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De novo DHDDS varia...
De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus
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- Galosi, Serena (författare)
- Sapienza University of Rome
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- Edani, Ban H (författare)
- Yale University
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- Martinelli, Simone (författare)
- Washington University School of Medicine
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visa fler...
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- Hansikova, Hana (författare)
- Charles University in Prague
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- Eklund, Erik A (författare)
- Lund University,Lunds universitet,Epilepsicentrum,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Epilepsy Center,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund
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Caputi, Caterina (författare)
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Masuelli, Laura (författare)
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Corsten-Janssen, Nicole (författare)
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- Srour, Myriam (författare)
- McGill University
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- Oegema, Renske (författare)
- University Medical Center Utrecht
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- Bosch, Daniëlle G M (författare)
- University Medical Center Utrecht
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- Ellis, Colin A (författare)
- Indiana University of Pennsylvania
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Amlie-Wolf, Louise (författare)
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- Accogli, Andrea (författare)
- McGill University
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- Atallah, Isis (författare)
- Geneva University Hospital
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- Averdunk, Luisa (författare)
- University Hospital of Düsseldorf
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- Barañano, Kristin W (författare)
- Johns Hopkins University
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- Bei, Roberto (författare)
- Tor Vergata University Hospital
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Bagnasco, Irene (författare)
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Brusco, Alfredo (författare)
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- Demarest, Scott (författare)
- The Children's Hospital, Aurora
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Alaix, Anne-Sophie (författare)
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Di Bonaventura, Carlo (författare)
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- Distelmaier, Felix (författare)
- University Hospital of Düsseldorf
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Elmslie, Frances (författare)
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- Gan-Or, Ziv (författare)
- McGill University
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- Good, Jean-Marc (författare)
- Geneva University Hospital
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- Gripp, Karen (författare)
- Nemours Alfred I. duPont Hospital for Children
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- Kamsteeg, Erik-Jan (författare)
- Radboud University Medical Center
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- Macnamara, Ellen (författare)
- National Health Research Institutes Taiwan (NHRI)
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- Marcelis, Carlo (författare)
- Radboud University Medical Center
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Mercier, Noëlle (författare)
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- Peeden, Joseph (författare)
- University of Tennessee
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Pizzi, Simone (författare)
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Pannone, Luca (författare)
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- Shinawi, Marwan (författare)
- Washington University School of Medicine
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- Toro, Camilo (författare)
- National Health Research Institutes Taiwan (NHRI)
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- Verbeek, Nienke E (författare)
- University Medical Center Utrecht
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- Venkateswaran, Sunita (författare)
- Children's Hospital of Eastern Ontario
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- Wheeler, Patricia G (författare)
- Arnold Palmer Hospital for Children and Women
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- Zdrazilova, Lucie (författare)
- Charles University in Prague,General University Hospital in Prague
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- Zhang, Rong (författare)
- Yale University
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Zorzi, Giovanna (författare)
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- Guerrini, Renzo (författare)
- University of Florence
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- Sessa, William C (författare)
- Yale University
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- Lefeber, Dirk (författare)
- Radboud University Medical Center
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Tartaglia, Marco (författare)
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- Hamdan, Fadi F (författare)
- Centre Hospitalier Universitaire Sainte-Justine,University of Montreal
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- Grabińska, Kariona A (författare)
- Yale University
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Leuzzi, Vincenzo (författare)
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(creator_code:org_t)
- 2021-08-11
- 2022
- Engelska.
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 145:1, s. 208-223
- Relaterad länk:
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http://dx.doi.org/10...
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https://iris.unito.i...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Pediatrik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Pediatrics (hsv//eng)
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- art (ämneskategori)
- ref (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Galosi, Serena
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Edani, Ban H
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Martinelli, Simo ...
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Hansikova, Hana
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Eklund, Erik A
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Caputi, Caterina
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visa fler...
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Masuelli, Laura
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Corsten-Janssen, ...
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Srour, Myriam
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Oegema, Renske
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Bosch, Daniëlle ...
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Ellis, Colin A
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Amlie-Wolf, Loui ...
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Accogli, Andrea
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Atallah, Isis
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Averdunk, Luisa
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Barañano, Kristi ...
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Bei, Roberto
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Bagnasco, Irene
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Brusco, Alfredo
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Demarest, Scott
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Alaix, Anne-Soph ...
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Di Bonaventura, ...
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Distelmaier, Fel ...
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Elmslie, Frances
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Gan-Or, Ziv
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Good, Jean-Marc
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Gripp, Karen
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Kamsteeg, Erik-J ...
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Macnamara, Ellen
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Marcelis, Carlo
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Mercier, Noëlle
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Peeden, Joseph
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Pizzi, Simone
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Pannone, Luca
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Shinawi, Marwan
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Toro, Camilo
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Verbeek, Nienke ...
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Venkateswaran, S ...
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Wheeler, Patrici ...
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Zdrazilova, Luci ...
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Zhang, Rong
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Zorzi, Giovanna
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Guerrini, Renzo
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Sessa, William C
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Lefeber, Dirk
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Tartaglia, Marco
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Hamdan, Fadi F
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Grabińska, Kario ...
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Leuzzi, Vincenzo
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- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Neurologi
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Pediatrik
- Artiklar i publikationen
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Brain : a journa ...
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Brain
- Av lärosätet
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Lunds universitet