & Churchich, J. E. (1992) J. Biol. Chem. 267, 7215–7216]. Apart from a few minor differences, the two sequences are completely different in the segment of protein comprising the 36 residues at positions 107–142. Insertion of a cytosine between bases 402 and 403 in the cDNA sequence, together with deletion of the guanine at position 510, results in a DNA sequence which predicts exactly the amino acid sequence determined by peptide analysis in the present work. The mammalian enzyme has approximately 44% sequence identity with the same enzyme from two unicellular eukaryotes (Saccharomyces cerevisiae, Aspergillus nidulans) and 22% identity with that from Escherichia coli.

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Hyper-β-Alaninemia Associated with β-Aminoaciduria and γ-Aminobutyricaciduria, Somnolence and Seizures

Cited by 111 publications

References 28 publications

Localization of the membrane defect in transepithelial transport of taurine by parallel studies in vivo and in vitro in hypertaurinuric mice.

Localization of the membrane defect in transepithelial transport of taurine by parallel studies in vivo and in vitro in hypertaurinuric mice.

Inborn errors of pyrimidine degradation: Clinical, biochemical and molecular aspects

Protein structure of pig liver 4‐aminobutyrate aminotransferase and comparison with a cDNA‐deduced sequence

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