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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....

. 2022 ; 145 (1) : 208-223. [pub] 20220329

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural

Persistent link   https://www.medvik.cz/link/bmc22019105

Grant support
R35 HL139945 NHLBI NIH HHS - United States
R01 DK125492 NIDDK NIH HHS - United States

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.

AOU Meyer Pediatric Neurology Neurogenetics and Neurobiology Unit and Laboratories Meyer Children's Hospital University of Florence Florence 50139 Italy

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 Clinical Sciences and Translational Medicine University of Rome 'Tor Vergata' Rome 00133 Italy

Department of Experimental Medicine Sapienza University Rome 00161 Italy

Department of General Pediatrics Neonatology and Pediatric Cardiology Medical Faculty and University Hospital Düsseldorf Heinrich Heine University Düsseldorf 40225 Germany

Department of Genetics University Medical Center Utrecht Utrecht 3584 CX The Netherlands

Department of Genetics University of Groningen University Medical Center Groningen Groningen 9700 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 Medical Sciences University of Torino and Medical Genetics Unit Città della Salute e della Scienza University Hospital Turin 10126 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 Translational Metabolic Laboratory Donders Institute for Brain Cognition and Behavior Radboud University Medical Centre Nijmegen 6525 AJ The Netherlands

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 Pediatric Neurology IRCCS Foundation Carlo Besta Neurological Institute Milan 20133 Italy

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Prague 12808 Czech Republic

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 Genetic Medicine Lausanne University Hospital and University of Lausanne Lausanne 1011 Switzerland

Division of Medical Genetics Department of Pediatrics CHU Sainte Justine and University of Montreal Montreal QC H3T1C5 Canada

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

East Tennessee Children's Hospital University of Tennessee Department of Medicine Knoxville TN 37916 USA

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

Service d'Epileptologie et Médecine du handicap Hôpital Neurologique Institution de Lavigny Lavigny 1175 Switzerland

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

References provided by Crossref.org

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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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