3-Methylglutaconic Aciduria

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Saskia B Wortmann - One of the best experts on this subject based on the ideXlab platform.

  • clpb mutations cause 3 methylglutaconic Aciduria progressive brain atrophy intellectual disability congenital neutropenia cataracts movement disorder
    American Journal of Human Genetics, 2015
    Co-Authors: Saskia B Wortmann, Szymon Zietkiewicz, Maria Kousi, Radek Szklarczyk, Tobias B Haack, Soren W Gersting, Ania C Muntau, Aleksandar Rakovic, Herma G Renkema, Richard J. Rodenburg
    Abstract:

    We studied a group of individuals with elevated urinary excretion of 3-Methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death. Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. CLPB encodes caseinolytic peptidase B homolog ClpB, a member of the AAA+ protein family. To evaluate the relevance of CLPB in the pathogenesis of this syndrome, we developed a zebrafish model and an in vitro assay to measure ATPase activity. Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA. Consistent with these data, the loss-of-function effect of one of the identified variants (c.1222A>G [p.Arg408Gly]) was supported further by in vitro evidence with the mutant peptides abolishing ATPase function. Additionally, we show that CLPB interacts biochemically with ATP2A2, known to be involved in apoptotic processes in severe congenital neutropenia (SCN) 3 (Kostmann disease [caused by HAX1 mutations]). Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-Methylglutaconic Aciduria.

  • leucine loading test is only discriminative for 3 methylglutaconic Aciduria due to auh defect
    JIMD Reports, 2014
    Co-Authors: Saskia B Wortmann, Silvia Sequeira, Ron A Wevers, Leo A J Kluijtmans, Eva Morava
    Abstract:

    Currently, six inborn errors of metabolism with 3-Methylglutaconic Aciduria as discriminative feature are known. The “Primary 3-Methylglutaconic Aciduria,” 3-methylglutaconyl-CoA hydratase deficiency or AUH defect, is a disorder of leucine catabolism. For all other subtypes, also denoted “Secondary 3-Methylglutaconic Acidurias” (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome, OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect, “not otherwise specified (NOS) 3-MGA-uria”), the origin of 3-Methylglutaconic Aciduria remains enigmatic but is hypothesized to be independent from leucine catabolism. Here we show the results of leucine loading test in 21 patients with different inborn errors of metabolism who present with 3-Methylglutaconic Aciduria. After leucine loading urinary 3-Methylglutaconic acid levels increased only in the patients with an AUH defect. This strongly supports the hypothesis that 3-Methylglutaconic Aciduria is independent from leucine breakdown in other inborn errors of metabolism with 3-Methylglutaconic Aciduria and also provides a simple test to discriminate between primary and secondary 3-Methylglutaconic Aciduria in regular patient care.

  • 3 methylglutaconic Aciduria lessons from 50 genes and 977 patients
    Journal of Inherited Metabolic Disease, 2013
    Co-Authors: Saskia B Wortmann, Jessica Nouws, Edwin P. Kaauwen, Tjitske Kleefstra, Lisbeth Tranebjaerg, Jörn Oliver Sass, Richard J. Rodenburg, Maaike De Vries, Leo A J Kluijtmans, Pirjo Isohanni
    Abstract:

    Elevated urinary excretion of 3-Methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-Methylglutaconic Aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-Methylglutaconic Aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-Methylglutaconic Aciduria. Three percent of all urine samples of the patients referred showed 3-Methylglutaconic Aciduria, often in correlation with disorders not reported earlier in association with 3-Methylglutaconic Aciduria (e.g. organic Acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-Methylglutaconic Aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-Methylglutaconic Aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-Methylglutaconic Aciduria as discriminative feature.

