BIOTIN-RESPONSIVE Β-Methylcrotonylglycinuria

Gompertz, D.; Draffan, G. H.; Watts, Jennifer L.; Hull, D

doi:10.1016/s0140-6736(71)90009-2

Cited by 155 publications

(45 citation statements)

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“…This is also consistent with an effect of biotin treatment. When the patient was acutely ill, he had excreted 100-150 mglday of tiglylglycine (14). The absence of tiglylglycine in urine at the time of this study was consistent with the finding of relatively low levels of excretion of 3-hydroxypropionic acid and methylcitric acid.…”

Section: Discussionsupporting

confidence: 82%

“…At that time, excretion of 3-methylcrotonylglycine was 50-250 mgl day, whereas that of 3-hydroxyisovaleric acid was consistently less (14). Following treatment at that time with 1 0 mg biotin/ day, these metabolites were not detectable (14). A s the patient Fig.…”

Section: Discussionmentioning

confidence: 87%

“…This boy (JR) was the patient originally reported by Gompertz, Hull, and colleagues (14) under the designation of biotinresponsive /3-methylcrotonylglycinuria. It is important to distinguish this patient from the patient with biotin-responsive propionic acidemia also reported by Hull, Gompertz, and colleagues (6).…”

Section: Discussionmentioning

confidence: 91%

“…Propionyl-CoA carboxylase was assayed by the incubation severe ketoacidosis and the fact that he was found to excrete of 5 x 106 cells (about 1 mg protein) in 1.5 ml at 30° for 30 min tiglylglycine (13,14). Tiglylglycine is a metabolite of isoleucine.…”

mentioning

confidence: 99%

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Propionyl-CoA Carboxylase Deficiency in a Patient with Biotin-responsive 3-Methylcrotonylglycinuria

et al. 1977

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Summary MATERIALS AND METHODSThe abnormal metabolites 3-hjdroxypropionic acid (1.6-4.0 SUBJECT mglday) and methylcitric acid (3.7-5.8 mglday) were identified and quantitated in the urine of a patient in whom biotin-responAt the times the urine samples were collected for analysis, the sive 3-methylcrotonylglycinuria and deficiency of 3-methylcro-patient J R was 21 or 23 months of age. His weight was 11 kg tonyl-CoA carboxylase had previously been documented. The and his height 81.6 cm. His level of development was normal for level of excretion of these metabolites was in the lower range of his age. H e was receiving 0.5 mg/day biotin, and a protein intake those found in patients with propionic acidemia in whom there is of about 3.2-3.6 g/kg.day. The patient was in excellent condia deficiency of propionyl-CoA carboxylase. The activity of this tion and not ketotic or acidotic. Specimens were obtained with enzyme in fibroblasts derived from the patient and grown in informed consent. media low in biotin was 4% of normal. This is in the range of ANALYSIS OF URINE patients with propionyl-CoA carboxylase deficiency. Documented deficiency in this patient of two carboxylases, both of Urinary organic acids were analyzed quantitatively by liquid which contain biotin, suggests that the primary defect is in the partition chromatography on H2S04-hydrated silicic acid eluted metabolism of biotin.with a gradient of t-amyl alcohol in chloroform. The eluted acids were continuously titrated by mixing with sodium o-nitrophenol (16, 21) and the titration of the indicator was recorded spectrophotometrically by the increase in absorbance at 350 nm. Some Speculation analyses were performed at twice the usual flow rate to shorten ~h~ deficiency of two mitochon~rial carboxylases in a patient the time of analysis to 3.5 hr. Equivalents of acid were calculated suggests the presence of a fundamental defect in either the from peak areas relative to pcak areas of standards. Fractions transport of biotin or in the holocarboxylase synthetase that obtained from liquid partition chromatography were analyzed attaches biotin covalently to both carboxylases. further by gas liquid chromatography (GLC) and mass spectrometry (GCMS) of the trimethylsilyl (TMS) derivatives on Dexsil 300 using an H P 402 gas chromatograph and an LKB 9000 gas chromatograph-mass spcctromcter as previously dc-3-Methylcrotonylglycinuria is a rare inborn error uf leucine scribed (21). Rctcntion times on GLC were expressed as metabolism which is characterized by excessive excretion of 3-methylcne unit (MU) values by co-injection of even-numbered methylcrotonylglycine and 3-hydroxyisovaleric acid. The second alkancs. Acids cocluted on the liquid partition chromatography patient reported differed from the first (10, 20) in that he was system were quantitated by GLC. severely ketoacidotic, and he responded both clinically and biochemically to biotin (14). Biotin is a cofactor of 3-methylcro-ENZYME ASSAY ton~l-CoA carboxylase. Deficiency of 3-meth~lcroton~l-CoA Fibroblasts derived f...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

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Propionyl-CoA Carboxylase Deficiency in a Patient with Biotin-responsive 3-Methylcrotonylglycinuria

et al. 1977

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“…We assume that formation of Af-tiglylglycine is a detoxifying mechanism to rid the organism of this highly toxic organic acid. It is interesting to note that iV-tiglylglycine is also present in abnormal amounts in /?-methylcrotonylglycinuria of the biotin-responsive type [4,5], and the nonconjugated tiglate derivative is also present in abnormal amounts in some patients with propionicacidemia [13]. The mechanism (or mechanisms) for accumulation of this potent metabolite in such diverse metabolic disorders encourages us to believe that several different metabolites may inhibit tiglic acid oxidation.…”

Section: Discussionmentioning

confidence: 99%

An Inherited Disorder of Isoleucine Catabolism Causing Accumulation of α-Methylacetoacetate and α-Methyl-β-hydroxybutyrate, and Intermittent Metabolic Acidosis

et al. 1973

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ExtractAt least 15 apparently inherited disorders of branched chain amino acid catabolism are now known; the 12th in chronological order of discovery is described in this report. It is a partial defect of the pathway of isoleucine oxidation beyond the level of oxidative decarboxylation and prior to the oxidation of propionate. The impairment of isoleucine catabolism appears to be situated at the "thiolase" reaction which converts a-methylacetoacetyl coenzyme A (CoA) to propionyl-CoA and acetyl-CoA. Two pedigrees (B and M) were investigated in detail. A third (S pedigree) has been brought to our attention for analysis of metabolites in urine but we have not performed additional studies in the latter. Each propositus was ascertained because of intermittent, odorless metabolic acidosis usually precipitated by intercurrent infection. Lethargy and coma occurred frequently during the periods of acidosis. One M sib, also presumably affected, died abroad in such an episode. Symptoms can be ameliorated by a low protein diet and careful attention to the management of intercurrent illness.A large excess of a-methyl-|8-hydroxybutyrate and a seemingly smaller excess of a-methylacetoacetate is present at all times in the urine of the three propositions. The M and S propositi also excrete i\f-tiglylglycine. The amounts of these unusual metabolites increase severalfold during acidosis and after a dietary load of L-isoleucine (75 mg/kg, 3 times daily for 2 days). The urine also contains butanone, particularly during acidosis. The amount of propionate and of glycine and other amino acids in blood and urine is always normal in our patients. Oxidation of L-isoleucine-U-14 G to GO 2 by cultured skin fibroblasts is about 45% of normal in the B propositus. The precise nature and location of the enzyme defect awaits clarification.Studies of family members reveal that presumed obligate heterozygotes excrete a small excess of a-methyl-8-hydroxybutyrate at all times; the amount can be increased by L-isoleucine feeding. The condition is apparently inherited in autosomal recessive fashion. It is likely that more than one form of mutant allele is responsible for the condition, as it is found in the three different pedigrees described here. Speculation

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