104 results on '"Mayr, J.A."'
Search Results
2. Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.
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Vogel, G.F., Mozer-Glassberg, Y., Landau, Y.E., Schlieben, L.D., Prokisch, H., Feichtinger, R.G., Mayr, J.A., Brennenstuhl, H., Schröter, J., Pechlaner, A., Alkuraya, F.S., Baker, J.J., Barcia, G., Baric, I., Braverman, N., Burnyte, B., Christodoulou, J., Ciara, E., Coman, D., Das, A.M., Darin, N., Marina, A. Della, Distelmaier, F., Eklund, E.A., Ersoy, M., Fang, W., Gaignard, P., Ganetzky, R.D., Gonzales, E., Howard, C., Hughes, J., Konstantopoulou, V., Kose, M., Kerr, M., Khan, A., Lenz, D., McFarland, R., Margolis, M.G., Morrison, K., Müller, T., Murayama, K., Nicastro, E., Pennisi, A., Peters, Heidi, Piekutowska-Abramczuk, D., Rötig, A., Santer, R., Scaglia, F., Schiff, M., Shagrani, M., Sharrard, M., Soler-Alfonso, C., Staufner, C., Storey, I., Stormon, M., Taylor, R.W., Thorburn, D.R., Teles, E.L., Wang, J.S., Weghuber, D., Wortmann, S.B., Vogel, G.F., Mozer-Glassberg, Y., Landau, Y.E., Schlieben, L.D., Prokisch, H., Feichtinger, R.G., Mayr, J.A., Brennenstuhl, H., Schröter, J., Pechlaner, A., Alkuraya, F.S., Baker, J.J., Barcia, G., Baric, I., Braverman, N., Burnyte, B., Christodoulou, J., Ciara, E., Coman, D., Das, A.M., Darin, N., Marina, A. Della, Distelmaier, F., Eklund, E.A., Ersoy, M., Fang, W., Gaignard, P., Ganetzky, R.D., Gonzales, E., Howard, C., Hughes, J., Konstantopoulou, V., Kose, M., Kerr, M., Khan, A., Lenz, D., McFarland, R., Margolis, M.G., Morrison, K., Müller, T., Murayama, K., Nicastro, E., Pennisi, A., Peters, Heidi, Piekutowska-Abramczuk, D., Rötig, A., Santer, R., Scaglia, F., Schiff, M., Shagrani, M., Sharrard, M., Soler-Alfonso, C., Staufner, C., Storey, I., Stormon, M., Taylor, R.W., Thorburn, D.R., Teles, E.L., Wang, J.S., Weghuber, D., and Wortmann, S.B.
- Abstract
01 juni 2023, Item does not contain fulltext, PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.
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- 2023
3. Treatment of Mitochondrial Phenylalanyl-tRNa-Synthetase Deficiency (FARS2) with Oral Phenylalanine.
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Oswald, S.L., Steinbrücker, K., Achleitner, M.T., Göschl, E., Bittner, R.E., Schmidt, W.M., Tiefenthaler, E., Hammerl, E., Eisl, A., Mayr, D., Mayr, J.A., Wortmann, S.B., Oswald, S.L., Steinbrücker, K., Achleitner, M.T., Göschl, E., Bittner, R.E., Schmidt, W.M., Tiefenthaler, E., Hammerl, E., Eisl, A., Mayr, D., Mayr, J.A., and Wortmann, S.B.
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Contains fulltext : 296797.pdf (Publisher’s version ) (Closed access), OBJECTIVE: By loading transfer RNAs with their cognate amino acids, aminoacyl-tRNA synthetases (ARS) are essential for protein translation. Both cytosolic ARS1-deficiencies and mitochondrial ARS2 deficiencies can cause severe diseases. Amino acid supplementation has shown to positively influence the clinical course of four individuals with cytosolic ARS1 deficiencies. We hypothesize that this intervention could also benefit individuals with mitochondrial ARS2 deficiencies. METHODS: This study was designed as a N-of-1 trial. Daily oral L-phenylalanine supplementation was used in a 3-year-old girl with FARS2 deficiency. A period without supplementation was implemented to discriminate the effects of treatment from age-related developments and continuing physiotherapy. Treatment effects were measured through a physiotherapeutic testing battery, including movement assessment battery for children, dynamic gait index, gross motor function measure 66, and quality of life questionnaires. RESULTS: The individual showed clear improvement in all areas tested, especially in gross motor skills, movement abilities, and postural stability. In the period without supplementation, she lost newly acquired motor skills but regained these upon restarting supplementation. No adverse effects and good tolerance of treatment were observed. INTERPRETATION AND CONCLUSION: Our positive results encourage further studies both on L-phenylalanine for other individuals with FARS2 deficiency and the exploration of this treatment rationale for other ARS2 deficiencies. Additionally, treatment costs were relatively low at 1.10 €/day.
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- 2023
4. Case Report-An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions.
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Feichtinger, R.G., Preisel, M., Brugger, K., Wortmann, S.B., Mayr, J.A., Feichtinger, R.G., Preisel, M., Brugger, K., Wortmann, S.B., and Mayr, J.A.
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Contains fulltext : 294362.pdf (Publisher’s version ) (Open Access), BACKGROUND: Heterozygous, large-scale deletions at 14q24.3-31.1 affecting the neurexin-3 gene have been associated with neurodevelopmental disorders such as autism. Both "de novo" occurrences and inheritance from a healthy parent suggest incomplete penetrance and expressivity, especially in autism spectrum disorder. NRXN3 encodes neurexin-3, a neuronal cell surface protein involved in cell recognition and adhesion, as well as mediating intracellular signaling. NRXN3 is expressed in two distinct isoforms (alpha and beta) generated by alternative promoters and splicing. MM/Results: Using exome sequencing, we identified a monoallelic frameshift variant c.159_160del (p.Gln54AlafsTer50) in the NRXN3 beta isoform (NM_001272020.2) in a 5-year-old girl with developmental delay, autism spectrum disorder, and behavioral issues. This variant was inherited from her mother, who did not have any medical complaints. DISCUSSION: This is the first detailed report of a loss-of-function variant in NRXN3 causing an identical phenotype, as reported for heterozygous large-scale deletions in the same genomic region, thereby confirming NRXN3 as a novel gene for neurodevelopmental disorders with autism.
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- 2023
5. PPA1 Deficiency Causes a Deranged Galactose Metabolism Recognizable in Neonatal Screening.
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Achleitner, M.T., Jans, J.J., Ebner, L., Spenger, J., Konstantopoulou, V., Feichtinger, R.G., Brugger, K., Mayr, D., Wevers, R.A., Thiel, C, Wortmann, S.B., Mayr, J.A., Achleitner, M.T., Jans, J.J., Ebner, L., Spenger, J., Konstantopoulou, V., Feichtinger, R.G., Brugger, K., Mayr, D., Wevers, R.A., Thiel, C, Wortmann, S.B., and Mayr, J.A.
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Contains fulltext : 300179.pdf (Publisher’s version ) (Open Access), Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. Diagnostic workup did not reveal abnormalities in any of the known disease-causing enzymes involved in galactose metabolism. Using whole-exome sequencing, we identified a homozygous missense variant in PPA1 encoding the cytosolic pyrophosphatase 1 (PPA1), c.557C>T (p.Thr186Ile). The enzyme activity of PPA1 was determined using a colorimetric assay, and the protein content was visualized via western blotting in skin fibroblasts from one of the affected individuals. The galactolytic activity of the affected fibroblasts was determined by measuring extracellular acidification with a Seahorse XFe96 analyzer. PPA1 activity decreased to 22% of that of controls in the cytosolic fraction of homogenates from patient fibroblasts. PPA1 protein content decreased by 50% according to western blot analysis, indicating a reduced stability of the variant protein. The extracellular acidification rate was reduced in patient fibroblasts when galactose was used as a substrate. Untargeted metabolomics of blood samples revealed an elevation of other metabolites related to pyrophosphate metabolism. Besides hyperbilirubinemia in the neonatal period in one child, both children were clinically unremarkable at the ages of 3 and 14 years, respectively. We hypothesize that the observed metabolic derangement is a possible mild manifestation of PPA1 deficiency. Unresolved abnormalities in galactosemia screening might result in the identification of more individuals with PPA1 deficiency, a newly discovered inborn metabolic disorder (IMD).
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- 2023
6. MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum
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Bader, Ingrid, Decker, E., Mayr, J.A., Lunzer, V., Koch, J., Boltshauser, E., Sperl, W., Pietsch, P., Ertl-Wagner, B., Bolz, H., Bergmann, C., and Rittinger, O.
