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  1. Article ; Online: Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency.

    Van Bergen, Nicole J / Walvekar, Adhish S / Patraskaki, Myrto / Sikora, Tim / Linster, Carole L / Christodoulou, John

    Journal of inherited metabolic disease

    2022  Volume 45, Issue 6, Page(s) 1028–1038

    Abstract: The central cofactors NAD(P)H are prone to damage by hydration, resulting in formation of redox-inactive derivatives designated NAD(P)HX. The highly conserved enzymes NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) function to repair ... ...

    Abstract The central cofactors NAD(P)H are prone to damage by hydration, resulting in formation of redox-inactive derivatives designated NAD(P)HX. The highly conserved enzymes NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) function to repair intracellular NAD(P)HX. Recently, pathogenic variants in both the NAXD and NAXE genes were associated with rapid deterioration and death after an otherwise trivial fever, infection, or illness in young patients. As more patients are identified, distinct clinical features are emerging depending on the location of the pathogenic variant. In this review, we carefully catalogued the clinical features of all published NAXD deficiency patients and found distinct patterns in clinical presentations depending on which subcellular compartment is affected by the enzymatic deficiency. Exon 1 of NAXD contains a mitochondrial propeptide, and a unique cytosolic isoform is initiated from an alternative start codon in exon 2. NAXD deficiency patients with variants that affect both the cytosolic and mitochondrial isoforms present with neurological defects, seizures and skin lesions. Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration. This suggests that cytosolic NAD(P)HX repair may protect from neurological damage, whereas muscle fibres may be more sensitive to mitochondrial NAD(P)HX damage. A deeper understanding of the clinical phenotype may facilitate rapid identification of new cases and allow earlier therapeutic intervention. Niacin-based therapies are promising, but advances in disease modelling for both NAXD and NAXE deficiency may identify more specific compounds as targeted treatments. In this review, we found distinct patterns in the clinical presentations of NAXD deficiency patients based on the location of the pathogenic variant, which determines the subcellular compartment that is affected by the enzymatic deficiency.
    MeSH term(s) Humans ; NAD/metabolism ; Racemases and Epimerases/metabolism ; Mitochondria/metabolism ; Metabolic Diseases/metabolism ; Seizures/metabolism
    Chemical Substances NAD (0U46U6E8UK) ; Racemases and Epimerases (EC 5.1.-)
    Language English
    Publishing date 2022-08-07
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 438341-2
    ISSN 1573-2665 ; 0141-8955
    ISSN (online) 1573-2665
    ISSN 0141-8955
    DOI 10.1002/jimd.12541
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1508: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  2. Article ; Online: Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma.

    Van Bergen, Nicole J / Gunanayagam, Karen / Bournazos, Adam M / Walvekar, Adhish S / Warmoes, Marc O / Semcesen, Liana N / Lunke, Sebastian / Bommireddipalli, Shobhana / Sikora, Tim / Patraskaki, Myrto / Jones, Dean L / Garza, Denisse / Sebire, Dale / Gooley, Samuel / McLean, Catriona A / Naidoo, Parm / Rajasekaran, Mugil / Stroud, David A / Linster, Carole L /
    Wallis, Mathew / Cooper, Sandra T / Christodoulou, John

    International journal of molecular sciences

    2023  Volume 24, Issue 4

    Abstract: We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is ... ...

    Abstract We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous
    MeSH term(s) Adult ; Child ; Child, Preschool ; Humans ; Hydro-Lyases/metabolism ; Mitochondria/metabolism ; NAD/metabolism ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Proteomics ; Brain Concussion/complications ; Brain Concussion/genetics ; Brain Diseases, Metabolic/etiology ; Brain Diseases, Metabolic/genetics
    Chemical Substances Hydro-Lyases (EC 4.2.1.-) ; NAD (0U46U6E8UK) ; NAXD protein, human (EC 4.2.1.93)
    Language English
    Publishing date 2023-02-10
    Publishing country Switzerland
    Document type Case Reports
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24043582
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: SOD2 in skeletal muscle: New insights from an inducible deletion model.

