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  • 1
    Language: German
    In: Kinder- und Jugendmedizin, 2007, Vol.7(01), pp.45-53
    ISSN: 1617-0288
    E-ISSN: 2567-577X
    Source: Thieme Publishing Group (via CrossRef)
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  • 2
    Language: English
    In: The American Journal of Human Genetics, 08 August 2013, Vol.93(2), pp.211-223
    Description: The human mitochondrial genome encodes RNA components of its own translational machinery to produce the 13 mitochondrial-encoded subunits of the respiratory chain. Nuclear-encoded gene products are essential for all processes within the organelle, including RNA processing. Transcription of the mitochondrial genome generates large polycistronic transcripts punctuated by the 22 mitochondrial (mt) tRNAs that are conventionally cleaved by the RNase P-complex and the RNase Z activity of ELAC2 at 5′ and 3′ ends, respectively. We report the identification of mutations in in five individuals with infantile hypertrophic cardiomyopathy and complex I deficiency. We observed accumulated mtRNA precursors in affected individuals muscle and fibroblasts. Although mature mt-tRNA, mt-mRNA, and mt-rRNA levels were not decreased in fibroblasts, the processing defect was associated with impaired mitochondrial translation. Complementation experiments in mutant cell lines restored RNA processing and a yeast model provided additional evidence for the disease-causal role of defective , thereby linking mtRNA processing to human disease.
    Keywords: Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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  • 3
    Language: English
    In: The American Journal of Human Genetics, 01 December 2016, Vol.99(6), pp.1325-1337
    Description: Pyridoxal 5′-phosphate (PLP), the active form of vitamin B , functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), , which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An mutant lacking the homolog (Δ ) is pyridoxine sensitive; complementation with human restored growth whereas encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.
    Keywords: Epilepsy ; Prosc ; Yggs ; Pyridoxine ; Pyridoxal 5’-Phosphate ; Homeostasis ; Microcephaly ; Vitamin B6 ; Treatment ; Developmental Delay ; Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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  • 4
    In: Neuropediatrics, 2018, Vol.49
    In: Neuropediatrics, 2018, Vol.49, pp.S1-S69
    Keywords: Award Ceremony of the Society of Neuropediatrics and Free Presentations
    ISSN: 0174-304X
    E-ISSN: 1439-1899
    Source: Thieme Publishing Group
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  • 5
    Language: English
    In: The American Journal of Human Genetics, 06 August 2015, Vol.97(2), pp.319-328
    Description: Deficiencies in respiratory-chain complexes lead to a variety of clinical phenotypes resulting from inadequate energy production by the mitochondrial oxidative phosphorylation system. Defective expression of mtDNA-encoded genes, caused by mutations in either the mitochondrial or nuclear genome, represents a rapidly growing group of human disorders. By whole-exome sequencing, we identified two unrelated individuals carrying compound heterozygous variants in (tRNA methyltransferase 5). encodes a mitochondrial protein with strong homology to members of the class I-like methyltransferase superfamily. Both affected individuals presented with lactic acidosis and evidence of multiple mitochondrial respiratory-chain-complex deficiencies in skeletal muscle, although the clinical presentation of the two affected subjects was remarkably different; one presented in childhood with failure to thrive and hypertrophic cardiomyopathy, and the other was an adult with a life-long history of exercise intolerance. Mutations in were associated with the hypomodification of a guanosine residue at position 37 (G37) of mitochondrial tRNA; this hypomodification was particularly prominent in skeletal muscle. Deficiency of the G37 modification was also detected in human cells subjected to RNAi. The pathogenicity of the detected variants was further confirmed in a heterologous yeast model and by the rescue of the molecular phenotype after re-expression of wild-type cDNA in cells derived from the affected individuals. Our study highlights the importance of post-transcriptional modification of mitochondrial tRNAs for faithful mitochondrial function.