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- 2016
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7. Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes
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Zech, M., Kopajtich, R., Steinbrücker, K., Bris, C., Gueguen, N., Feichtinger, R.G., Achleitner, M.T., Duzkale, N., Périvier, M., Koch, J., Engelhardt, H., Freisinger, P., Wagner, M., Brunet, T., Berutti, R., Smirnov, D., Navaratnarajah, T., Rodenburg, R.J.T., Pais, L.S., Austin-Tse, C., O'Leary, M., Boesch, S., Jech, R., Bakhtiari, S., Jin, S.C., Wilbert, F., Kruer, M.C., Wortmann, S.B., Eckenweiler, M., Mayr, J.A., Distelmaier, F., Steinfeld, R., Winkelmann, J., Prokisch, H., Zech, M., Kopajtich, R., Steinbrücker, K., Bris, C., Gueguen, N., Feichtinger, R.G., Achleitner, M.T., Duzkale, N., Périvier, M., Koch, J., Engelhardt, H., Freisinger, P., Wagner, M., Brunet, T., Berutti, R., Smirnov, D., Navaratnarajah, T., Rodenburg, R.J.T., Pais, L.S., Austin-Tse, C., O'Leary, M., Boesch, S., Jech, R., Bakhtiari, S., Jin, S.C., Wilbert, F., Kruer, M.C., Wortmann, S.B., Eckenweiler, M., Mayr, J.A., Distelmaier, F., Steinfeld, R., Winkelmann, J., and Prokisch, H.
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Item does not contain fulltext, OBJECTIVE: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. METHODS: Whole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients. RESULTS: We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants' pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). INTERPRETA
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- 2022
8. A case report: New-onset refractory status epilepticus in a patient with FASTKD2-related mitochondrial disease.
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Astner-Rohracher, A., Mauritz, M., Leitinger, M., Rossini, F., Kalss, G., Neuray, C., Retter, E., Wortmann, S.B., Achleitner, M.T., Mayr, J.A., Trinka, E., Astner-Rohracher, A., Mauritz, M., Leitinger, M., Rossini, F., Kalss, G., Neuray, C., Retter, E., Wortmann, S.B., Achleitner, M.T., Mayr, J.A., and Trinka, E.
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Item does not contain fulltext, OBJECTIVES: New-onset refractory status epilepticus (NORSE) is associated with high morbidity and mortality. Despite extensive work-up, the underlying etiology remains unknown in 50% of affected individuals. Mitochondrial disorders represent rare causes of NORSE. Biallelic variants in FASTKD2 were reported as a cause of infantile encephalomyopathy with refractory epilepsy. CASE DESCRIPTION: In the study, we report a previously healthy 14-year-old with a new, homozygous FASTKD2 variant presenting with NORSE. Following a seizure-free period of 7 years, he experienced another super-refractory SE and subsequently developed drug-resistant focal epilepsy, mild myopathy, optic atrophy, and discrete psychomotor slowing. Structural MRI at the time of NORSE showed right temporo-parieto-occipital FLAIR hyperintensity and diffusion restriction, with extensive right hemispheric atrophy at the age of 22 years. Whole-exome sequencing revealed a novel homozygous loss of function variant [c.(1072C>T);(1072C>T)] [p.(Arg358Ter);(Arg358Ter)] in FASTKD2 (NM_001136193), resulting in a premature termination codon in the protein-coding region and loss of function of FASTKD2. Oxidative phosphorylation (OXPHOS) in muscle and skin fibroblasts was unremarkable. CONCLUSION: This is the first case of a normally developed adolescent with a new homozygous loss of function variant in FASTKD2, manifesting with NORSE. The phenotypical spectrum of FASTKD2-related mitochondrial disease is heterogeneous, ranging from recurrent status epilepticus and refractory focal epilepsy in an adolescent with normal cognitive development to severe forms of infantile mitochondrial encephalopathy. Although mitochondrial diseases are rare causes of NORSE, clinical features such as young age at onset and multi-system involvement should trigger genetic testing. Early diagnosis is essential for counseling and treatment considerations.
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- 2022
9. Clinical implementation of RNA sequencing for Mendelian disease diagnostics
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Yépez, V.A., Gusic, M., Kopajtich, R., Mertes, C., Smith, N.H., Alston, C.L., Ban, R., Beblo, S., Berutti, R., Blessing, H., Ciara, E., Distelmaier, F., Freisinger, P., Häberle, J., Hayflick, S.J., Hempel, M., Itkis, Y.S., Kishita, Y., Klopstock, T., Krylova, T.D., Lamperti, C., Lenz, D., Makowski, C., Mosegaard, S., Müller, M.F., Muñoz-Pujol, G., Nadel, A., Ohtake, A., Okazaki, Y., Procopio, E., Schwarzmayr, T., Smet, J., Staufner, C., Stenton, S.L., Strom, T.M., Terrile, C., Tort, F., Coster, R. van, Vanlander, A., Wagner, M., Xu, M., Fang, F., Ghezzi, D., Mayr, J.A., Piekutowska-Abramczuk, D., Ribes, A., Rötig, A., Taylor, R.W., Wortmann, S.B., Murayama, K., Meitinger, T., Gagneur, J., Prokisch, H., Yépez, V.A., Gusic, M., Kopajtich, R., Mertes, C., Smith, N.H., Alston, C.L., Ban, R., Beblo, S., Berutti, R., Blessing, H., Ciara, E., Distelmaier, F., Freisinger, P., Häberle, J., Hayflick, S.J., Hempel, M., Itkis, Y.S., Kishita, Y., Klopstock, T., Krylova, T.D., Lamperti, C., Lenz, D., Makowski, C., Mosegaard, S., Müller, M.F., Muñoz-Pujol, G., Nadel, A., Ohtake, A., Okazaki, Y., Procopio, E., Schwarzmayr, T., Smet, J., Staufner, C., Stenton, S.L., Strom, T.M., Terrile, C., Tort, F., Coster, R. van, Vanlander, A., Wagner, M., Xu, M., Fang, F., Ghezzi, D., Mayr, J.A., Piekutowska-Abramczuk, D., Ribes, A., Rötig, A., Taylor, R.W., Wortmann, S.B., Murayama, K., Meitinger, T., Gagneur, J., and Prokisch, H.
- Abstract
Contains fulltext : 283137.pdf (Publisher’s version ) (Open Access), BACKGROUND: Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics. METHODS: We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage. RESULTS: We detected on average 12,500 genes per sample including around 60% of all disease genes-a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions. CONCLUSION: Together, these results show that streamlined experimental and computational processes can
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- 2022
10. Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier
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Bölsterli, B.K., Boltshauser, E., Palmieri, L., Spenger, J., Brunner-Krainz, M., Distelmaier, F., Freisinger, P., Geis, T., Gropman, A.L., Häberle, J., Hentschel, J., Jeandidier, B., Karall, D., Keren, B., Klabunde-Cherwon, A., Konstantopoulou, V., Kottke, R., Lasorsa, F.M., Makowski, C., Mignot, C., Tuura, R. O'Gorman, Porcelli, V., Santer, R., Sen, K., Steinbrücker, K., Syrbe, S., Wagner, M., Ziegler, A., Zöggeler, T., Mayr, J.A., Prokisch, H., Wortmann, S.B., Bölsterli, B.K., Boltshauser, E., Palmieri, L., Spenger, J., Brunner-Krainz, M., Distelmaier, F., Freisinger, P., Geis, T., Gropman, A.L., Häberle, J., Hentschel, J., Jeandidier, B., Karall, D., Keren, B., Klabunde-Cherwon, A., Konstantopoulou, V., Kottke, R., Lasorsa, F.M., Makowski, C., Mignot, C., Tuura, R. O'Gorman, Porcelli, V., Santer, R., Sen, K., Steinbrücker, K., Syrbe, S., Wagner, M., Ziegler, A., Zöggeler, T., Mayr, J.A., Prokisch, H., and Wortmann, S.B.
- Abstract
Contains fulltext : 283140.pdf (Publisher’s version ) (Open Access), The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.
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- 2022
11. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement
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Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., Houlden, H., Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., and Houlden, H.
