Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients

Background Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. Methods In this observational study, we reviewed clinical and laboratory information of the...

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Bibliographic Details
Published in:	Journal of neurology Vol. 270; no. 9; pp. 4219 - 4234
Main Authors:	Benzoni, Chiara, Moscatelli, Marco, Farina, Laura, Magri, Stefania, Ciano, Claudia, Scaioli, Vidmer, Alverà, Sara, Cammarata, Gabriella, Bianchi-Marzoli, Stefania, Castellani, Massimo, Zito, Felicia Margherita, Marotta, Giorgio, Piacentini, Sylvie, Villacara, Alberto, Mantegazza, Renato, Gellera, Cinzia, Durães, João, Gouveia, Ana, Matos, Anabela, do Carmo Macário, Maria, Pareyson, Davide, Taroni, Franco, Di Bella, Daniela, Salsano, Ettore
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2023 Springer Nature B.V
Subjects:	Adolescent Adult Cognitive ability Demyelinating Diseases Eukaryotic Initiation Factor-2B - genetics Female Humans Leukodystrophy Leukoencephalopathies - diagnostic imaging Leukoencephalopathies - genetics Lysosomal Storage Diseases Magnetic Resonance Imaging Male Medicine Medicine & Public Health Middle Aged Mutation Mutation - genetics Myelin Neurodegenerative Diseases Neuroimaging Neurology Neuroradiology Neurosciences Observational Studies as Topic Original Communication Patients Pediatrics Phenotypes Positron emission tomography Spectroscopy Spectrum analysis Stroke Substantia alba White Matter - diagnostic imaging Young Adult Leukodystrophies Stroke MRI Genetic leukoencephalopathies PET
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Summary:	Background Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. Methods In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019. Results We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1 H-spectroscopy primarily showed N -acetyl-aspartate reduction; 18 fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2 . Conclusions AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	0340-5354 1432-1459
DOI:	10.1007/s00415-023-11762-7