Database : MEDLINE
Search on : multiple and carboxylase and deficiency [Words]
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[PMID]: 29307858
[Au] Autor:Larson AA; Balasubramaniam S; Christodoulou J; Burrage LC; Marom R; Graham BH; Diaz GA; Glamuzina E; Hauser N; Heese B; Horvath G; Mattman A; van Karnebeek C; Lane Rutledge S; Williamson A; Estrella L; Van Hove JKL; Weisfeld-Adams JD
[Ad] Address:Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA; Inherited Metabolic Diseases Clinic, Children's Hospital Colorado, Aurora, CO, USA. Electronic address: austin.larson@ucdenver.edu.
[Ti] Title:Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6.
[So] Source:Mitochondrion;, 2018 Jan 04.
[Is] ISSN:1872-8278
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m.8993T>G in high heteroplasmy or homoplasmy. Most patients were ascertained on newborn screening; most had normal enzymatic or molecular genetic testing to exclude biotinidase and holocarboxylase synthetase deficiencies. MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up. These cases expand the biochemical phenotype associated with MT-ATP6 mutations, especially m.8993T>G, to include acylcarnitine abnormalities mimicking carboxylase deficiency states. Clinicians should be aware of this association and its implications for newborn screening, and consider mtDNA sequencing in patients exhibiting similar acylcarnitine abnormalities that are biotin-unresponsive and in whom other enzymatic deficiencies have been excluded.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180116
[Lr] Last revision date:180116
[St] Status:Publisher

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[PMID]: 29159707
[Au] Autor:Chapman KA; Ostrovsky J; Rao M; Dingley SD; Polyak E; Yudkoff M; Xiao R; Bennett MJ; Falk MJ
[Ad] Address:Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
[Ti] Title:Propionyl-CoA carboxylase pcca-1 and pccb-1 gene deletions in Caenorhabditis elegans globally impair mitochondrial energy metabolism.
[So] Source:J Inherit Metab Dis;, 2017 Nov 20.
[Is] ISSN:1573-2665
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Propionic acidemia (PA) is a classical inborn error of metabolism with high morbidity that results from the inability of the propionyl-CoA carboxylase (PCC) enzyme to convert propionyl-CoA to methylmalonyl-CoA. PA is inherited in an autosomal recessive fashion due to functional loss of both alleles of either PCCA or PCCB. These genes are highly conserved across evolutionarily diverse species and share extensive similarity with pcca-1 and pccb-1 in the nematode, Caenorhabditis elegans. Here, we report the global metabolic effects of deletion in a single PCC gene, either pcca-1 or pccb-1, in C. elegans. Animal lifespan was significantly reduced relative to wild-type worms in both mutant strains, although to a greater degree in pcca-1. Mitochondrial oxidative phosphorylation (OXPHOS) capacity and efficiency as determined by direct polarography of isolated mitochondria were also significantly reduced in both mutant strains. While in vivo quantitation of mitochondrial physiology was normal in pccb-1 mutants, pcca-1 deletion mutants had significantly increased mitochondrial matrix oxidant burden as well as significantly decreased mitochondrial membrane potential and mitochondrial content. Whole worm steady-state free amino acid profiling by UPLC revealed reduced levels in both mutant strains of the glutathione precursor cysteine, possibly suggestive of increased oxidative stress. Intermediary metabolic flux analysis by GC/MS with 1,6- C -glucose further showed both PCC deletion strains had decreased accumulation of a distal tricarboxylic acid (TCA) cycle metabolic intermediate (+1 malate), isotopic enrichment in a proximal TCA cycle intermediate (+1 citrate), and increased +1 lactate accumulation. GC/MS analysis further revealed accumulation in the PCC mutants of a small amount of 3-hydroxypropionate, which appeared to be metabolized in C. elegans to oxalate through a unique metabolic pathway. Collectively, these detailed metabolic investigations in translational PA model animals with genetic-based PCC deficiency reveal their significantly dysregulated energy metabolism at multiple levels, including reduced mitochondrial OXPHOS capacity, increased oxidative stress, and inhibition of distal TCA cycle flux, culminating in reduced animal lifespan. These findings demonstrate that the pathophysiology of PA extends well beyond what has classically been understood as a single PCC enzyme deficiency with toxic precursor accumulation, and suggest that therapeutically targeting the globally disrupted energy metabolism may offer novel treatment opportunities for PA. SUMMARY: Two C. elegans model animals of propionic acidemia with single-gene pcca-1 or pccb-1 deletions have reduced lifespan with significantly reduced mitochondrial energy metabolism and increased oxidative stress, reflecting the disease's broader pathophysiology beyond a single enzyme deficiency with toxic precursor accumulation.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1711
[Cu] Class update date: 171121
[Lr] Last revision date:171121
[St] Status:Publisher
[do] DOI:10.1007/s10545-017-0111-x