  • inborn errors of metabolism with 3 methylglutaconic Aciduria as discriminative feature proper classification and nomenclature
    Journal of Inherited Metabolic Disease, 2013
    Co-Authors: Saskia B Wortmann, Johannes Zschocke, Wolfgang Sperl, P G Barth, Yair Anikster, Eva Morava, M Duran, Ron A Wevers
    Abstract:

    Increased urinary 3-Methylglutaconic acid excretion is a relatively common finding in metabolic disorders, especially in mitochondrial disorders. In most cases 3-Methylglutaconic acid is only slightly elevated and accompanied by other (disease specific) metabolites. There is, however, a group of disorders with significantly and consistently increased 3-Methylglutaconic acid excretion, where the 3-Methylglutaconic Aciduria is a hallmark of the phenotype and the key to diagnosis. Until now these disorders were labelled by roman numbers (I–V) in the order of discovery regardless of pathomechanism. Especially, the so called “unspecified” 3-Methylglutaconic Aciduria type IV has been ever growing, leading to biochemical and clinical diagnostic confusion. Therefore, we propose the following pathomechanism based classification and a simplified diagnostic flow chart for these “inborn errors of metabolism with 3-Methylglutaconic Aciduria as discriminative feature”. One should distinguish between “primary 3-Methylglutaconic Aciduria” formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, AUH defect) due to defective leucine catabolism and the—currently known—three groups of “secondary 3-Methylglutaconic Aciduria”. The latter should be further classified and named by their defective protein or the historical name as follows: i) defective phospholipid remodelling (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome) and ii) mitochondrial membrane associated disorders (OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect). The remaining patients with significant and consistent 3-Methylglutaconic Aciduria in whom the above mentioned syndromes have been excluded, should be referred to as “not otherwise specified (NOS) 3-MGA-uria” until elucidation of the underlying pathomechanism enables proper (possibly extended) classification.

  • mutations in the phospholipid remodeling gene serac1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness
    Nature Genetics, 2012
    Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Herma G Renkema, Thatjana Gardeitchik, Lisenka E L M Vissers, Janneke H M Schuurshoeijmakers, Wim Kulik, Martin Lammens, Christin Christin, Richard J. Rodenburg
    Abstract:

    Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-Methylglutaconic Aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking.

Richard J. Rodenburg - One of the best experts on this subject based on the ideXlab platform.

  • clpb mutations cause 3 methylglutaconic Aciduria progressive brain atrophy intellectual disability congenital neutropenia cataracts movement disorder
    American Journal of Human Genetics, 2015
    Co-Authors: Saskia B Wortmann, Szymon Zietkiewicz, Maria Kousi, Radek Szklarczyk, Tobias B Haack, Soren W Gersting, Ania C Muntau, Aleksandar Rakovic, Herma G Renkema, Richard J. Rodenburg
    Abstract:

    We studied a group of individuals with elevated urinary excretion of 3-Methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death. Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. CLPB encodes caseinolytic peptidase B homolog ClpB, a member of the AAA+ protein family. To evaluate the relevance of CLPB in the pathogenesis of this syndrome, we developed a zebrafish model and an in vitro assay to measure ATPase activity. Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA. Consistent with these data, the loss-of-function effect of one of the identified variants (c.1222A>G [p.Arg408Gly]) was supported further by in vitro evidence with the mutant peptides abolishing ATPase function. Additionally, we show that CLPB interacts biochemically with ATP2A2, known to be involved in apoptotic processes in severe congenital neutropenia (SCN) 3 (Kostmann disease [caused by HAX1 mutations]). Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-Methylglutaconic Aciduria.

  • 3 methylglutaconic Aciduria lessons from 50 genes and 977 patients
    Journal of Inherited Metabolic Disease, 2013
    Co-Authors: Saskia B Wortmann, Jessica Nouws, Edwin P. Kaauwen, Tjitske Kleefstra, Lisbeth Tranebjaerg, Jörn Oliver Sass, Richard J. Rodenburg, Maaike De Vries, Leo A J Kluijtmans, Pirjo Isohanni
    Abstract:

    Elevated urinary excretion of 3-Methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-Methylglutaconic Aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-Methylglutaconic Aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-Methylglutaconic Aciduria. Three percent of all urine samples of the patients referred showed 3-Methylglutaconic Aciduria, often in correlation with disorders not reported earlier in association with 3-Methylglutaconic Aciduria (e.g. organic Acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-Methylglutaconic Aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-Methylglutaconic Aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-Methylglutaconic Aciduria as discriminative feature.