- Abstract
Contains fulltext : 283148.pdf (Publisher’s version ) (Open Access), Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K(+)/H(+) exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K(+) efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial patholog
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- 2022
12. How to proceed after 'negative' exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques
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Wortmann, S.B., Oud, M.M., Alders, M., Coene, K.L.M., Crabben, S.N. van der, Feichtinger, R.G., Garanto, A., Hoischen, A., Langeveld, M., Lefeber, D.J., Mayr, J.A., Ockeloen, C.W., Prokisch, H., Rodenburg, R.J., Waterham, H.R., Wevers, R.A., Warrenburg, B.P.C. van de, Willemsen, M.A.A.P., Wolf, N.I., Vissers, L.E.L.M., Karnebeek, C.D. van, Wortmann, S.B., Oud, M.M., Alders, M., Coene, K.L.M., Crabben, S.N. van der, Feichtinger, R.G., Garanto, A., Hoischen, A., Langeveld, M., Lefeber, D.J., Mayr, J.A., Ockeloen, C.W., Prokisch, H., Rodenburg, R.J., Waterham, H.R., Wevers, R.A., Warrenburg, B.P.C. van de, Willemsen, M.A.A.P., Wolf, N.I., Vissers, L.E.L.M., and Karnebeek, C.D. van
- Abstract
Contains fulltext : 282561.pdf (Publisher’s version ) (Open Access), Exome sequencing (ES) in the clinical setting of inborn metabolic diseases (IMDs) has created tremendous improvement in achieving an accurate and timely molecular diagnosis for a greater number of patients, but it still leaves the majority of patients without a diagnosis. In parallel, (personalized) treatment strategies are increasingly available, but this requires the availability of a molecular diagnosis. IMDs comprise an expanding field with the ongoing identification of novel disease genes and the recognition of multiple inheritance patterns, mosaicism, variable penetrance, and expressivity for known disease genes. The analysis of trio ES is preferred over singleton ES as information on the allelic origin (paternal, maternal, "de novo") reduces the number of variants that require interpretation. All ES data and interpretation strategies should be exploited including CNV and mitochondrial DNA analysis. The constant advancements in available techniques and knowledge necessitate the close exchange of clinicians and molecular geneticists about genotypes and phenotypes, as well as knowledge of the challenges and pitfalls of ES to initiate proper further diagnostic steps. Functional analyses (transcriptomics, proteomics, and metabolomics) can be applied to characterize and validate the impact of identified variants, or to guide the genomic search for a diagnosis in unsolved cases. Future diagnostic techniques (genome sequencing [GS], optical genome mapping, long-read sequencing, and epigenetic profiling) will further enhance the diagnostic yield. We provide an overview of the challenges and limitations inherent to ES followed by an outline of solutions and a clinical checklist, focused on establishing a diagnosis to eventually achieve (personalized) treatment.
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- 2022
13. Mitochondrial Disease and Hearing Loss in Children: A Systematic Review
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Roesch, S., O'Sullivan, A., Zimmermann, G., Mair, A., Lipuš, C., Mayr, J.A., Wortmann, S.B., Rasp, G., Roesch, S., O'Sullivan, A., Zimmermann, G., Mair, A., Lipuš, C., Mayr, J.A., Wortmann, S.B., and Rasp, G.
- Abstract
Item does not contain fulltext, OBJECTIVES: Hearing loss is a clinical symptom, frequently mentioned in the context of mitochondrial disease. With no cure available for mitochondrial disease, supportive treatment of clinical symptoms like hearing loss is of the utmost importance. The aim of this study was to summarize current knowledge on hearing loss in genetically proven mitochondrial disease in children and deduce possible and necessary consequences in patient care. METHODS: Systematic literature review, including Medline, Embase, and Cochrane library. Review protocol was established and registered prior to conduction (International prospective register of systematic reviews-PROSPERO: CRD42020165356). Conduction of this review was done in accordance with MOOSE criteria. RESULTS: A total of 23 articles, meeting predefined criteria and providing sufficient information on 75 individuals with childhood onset hearing loss was included for analysis. Both cochlear and retro-cochlear origin of hearing loss can be identified among different types of mitochondrial disease. Analysis was hindered by inhomogeneous reporting and methodical limitations. CONCLUSION: Overall, the findings do not allow for a general statement on hearing loss in children with mitochondrial disease. Retro-cochlear hearing loss seems to be found more often than expected. A common feature appears to be progression of hearing loss over time. However, hearing loss in these patients shows manifold characteristics. Therefore, awareness of mitochondrial disease as a possible causative background is important for otolaryngologists. Future attempts rely on standardized reporting and long-term follow-up. LEVEL OF EVIDENCE: NA Laryngoscope, 132:2459-2472, 2022.
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- 2022
14. Congenital disorders of glycosylation with defective fucosylation
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Hüllen, A., Falkenstein, K., Weigel, C., Huidekoper, H., Naumann-Bartsch, N., Spenger, J., Feichtinger, R.G., Schaefers, J., Frenz, S., Kotlarz, D., Momen, T., Khoshnevisan, R., Riedhammer, K.M., Santer, R., Herget, T., Rennings, A.J., Lefeber, D.J., Mayr, J.A., Thiel, C, Wortmann, S.B., Hüllen, A., Falkenstein, K., Weigel, C., Huidekoper, H., Naumann-Bartsch, N., Spenger, J., Feichtinger, R.G., Schaefers, J., Frenz, S., Kotlarz, D., Momen, T., Khoshnevisan, R., Riedhammer, K.M., Santer, R., Herget, T., Rennings, A.J., Lefeber, D.J., Mayr, J.A., Thiel, C, and Wortmann, S.B.
- Abstract
Item does not contain fulltext, Fucosylation is essential for intercellular and intracellular recognition, cell-cell interaction, fertilization, and inflammatory processes. Only five types of congenital disorders of glycosylation (CDG) related to an impaired fucosylation have been described to date: FUT8-CDG, FCSK-CDG, POFUT1-CDG SLC35C1-CDG, and the only recently described GFUS-CDG. This review summarizes the clinical findings of all hitherto known 25 patients affected with those defects with regard to their pathophysiology and genotype. In addition, we describe five new patients with novel variants in the SLC35C1 gene. Furthermore, we discuss the efficacy of fucose therapy approaches within the different defects.
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- 2021
15. De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder
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Dias, C., Pfundt, R.P., Kleefstra, T., Schuurs-Hoeijmakers, J.H.M., Boon, E.M., Hagen, J.M. van, Zwijnenburg, P., Weiss, M.M., Keren, B., Mignot, C., Isapof, A., Weiss, K., Hershkovitz, T., Iascone, M., Maitz, S., Feichtinger, R.G., Kotzot, D., Mayr, J.A., Ben-Omran, T., Mahmoud, L., Pais, L.S., Walsh, C.A., Shashi, V., Sullivan, J.A., Stong, N., Lecoquierre, F., Guerrot, A.M., Charollais, A., Rodan, L.H., Dias, C., Pfundt, R.P., Kleefstra, T., Schuurs-Hoeijmakers, J.H.M., Boon, E.M., Hagen, J.M. van, Zwijnenburg, P., Weiss, M.M., Keren, B., Mignot, C., Isapof, A., Weiss, K., Hershkovitz, T., Iascone, M., Maitz, S., Feichtinger, R.G., Kotzot, D., Mayr, J.A., Ben-Omran, T., Mahmoud, L., Pais, L.S., Walsh, C.A., Shashi, V., Sullivan, J.A., Stong, N., Lecoquierre, F., Guerrot, A.M., Charollais, A., and Rodan, L.H.
- Abstract
Item does not contain fulltext, TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the genetic mechanism and clinical phenotype have remained incompletely characterized. We present here a comprehensive genetic and phenotypic description of 11 individuals who have been identified to carry de novo variants in TCF7L2, both truncating and missense. Missense variation is clustered in or near a high mobility group box domain, involving this region in these variants' pathogenicity. All affected individuals present with developmental delays in childhood, but most ultimately achieved normal intelligence or had only mild intellectual disability. Myopia was present in approximately half of the individuals, and some individuals also possessed dysmorphic craniofacial features, orthopedic abnormalities, or neuropsychiatric comorbidities including autism and attention-deficit/hyperactivity disorder (ADHD). We thus present an initial clinical and genotypic spectrum associated with variation in TCF7L2, which will be important in informing both medical management and future research.
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- 2021
16. Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency
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Wortmann, S.B., Ziętkiewicz, S., Guerrero-Castillo, S., Feichtinger, R.G., Wagner, M., Russell, J., Ellaway, C., Mróz, D., Wyszkowski, H., Weis, D., Hannibal, I., Stülpnagel, C. von, Cabrera-Orefice, A., Lichter-Konecki, U., Gaesser, J., Windreich, R., Myers, K.C., Lorsbach, R., Dale, R.C., Gersting, S., Prada, C.E., Christodoulou, J., Wolf, N.I., Venselaar, H., Mayr, J.A., Wevers, R.A., Wortmann, S.B., Ziętkiewicz, S., Guerrero-Castillo, S., Feichtinger, R.G., Wagner, M., Russell, J., Ellaway, C., Mróz, D., Wyszkowski, H., Weis, D., Hannibal, I., Stülpnagel, C. von, Cabrera-Orefice, A., Lichter-Konecki, U., Gaesser, J., Windreich, R., Myers, K.C., Lorsbach, R., Dale, R.C., Gersting, S., Prada, C.E., Christodoulou, J., Wolf, N.I., Venselaar, H., Mayr, J.A., and Wevers, R.A.