    Zhuang, Aowen / Yang, Christine / Liu, Yingying / Tan, Yanie / Bond, Simon T / Walker, Shannen / Sikora, Tim / Laskowski, Adrienne / Sharma, Arpeeta / de Haan, Judy B / Meikle, Peter J / Shimizu, Takahiko / Coughlan, Melinda T / Calkin, Anna C / Drew, Brian G

    Redox biology

    2021  Volume 47, Page(s) 102135

    Abstract: Metabolic conditions such as obesity, insulin resistance and glucose intolerance are frequently associated with impairments in skeletal muscle function and metabolism. This is often linked to dysregulation of homeostatic pathways including an increase in ...

    Abstract Metabolic conditions such as obesity, insulin resistance and glucose intolerance are frequently associated with impairments in skeletal muscle function and metabolism. This is often linked to dysregulation of homeostatic pathways including an increase in reactive oxygen species (ROS) and oxidative stress. One of the main sites of ROS production is the mitochondria, where the flux of substrates through the electron transport chain (ETC) can result in the generation of oxygen free radicals. Fortunately, several mechanisms exist to buffer bursts of intracellular ROS and peroxide production, including the enzymes Catalase, Glutathione Peroxidase and Superoxide Dismutase (SOD). Of the latter, there are two intracellular isoforms; SOD1 which is mostly cytoplasmic, and SOD2 which is found exclusively in the mitochondria. Developmental and chronic loss of these enzymes has been linked to disease in several studies, however the temporal effects of these disturbances remain largely unexplored. Here, we induced a post-developmental (8-week old mice) deletion of SOD2 in skeletal muscle (SOD2-iMKO) and demonstrate that 16 weeks of SOD2 deletion leads to no major impairment in whole body metabolism, despite these mice displaying alterations in aspects of mitochondrial abundance and voluntary ambulatory movement. This is likely partly explained by the suggestive data that a compensatory response may exist from other redox enzymes, including catalase and glutathione peroxidases. Nevertheless, we demonstrated that inducible SOD2 deletion impacts on specific aspects of muscle lipid metabolism, including the abundance of phospholipids and phosphatidic acid (PA), the latter being a key intermediate in several cellular signaling pathways. Thus, our findings suggest that post-developmental deletion of SOD2 induces a more subtle phenotype than previous embryonic models have shown, allowing us to highlight a previously unrecognized link between SOD2, mitochondrial function and bioactive lipid species including PA.
    MeSH term(s) Animals ; Mice ; Mitochondria/genetics ; Mitochondria/metabolism ; Muscle, Skeletal/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase/metabolism
    Chemical Substances Reactive Oxygen Species ; Superoxide Dismutase (EC 1.15.1.1) ; superoxide dismutase 2 (EC 1.15.1.1)
    Language English
    Publishing date 2021-09-14
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2701011-9
    ISSN 2213-2317 ; 2213-2317
    ISSN (online) 2213-2317
    ISSN 2213-2317
    DOI 10.1016/j.redox.2021.102135
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Tissue-specific expression of Cas9 has no impact on whole-body metabolism in four transgenic mouse lines.

    Bond, Simon T / Zhuang, Aowen / Yang, Christine / Gould, Eleanor A M / Sikora, Tim / Liu, Yingying / Fu, Ying / Watt, Kevin I / Tan, Yanie / Kiriazis, Helen / Lancaster, Graeme I / Gregorevic, Paul / Henstridge, Darren C / McMullen, Julie R / Meikle, Peter J / Calkin, Anna C / Drew, Brian G

    Molecular metabolism

    2021  Volume 53, Page(s) 101292

    Abstract: Objective: CRISPR/Cas9 technology has revolutionized gene editing and fast tracked our capacity to manipulate genes of interest for the benefit of both research and therapeutic applications. Whilst many advances have, and continue to be made in this ... ...