  • mutations in the phospholipid remodeling gene serac1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness
    Nature Genetics, 2012
    Co-Authors: Saskia B Wortmann, Leo A J Kluijtmans, Herma G Renkema, Thatjana Gardeitchik, Lisenka E L M Vissers, Janneke H M Schuurshoeijmakers, Wim Kulik, Martin Lammens, Christin Christin, Richard J. Rodenburg
    Abstract:

    Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-Methylglutaconic Aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking.

  • biochemical and genetic analysis of 3 methylglutaconic Aciduria type iv a diagnostic strategy
    Brain, 2009
    Co-Authors: Saskia B Wortmann, An I Jonckheere, Katrin Heldt, Marjan Huizing, Udo Wendel, Lambertus P Van Den Heuvel, Richard J. Rodenburg, Maaike De Vries, Leo A J Kluijtmans, Udo F H Engelke
    Abstract:

    The heterogeneous group of 3-Methylglutaconic Aciduria type IV consists of patients with various organ involvement and mostly progressive neurological impairment in combination with 3-Methylglutaconic Aciduria and biochemical features of dysfunctional oxidative phosphorylation. Here we describe the clinical and biochemical phenotype in 18 children and define 4 clinical subgroups (encephalomyopathic, hepatocerebral, cardiomyopathic, myopathic). In the encephalomyopathic group with neurodegenerative symptoms and respiratory chain complex I deficiency, two of the children, presenting with mild Methylmalonic Aciduria, Leigh-like encephalomyopathy, dystonia and deafness, harboured SUCLA2 mutations. In children with a hepatocerebral phenotype most patients presented with complex I deficiency and mtDNA-depletion, three of which carried POLG1-mutations. In the cardiomyopathic subgroup most patients had complex V deficiency and an overlapping phenotype with that previously described in isolated complex V deficiency, in three patients a TMEM70 mutation was confirmed. In one male with a pure myopathic form and severe combined respiratory chain disorder, based on the pathogenomic histology of central core disease, RYR1 mutations were detected. In our patient group the presence of the biochemical marker 3-Methylglutaconic acid was indicative for nuclear coded respiratory chain disorders. By delineating patient-groups we elucidated the genetic defect in 10 out of 18 children. Depending on the clinical and biochemical phenotype we suggest POLG1, SUCLA2, TMEM70 and RYR1 sequence analysis and mtDNA-depletion studies in children with 3-Methylglutaconic Aciduria type IV.

  • association of 3 methylglutaconic Aciduria with sensori neural deafness encephalopathy and leigh like syndrome megdel association in four patients with a disorder of the oxidative phosphorylation
    Molecular Genetics and Metabolism, 2006
    Co-Authors: Saskia B Wortmann, Ference J Loupatty, T J De Koning, Marjan Huizing, Ron A Wevers, Jan A.m. Smeitink, Richard J. Rodenburg, Leo A J Kluijtmans, Udo F H Engelke, Eva Morava
    Abstract:

    In this paper, we describe a distinct clinical subtype of 3-Methylglutaconic Aciduria. 3-Methylglutaconic Aciduria is a group of different metabolic disorders biochemically characterized by increased urinary excretion of 3-Methylglutaconic acid. We performed biochemical and genetic investigations, including urine organic acid analysis, NMR spectroscopy, measurement of 3-methylglutaconyl-CoA hydratase activity, cardiolipin levels, OPA3 gene analysis and measurement of the oxidative phosphorylation in four female patients with 3-Methylglutaconic Aciduria. 3-Methylglutaconic Aciduria type I, Barth syndrome, and Costeff syndrome were excluded as the activity of 3-methylglutaconyl-CoA hydratase, the cardiolipin levels, and molecular analysis of the OPA3 gene, respectively, showed no abnormalities. The children presented with characteristic association of hearing loss and the neuro-radiological evidence of Leigh disease. They also had neonatal hypotonia, recurrent lactic acidemia, episodes with hypoglycemia and severe recurrent infections, feeding difficulties, failure to thrive, developmental delay, and progressive spasticity with extrapyramidal symptoms. Our patients were further biochemically characterized by a mitochondrial dysfunction and persistent urinary excretion of 3-Methylglutaconic acid.