- Abstract
Contains fulltext : 238254.pdf (Publisher’s version ) (Closed access), PURPOSE: To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive. METHODS: We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing. RESULTS: In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1. CONCLUSION: Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1.
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- 2021
17. PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families
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Guimier, A., Achleitner, M.T., Bellaing, A. Moreau de, Edwards, M., Pontual, L. de, Mittal, K, Dunn, K.E., Grove, M.E., Tysoe, C.J., Dimartino, C., Cameron, J., Kanthi, A., Shukla, A., Broek, F. van den, Chatterjee, D., Alston, C.L., Knowles, C.V., Brett, L., Till, J.A., Homfray, T., French, P., Spentzou, G., Elserafy, N.A., Lichkus, K.S., Sankaran, B.P., Kennedy, H.L., George, P.M., Kidd, A., Wortmann, S.B., Fisk, D.G., Koopmann, T.T., Rafiq, M.A., Merker, J.D., Parikh, S., Ahimaz, P., Weintraub, R.G., Ma, A.S., Turner, C., Ellaway, C.J., Phillips, L.K., Thorburn, D.R., Chung, W.K., Kana, S.L., Faye-Petersen, O.M., Thompson, M.L., Janin, A., McLeod, K., McGowan, R., McFarland, R., Girisha, K.M., Morris-Rosendahl, D.J., Hurst, A.C.E., Turner, C.L., Hamilton, R.M., Taylor, R.W., Bajolle, F., Gordon, C.T., Amiel, J., Mayr, J.A., Doudney, K., Guimier, A., Achleitner, M.T., Bellaing, A. Moreau de, Edwards, M., Pontual, L. de, Mittal, K, Dunn, K.E., Grove, M.E., Tysoe, C.J., Dimartino, C., Cameron, J., Kanthi, A., Shukla, A., Broek, F. van den, Chatterjee, D., Alston, C.L., Knowles, C.V., Brett, L., Till, J.A., Homfray, T., French, P., Spentzou, G., Elserafy, N.A., Lichkus, K.S., Sankaran, B.P., Kennedy, H.L., George, P.M., Kidd, A., Wortmann, S.B., Fisk, D.G., Koopmann, T.T., Rafiq, M.A., Merker, J.D., Parikh, S., Ahimaz, P., Weintraub, R.G., Ma, A.S., Turner, C., Ellaway, C.J., Phillips, L.K., Thorburn, D.R., Chung, W.K., Kana, S.L., Faye-Petersen, O.M., Thompson, M.L., Janin, A., McLeod, K., McGowan, R., McFarland, R., Girisha, K.M., Morris-Rosendahl, D.J., Hurst, A.C.E., Turner, C.L., Hamilton, R.M., Taylor, R.W., Bajolle, F., Gordon, C.T., Amiel, J., Mayr, J.A., and Doudney, K.
- Abstract
Item does not contain fulltext
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- 2021
18. Mitochondriopathien: Ein Update
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Sperl, W., Prokisch, H., Karall, D., Mayr, J.A., and Freisinger, P.
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- 2011
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19. Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation
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Rymen, D., Lindhout, M., Spanou, M., Ashrafzadeh, F., Benkel, I., Betzler, C., Coubes, C., Hartmann, H., Kaplan, J.D., Ballhausen, D., Koch, J., Lotte, J., Mohammadi, M.H., Rohrbach, M., Dinopoulos, A., Wermuth, M., Willis, D., Brugger, K., Wevers, R.A., Boltshauser, E., Bierau, J., Mayr, J.A., Wortmann, S.B., Rymen, D., Lindhout, M., Spanou, M., Ashrafzadeh, F., Benkel, I., Betzler, C., Coubes, C., Hartmann, H., Kaplan, J.D., Ballhausen, D., Koch, J., Lotte, J., Mohammadi, M.H., Rohrbach, M., Dinopoulos, A., Wermuth, M., Willis, D., Brugger, K., Wevers, R.A., Boltshauser, E., Bierau, J., Mayr, J.A., and Wortmann, S.B.
- Abstract
Contains fulltext : 229600.pdf (Publisher’s version ) (Closed access)
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- 2020
20. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?
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Repp, B.M. (Birgit M.), Mastantuono, E. (Elisa), Alston, C.L. (Charlotte L.), Schiff, M. (Manuel), Haack, T.B. (Tobias B.), Rötig, A. (Agns), Ardissone, A. (Anna), Lombès, A. (Anne), Catarino, C.F.B.S., Diodato, D. (Daria), Schottmann, G. (Gudrun), Poulton, J. (Joanna), Burlina, A.B. (Alberto), Jonckheere, A. (An), Munnich, A. (Arnold), Rolinski, B. (Boris), Ghezzi, D. (Daniele), Rokicki, D. (Dariusz), Wellesley, D. (Diana), Martinelli, D. (Diego), Wenhong, D. (Ding), Lamantea, E. (Eleonora), Østergaard, E. (Elsebet), Pronicka, E. (Ewa), Pierre, G. (Germaine), Smeets, H.J.M. (Hubert), Wittig, I. (Ilka), Scurr, I. (Ingrid), Coo, I.F.M. (René) de, Moroni, I. (Isabella), Smet, J. (Joél), Mayr, J.A. (Johannes A.), Dai, L. (Lifang), Meirleir, L. (Linda) de, Schuelke, M. (Markus), Zeviani, M. (Massimo), Morscher, R.J. (Raphael J.), McFarland, R. (Robert), Seneca, S. (S.), Klopstock, T. (Thomas), Meitinger, T. (Thomas), Wieland, T. (Thomas), Strom, T.M. (Tim), Herberg, U. (Ulrike), Ahting, U. (Uwe), Sperl, W. (Wolfgang), Nassogne, M.C. (M.), Ling, H. (Han), Fang, F. (Fang), Freisinger, P. (Peter), Coster, R.N.A. (R. N A) van, Strecker, V. (Valentina), Taylor, R.W. (Robert William), Häberle, J. (Johannes), Vockley, J. (Jerry), Prokisch, H. (Holger), Wortmann, S.B. (S.), Repp, B.M. (Birgit M.), Mastantuono, E. (Elisa), Alston, C.L. (Charlotte L.), Schiff, M. (Manuel), Haack, T.B. (Tobias B.), Rötig, A. (Agns), Ardissone, A. (Anna), Lombès, A. (Anne), Catarino, C.F.B.S., Diodato, D. (Daria), Schottmann, G. (Gudrun), Poulton, J. (Joanna), Burlina, A.B. (Alberto), Jonckheere, A. (An), Munnich, A. (Arnold), Rolinski, B. (Boris), Ghezzi, D. (Daniele), Rokicki, D. (Dariusz), Wellesley, D. (Diana), Martinelli, D. (Diego), Wenhong, D. (Ding), Lamantea, E. (Eleonora), Østergaard, E. (Elsebet), Pronicka, E. (Ewa), Pierre, G. (Germaine), Smeets, H.J.M. (Hubert), Wittig, I. (Ilka), Scurr, I. (Ingrid), Coo, I.F.M. (René) de, Moroni, I. (Isabella), Smet, J. (Joél), Mayr, J.A. (Johannes A.), Dai, L. (Lifang), Meirleir, L. (Linda) de, Schuelke, M. (Markus), Zeviani, M. (Massimo), Morscher, R.J. (Raphael J.), McFarland, R. (Robert), Seneca, S. (S.), Klopstock, T. (Thomas), Meitinger, T. (Thomas), Wieland, T. (Thomas), Strom, T.M. (Tim), Herberg, U. (Ulrike), Ahting, U. (Uwe), Sperl, W. (Wolfgang), Nassogne, M.C. (M.), Ling, H. (Han), Fang, F. (Fang), Freisinger, P. (Peter), Coster, R.N.A. (R. N A) van, Strecker, V. (Valentina), Taylor, R.W. (Robert William), Häberle, J. (Johannes), Vockley, J. (Jerry), Prokisch, H. (Holger), and Wortmann, S.B. (S.)