    Abstract Objective: CRISPR/Cas9 technology has revolutionized gene editing and fast tracked our capacity to manipulate genes of interest for the benefit of both research and therapeutic applications. Whilst many advances have, and continue to be made in this area, perhaps the most utilized technology to date has been the generation of knockout cells, tissues and animals. The advantages of this technology are many fold, however some questions still remain regarding the effects that long term expression of foreign proteins such as Cas9, have on mammalian cell function. Several studies have proposed that chronic overexpression of Cas9, with or without its accompanying guide RNAs, may have deleterious effects on cell function and health. This is of particular concern when applying this technology in vivo, where chronic expression of Cas9 in tissues of interest may promote disease-like phenotypes and thus confound the investigation of the effects of the gene of interest. Although these concerns remain valid, no study to our knowledge has yet to demonstrate this directly.
    Methods: In this study we used the lox-stop-lox (LSL) spCas9 ROSA26 transgenic (Tg) mouse line to generate four tissue-specific Cas9-Tg models that express Cas9 in the heart, liver, skeletal muscle or adipose tissue. We performed comprehensive phenotyping of these mice up to 20-weeks of age and subsequently performed molecular analysis of their organs.
    Results: We demonstrate that Cas9 expression in these tissues had no detrimental effect on whole body health of the animals, nor did it induce any tissue-specific effects on whole body energy metabolism, liver health, inflammation, fibrosis, heart function or muscle mass.
    Conclusions: Our data suggests that these models are suitable for studying the tissue specific effects of gene deletion using the LSL-Cas9-Tg model, and that phenotypes observed utilizing these models can be confidently interpreted as being gene specific, and not confounded by the chronic overexpression of Cas9.
    MeSH term(s) Animals ; CRISPR-Associated Protein 9/genetics ; CRISPR-Cas Systems/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Phenotype
    Chemical Substances CRISPR-Associated Protein 9 (EC 3.1.-)
    Language English
    Publishing date 2021-07-08
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2708735-9
    ISSN 2212-8778 ; 2212-8778
    ISSN (online) 2212-8778
    ISSN 2212-8778
    DOI 10.1016/j.molmet.2021.101292
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Integrated multi-omics for rapid rare disease diagnosis on a national scale.

    Lunke, Sebastian / Bouffler, Sophie E / Patel, Chirag V / Sandaradura, Sarah A / Wilson, Meredith / Pinner, Jason / Hunter, Matthew F / Barnett, Christopher P / Wallis, Mathew / Kamien, Benjamin / Tan, Tiong Y / Freckmann, Mary-Louise / Chong, Belinda / Phelan, Dean / Francis, David / Kassahn, Karin S / Ha, Thuong / Gao, Song / Arts, Peer /
    Jackson, Matilda R / Scott, Hamish S / Eggers, Stefanie / Rowley, Simone / Boggs, Kirsten / Rakonjac, Ana / Brett, Gemma R / de Silva, Michelle G / Springer, Amanda / Ward, Michelle / Stallard, Kirsty / Simons, Cas / Conway, Thomas / Halman, Andreas / Van Bergen, Nicole J / Sikora, Tim / Semcesen, Liana N / Stroud, David A / Compton, Alison G / Thorburn, David R / Bell, Katrina M / Sadedin, Simon / North, Kathryn N / Christodoulou, John / Stark, Zornitza

    Nature medicine

    2023  Volume 29, Issue 7, Page(s) 1681–1691

    Abstract: Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ... ...

    Abstract Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner.
    MeSH term(s) Infant ; Child ; Humans ; Rare Diseases/diagnosis ; Rare Diseases/genetics ; Rare Diseases/therapy ; Critical Illness ; Multiomics ; Whole Genome Sequencing/methods ; Exome Sequencing
    Language English
    Publishing date 2023-06-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-023-02401-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4212: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 39: Show issues

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