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. 2021 Mar;28(3):934-944.
doi: 10.1111/ene.14646. Epub 2020 Dec 3.

Hypomyelinating leukodystrophies in adults: Clinical and genetic features

Daniela Di Bella  1 , Stefania Magri  1 , Chiara Benzoni  2 , Laura Farina  3   4 , Carmelo Maccagnano  3 , Elisa Sarto  1 , Marco Moscatelli  3 , Silvia Baratta  1 , Claudia Ciano  5 , Sylvie H M J Piacentini  6 , Lara Draghi  6 , Elena Mauro  2 , Davide Pareyson  2 , Cinzia Gellera  1 , Franco Taroni  1 , Ettore Salsano  2   7
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Hypomyelinating leukodystrophies in adults: Clinical and genetic features

Daniela Di Bella et al. Eur J Neurol. 2021 Mar.

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.

Keywords: genetic leukoencephalopathies; hypomyelination; leukodystrophies; peroxisome biogenesis disorders; spastic paraplegias.

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REFERENCES

    1. van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol. 2017;134(3):351-382. https://doi.org/10.1007/s00401-017-1739-1
    1. van der Knaap MS, Schiffmann R, Mochel F, Wolf NI. Diagnosis, prognosis, and treatment of leukodystrophies. Lancet Neurol. 2019;18(10):962-972. https://doi.org/10.1016/S1474-4422(19)30143-7
    1. Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009;72(8):750-759. https://doi.org/10.1212/01.wnl.0000343049.00540.c8
    1. Lynch DS, Wade C, Paiva ARBd, et al. Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era. J Neurol Neurosurg Psychiatry. 2019;90(5):543-554. https://doi.org/10.1136/jnnp-2018-319481
    1. Barkovich AJ, Kjos BO, Jackson DE, Norman D. Normal maturation of the neonatal and infant brain: MR imaging at 1.5 T. Radiology. 1988;166(1 Pt 1):173-180. https://doi.org/10.1148/radiology.166.1.3336675

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