University of Oulu

Stellingwerff, M. D., Figuccia, S., Bellacchio, E., Alvarez, K., Castiglioni, C., Topaloglu, P., Stutterd, C. A., Erasmus, C. E., Sanchez‐Valle, A., Lebon, S., Hughes, S., Schmitt-Mechelke, T., Vasco, G., Chow, G., Rahikkala, E., Dallabona, C., Okuma, C., Aiello, C., Goffrini, P., … Van der Knaap, M. S. (2021). LBSL. Neurology Genetics, 7(2), e559.

LBSL case series and DARS2 variant analysis in early severe forms with unexpected presentations

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Author: Stellingwerff, Menno D.1; Figuccia, Sonia2; Bellacchio, Emanuele3;
Organizations: 1Department of Child Neurology, Emma Childrens Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience, The Netherlands
2Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Italy
3Area di Ricerca Genetica e Malattie Rare
4Ospedale Pediatrico Bambino Gesu, IRCCS, Rome, Italy; Laboratory of Oncology and Molecular Genetics
5Clınica las Condes, Santiago, Chile; Department of Pediatric Neurology
6Clınica Las Condes, Santiago, Chile; Division of Child Neurology
7Department of Neurology, Istanbul Faculty of Medicine, Turkey; Department of Paediatrics
8Royal Childrens Hospital, Murdoch Childrens Research Institute and University of Melbourne, Victoria, Australia; Pediatric Neurology
9Radboud University Medical Center, Amalia Childrens Hospital, Nijmegen, The Netherlands; Department of Pediatrics
10University of South Florida, Tampa; Unit of Pediatric Neurology and Neurorehabilitation
11Department WomanMother-Child, Lausanne University Hospital, Switzerland; Community Pediatrics, Royal Berkshire Hospital, Reading, United Kingdom
12Neuropediatric Department, Childrens Hospital, Luzern, Switzerland
13Unit of Neurorehabilitation, Department of Neurosciences, Bambino Gesu Children’s Research Hospital, IRCCS, Rome, Italy
14Paediatric Neurology, Nottingham Childrens Hospital, United Kingdom
15PEDEGO Research Unit, Medical Research Center and Department of Clinical Genetics, University of Oulu and Oulu University Hospital, Finland
16Radiology, Clınica las Condes, Santiago, Chile
17Unit of Neuromuscular and Neurodegenerative Disorders, Area di Ricerca Genetica e Malattie Rare and Department of Neurosciences, Bambino Gesu Children’s Research Hospital, IRCCS, Rome, Italy
18Department of Child Neurology, Emma Childrens Hospital and Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
Persistent link:
Language: English
Published: Wolters Kluwer, 2021
Publish Date: 2021-08-26


Objective: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes.

Methods: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants’ impact on mtAspRS structure and mitochondrial function.

Results: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-59-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function.

Conclusions: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.

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Series: Neurology. Genetics
ISSN: 2376-7839
ISSN-E: 2376-7839
ISSN-L: 2376-7839
Volume: 7
Issue: 2
Article number: e559
DOI: 10.1212/NXG.0000000000000559
Type of Publication: A1 Journal article – refereed
Field of Science: 3124 Neurology and psychiatry
3111 Biomedicine
Funding: This study was supported in part by a grant from Ricerca Corrente of the Italian Ministry of Health to ESB and grant RF-2016-02361241 from the Italian Ministry of Health to PG and ESB. The study has benefited from the equipment and framework of the COMP-HUB Initiative, funded by the Departments of Excellence program of the Italian Ministry for Education, University and Research (MIUR, 2018–2022). CAS was supported by the RCH/MCRI Flora Suttie Neurogenetics Fellowship made possible by the Macquarie and Thyne-Reid Foundations.
Copyright information: Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.