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[PMID]: 29158261
[Au] Autor:Watts JS; Morton DG; Kemphues KJ; Watts JL
[Ad] Address:Washington State University, United States.
[Ti] Title:The biotin-ligating protein BPL-1 is critical for lipid biosynthesis and polarization of the embryo.
[So] Source:J Biol Chem;, 2017 Nov 20.
[Is] ISSN:1083-351X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Biotin is an essential cofactor for multiple metabolic reactions catalyzed by carboxylases. Biotin is covalently linked to apoproteins by holocarboxylase synthetase (HCS). Accordingly, some mutations in HCS cause holocarboxylase deficiency, a rare metabolic disorder that can be life threatening if left untreated. However, the long-term effects of HCS deficiency are poorly understood. Here, we report our investigations of bpl-1, which encodes the C. elegans ortholog of HCS. We found that mutations in the biotin-binding region of bpl-1 are maternal-effect lethal, and cause defects in embryonic polarity establishment, meiosis, and the integrity of the eggshell permeability barrier. We confirmed that BPL-1 biotinylates four carboxylase enzymes, and we demonstrate that BPL-1 is required for efficient de novo fatty acid biosynthesis. We also show that the lack of larval growth defects as well as nearly normal fatty acid composition in young adult worms is due to sufficient fatty acid precursors provided by dietary bacteria. However, BPL-1 disruption strongly decreased levels of polyunsaturated fatty acids in embryos produced by bpl-1 mutant hermaphrodites, revealing a critical role for BPL-1 in lipid biosynthesis during embryogenesis, and demonstrating that dietary fatty acids and lipid precursors are not adequate to support early embryogenesis in the absence of BPL-1. Our findings highlight that studying BPL-1function in C. elegans could help dissect the roles of this important metabolic enzyme under different environmental and dietary conditions.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1711
[Cu] Class update date: 171121
[Lr] Last revision date:171121
[St] Status:Publisher

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[PMID]: 29076057
[Au] Autor:Morava E; Baumgartner M; Patterson M; Rahman S; Zschocke J; Peters V
[Ad] Address:Tulane University Medical School, New Orleans, Louisiana, USA.
[Ti] Title:Erratum: Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD).
[So] Source:JIMD Rep;33:111, 2017.
[Is] ISSN:2192-8304
[Cp] Country of publication:Germany
[La] Language:eng
[Pt] Publication type:PUBLISHED ERRATUM
[Em] Entry month:1710
[Cu] Class update date: 171104
[Lr] Last revision date:171104
[St] Status:In-Data-Review
[do] DOI:10.1007/8904_2017_588