Orly Elpeleg - One of the best experts on this subject based on the ideXlab platform.

  • mitochondrial hepato encephalopathy due to deficiency of qil1 mic13 c19orf70 a micos complex subunit
    European Journal of Human Genetics, 2016
    Co-Authors: Avraham Zeharia, Ann Saada, Avraham Shaag, Jonathan R Friedman, Ana Tobar, Osnat Konen, Yacov Fellig, Jodi Nunnari, Orly Elpeleg
    Abstract:

    The mitochondrial inner membrane possesses distinct subdomains including cristae, which are lamellar structures invaginated into the mitochondrial matrix and contain the respiratory complexes. Generation of inner membrane domains requires the complex interplay between the respiratory complexes, mitochondrial lipids and the recently identified mitochondrial contact site and cristae organizing system (MICOS) complex. Proper organization of the mitochondrial inner membrane has recently been shown to be important for respiratory function in yeast. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with a neurodegenerative disorder accompanied by hyperlactatemia, 3-Methylglutaconic Aciduria, disturbed hepatocellular function with abnormal cristae morphology in liver and cerebellar and vermis atrophy, which suggest mitochondrial dysfunction. Using homozygosity mapping and exome sequencing the patients were found to be homozygous for the p.(Gly15Glufs*75) variant in the QIL1/MIC13 (C19orf70) gene. QIL1/MIC13 is a constituent of MICOS, a six subunit complex that helps to form and/or stabilize cristae junctions and determine the placement, distribution and number of cristae within mitochondria. In patient fibroblasts both MICOS subunits QIL1/MIC13 and MIC10 were absent whereas MIC60 was present in a comparable abundance to that of the control. We conclude that QIL1/MIC13 deficiency in human, is associated with disassembly of the MICOS complex, with the associated aberration of cristae morphology and mitochondrial respiratory dysfunction. 3-Methylglutaconic Aciduria is associated with variants in genes encoding mitochondrial inner membrane organizing determinants, including TAZ, DNAJC19, SERAC1 and QIL1/MIC13.

  • deficiency of htra2 omi is associated with infantile neurodegeneration and 3 methylglutaconic Aciduria
    Journal of Medical Genetics, 2016
    Co-Authors: Hanna Mandel, Simon Edvardson, Dorit Goldsher, Shotaro Saita, Chaim Jalas, Avraham Shaag, Euvgeni Vlodavsky, Thomas Langer, Orly Elpeleg
    Abstract:

    Background Cell survival critically depends on the integrity of mitochondria, which play a pivotal role during apoptosis. Extensive mitochondrial damage promotes release of pro-apoptotic factors from the intermembrane space of mitochondria. Released mitochondrial proteins include Smac/DIABLO and HTRA2/Omi, which inhibit the cytosolic E3 ubiquitin ligase XIAP and other inhibitors of apoptosis proteins. Aims Here we investigated the cause of extreme hypertonia at birth, alternating with hypotonia, with the subsequent appearance of extrapyramidal symptoms, lack of psychomotor development, microcephaly, intractable seizures and early death in four patients from two unrelated families. The patients showed lactic acidemia, 3-Methylglutaconic Aciduria, intermittent neutropenia, evolving brain atrophy and disturbed cristae structure in muscle mitochondria. Methods and results Using whole-exome sequencing, we identified missplicing mutation and a 5 bp deletion in HTRA2 , encoding HTRA2/Omi. This protein was completely absent from the patients9 fibroblasts, whose growth was impaired and which were hypersensitive to apoptosis. Expression of HtrA2/Omi or of the proteolytically inactive HTRA2/Omi protein restored the cells9 apoptotic resistance. However, cell growth was only restored by the proteolytically active protein. Conclusions This is the first report of recessive deleterious mutations in HTRA2 in human. The clinical phenotype, the increased apoptotic susceptibility and the impaired cell growth recapitulate those observed in the Htra2 knockout mice and in mutant mice with proteolytically inactive HTRA2/Omi. Together, they underscore the importance of both chaperone and proteolytic activities of HTRA2/Omi for balanced apoptosis sensitivity and for brain development. Absence of HTRA2/Omi is associated with severe neurodegenerative disorder of infancy, abnormal mitochondria, 3-Methylglutaconic Aciduria and increased sensitivity to apoptosis.