- Abstract
Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and s
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- 2018
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21. Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies
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Feichtinger, R.G., Brunner-Krainz, M., Alhaddad, B., Wortmann, S.B., Kovács-Nagy, R., Stojakovic, T., Erwa, W., Resch, B., Windischhofer, W., Verheyen, S., Uhrig, S., Windpassinger, C., Locker, F., Makowski, C., Strom, T.M., Meitinger, T., Prokisch, H., Sperl, W., Haack, T.B., and Mayr, J.A.
- Subjects
Article Subject ,lcsh:Cytology ,lcsh:QH573-671 - Abstract
Vertebrate respiratory chain complex III consists of eleven subunits. Mutations in five subunits either mitochondrial (MT-CYB) or nuclear (CYC1, UQCRC2, UQCRB, and UQCRQ) encoded have been reported. Defects in five further factors for assembly (TTC19, UQCC2, and UQCC3) or iron-sulphur cluster loading (BCS1L and LYRM7) cause complex III deficiency. Here, we report a second patient with UQCC2 deficiency. This girl was born prematurely; pregnancy was complicated by intrauterine growth retardation and oligohydramnios. She presented with respiratory distress syndrome, developed epileptic seizures progressing to status epilepticus, and died at day 33. She had profound lactic acidosis and elevated urinary pyruvate. Exome sequencing revealed two homozygous missense variants in UQCC2, leading to a severe reduction of UQCC2 protein. Deficiency of complexes I and III was found enzymatically and on the protein level. A review of the literature on genetically distinct complex III defects revealed that, except TTC19 deficiency, the biochemical pattern was very often a combined respiratory chain deficiency. Besides complex III, typically, complex I was decreased, in some cases complex IV. In accordance with previous observations, the presence of assembled complex III is required for the stability or assembly of complexes I and IV, which might be related to respirasome/supercomplex formation.
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- 2017
22. Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy
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Habarou, F., Hamel, Y., Haack, T.B., Feichtinger, R.G., Lebigot, E., Marquardt, I., Busiah, K., Laroche, C., Madrange, M., Grisel, C., Pontoizeau, C., Eisermann, M., Boutron, A., Chretien, D., Chadefaux-Vekemans, B., Barouki, R., Bole-Feysot, C., Nitschke, P., Goudin, N., Boddaert, N., Nemazanyy, I., Delahodde, A., Kolker, S., Rodenburg, R.J.T., Korenke, G.C., Meitinger, T., Strom, T.M., Prokisch, H., Rotig, A., Ottolenghi, C., Mayr, J.A., Lonlay, P. de, Habarou, F., Hamel, Y., Haack, T.B., Feichtinger, R.G., Lebigot, E., Marquardt, I., Busiah, K., Laroche, C., Madrange, M., Grisel, C., Pontoizeau, C., Eisermann, M., Boutron, A., Chretien, D., Chadefaux-Vekemans, B., Barouki, R., Bole-Feysot, C., Nitschke, P., Goudin, N., Boddaert, N., Nemazanyy, I., Delahodde, A., Kolker, S., Rodenburg, R.J.T., Korenke, G.C., Meitinger, T., Strom, T.M., Prokisch, H., Rotig, A., Ottolenghi, C., Mayr, J.A., and Lonlay, P. de
- Abstract
Item does not contain fulltext, Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (alpha-oxoglutarate dehydrogenase [alpha-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals' fibroblasts showed reduced oxygen consumption rates, PDHc, alpha-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, alpha-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.
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- 2017
23. CAD mutations and uridine-responsive epileptic encephalopathy
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Koch, J., Mayr, J.A., Alhaddad, B., Rauscher, C., Bierau, J., Kovacs-Nagy, R., Coene, K.L.M., Bader, I., Holzhacker, M., Prokisch, H., Venselaar, H., Wevers, R.A., Distelmaier, F., Polster, T., Leiz, S., Betzler, C., Strom, T.M., Sperl, W., Meitinger, T., Wortmann, S.B., Haack, T.B., Koch, J., Mayr, J.A., Alhaddad, B., Rauscher, C., Bierau, J., Kovacs-Nagy, R., Coene, K.L.M., Bader, I., Holzhacker, M., Prokisch, H., Venselaar, H., Wevers, R.A., Distelmaier, F., Polster, T., Leiz, S., Betzler, C., Strom, T.M., Sperl, W., Meitinger, T., Wortmann, S.B., and Haack, T.B.
- Abstract
Contains fulltext : 169910.pdf (publisher's version ) (Closed access), Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening.
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- 2017
24. Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy
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Wortmann, S.B., Timal-Stevenson, S., Venselaar, H., Wintjes, L.T., Kopajtich, R., Feichtinger, R.G., Onnekink, C., Mühlmeister, M., Brandt, U., Smeitink, J.A.M., Veltman, J.A., Sperl, W., Lefeber, D.J., Pruijn, G., Stojanovic, V., Freisinger, P., Spronsen, F. van, Derks, T.G., Veenstra-Knol, H.E., Mayr, J.A., Rötig, A., Tarnopolsky, M., Prokisch, H., Rodenburg, R.J.T., Wortmann, S.B., Timal-Stevenson, S., Venselaar, H., Wintjes, L.T., Kopajtich, R., Feichtinger, R.G., Onnekink, C., Mühlmeister, M., Brandt, U., Smeitink, J.A.M., Veltman, J.A., Sperl, W., Lefeber, D.J., Pruijn, G., Stojanovic, V., Freisinger, P., Spronsen, F. van, Derks, T.G., Veenstra-Knol, H.E., Mayr, J.A., Rötig, A., Tarnopolsky, M., Prokisch, H., and Rodenburg, R.J.T.
- Abstract
Contains fulltext : 182439.pdf (publisher's version ) (Closed access)
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- 2017
25. 532 Variable but distinct metabolic signature in malignant melanoma
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Lang, R., primary, Feichtinger, R.G., additional, Geilberger, R., additional, Rathje, F., additional, Mayr, J.A., additional, Sperl, W., additional, Bauer, J.W., additional, Hauser-Kronberger, C., additional, Emberger, M., additional, and Kofler, B., additional
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- 2017
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26. Spectrum of combined respiratory chain defects
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Mayr, J.A., Haack, T.B., Freisinger, P., Karall, D., Makowski, C.C., Koch, J., Feichtinger, R.G., Zimmermann, F.A., Rolinski, B., Ahting, U., Meitinger, T., Prokisch, H., and Sperl, W.J.K.
- Abstract
Inherited disorders of mitochondrial energy metabolism form a large and heterogeneous group of metabolic diseases. More than 250 gene defects have been reported to date and this number continues to grow. Mitochondrial diseases can be grouped into (1) disorders of oxidative phosphorylation (OXPHOS) subunits and their assembly factors, (2) defects of mitochondrial DNA, RNA and protein synthesis, (3) defects in the substrate-generating upstream reactions of OXPHOS, (4) defects in relevant cofactors and (5) defects in mitochondrial homeostasis. Deficiency of more than one respiratory chain enzyme is a common finding. Combined defects are found in 49 % of the known disease-causing genes of mitochondrial energy metabolism and in 57 % of patients with OXPHOS defects identified in our diagnostic centre. Combined defects of complexes I, III, IV and V are typically due to deficiency of mitochondrial DNA replication, RNA metabolism or translation. Defects in cofactors can result in combined defects of various combinations, and defects of mitochondrial homeostasis can result in a generalised decrease of all OXPHOS enzymes. Noteworthy, identification of combined defects can be complicated by different degrees of severity of each affected enzyme. Furthermore, even defects of single respiratory chain enzymes can result in combined defects due to aberrant formation of respiratory chain supercomplexes. Combined OXPHOS defects have a great variety of clinical manifestations in terms of onset, course severity and tissue involvement. They can present as classical encephalomyopathy but also with hepatopathy, nephropathy, haematologic findings and Perrault syndrome in a subset of disorders.
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- 2015
27. TMEM70 deficiency: long-term outcome of 48 patients
- Author
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Magner, M., Dvorakova, V., Tesarova, M., Mazurova, S., Hansikova, H., Zahorec, M., Brennerova, K., Bzduch, V., Spiegel, R., Horovitz, Y., Mandel, H., Eminoglu, F.T., Mayr, J.A., Koch, J., Martinelli, D., Bertini, E., Konstantopoulou, V., Smet, J., Rahman, S., Broomfield, A., Stojanovic, V., Dionisi-Vici, C., Coster, R. van, Morava, E., Sperl, W., Zeman, J., and Honzik, T.
