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De novo DHDDS varia...
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Galosi, SerenaSapienza University of Rome
(author)
De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2021-08-11
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Oxford University Press (OUP),2022
Numbers
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LIBRIS-ID:oai:lup.lub.lu.se:b695c96e-8b0a-4897-b132-6d4ef5895781
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https://lup.lub.lu.se/record/b695c96e-8b0a-4897-b132-6d4ef5895781URI
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https://doi.org/10.1093/brain/awab299DOI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
Notes
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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.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Edani, Ban HYale University
(author)
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Martinelli, SimoneWashington University School of Medicine
(author)
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Hansikova, HanaCharles University in Prague
(author)
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Eklund, Erik ALund 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(Swepub:lu)medk-eek
(author)
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Caputi, Caterina
(author)
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Masuelli, Laura
(author)
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Corsten-Janssen, Nicole
(author)
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Srour, MyriamMcGill University
(author)
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Oegema, RenskeUniversity Medical Center Utrecht
(author)
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Bosch, Daniëlle G MUniversity Medical Center Utrecht
(author)
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Ellis, Colin AIndiana University of Pennsylvania
(author)
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Amlie-Wolf, Louise
(author)
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Accogli, AndreaMcGill University
(author)
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Atallah, IsisGeneva University Hospital
(author)
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Averdunk, LuisaUniversity Hospital of Düsseldorf
(author)
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Barañano, Kristin WJohns Hopkins University
(author)
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Bei, RobertoTor Vergata University Hospital
(author)
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Bagnasco, Irene
(author)
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Brusco, Alfredo
(author)
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Demarest, ScottThe Children's Hospital, Aurora
(author)
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Alaix, Anne-Sophie
(author)
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Di Bonaventura, Carlo
(author)
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Distelmaier, FelixUniversity Hospital of Düsseldorf
(author)
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Elmslie, Frances
(author)
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Gan-Or, ZivMcGill University
(author)
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Good, Jean-MarcGeneva University Hospital
(author)
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Gripp, KarenNemours Alfred I. duPont Hospital for Children
(author)
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Kamsteeg, Erik-JanRadboud University Medical Center
(author)
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Macnamara, EllenNational Health Research Institutes Taiwan (NHRI)
(author)
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Marcelis, CarloRadboud University Medical Center
(author)
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Mercier, Noëlle
(author)
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Peeden, JosephUniversity of Tennessee
(author)
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Pizzi, Simone
(author)
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Pannone, Luca
(author)
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Shinawi, MarwanWashington University School of Medicine
(author)
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Toro, CamiloNational Health Research Institutes Taiwan (NHRI)
(author)
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Verbeek, Nienke EUniversity Medical Center Utrecht
(author)
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Venkateswaran, SunitaChildren's Hospital of Eastern Ontario
(author)
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Wheeler, Patricia GArnold Palmer Hospital for Children and Women
(author)
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Zdrazilova, LucieGeneral University Hospital in Prague,Charles University in Prague
(author)
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Zhang, RongYale University
(author)
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Zorzi, Giovanna
(author)
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Guerrini, RenzoUniversity of Florence
(author)
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Sessa, William CYale University
(author)
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Lefeber, DirkRadboud University Medical Center
(author)
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Tartaglia, Marco
(author)
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Hamdan, Fadi FUniversity of Montreal,Centre Hospitalier Universitaire Sainte-Justine
(author)
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Grabińska, Kariona AYale University
(author)
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Leuzzi, Vincenzo
(author)
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Sapienza University of RomeYale University
(creator_code:org_t)
Related titles
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In:Brain : a journal of neurology: Oxford University Press (OUP)145:1, s. 208-2231460-2156
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In:Brain: Oxford University Press (OUP)145:1, s. 208-2230006-8950
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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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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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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Neurology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Pediatrics
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Brain : a journa ...
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Brain
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Lund University