  • type iii 3 methylglutaconic Aciduria optic atrophy plus syndrome or costeff optic atrophy syndrome identification of the opa3 gene and its founder mutation in iraqi jews
    American Journal of Human Genetics, 2001
    Co-Authors: Yair Anikster, Avraham Shaag, William A Gahl, Robert Kleta, Orly Elpeleg
    Abstract:

    Type III 3-Methylglutaconic Aciduria (MGA) (MIM 258501) is a neuro-ophthalmologic syndrome that consists of early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction, and cognitive deficit. Urinary excretion of 3-Methylglutaconic acid and of 3-methylglutaric acid is increased. The disorder has been reported in ∼40 patients of Iraqi Jewish origin, allowing the mapping of the disease to chromosome 19q13.2-q13.3, by linkage analysis. To isolate the causative gene, OPA3, we sequenced four genes within the critical interval and identified, in the intronic sequence of a gene corresponding to cDNA clone FLJ22187, a point mutation that segregated with the type III MGA phenotype. The FLJ22187-cDNA clone, which we identified as the OPA3 gene, consists of two exons and encodes a peptide of 179 amino acid residues. Northern blot analysis revealed a primary transcript of ∼5.0 kb that was ubiquitously expressed, most prominently in skeletal muscle and kidney. Within the brain, the cerebral cortex, the medulla, the cerebellum, and the frontal lobe, compared to other parts of the brain, had slightly increased expression. The intronic G→C mutation abolished mRNA expression in fibroblasts from affected patients and was detected in 8 of 85 anonymous Israeli individuals of Iraqi Jewish origin. Milder mutations in OPA3 should be sought in patients with optic atrophy with later onset, even in the absence of additional neurological abnormalities.

Yair Anikster - One of the best experts on this subject based on the ideXlab platform.

  • inborn errors of metabolism with 3 methylglutaconic Aciduria as discriminative feature proper classification and nomenclature
    Journal of Inherited Metabolic Disease, 2013
    Co-Authors: Saskia B Wortmann, Johannes Zschocke, Wolfgang Sperl, P G Barth, Yair Anikster, Eva Morava, M Duran, Ron A Wevers
    Abstract:

    Increased urinary 3-Methylglutaconic acid excretion is a relatively common finding in metabolic disorders, especially in mitochondrial disorders. In most cases 3-Methylglutaconic acid is only slightly elevated and accompanied by other (disease specific) metabolites. There is, however, a group of disorders with significantly and consistently increased 3-Methylglutaconic acid excretion, where the 3-Methylglutaconic Aciduria is a hallmark of the phenotype and the key to diagnosis. Until now these disorders were labelled by roman numbers (I–V) in the order of discovery regardless of pathomechanism. Especially, the so called “unspecified” 3-Methylglutaconic Aciduria type IV has been ever growing, leading to biochemical and clinical diagnostic confusion. Therefore, we propose the following pathomechanism based classification and a simplified diagnostic flow chart for these “inborn errors of metabolism with 3-Methylglutaconic Aciduria as discriminative feature”. One should distinguish between “primary 3-Methylglutaconic Aciduria” formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, AUH defect) due to defective leucine catabolism and the—currently known—three groups of “secondary 3-Methylglutaconic Aciduria”. The latter should be further classified and named by their defective protein or the historical name as follows: i) defective phospholipid remodelling (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome) and ii) mitochondrial membrane associated disorders (OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect). The remaining patients with significant and consistent 3-Methylglutaconic Aciduria in whom the above mentioned syndromes have been excluded, should be referred to as “not otherwise specified (NOS) 3-MGA-uria” until elucidation of the underlying pathomechanism enables proper (possibly extended) classification.