- Subjects
Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] - Abstract
Contains fulltext : 154072.pdf (Publisher’s version ) (Closed access)
- Published
- 2015
28. Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype
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Koch, J., Freisinger, P., Feichtinger, R.G., Zimmermann, F.A., Rauscher, C., Wagentristl, H.P., Konstantopoulou, V., Seidl, R., Haack, T.B., Prokisch, H., Ahting, U., Sperl, W., Mayr, J.A., and Maier, E.M.
- Subjects
Male ,Adolescent ,Loss of speech ,Research ,Infant, Newborn ,Infant ,Membrane Proteins ,Neurodegenerative Diseases ,Neurodegenerative disorder ,Leigh syndrome ,Regression ,Hypertrophic Olivary Nucleus Degeneration ,Leigh Syndrome ,Loss Of Speech ,Mitochondrial Respiratory Chain Complex Iii Deficiency ,Neonatal Lactic Acidosis ,Neurodegenerative Disorder ,Ttc19 ,Mitochondrial Proteins ,Neonatal lactic acidosis ,Gene Expression Regulation ,Child, Preschool ,Mutation ,Mitochondrial respiratory chain complex III deficiency ,TTC19 ,Humans ,Female ,Amino Acid Sequence ,Hypertrophic olivary nucleus degeneration ,Cloning, Molecular ,Child - Abstract
BACKGROUND: TTC19 deficiency is a progressive neurodegenerative disease associated with isolated mitochondrial respiratory chain (MRC) complex III deficiency and loss-of-function mutations in the TT19 gene in the few patients reported so far. METHODS: We performed exome sequencing and selective mutational analysis of TTC19, respectively, in patients from three unrelated families presenting with initially unspecific clinical signs of muscular hypotonia and global developmental delay followed by regression, ataxia, loss of speech, and rapid neurological deterioration. One patient showed severe lactic acidosis at the neonatal age and during intercurrent illness. RESULTS: We identified homozygous mutations in all three index cases, in two families novel missense mutations (c.544T > C/p.Leu185Pro; c.917T > C/p.Leu324Pro). The younger sister of the severely affected patient 3 showed only mild delay of motor skills and muscular hypotonia so far but is also homozygous for the same mutation. Notably, one patient revealed normal activities of MRC complex III in two independent muscle biopsies. Neuroimaging of the severely affected patients demonstrated lesions in putamen and caudate nuclei, cerebellar atrophy, and the unusual finding of hypertrophic olivary nuclei degeneration. Reviewing the literature revealed striking similarities regarding neuroimaging and clinical course in pediatric patients with TTC19 deficiency: patterns consistent with Leigh or Leigh-like syndrome were found in almost all, hypertrophic olivary nucleus degeneration in all patients reported so far. The clinical course in pediatric patients is characterized by an initially unspecific developmental delay, followed by regression, progressive signs and symptoms of cerebellar, basal ganglia and brainstem affection, especially loss of speech and ataxia. Subsequently, neurological deterioration leading to a vegetative state occurs. CONCLUSIONS: Our findings add to the phenotypic, genetic, and biochemical spectrum of TTC19 deficiency. However, TTC19 deficient patients do show characteristic clinical and neuroimaging features, which may facilitate diagnosis of this yet rare disorder. Normal MRC complex III activity does not exclude the diagnosis.
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- 2014
29. Atypical Clinical Presentations of TAZ Mutations: An Underdiagnosed Cause of Growth Retardation?
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Thiels, C., Fleger, M., Huemer, M., Rodenburg, R.J.T., Vaz, F.M., Houtkooper, R.H., Haack, T.B., Prokisch, H., Feichtinger, R.G., Lucke, T., Mayr, J.A., Wortmann, S.B., Thiels, C., Fleger, M., Huemer, M., Rodenburg, R.J.T., Vaz, F.M., Houtkooper, R.H., Haack, T.B., Prokisch, H., Feichtinger, R.G., Lucke, T., Mayr, J.A., and Wortmann, S.B.
- Abstract
Item does not contain fulltext, Barth syndrome is known as a highly recognizable X-linked disorder typically presenting with the three hallmarks: (left ventricular non-compaction) cardiomyopathy, neutropenia, and 3-methylglutaconic aciduria. Furthermore, growth retardation, mild skeletal myopathy, and specific facial features as well as mitochondrial dysfunction in muscle are frequently seen. Underlying mutations are found in TAZ and lead to defective cardiolipin remodeling.Here, we report atypical clinical manifestations of TAZ mutations in two male patients initially presenting with growth retardation and very mild skeletal myopathy. As other phenotypic hallmarks were missing, Barth syndrome had not been suspected in these patients. One of them has been incidentally diagnosed in the frame of an in-depth cardiolipin research analysis, while the underlying genetic defect was unexpectedly identified in the second one by exome sequencing. CONCLUSION: These cases underline that TAZ mutations might well be an underdiagnosed cause of skeletal myopathy and growth retardation and do not necessarily manifest with the full clinical picture of Barth syndrome.
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- 2016
30. Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2
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Kennedy, H., Haack, T.B., Hartill, V., Matakovic, L., Baumgartner, E.R., Potter, H., Mackay, R., Alston, C.L., O'Sullivan, S., McFarland, R., Connolly, G., Gannon, C., King, R., Mead, S., Crozier, I., Chan, W., Florkowski, C.M., Sage, M., Hofken, T., Alhaddad, B., Kremer, L.S., Kopajtich, R., Feichtinger, R.G., Sperl, W., Rodenburg, R.J.T., Minet, J.C., Dobbie, A., Strom, T.M., Meitinger, T., George, P.M., Johnson, C.A., Taylor, R.W., Prokisch, H., Doudney, K., Mayr, J.A., Kennedy, H., Haack, T.B., Hartill, V., Matakovic, L., Baumgartner, E.R., Potter, H., Mackay, R., Alston, C.L., O'Sullivan, S., McFarland, R., Connolly, G., Gannon, C., King, R., Mead, S., Crozier, I., Chan, W., Florkowski, C.M., Sage, M., Hofken, T., Alhaddad, B., Kremer, L.S., Kopajtich, R., Feichtinger, R.G., Sperl, W., Rodenburg, R.J.T., Minet, J.C., Dobbie, A., Strom, T.M., Meitinger, T., George, P.M., Johnson, C.A., Taylor, R.W., Prokisch, H., Doudney, K., and Mayr, J.A.
- Abstract
Contains fulltext : 171563.pdf (Publisher’s version ) (Open Access), We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.
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- 2016
31. Cofactor deficiency in mitochondrial diseases
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Mataković, Lavinija, primary, Feichtinger, R., additional, Sperl, W., additional, Holzerová, E., additional, Prokisch, H., additional, Haack, T., additional, and Mayr, J.A., additional
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- 2016
- Full Text
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32. The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders
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Sperl, W., Fleuren, L., Freisinger, P., Haack, T.B., Ribes, A., Feichtinger, R.G., Rodenburg, R.J., Zimmermann, F.A., Koch, J., Rivera, I., Prokisch, H., Smeitink, J.A.M., Mayr, J.A., Sperl, W., Fleuren, L., Freisinger, P., Haack, T.B., Ribes, A., Feichtinger, R.G., Rodenburg, R.J., Zimmermann, F.A., Koch, J., Rivera, I., Prokisch, H., Smeitink, J.A.M., and Mayr, J.A.
- Abstract
Contains fulltext : 154261.pdf (publisher's version ) (Closed access)
- Published
- 2015
33. Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement
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Haack, T.B., Jackson, C.B., Murayama, K., Kremer, L.S., Schaller, A., Kotzaeridou, U., Vries, M.C. de, Schottmann, G., Santra, S., Büchner, B., Wieland, T., Graf, E., Freisinger, P., Eggimann, S., Ohtake, A., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Sauer, S., Memari, Y., Kolb-Kokocinski, A., Durbin, R., Hasselmann, O., Cremer, K., Albrecht, B., Wieczorek, D., Engels, H., Hahn, D., Zink, A.M., Alston, C.L., Taylor, R.W., Rodenburg, R.J., Trollmann, R., Sperl, W., Strom, T.M., Hoffmann, G.F., Mayr, J.A., Meitinger, T., Bolognini, R., Schuelke, M., Nuoffer, J.M., Kölker, S., Prokisch, H., Klopstock, T., Haack, T.B., Jackson, C.B., Murayama, K., Kremer, L.S., Schaller, A., Kotzaeridou, U., Vries, M.C. de, Schottmann, G., Santra, S., Büchner, B., Wieland, T., Graf, E., Freisinger, P., Eggimann, S., Ohtake, A., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Sauer, S., Memari, Y., Kolb-Kokocinski, A., Durbin, R., Hasselmann, O., Cremer, K., Albrecht, B., Wieczorek, D., Engels, H., Hahn, D., Zink, A.M., Alston, C.L., Taylor, R.W., Rodenburg, R.J., Trollmann, R., Sperl, W., Strom, T.M., Hoffmann, G.F., Mayr, J.A., Meitinger, T., Bolognini, R., Schuelke, M., Nuoffer, J.M., Kölker, S., Prokisch, H., and Klopstock, T.
