Five Patients with a Biotin-Responsive Defect in Holocarboxylase Formation: Evaluation of Responsiveness to Biotin Therapy in Vivo and Comparative Biochemical Studies in Vi1

Suormala, Terttu; Fowler, Brian; Durán, Marinus; Burtscher, A.; Fuchshuber, Arno; Tratzmüller, Robert; Lenze, Michael J; Raab, K; Baur, Barbara; Wick, H; Baumgartner, R.

doi:10.1203/00006450-199705000-00011

Cited by 49 publications

(32 citation statements)

References 20 publications

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“…The possibility of biotinidase deficiency was also excluded since the biotinidase activity of NWU001 in serum was 6.2 nmol/min/ mL which is within the reference range of 3.5 -12 nmol/min/mL [43].…”

Section: Results Inmentioning

confidence: 99%

“…For the assay of the level of specific activity and kinetics of MCC, fibroblasts were grown in the routine culture medium supplemented with 10% FCS. This medium is biotin sufficient containing 9 nmol/L biotin, contributed by the natural biotin content of FCS, which is 5-times the mean normal plasma biotin concentration in humans (1.8 nmol/L, range 0.6-4.8, n la lb This article is available from: //www.raredisorders.imedpub.com/ = 126) [41,42]. To determine the sensitivity to the activator K + , MCC activity was measured with and without 50 mmol/L (optimal concentration) and 100 mmol/L KCl in the assay mixture.…”

Section: Enzyme Assaysmentioning

confidence: 99%

“…Holocarboylase synthetase (HCS) activity was estimated indirectly by measuring the sensitivity of fibroblast MCC and PCC activities on biotin depletion of the culture medium [43]. Cells were grown in parallel in a medium with low and high biotin concentration and assayed for MCC and PCC activity.…”

Section: Enzyme Assaysmentioning

confidence: 99%

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Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

Berg¹,

Erasmus²,

Suormala³

et al. 2016

J Rare Disord Diagn Ther

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We report on the first case of marginal 3-methylcrotonyl-CoA carboxylase (MCC) deficiency in South Africa. Urinary 3-hydroxyisovaleric acid and 3-methylcrotonylglycine were detected in four males of a non-consanguineous family. Only the index patient (NWU001) had non-specific symptoms, the others were asymptomatic. The inherited metabolite profile and partially reduced MCC activity were indicative of marginal MCC deficiency. In vivo L-leucine loading confirmed a reduced flux through the leucine degradation pathway. No known deleterious mutations were detected in the open reading frames of MCCC1 and MCCC2. NWU001 was heterozygous for a SNP in MCCC1 (rs2270968; c.1391A>C, p.H464P). NWU002 was heterozygous for a MCCC2 splice variant which skips exon 7 and causes an in frame deletion of 38 amino acids that is identical to a predicted shorter MCCC2 isoform-2 (Q9HCC0-2). Whole genome expression profiles from cultured skin fibroblasts of NWU001 and NWU002 and two healthy adults using Affymetrix ® HuExST1.0 arrays detected 14237 significantly differentially expressed transcript IDs of which only 1277 have known annotation and gene association. The underlying molecular interactions, secondary signalling responses and functional relationships of these 1277 transcripts were inspected following a knowledge-based functional analyses approach using Ingenuity Pathway Analysis software. The transcriptome had a footprint of oxidative stress, disruption of energy homeostasis, inflammation, impaired cellular maintenance and repair mechanisms. Of note was the significant up regulation of the fatty acid amide hydrolase variant 2 (FAAH2) HuChrX transcript in the anandamide degradation canonical pathway. The observations that the two MCC transcripts were not significantly differentially expressed and that more than 90% of the significantly differently expressed transcripts are still poorly annotated further support the notion that secondary factors other than the MCC loci impact on the MCC deficiency phenome.

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Section: Results Inmentioning

confidence: 99%

Section: Enzyme Assaysmentioning

confidence: 99%

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Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

Berg¹,

Erasmus²,

Suormala³

et al. 2016

J Rare Disord Diagn Ther

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“…The main laboratory findings are metabolic acidosis, lactic acidosis, ketosis, hyperammonemia, and organic aciduria showing a typical urinary excretion pattern (Nyhan and Ozand, 1998). Clinical and biochemical findings usually improve markedly following treatment with pharmacological doses of biotin, but some patients have been reported as only partially biotin responsive (Wolf et al, 1981;Suormala et al, 1997;Morrone et al, 2002). *Correspondence to: Enrico Zammarchi, Department of Pediatrics, Meyer Children's Hospital, Via Luca Giordano 13, 50132 Florence, Italy.…”

Section: Introductionmentioning

confidence: 99%

First prenatal molecular diagnosis in a family with holocarboxylase synthetase deficiency

et al. 2005

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Objectives We report on the first prenatal molecular diagnosis of holocarboxylase synthetase (HLCS) deficiency in the fourth pregnancy of an at-risk family. This disorder is a rare autosomal recessive inborn error of metabolism, leading to a multiple carboxylase defect (MCD). HLCSD diagnosis was performed postmortem in the proband on DNA from autoptic biological material. Molecular analysis of the proband's entire HLCS gene by direct sequencing identified the R508W amino acid change, at the homozygous status.Methods Fetal DNA was isolated from chorionic villus sampling at 11 weeks of gestation. Direct sequencing of exon 6 of the fetal HLCS gene was performed. ResultsThe R508W mutation was identified in the fetal DNA at the homozygous level. The genetic lesion was confirmed on abortive tissue.Conclusion Molecular diagnosis has several advantages over enzymatic activity assay of carboxylases in chorionic villi or amniocytes. It can be performed earlier, is faster, and the response time is shorter.

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“…Many symptoms of HLCS are also seen in biotinidase deficiency (MIM] 253260), another type of MCD. Some patients become symptomatic in the later infantile period, at the age of several months to years [Chikaoka et al, 1992;Gibson et al, 1996;Suormala et al, 1997Suormala et al, , 1998]. All patients with HLCS deficiency reported thus far have responded to biotin administration.…”

Section: Introductionmentioning

confidence: 99%

Mutations in the holocarboxylase synthetase geneHLCS

et al. 2005

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Five Patients with a Biotin-Responsive Defect in Holocarboxylase Formation: Evaluation of Responsiveness to Biotin Therapy in Vivo and Comparative Biochemical Studies in Vi1

Cited by 49 publications

References 20 publications

Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

First prenatal molecular diagnosis in a family with holocarboxylase synthetase deficiency

Mutations in the holocarboxylase synthetase geneHLCS

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