  • opa3 mutated in 3 methylglutaconic Aciduria type iii encodes two transcripts targeted primarily to mitochondria
    Molecular Genetics and Metabolism, 2010
    Co-Authors: Marjan Huizing, Heidi Dorward, William A Gahl, Lien Ly, Enriko Klootwijk, Robert Kleta, Flemming Skovby, Benjamin Feldman, Yair Anikster
    Abstract:

    Abstract 3-Methylglutaconic Aciduria type III (3-MGCA type III), caused by recessive mutations in the 2-exon gene OPA3 , is characterized by early-onset bilateral optic atrophy, later-onset extrapyramidal dysfunction, and increased urinary excretion of 3-Methylglutaconic acid and 3-methylglutaric acid. Here we report the identification of a novel third OPA3 coding exon, the apparent product of a segmental duplication event, resulting in two gene transcripts, OPA3A and OPA3B . OPA3A deficiency (as in optic atrophy type 3) causes up-regulation of OPA3B . OPA3 protein function remains unknown, but it contains a putative mitochondrial leader sequence, mitochondrial sorting signal and a peroxisomal sorting signal. Our green fluorescent protein tagged OPA3 expression studies found its localization to be predominantly mitochondrial. These findings thus place the cellular metabolic defect of 3-MGCA type III in the mitochondrion rather than the peroxisome and implicate loss of OPA3A rather than gain of OPA3B in disease etiology.

  • type iii 3 methylglutaconic Aciduria optic atrophy plus syndrome or costeff optic atrophy syndrome identification of the opa3 gene and its founder mutation in iraqi jews
    American Journal of Human Genetics, 2001
    Co-Authors: Yair Anikster, Avraham Shaag, William A Gahl, Robert Kleta, Orly Elpeleg
    Abstract:

    Type III 3-Methylglutaconic Aciduria (MGA) (MIM 258501) is a neuro-ophthalmologic syndrome that consists of early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction, and cognitive deficit. Urinary excretion of 3-Methylglutaconic acid and of 3-methylglutaric acid is increased. The disorder has been reported in ∼40 patients of Iraqi Jewish origin, allowing the mapping of the disease to chromosome 19q13.2-q13.3, by linkage analysis. To isolate the causative gene, OPA3, we sequenced four genes within the critical interval and identified, in the intronic sequence of a gene corresponding to cDNA clone FLJ22187, a point mutation that segregated with the type III MGA phenotype. The FLJ22187-cDNA clone, which we identified as the OPA3 gene, consists of two exons and encodes a peptide of 179 amino acid residues. Northern blot analysis revealed a primary transcript of ∼5.0 kb that was ubiquitously expressed, most prominently in skeletal muscle and kidney. Within the brain, the cerebral cortex, the medulla, the cerebellum, and the frontal lobe, compared to other parts of the brain, had slightly increased expression. The intronic G→C mutation abolished mRNA expression in fibroblasts from affected patients and was detected in 8 of 85 anonymous Israeli individuals of Iraqi Jewish origin. Milder mutations in OPA3 should be sought in patients with optic atrophy with later onset, even in the absence of additional neurological abnormalities.

Ronald J A Wanders - One of the best experts on this subject based on the ideXlab platform.