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[PMID]: 28564555
[Au] Autor:León-Del-Río A; Valadez-Graham V; Gravel RA
[Ad] Address:Programa de Investigación de Cáncer de Mama y Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de Mexico 04500, México; email: leon@biomedicas.unam.mx.
[Ti] Title:Holocarboxylase Synthetase: A Moonlighting Transcriptional Coregulator of Gene Expression and a Cytosolic Regulator of Biotin Utilization.
[So] Source:Annu Rev Nutr;37:207-223, 2017 Aug 21.
[Is] ISSN:1545-4312
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The vitamin biotin is an essential nutrient for the metabolism and survival of all organisms owing to its function as a cofactor of enzymes collectively known as biotin-dependent carboxylases. These enzymes use covalently attached biotin as a vector to transfer a carboxyl group between donor and acceptor molecules during carboxylation reactions. In human cells, biotin-dependent carboxylases catalyze key reactions in gluconeogenesis, fatty acid synthesis, and amino acid catabolism. Biotin is attached to apocarboxylases by a biotin ligase: holocarboxylase synthetase (HCS) in mammalian cells and BirA in microbes. Despite their evolutionary distance, these proteins share structural and sequence similarities, underscoring their importance across all life forms. However, beyond its role in metabolism, HCS participates in the regulation of biotin utilization and acts as a nuclear transcriptional coregulator of gene expression. In this review, we discuss the function of HCS and biotin in metabolism and human disease, a putative role for the enzyme in histone biotinylation, and its participation as a nuclear factor in chromatin dynamics. We suggest that HCS be classified as a moonlighting protein, with two biotin-dependent cytosolic metabolic roles and a distinct biotin-independent nuclear coregulatory function.
[Mh] MeSH terms primary: Biotin/metabolism
Carbon-Nitrogen Ligases/metabolism
[Mh] MeSH terms secundary: Biotinylation
Chromatin/metabolism
Cytosol/metabolism
Gene Expression Regulation
Histones/metabolism
Humans
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Nm] Name of substance:0 (Chromatin); 0 (Histones); 6SO6U10H04 (Biotin); EC 6.3.- (Carbon-Nitrogen Ligases); EC 6.3.4.- (holocarboxylase synthetases)
[Em] Entry month:1710
[Cu] Class update date: 171002
[Lr] Last revision date:171002
[Js] Journal subset:IM
[Da] Date of entry for processing:170601
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-nutr-042617-104653

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[PMID]: 28498829
[Au] Autor:Borsatto T; Sperb-Ludwig F; Lima SE; S Carvalho MR; S Fonseca PA; S Camelo J; M Ribeiro E; F V de Medeiros P; M Lourenço C; F M de Souza C; Boy R; Félix TM; M Bittar C; L C Pinto L; C Neto E; J Blom H; D Schwartz IV
[Ad] Address:Post Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
[Ti] Title:Biotinidase deficiency: Genotype-biochemical phenotype association in Brazilian patients.
[So] Source:PLoS One;12(5):e0177503, 2017.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:INTRODUCTION: The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity. METHODS: All exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed. RESULTS: Most individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337T>C (p.L446P), c.1466A>G (p.N489S) and c.962G>A (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183G>A, c.-315A>G and c.-514C>T were present in heterozygosis in 5/17 discordant patients. In addition, c.-183G>A and c.-514C>T were also present in 10/37 concordant patients. CONCLUSIONS: The variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity.
[Mh] MeSH terms primary: Biotinidase Deficiency/metabolism
Biotinidase/metabolism
[Mh] MeSH terms secundary: Adolescent
Biotinidase/genetics
Biotinidase Deficiency/genetics
Biotinidase Deficiency/pathology
Brazil
Child
Child, Preschool
Computational Biology
Cross-Sectional Studies
Female
Genetic Association Studies
Genotype
Humans
Infant
Male
[Pt] Publication type:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Name of substance:EC 3.5.1.12 (Biotinidase)
[Em] Entry month:1709
[Cu] Class update date: 170907
[Lr] Last revision date:170907
[Js] Journal subset:IM
[Da] Date of entry for processing:170513
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0177503