    Keywords: Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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  • 6
    Language: English
    In: Annals of Hematology, 2011, Vol.90(7), pp.857-859
    Description: Byline: Ellen Ritter (1), Ralf A. Husain (2), Katrin Hinderhofer (4), Tino Prell (3), Hans-Jorg Fricke (1), Sebastian Scholl (1), Andreas Hochhaus (1), Paul La Rosee (1) Author Affiliation: (1) Abteilung Hamatologie und Onkologie, Klinik fur Innere Medizin II, Universitatsklinikum Jena, 07747, Jena, Germany (2) Klinik fur Kinder- und Jugendmedizin, Universitatsklinikum Jena, Jena, Germany (3) Hans-Berger-Klinik fur Neurologie, Universitatsklinikum Jena, Jena, Germany (4) Institut fur Humangenetik, Universitat Heidelberg, Heidelberg, Germany Article History: Registration Date: 09/10/2010 Received Date: 06/10/2010 Accepted Date: 09/10/2010 Online Date: 09/11/2010
    Keywords: Lymphomas -- Drug Therapy ; Lymphomas -- Genetic Aspects ; Ornithine ; Cancer Treatment;
    ISSN: 0939-5555
    E-ISSN: 1432-0584
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  • 7
    Language: English
    In: European Journal of Paediatric Neurology, January 2014, Vol.18(1), pp.30-37
    Description: Aicardi–Goutières syndrome (AGS) is a genetically determined early-onset encephalopathy with variable phenotype, including neurologic manifestations such as dystonia, spasticity, epileptic seizures, progressive microcephaly, and severe developmental delay. The aim of our study was the characterization of epilepsy, one of the most frequent and severe AGS manifestations, in molecularly confirmed patients. We reviewed the medical records, EEG, and CT/MRI findings in 16 patients aged 1–22 years that carried AGS1-5 mutations. Epilepsy manifested in 12 (75%) patients and took a refractory course in 9 (56%). 4 (25%) patients presented with seizures in the first four weeks and 11 (69%) altogether in the first year of life. Spasms were reported in 3 (19%) patients, focal seizures in 4 (25%), myoclonic in 5 (31%), symmetric or asymmetric tonic in 11 (69%), generalized tonic–clonic in 3 (19%) and status epilepticus in 4 (25%). EEG recordings initially showed a slow and disorganized background, followed by a regional intermittent theta/delta slow, while obvious multifocal or generalized epileptic discharges were only observed at follow-up. None of these EEG features were specific of AGS. There was no discernible correlation between the genotype and epilepsy onset, seizure types and epilepsy evolution. Epilepsy severity did not correspond to neuroimaging pathology. Epilepsy constitutes a cardinal feature of AGS, characterized by early onset, predominantly tonic semiology and a refractory course. The early discrimination of epileptic seizures from paroxysmal dystonia poses a challenge for neuropaediatricians, considering the initially inconspicuous or non-specific EEG findings. This study underlines the necessity of a more systematic serial evaluation of AGS patients using long-term video-EEG recordings.
    Keywords: Aicardi–Goutières Syndrome ; Epilepsy ; Leukoencephalopathy ; Dystonia ; Spasms ; Status Epilepticus ; Medicine
    ISSN: 1090-3798
    E-ISSN: 1532-2130
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  • 8
    In: Neuropediatrics, 2018, Vol.49
    In: Neuropediatrics, 2018, Vol.49, pp.S1-S69
    Keywords: Neurogenetics
    ISSN: 0174-304X
    E-ISSN: 1439-1899
    Source: Thieme Publishing Group
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  • 9
    Language: English
    In: Molecular Genetics and Metabolism, January 2018, Vol.123(1), pp.28-42
    Description: Mitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10). Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. The cases of two female siblings, who presented at 1 and 2 years of life with seizures, global developmental delay, hypotonia, elevated lactate and complex I and IV deficiency on muscle biopsy but without cardiomyopathy, are presented in detail. For the description of phenotypic features, the denominator varies as the literature was insufficient to allow for complete ascertainment of all data for the 35 cases. An extensive review of all known MTO1 deficiency cases revealed the most common features at presentation to be lactic acidosis (LA) (21/34; 62% cases) and hypertrophic cardiomyopathy (15/34; 44% cases). Eventually lactic acidosis and hypertrophic cardiomyopathy are described in 35/35 (100%) and 27/34 (79%) of patients with MTO1 deficiency, respectively; with global developmental delay/intellectual disability present in 28/29 (97%), feeding difficulties in 17/35 (49%), failure to thrive in 12/35 (34%), seizures in 12/35 (34%), optic atrophy in 11/21 (52%) and ataxia in 7/34 (21%). There are 19 different pathogenic variants identified in these 35 cases: one splice-site, 3 frameshift and 15 missense variants. None have bi-allelic variants that completely inactivate MTO1; however, patients where one variant is truncating ( frameshift) while the second one is a missense appear to have a more severe, even fatal, phenotype. These data suggest that complete loss of MTO1 is not viable. A ketogenic diet may have exerted a favourable effect on seizures in 2/5 patients. MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. The diagnosis should be suspected on clinical features and the presence of markers of mitochondrial dysfunction in body fluids, especially low residual complex I, III and IV activity in muscle. Molecular confirmation is required and targeted genomic testing may be the most efficient approach. Although subjective clinical improvement was observed in a small number of patients on therapies such as ketogenic diet and dichloroacetate, no evidence-based effective therapy exists.
    Keywords: Mitochondrial Disease ; Lactic Acidosis ; Cardiomyopathy ; Ketogenic Diet ; Mitochondrial Translation Optimization 1 ; Oxidative Phosphorylation Defect ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 1096-7192
    E-ISSN: 1096-7206
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  • 10
    Language: German
    Description: Berlin, Humboldt-Univ., Diss., 2004.
    Source: Networked Digital Library of Theses and Dissertations
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