  • direct nonisotopic assay of 3 methylglutaconyl coa hydratase in cultured human skin fibroblasts to specifically identify patients with 3 methylglutaconic Aciduria type i
    Clinical Chemistry, 2004
    Co-Authors: Ference J Loupatty, Lodewijk Ijlst, M Duran, Jos P N Ruiter, Ronald J A Wanders
    Abstract:

    3-Methylglutaconic Aciduria (3MGA) type I (McKusick 250950) is biochemically characterized by increased excretion of 3-Methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid in urine. Affected individuals display a range of clinical manifestations varying from mildly delayed speech development to severe neurologic involvement (1)(2). 3MGA type I is an autosomal recessive disorder caused by a deficiency of 3-methylglutaconyl-CoA hydratase (3MGH; EC 4.2.1.18). Three additional forms of 3MGA have been recognized—type II (Barth syndrome, McKusick 302060); type III (Costeff syndrome, McKusick 258501); and type IV (“unspecified”, McKusick 250951)—all characterized by normal hydratase activities (3). Recently, the gene encoding 3MGH was identified by two independent groups (4)(5). As shown in Fig. 1A⇓ , this mitochondrial enzyme catalyzes the penultimate step in leucine catabolism, which is the reversible conversion of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Eleven patients have been described with isolated 3MGH deficiency (1)(2)(5)(6)(7)(8)(9)(10)(11). The hydratase deficiency in these patients was identified by use of a radioactive enzyme assay measuring three consecutive steps of leucine degradation, from 3-methylcrotonyl-CoA to acetoacetic acid (12). However, this procedure lacks specificity and is labor-intensive because of the need to purify the coupling enzyme, 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4), from bovine liver. Furthermore, the assay is not very practical for use in clinical laboratories because it involves the use of radiochemicals. The need to differentiate patients with 3MGA type I from patients with other forms of 3MGA requires the availability of a sensitive and specific enzyme assay. From our knowledge that, in general, hydratase reactions are readily reversible and that 3-methylglutaconyl-CoA is not commercially available, we studied the 3MGH activity in the reverse direction, using HMG-CoA as a substrate. We quantified the formation of 3-methylglutaconyl-CoA by reversed-phase HPLC with ultraviolet …

  • x linked cardioskeletal myopathy and neutropenia barth syndrome an update
    American Journal of Medical Genetics Part A, 2004
    Co-Authors: P G Barth, M Duran, Frederic M Vaz, J Lam, Fredoen Valianpour, Valerie M Bowen, Ronald J A Wanders
    Abstract:

    X-linked cardioskeletal myopathy and neutropenia (Barth syndrome, MIM302060, BTHS) is a disorder with mitochondrial functional impairments and 3-Methylglutaconic Aciduria that maps to Xq28. The associated G4.5 or TAZ gene has been identified but the encoded proteins have not yet been characterized. Following the prediction that the gene encodes one or more acyltransferases, lipid studies have shown a deficiency of cardiolipin, especially its tetralinoleoyl form (L(4)-CL). Deficiency of L(4)-CL was subsequently demonstrated in a variety of tissues, and determination in thrombocytes or cultured skin fibroblasts is now the most specific biochemical test available. BTHS is the first identified inborn error of metabolism that directly affects cardiolipin, a component of the inner mitochondrial membrane, necessary for proper functioning of the electron transport chain. We report here the finding of deficient docosahexaenoic acid and arachidonic acid in a proportion of patients with BTHS. The initial impression of a uniformly lethal infantile disease has to be modified. Age distribution in 54 living patients ranges between 0 and 49 years and peaks around puberty. Mortality is the highest in the first 4 years. The apex of the survival curve around puberty and the emergence of adults may reflect a dynamic shift towards increased survival. This trend is exemplified in a large pedigree previously published.