- Abstract
Contains fulltext : 154949.pdf (publisher's version ) (Open Access)
- Published
- 2015
34. Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations
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Huemer, M., Karall, D., Schossig, A., Abdenur, J.E., Jasmi, F. Al, Biagosch, C., Distelmaier, F., Freisinger, P., Graham, B.H., Haack, T.B., Hauser, N., Hertecant, J., Ebrahimi-Fakhari, D., Konstantopoulou, V., Leydiker, K., Lourenco, C.M., Scholl-Burgi, S., Wilichowski, E., Wolf, N.I., Wortmann, S.B., Taylor, R.W., Mayr, J.A., Bonnen, P.E., Sperl, W., Prokisch, H., McFarland, R., Huemer, M., Karall, D., Schossig, A., Abdenur, J.E., Jasmi, F. Al, Biagosch, C., Distelmaier, F., Freisinger, P., Graham, B.H., Haack, T.B., Hauser, N., Hertecant, J., Ebrahimi-Fakhari, D., Konstantopoulou, V., Leydiker, K., Lourenco, C.M., Scholl-Burgi, S., Wilichowski, E., Wolf, N.I., Wortmann, S.B., Taylor, R.W., Mayr, J.A., Bonnen, P.E., Sperl, W., Prokisch, H., and McFarland, R.
- Abstract
Contains fulltext : 154784.pdf (publisher's version ) (Closed access), FBXL4 deficiency is a recently described disorder of mitochondrial maintenance associated with a loss of mitochondrial DNA in cells. To date, the genetic diagnosis of FBXL4 deficiency has been established in 28 individuals. This paper retrospectively reviews proxy-reported clinical and biochemical findings and evaluates brain imaging, morphological and genetic data in 21 of those patients. Neonatal/early-onset severe lactic acidosis, muscular hypotonia, feeding problems and failure to thrive is the characteristic pattern at first presentation. Facial dysmorphic features are present in 67 % of cases. Seven children died (mean age 37 months); 11 children were alive (mean age at follow-up 46 months), three children were lost to follow-up. All survivors developed severe psychomotor retardation. Brain imaging was non-specific in neonates but a later-onset, rapidly progressive brain atrophy was noted. Elevated blood lactate and metabolic acidosis were observed in all individuals; creatine kinase was elevated in 45 % of measurements. Diagnostic workup in patient tissues and cells revealed a severe combined respiratory chain defect with a general decrease of enzymes associated with mitochondrial energy metabolism and a relative depletion of mitochondrial DNA content. Mutations were detected throughout the FBXL4 gene albeit with no clear delineation of a genotype-phenotype correlation. Treatment with "mitochondrial medications" did not prove effective. In conclusion, a clinical pattern of early-onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of FBXL4. Establishment of the diagnosis permits genetic counselling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis.
- Published
- 2015
35. WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease
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Vodopiutz, J. (Julia), Seidl, R. (Rainer), Prayer, D. (Daniela), Khan, M.I. (M. Imran), Mayr, J.A. (Johannes A.), Streubel, B. (Berthold), Steiß, J.-O. (Jens-Oliver), Hahn, A. (Andreas), Csaicsich, D. (Dagmar), Castro, C. (Christel), Assoum, M. (Mirna), Müller, T. (Thomas), Wieczorek, D. (Dagmar), Mancini, G.M.S. (Grazia), Sadowski, C.E. (Carolin E.), Lévy, N. (Nicolas), Megarbane, A. (Andre), Godbole, K. (Koumudi), Schanze, D. (Denny), Hildebrandt, F. (Friedhelm), Delague, V. (Valérie), Janecke, A.R. (Andreas), Zenker, M. (Martin), Vodopiutz, J. (Julia), Seidl, R. (Rainer), Prayer, D. (Daniela), Khan, M.I. (M. Imran), Mayr, J.A. (Johannes A.), Streubel, B. (Berthold), Steiß, J.-O. (Jens-Oliver), Hahn, A. (Andreas), Csaicsich, D. (Dagmar), Castro, C. (Christel), Assoum, M. (Mirna), Müller, T. (Thomas), Wieczorek, D. (Dagmar), Mancini, G.M.S. (Grazia), Sadowski, C.E. (Carolin E.), Lévy, N. (Nicolas), Megarbane, A. (Andre), Godbole, K. (Koumudi), Schanze, D. (Denny), Hildebrandt, F. (Friedhelm), Delague, V. (Valérie), Janecke, A.R. (Andreas), and Zenker, M. (Martin)
- Abstract
Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with brain anomalies including CA in some cases, intellectual disability, and early-infantile-onset nephrotic syndrome. Very recently, WDR73 deficiency was identified as the cause of GMS in five individuals. To evaluate the role of WDR73 mutations as a cause of GMS and other forms of syndromic CA, we performed Sanger or exome sequencing in 51 unrelated patients with CA and variable brain anomalies and in 40 unrelated patients with a diagnosis of GMS. We identified 10 patients from three CA and from two GMS families with WDR73 mutations including the original family described with CA, mental retardation, optic atrophy, and skin abnormalities (CAMOS). There were five novel mutations, of which two were truncating and three were missense mutations affecting highly conserved residues. Individuals carrying homozygous WDR73 mutations mainly presented with a pattern of neurological and neuroimaging findings as well as intellectual disability, while kidney involvement was variable. We document postnatal onset of CA, a retinopathy, basal ganglia degeneration, and short stature as novel features of WDR73-related disease, and define WDR73-related disease as a new entity of infantile neurodegeneration.
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- 2015
- Full Text
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36. Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy
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Gai, X., Ghezzi, D., Johnson, M.A., Biagosch, C., Shamseldin, H.E., Haack, T.B., Reyes, A., Tsukikawa, M., Sheldon, C.A., Srinivasan, S., Gorza, M., Kremer, L.S., Wieland, T., Strom, T.M., Polyak, E., Place, E., Consugar, M., Ostrovsky, J., Vidoni, S., Robinson, A.J., Wong, L.J., Sondheimer, N., Salih, M.A., Al-Jishi, E., Raab, C.P., Bean, C., Furlan, F., Parini, R., Lamperti, C., Mayr, J.A., Konstantopoulou, V., Huemer, M.-T., Pierce, E.A., Meitinger, T., Freisinger, P., Sperl, W., Prokisch, H., Alkuraya, F.S., Falk, M.J., and Zeviani, M.
- Abstract
Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy.
- Published
- 2013
37. OP6 – 2631: Decreased free-thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in Leigh syndrome patients
- Author
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Escobar, J.D. Ortigoza, primary, Molero-Luis, M., additional, Arias, A., additional, Darin, N., additional, Casado, M., additional, Serrano, M., additional, Tondo, M., additional, Mayr, J.A., additional, Ribes, A., additional, Artuch, R., additional, and Pérez-Dueñas, B., additional
- Published
- 2015
- Full Text
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38. Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening
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Haack, T.B., Gorza, M., Danhauser, K., Mayr, J.A., Haberberger, B., Wieland, T., Kremer, L., Strecker, V., Graf, E., Memari, Y., Ahting, U., Kopajtich, R., Wortmann, S.B., Rodenburg, R.J.T., Kotzaeridou, U., Hoffmann, G.F., Sperl, W., Wittig, I., Wilichowski, E., Schottmann, G., Schuelke, M., Plecko, B., Stephani, U., Strom, T.M., Meitinger, T., Prokisch, H., Freisinger, P., Haack, T.B., Gorza, M., Danhauser, K., Mayr, J.A., Haberberger, B., Wieland, T., Kremer, L., Strecker, V., Graf, E., Memari, Y., Ahting, U., Kopajtich, R., Wortmann, S.B., Rodenburg, R.J.T., Kotzaeridou, U., Hoffmann, G.F., Sperl, W., Wittig, I., Wilichowski, E., Schottmann, G., Schuelke, M., Plecko, B., Stephani, U., Strom, T.M., Meitinger, T., Prokisch, H., and Freisinger, P.
