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De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus
S. Galosi, BH. Edani, S. Martinelli, H. Hansikova, EA. Eklund, C. Caputi, L. Masuelli, N. Corsten-Janssen, M. Srour, R. Oegema, DGM. Bosch, CA. Ellis, L. Amlie-Wolf, A. Accogli, I. Atallah, L. Averdunk, KW. Barañano, R. Bei, I. Bagnasco, A....
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Extramural
Grantová podpora
R35 HL139945
NHLBI NIH HHS - United States
R01 DK125492
NIDDK NIH HHS - United States
Odkazy
PubMed
34382076
DOI
10.1093/brain/awab299
Knihovny.cz E-zdroje
- MeSH
- alkyltransferasy a aryltransferasy * MeSH
- dítě MeSH
- dolichol metabolismus MeSH
- lidé MeSH
- myoklonus * MeSH
- neurodegenerativní nemoci * genetika MeSH
- retinopathia pigmentosa * genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
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 fibres 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.
Arnold Palmer Hospital for Children Orlando FL 32806 USA
Children's Hospital Colorado Aurora CO 80045 USA
Department of Clinical Genetics Radboud University Medical Centre Nijmegen 6525 The Netherlands
Department of Experimental Medicine Sapienza University Rome 00161 Italy
Department of Genetics University Medical Center Utrecht Utrecht 3584 CX The Netherlands
Department of Human Genetics McGill University Montréal QC H3A 0C7 Canada
Department of Human Genetics Radboud University Medical Centre Nijmegen 6525 The Netherlands
Department of Human Neuroscience Sapienza University Rome 00185 Italy
Department of Neurology and Neurosurgery McGill University Montreal QC H4A 3J1 Canada
Department of Neurology Johns Hopkins School of Medicine Baltimore MD 21287 USA
Department of Neurology University of Pennsylvania Philadelphia PA 19104 USA
Department of Oncology and Molecular Medicine Istituto Superiore di Sanità Rome 00161 Italy
Department of Pediatrics McGill University Montreal QC H4A 3J1 Canada
Department of Pediatrics University of Colorado School of Medicine Aurora CO 80045 USA
Department of Pediatrics Washington University School of Medicine St Louis MO 63110 USA
Department of Pharmacology Yale University School of Medicine New Haven CT 06520 USA
Division of Medical Genetics Nemours A 1 duPont Hospital for Children Wilmington DE 19803 USA
Division of Neurology Children's Hospital of Eastern Ontario Ottawa ON K1H 8L1 Canada
Division of Neuropsychiatry Epilepsy Center for Children Martini Hospital Turin 10128 Italy
Genetics and Rare Diseases Research Division Ospedale Pediatrico Bambino Gesù IRCCS Rome 00146 Italy
Hopital Universitaire Necker Enfants Malades APHP Paris 75015 France
Montréal Neurological Institute and Hospital McGill University Montreal QC H3A 2B4 Canada
Section for Pediatrics Department of Clinical Sciences Lund University Lund 22184 Sweden
South West Thames Regional Genetics Service St George's Healthcare NHS Trust London SW17 0QT UK
Undiagnosed Diseases Program National Institutes of Health Bethesda MD 20892 2152 USA
Vascular Biology and Therapeutics Program Yale University School of Medicine New Haven CT 06520 USA
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- $a De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus / $c S. Galosi, BH. Edani, S. Martinelli, H. Hansikova, EA. Eklund, C. Caputi, L. Masuelli, N. Corsten-Janssen, M. Srour, R. Oegema, DGM. Bosch, CA. Ellis, L. Amlie-Wolf, A. Accogli, I. Atallah, L. Averdunk, KW. Barañano, R. Bei, I. Bagnasco, A. Brusco, S. Demarest, AS. Alaix, C. Di Bonaventura, F. Distelmaier, F. Elmslie, Z. Gan-Or, JM. Good, K. Gripp, EJ. Kamsteeg, E. Macnamara, C. Marcelis, N. Mercier, J. Peeden, S. Pizzi, L. Pannone, M. Shinawi, C. Toro, NE. Verbeek, S. Venkateswaran, PG. Wheeler, L. Zdrazilova, R. Zhang, G. Zorzi, R. Guerrini, WC. Sessa, DJ. Lefeber, M. Tartaglia, FF. Hamdan, KA. Grabińska, V. Leuzzi
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- $a 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 fibres 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.
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