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[PMID]: 28492150
[Au] Autor:Sherazi NA; Khan AH; Jafri L; Jamil A; Khan NA; Afroze B
[Ad] Address:Departments of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi.
[Ti] Title:Selective Screening for Organic Acidurias and Amino Acidopathies in Pakistani Children.
[So] Source:J Coll Physicians Surg Pak;27(4):218-221, 2017 Apr.
[Is] ISSN:1681-7168
[Cp] Country of publication:Pakistan
[La] Language:eng
[Ab] Abstract:OBJECTIVE: To determine the frequency of organic acidurais (OA) and amino acidopathies (AA) in selected high-risk patients screened in two years. STUDY DESIGN: Retrospective Observational study. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital (AKUH), Karachi, from January 2013 to December 2014. METHODOLOGY: Patients with OA and AA were included in the study and patients with IMDs other than OA and AA were excluded. Amino acids and organic acids were analyzed on high performance liquid chromatography and gas chromatography-mass spectrometry respectively. Clinical data and chromatograms of patients screened for IMDs were reviewed by chemical pathologist and metabolic physician. RESULTS: Eighty-eight cases (4.7%) were diagnosed including 41 OA (46.5%), 28 AA (31.8%) and 19 others (21.5%) from 1,866 specimens analyzed. Median age of the patients was 1.1 years, with high consanguinity rate (64.8%). Among OA, methyl CoA mutase deficiency was diagnosed in 9 (10.2%) and was suspected in 2 (2.3%) cases. Five (5.7%) cases of MHBD (2-methyl-3-hydroxybutyryl-CoA), 4 (4.5%) each of PPA (propionic aciduria) and HMG-CoA lyase deficiency, 3 (3.4%) cases each of IVA (isovaleric aciduria), multiple carboxylase deficiency, fructose-1, 6-biphosphatase deficiency, fumarase deficiency, GA-1 (glutaric aciduria type 1) and 2 (2.3%) cases of EMA (ethyl-malonic aciduria). AA included 8 (9.1%) cases of MSUD (maple syrup urine disease), 6 (6.8%) cases of CBS (cystathionine beta-synthetase) and UCDs (urea cycle disorders) each, 5 (5.7%) cases of hyperphenylalaninemia and 3 (3.4%) cases of hyperprolinemia were reported. Other inherited metabolic disorders included: 9 (10.2%) cases of intracellular cobalamin defects, 2 (2.3%) cases each of alkaptonuria, Canavan's disease, SUCL (succinate CoA ligase) deficiency, and 1 (1.1%) case each of DPD (dihydropyrimidine) deficiency, GA-2, NKH (non-ketotic hyperglycinemia), AADC (aromatic amino acid decarboxylase) deficiency. CONCLUSION: This study presents frequency of OA and AA in the high-risk Pakistani pediatric population analyzed locally.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1705
[Cu] Class update date: 170511
[Lr] Last revision date:170511
[St] Status:In-Process
[do] DOI:2593

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[PMID]: 28125048
[Au] Autor:De Vilder EY; Debacker J; Vanakker OM
[Ad] Address:Center for Medical Genetics Ghent, Ghent University Hospital, Ghent 9000, Belgium. eva.devilder@ugent.be.
[Ti] Title:GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations.
[So] Source:Int J Mol Sci;18(2), 2017 Jan 25.
[Is] ISSN:1422-0067
[Cp] Country of publication:Switzerland
[La] Language:eng
[Ab] Abstract:Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype-phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations-a frequent problem in orphan diseases-we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype-phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.
[Mh] MeSH terms primary: Carbon-Carbon Ligases/genetics
Carbon-Carbon Ligases/metabolism
Genetic Association Studies
Genotype
Phenotype
[Mh] MeSH terms secundary: Blood Coagulation Disorders, Inherited/diagnosis
Blood Coagulation Disorders, Inherited/genetics
Carbon-Carbon Ligases/chemistry
Congenital Abnormalities/diagnosis
Congenital Abnormalities/genetics
Eye/pathology
Gene Knockout Techniques
Genetic Counseling
Genetic Predisposition to Disease
Humans
Mutation
Polymorphism, Single Nucleotide
Protein Interaction Domains and Motifs
Skin/metabolism
Skin/pathology
Vitamin K/metabolism
[Pt] Publication type:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Name of substance:12001-79-5 (Vitamin K); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.- (glutamyl carboxylase)
[Em] Entry month:1704
[Cu] Class update date: 170428
[Lr] Last revision date:170428
[Js] Journal subset:IM
[Da] Date of entry for processing:170127
[St] Status:MEDLINE