- Abstract
Item does not contain fulltext, Defects of mitochondrial oxidative phosphorylation (OXPHOS) are associated with a wide range of clinical phenotypes and time courses. Combined OXPHOS deficiencies are mainly caused by mutations of nuclear genes that are involved in mitochondrial protein translation. Due to their genetic heterogeneity it is almost impossible to diagnose OXPHOS patients on clinical grounds alone. Hence next generation sequencing (NGS) provides a distinct advantage over candidate gene sequencing to discover the underlying genetic defect in a timely manner. One recent example is the identification of mutations in MTFMT that impair mitochondrial protein translation through decreased formylation of Met-tRNA(Met). Here we report the results of a combined exome sequencing and candidate gene screening study. We identified nine additional MTFMT patients from eight families who were affected with Leigh encephalopathy or white matter disease, microcephaly, mental retardation, ataxia, and muscular hypotonia. In four patients, the causal mutations were identified by exome sequencing followed by stringent bioinformatic filtering. In one index case, exome sequencing identified a single heterozygous mutation leading to Sanger sequencing which identified a second mutation in the non-covered first exon. High-resolution melting curve-based MTFMT screening in 350 OXPHPOS patients identified pathogenic mutations in another three index cases. Mutations in one of them were not covered by previous exome sequencing. All novel mutations predict a loss-of-function or result in a severe decrease in MTFMT protein in patients' fibroblasts accompanied by reduced steady-state levels of complex I and IV subunits. Being present in 11 out of 13 index cases the c.626C>T mutation is one of the most frequent disease alleles underlying OXPHOS disorders. We provide detailed clinical descriptions on eleven MTFMT patients and review five previously reported cases.
- Published
- 2014
39. Thiamine-pyrophosphokinase-deficiency: Clinical and genotypic spectrum in 5 patients
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Freisinger, P., primary, Mayr, J.A., additional, Scheffner, T., additional, Makowski, C., additional, Koch, J., additional, Ahting, U., additional, Zimmermann, F.A., additional, Schlachter, K., additional, Prokisch, H., additional, and Sperl, W., additional
- Published
- 2013
- Full Text
- View/download PDF
40. Cofactor defects as a cause of mitochondrial encephalomyopathies
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Mayr, J.A., primary, Freisinger, P., additional, Haack, T., additional, Koch, J., additional, Zimmermann, F., additional, Prokisch, H., additional, and Sperl, W., additional
- Published
- 2013
- Full Text
- View/download PDF
41. Sengers syndrome is caused by a deficiency of the acylglycerol kinase
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Sperl, W., primary, Mayr, J.A., additional, Haack, T.B., additional, Zimmermann, F.A., additional, Meitinger, T., additional, and Prokisch, H., additional
- Published
- 2013
- Full Text
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42. Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome.
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Mayr, J.A., Haack, T.B., Graf, E., Zimmermann, F.A., Wieland, T., Haberberger, B., Superti-Furga, A., Kirschner, J., Steinmann, B., Baumgartner, M.R., Moroni, I., Lamantea, E., Zeviani, M., Rodenburg, R.J.T., Smeitink, J., Strom, T.M., Meitinger, T., Sperl, W., Prokisch, H., Mayr, J.A., Haack, T.B., Graf, E., Zimmermann, F.A., Wieland, T., Haberberger, B., Superti-Furga, A., Kirschner, J., Steinmann, B., Baumgartner, M.R., Moroni, I., Lamantea, E., Zeviani, M., Rodenburg, R.J.T., Smeitink, J., Strom, T.M., Meitinger, T., Sperl, W., and Prokisch, H.
- Abstract
Item does not contain fulltext, Exome sequencing of an individual with congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis, all typical symptoms of Sengers syndrome, discovered two nonsense mutations in the gene encoding mitochondrial acylglycerol kinase (AGK). Mutation screening of AGK in further individuals with congenital cataracts and cardiomyopathy identified numerous loss-of-function mutations in an additional eight families, confirming the causal nature of AGK deficiency in Sengers syndrome. The loss of AGK led to a decrease of the adenine nucleotide translocator in the inner mitochondrial membrane in muscle, consistent with a role of AGK in driving the assembly of the translocator as a result of its effects on phospholipid metabolism in mitochondria.
- Published
- 2012
43. Leigh disease with brainstem involvement in complex I deficiency due to assembly factor NDUFAF2 defect.
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Herzer, M., Koch, J., Prokisch, H., Rodenburg, R.J.T., Rauscher, C., Radauer, W., Forstner, R., Pilz, P., Rolinski, B., Freisinger, P., Mayr, J.A., Sperl, W., Herzer, M., Koch, J., Prokisch, H., Rodenburg, R.J.T., Rauscher, C., Radauer, W., Forstner, R., Pilz, P., Rolinski, B., Freisinger, P., Mayr, J.A., and Sperl, W.
- Abstract
01 februari 2010, Contains fulltext : 87232.pdf (publisher's version ) (Open Access), Mitochondrial NADH: ubiquinone oxidoreductase (complex I) deficiency accounts for most defects in mitochondrial oxidative phosphorylation. Pathogenic mutations have been described in all 7 mitochondrial and 12 of the 38 nuclear encoded subunits as well as in assembly factors by interfering with the building of the mature enzyme complex within the inner mitochondrial membrane. We now describe a male patient with a novel homozygous stop mutation in the NDUFAF2 gene. The boy presented with severe apnoea and nystagmus. MRI showed brainstem lesions without involvement of basal ganglia and thalamus, plasma lactate was normal or close to normal. He died after a fulminate course within 2 months after the first crisis. Neuropathology verified Leigh disease. We give a synopsis with other reported patients. Within the clinical spectrum of Leigh disease, patients with mutations in NDUFAF2 present with a distinct clinical pattern with predominantly brainstem involvement on MRI. The diagnosis should not be missed in spite of the normal lactate and lack of thalamus and basal ganglia changes on brain MRI.
- Published
- 2010
44. Mitochondriopathien
- Author
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Sperl, W., primary, Prokisch, H., additional, Karall, D., additional, Mayr, J.A., additional, and Freisinger, P., additional
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- 2011
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45. P04.4 Atypical myopathic presentation of Pearson Syndrome in early infancy: tissuespecific correlation of mutated mtDNA load and clinical presentation
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Reichhardt, M., primary, Bernert, G., additional, Sperl, W., additional, Mayr, J.A., additional, and Holub, M., additional
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- 2011
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46. Clinical heterogeneity in patients with mutations in the NDUFS4 gene of mitochondrial complex I.
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Budde, M.S., Heuvel, L.P.W.J. van den, Smeets, R.J.P., Skladal, D., Mayr, J.A., Boelen, C., Petruzzella, V., Papa, S., Smeitink, J.A.M., Budde, M.S., Heuvel, L.P.W.J. van den, Smeets, R.J.P., Skladal, D., Mayr, J.A., Boelen, C., Petruzzella, V., Papa, S., and Smeitink, J.A.M.
- Abstract
Item does not contain fulltext, A comparison of the clinical presentation, disease course and results of laboratory and imaging studies of all patients so far published with a NDUFS4 mutation are presented. This reveals marked clinical heterogeneity, even in patients with the same genotype.
- Published
- 2003
47. 146 Difficulty in the diagnosis of X-linked PDHC deficiency due to a large deletion affecting the PDHA1 gene
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Sperl, W., primary, Koch, J., additional, Rauscher, C., additional, Zschocke, J., additional, Fauth, C., additional, and Mayr, J.A., additional
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- 2010
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48. 147 Compound heterozygosity for mutations in TMEM70
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Sperl, W., primary, Bodamer, O., additional, Möslinger, D., additional, Koch, J., additional, Tesarova, M., additional, Zeman, J., additional, Houstek, J., additional, Kmoch, S., additional, and Mayr, J.A., additional
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- 2010
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49. Deficiency of mitochondrial ATP synthase of nuclear genetic origin
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Sperl, W., primary, Ješina, P., additional, Zeman, J., additional, Mayr, J.A., additional, DeMeirleir, L., additional, VanCoster, R., additional, Pícková, A., additional, Hansíková, H., additional, Houšt’ková, H., additional, Krejčík, Z., additional, Koch, J., additional, Smet, J., additional, Muss, W., additional, Holme, E., additional, and Houštěk, J., additional
- Published
- 2006
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50. Biochemical consequences of a pathogenic A3243G mtDNA mutation
- Author
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Mayr, J.A., primary, Zimmermann, F., additional, Meierhofer, D., additional, Schmeller, N., additional, Sperl, W., additional, and Kofler, B., additional
- Published
- 2006
- Full Text
- View/download PDF
Catalog
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