Hypomyelinating leukodystrophies in adults: Clinical and genetic features
Daniela Di Bella
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Data curation (lead), Formal analysis (lead), Investigation (lead), Writing - original draft (equal), Writing - review & editing (supporting)
Search for more papers by this authorStefania Magri
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Data curation (lead), Formal analysis (lead), Funding acquisition (supporting), Investigation (lead), Writing - original draft (equal), Writing - review & editing (supporting)
Search for more papers by this authorChiara Benzoni
Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (lead), Writing - original draft (equal), Writing - review & editing (supporting)
Search for more papers by this authorLaura Farina
Unit of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Neuroimaging Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy
Contribution: Data curation (equal), Formal analysis (lead), Investigation (equal), Writing - original draft (supporting), Writing - review & editing (equal)
Search for more papers by this authorCarmelo Maccagnano
Unit of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting)
Search for more papers by this authorElisa Sarto
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting)
Search for more papers by this authorMarco Moscatelli
Unit of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Data curation (supporting), Formal analysis (supporting), Investigation (supporting)
Search for more papers by this authorSilvia Baratta
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting)
Search for more papers by this authorClaudia Ciano
Unit of Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting), Writing - original draft (supporting)
Search for more papers by this authorSylvie H. M. J. Piacentini
Unit of Neuropsychology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting), Writing - original draft (supporting)
Search for more papers by this authorLara Draghi
Unit of Neuropsychology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting)
Search for more papers by this authorElena Mauro
Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Investigation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorDavide Pareyson
Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (equal), Investigation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorCinzia Gellera
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Data curation (equal), Formal analysis (equal), Funding acquisition (equal), Investigation (equal), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Franco Taroni
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Correspondence
Franco Taroni, Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Amadeo 42, 20133 Milan, Italy.
Email: [email protected]
Ettore Salsano, Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy.
Email: [email protected].
Contribution: Conceptualization (equal), Data curation (lead), Formal analysis (lead), Funding acquisition (lead), Investigation (supporting), Writing - review & editing (lead)
Search for more papers by this authorCorresponding Author
Ettore Salsano
Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Neuroscience PhD Program, University of Milano-Bicocca, Monza, Italy
Correspondence
Franco Taroni, Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Amadeo 42, 20133 Milan, Italy.
Email: [email protected]
Ettore Salsano, Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy.
Email: [email protected].
Contribution: Conceptualization (lead), Data curation (supporting), Formal analysis (lead), Investigation (lead), Supervision (lead), Writing - original draft (lead)
Search for more papers by this authorDaniela Di Bella
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Data curation (lead), Formal analysis (lead), Investigation (lead), Writing - original draft (equal), Writing - review & editing (supporting)
Search for more papers by this authorStefania Magri
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Data curation (lead), Formal analysis (lead), Funding acquisition (supporting), Investigation (lead), Writing - original draft (equal), Writing - review & editing (supporting)
Search for more papers by this authorChiara Benzoni
Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (lead), Writing - original draft (equal), Writing - review & editing (supporting)
Search for more papers by this authorLaura Farina
Unit of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Neuroimaging Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy
Contribution: Data curation (equal), Formal analysis (lead), Investigation (equal), Writing - original draft (supporting), Writing - review & editing (equal)
Search for more papers by this authorCarmelo Maccagnano
Unit of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting)
Search for more papers by this authorElisa Sarto
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting)
Search for more papers by this authorMarco Moscatelli
Unit of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Data curation (supporting), Formal analysis (supporting), Investigation (supporting)
Search for more papers by this authorSilvia Baratta
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting)
Search for more papers by this authorClaudia Ciano
Unit of Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting), Writing - original draft (supporting)
Search for more papers by this authorSylvie H. M. J. Piacentini
Unit of Neuropsychology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting), Writing - original draft (supporting)
Search for more papers by this authorLara Draghi
Unit of Neuropsychology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (supporting), Investigation (supporting)
Search for more papers by this authorElena Mauro
Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Investigation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorDavide Pareyson
Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Formal analysis (equal), Investigation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorCinzia Gellera
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Contribution: Data curation (equal), Formal analysis (equal), Funding acquisition (equal), Investigation (equal), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Franco Taroni
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Correspondence
Franco Taroni, Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Amadeo 42, 20133 Milan, Italy.
Email: [email protected]
Ettore Salsano, Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy.
Email: [email protected].
Contribution: Conceptualization (equal), Data curation (lead), Formal analysis (lead), Funding acquisition (lead), Investigation (supporting), Writing - review & editing (lead)
Search for more papers by this authorCorresponding Author
Ettore Salsano
Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Neuroscience PhD Program, University of Milano-Bicocca, Monza, Italy
Correspondence
Franco Taroni, Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Amadeo 42, 20133 Milan, Italy.
Email: [email protected]
Ettore Salsano, Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy.
Email: [email protected].
Contribution: Conceptualization (lead), Data curation (supporting), Formal analysis (lead), Investigation (lead), Supervision (lead), Writing - original draft (lead)
Search for more papers by this authorSee editorial by F. Mochel on page 733.
Abstract
Background and purpose
Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood.
Methods
We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near-normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy-targeted next generation sequencing panel.
Results
We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early-onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early-onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early-onset diseases with central hypomyelination/dysmyelination.
Conclusions
A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease-causing genes, including genes associated with severe early-onset HLDs, and genes causing peroxisome biogenesis disorders.
CONFLICT OF INTEREST
There are no competing financial or non-financial interests to report.
Open Research
DATA AVAILABILITY STATEMENT
All data relevant to this study are contained within the manuscript. Further data, including the variant calling files (VCFs) and brain magnetic resonance images, will be shared in anonymized form by request to the corresponding authors, F.T. and E.S., from any qualified investigator.
Supporting Information
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Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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