De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus
(2022) In Brain : a journal of neurology 145(1). p.208-223- Abstract
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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Brain : a journal of neurology
- volume
- 145
- issue
- 1
- pages
- 208 - 223
- publisher
- Oxford University Press
- external identifiers
-
- pmid:34382076
- scopus:85127320320
- ISSN
- 1460-2156
- DOI
- 10.1093/brain/awab299
- language
- English
- LU publication?
- yes
- id
- b695c96e-8b0a-4897-b132-6d4ef5895781
- date added to LUP
- 2021-10-11 23:57:06
- date last changed
- 2024-05-14 02:35:12
@article{b695c96e-8b0a-4897-b132-6d4ef5895781,
abstract = {{<p>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.</p>}},
author = {{Galosi, Serena and Edani, Ban H and Martinelli, Simone and Hansikova, Hana and Eklund, Erik A and Caputi, Caterina and Masuelli, Laura and Corsten-Janssen, Nicole and Srour, Myriam and Oegema, Renske and Bosch, Daniëlle G M and Ellis, Colin A and Amlie-Wolf, Louise and Accogli, Andrea and Atallah, Isis and Averdunk, Luisa and Barañano, Kristin W and Bei, Roberto and Bagnasco, Irene and Brusco, Alfredo and Demarest, Scott and Alaix, Anne-Sophie and Di Bonaventura, Carlo and Distelmaier, Felix and Elmslie, Frances and Gan-Or, Ziv and Good, Jean-Marc and Gripp, Karen and Kamsteeg, Erik-Jan and Macnamara, Ellen and Marcelis, Carlo and Mercier, Noëlle and Peeden, Joseph and Pizzi, Simone and Pannone, Luca and Shinawi, Marwan and Toro, Camilo and Verbeek, Nienke E and Venkateswaran, Sunita and Wheeler, Patricia G and Zdrazilova, Lucie and Zhang, Rong and Zorzi, Giovanna and Guerrini, Renzo and Sessa, William C and Lefeber, Dirk and Tartaglia, Marco and Hamdan, Fadi F and Grabińska, Kariona A and Leuzzi, Vincenzo}},
issn = {{1460-2156}},
language = {{eng}},
number = {{1}},
pages = {{208--223}},
publisher = {{Oxford University Press}},
series = {{Brain : a journal of neurology}},
title = {{De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus}},
url = {{http://dx.doi.org/10.1093/brain/awab299}},
doi = {{10.1093/brain/awab299}},
volume = {{145}},
year = {{2022}},
}