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[PMID]: 27856334
[Au] Autor:Jiang L; Boufersaoui A; Yang C; Ko B; Rakheja D; Guevara G; Hu Z; DeBerardinis RJ
[Ad] Address:Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Electronic address: lei3.jiang@utsouthwestern.edu.
[Ti] Title:Quantitative metabolic flux analysis reveals an unconventional pathway of fatty acid synthesis in cancer cells deficient for the mitochondrial citrate transport protein.
[So] Source:Metab Eng;43(Pt B):198-207, 2017 Sep.
[Is] ISSN:1096-7184
[Cp] Country of publication:Belgium
[La] Language:eng
[Ab] Abstract:The mitochondrial citrate transport protein (CTP), encoded by SLC25A1, accommodates bidirectional trafficking of citrate between the mitochondria and cytosol, supporting lipid biosynthesis and redox homeostasis. Genetic CTP deficiency causes a fatal neurodevelopmental syndrome associated with the accumulation of L- and D-2-hydroxyglutaric acid, and elevated CTP expression is associated with poor prognosis in several types of cancer, emphasizing the importance of this transporter in multiple human pathologies. Here we describe the metabolic consequences of CTP deficiency in cancer cells. As expected from the phenotype of CTP-deficient humans, somatic CTP loss in cancer cells induces broad dysregulation of mitochondrial metabolism, resulting in accumulation of lactate and of the L- and D- enantiomers of 2-hydroxyglutarate (2HG) and depletion of TCA cycle intermediates. It also eliminates mitochondrial import of citrate from the cytosol. To quantify the impact of CTP deficiency on metabolic flux, cells were cultured with a set of C-glucose and C-glutamine tracers with resulting data integrated by metabolic flux analysis (MFA). CTP-deficient cells displayed a major restructuring of central carbon metabolism, including suppression of pyruvate dehydrogenase (PDH) and induction of glucose-dependent anaplerosis through pyruvate carboxylase (PC). We also observed an unusual lipogenic pathway in which carbon from glucose supplies mitochondrial production of alpha-ketoglutarate (AKG), which is then trafficked to the cytosol and used to supply reductive carboxylation by isocitrate dehydrogenase 1 (IDH1). The resulting citrate is cleaved to produce lipogenic acetyl-CoA, thereby completing a novel pathway of glucose-dependent reductive carboxylation. In CTP deficient cells, IDH1 inhibition suppresses lipogenesis from either glucose or glutamine, implicating IDH1 as a required component of fatty acid synthesis in states of CTP deficiency.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1611
[Cu] Class update date: 170920
[Lr] Last revision date:170920
[St] Status:In-Process

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[PMID]: 27450367
[Au] Autor:Balasubramaniam S; Lewis B; Mock DM; Said HM; Tarailo-Graovac M; Mattman A; van Karnebeek CD; Thorburn DR; Rodenburg RJ; Christodoulou J
[Ad] Address:Metabolic Unit, Department of Rheumatology and Metabolic Medicine, Princess Margaret Hospital, Perth, WA, Australia. saras329@hotmail.com.
[Ti] Title:Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD).
[So] Source:JIMD Rep;33:99-107, 2017.
[Is] ISSN:2192-8304
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is a genetically heterogeneous, relentlessly progressive, devastating neurodegenerative disorder that usually presents in infancy or early childhood. A diagnosis of Leigh-like syndrome may be considered in individuals who do not fulfil the stringent diagnostic criteria but have features resembling Leigh syndrome.We describe a unique presentation of Leigh-like syndrome in a 3-year-old boy with elevated 3-hydroxyisovalerylcarnitine (C5-OH) on newborn screening (NBS). Subsequent persistent plasma elevations of C5-OH and propionylcarnitine (C3) as well as fluctuating urinary markers were suggestive of multiple carboxylase deficiency (MCD). Normal enzymology and mutational analysis of genes encoding holocarboxylase synthetase (HLCS) and biotinidase (BTD) excluded MCD. Biotin uptake studies were normal excluding biotin transporter deficiency. His clinical features at 13 months of age comprised psychomotor delay, central hypotonia, myopathy, failure to thrive, hypocitrullinemia, recurrent episodes of decompensation with metabolic keto-lactic acidosis and an episode of hyperammonemia. Biotin treatment from 13 months of age was associated with increased patient activity, alertness, and attainment of new developmental milestones, despite lack of biochemical improvements. Whole exome sequencing (WES) analysis failed to identify any other variants which could likely contribute to the observed phenotype, apart from the homoplasmic (100%) m.8993T>G variant initially detected by mitochondrial DNA (mtDNA) sequencing.Hypocitrullinemia has been reported in patients with the m.8993T>G variant and other mitochondrial disorders. However, persistent plasma elevations of C3 and C5-OH have previously only been reported in one other patient with this homoplasmic mutation. We suggest considering the m.8993T>G variant early in the diagnostic evaluation of MCD-like biochemical disturbances, particularly when associated with hypocitrullinemia on NBS and subsequent confirmatory tests. An oral biotin trial is also warranted.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1607
[Cu] Class update date: 171027
[Lr] Last revision date:171027
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.1007/8904_2016_559


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