  • only one splice variant of the human taz gene encodes a functional protein with a role in cardiolipin metabolism
    Journal of Biological Chemistry, 2003
    Co-Authors: Frederic M Vaz, P G Barth, Riekelt H Houtkooper, Fredoen Valianpour, Ronald J A Wanders
    Abstract:

    Barth syndrome (BTHS) is an X-linked recessive disorder caused by mutations in the TAZ gene and is characterized by cardiomyopathy, short stature, neutropenia, and 3-Methylglutaconic Aciduria. Recently it was found that BTHS patients exhibit a profound cardiolipin deficiency although the biosynthetic capacity to synthesize this lipid from its precursor phosphatidylglycerol is entirely normal. Like BTHS patients, a Saccharomyces cerevisiae strain, in which the yeast orthologue of the human TAZ gene has been disrupted, exhibits an abnormal cardiolipin profile as determined by tandem mass spectrometry. Additionally, this yeast strain grows poorly on non-fermentable carbon sources. We have used both properties of this yeast disruptant as a read-out system to test the physiological functionality of each of 12 different splice variants that have been reported for the human TAZ gene. Our results demonstrate that only the splice variant lacking exon 5 was able to complement the retarded growth of the yeast disruptant on selective plates and restore the cardiolipin profile to the wild type pattern. We conclude that this splice variant most likely represents the only physiologically important mRNA, at least with regard to cardiolipin metabolism.

  • 3 methylglutaconic Aciduria type i is caused by mutations in auh
    American Journal of Human Genetics, 2002
    Co-Authors: Lodewijk Ijlst, Ference J Loupatty, M Duran, Jos P N Ruiter, W Lehnert, Ronald J A Wanders
    Abstract:

    3-Methylglutaconic Aciduria type I is an autosomal recessive disorder clinically characterized by various symptoms ranging from delayed speech development to severe neurological handicap. This disorder is caused by a deficiency of 3-methylglutaconyl-CoA hydratase, one of the key enzymes of leucine degradation. This results in elevated urinary levels of 3-Methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. By heterologous expression in Escherichia coli, we show that 3-methylglutaconyl-CoA hydratase is encoded by the AUH gene, whose product had been reported elsewhere as an AU-specific RNA-binding protein. Mutation analysis of AUH in two patients revealed a nonsense mutation (R197X) and a splice-site mutation (IVS8-1G→A), demonstrating that mutations in AUH cause 3-Methylglutaconic Aciduria type I.

  • x linked cardioskeletal myopathy and neutropenia barth syndrome mim 302060
    Journal of Inherited Metabolic Disease, 1999
    Co-Authors: P G Barth, Ronald J A Wanders, P Vreken, E A M Janssen, J Lam, Frank Baas
    Abstract:

    X-linked cardioskeletal myopathy, neutropenia and abnormal mitochondria (MIM 302060) (synonyms: Barth syndrome, 3-Methylglutaconic Aciduria type II, endocardial fibroelastosis type 2) has been reported in patients and families from Europe, North America and Australia. Previous studies characterized the main components of the disease: dilated cardiomyopathy, skeletal myopathy, neutropenia, 3-Methylglutaconic Aciduria and diminished statural growth. Respiratory chain impairments have been found in several studies, without pinpointing a single enzyme complex. 3-Methylglutaconic Aciduria is shared with several other disorders that affect the respiratory chain. Previous studies excluded a block in the major pathway of leucine catabolism. We performed leucine loading, accompanied by fasting, in patients and observed a significant rise of 3-Methylglutaconic acid and 3-methylglutaric acid. Taken together with the absence of an enzymatic block in the major leucine catabolic route, the possibility remains that the increased basal excretion of 3-Methylglutaconic acid and other products of branched-chain amino acids is the result of overload of this pathway or — more likely — mitochondrial leakage. Linkage studies have localized the gene to the Xq28 region. The associated tafazzin gene (TAZ), has been fully characterized recently, and mutations located in conserved regions have been reported. Carrier detection and prenatal diagnosis have now become possible through mutation analysis. Sequence homology of the TAZ gene to a highly conserved superclass of acyltransferases (Neuwald's hypothesis) predicts a glycerophospholipid as the missing end product. This points to the (lipid) structure of the inner mitochondrial membrane as a promising new area of research.