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

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Abstract

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. 1H-spectroscopy primarily showed N-acetyl-aspartate reduction; 18fluorodeoxyglucose-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.

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Availability of data and materials

All data relevant to the study are included in the article or uploaded as supplementary information. Further data, including additional brain magnetic resonance images and the variant calling files (VCFs), will be shared in anonymized form by request to the corresponding author from any qualified investigator.

Code availability

Not applicable.

References

  1. Hanson FM, Hodgson RE, de Oliveira MIR et al (2022) Regulation and function of elF2B in neurological and metabolic disorders. Biosci Rep 42:BSR20211699. https://doi.org/10.1042/BSR20211699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. van der Knaap MS, Scheper GC (2011) Not all cystic leukoencephalopathies are “vanishing white matter.” Mol Genet Metab 103:413. https://doi.org/10.1016/j.ymgme.2011.04.011. (author reply 414)

    Article  CAS  PubMed  Google Scholar 

  3. van der Knaap MS, Pronk JC, Scheper GC (2006) Vanishing white matter disease. Lancet Neurol 5:413–423. https://doi.org/10.1016/S1474-4422(06)70440-9

    Article  PubMed  Google Scholar 

  4. Prass K, Brück W, Schröder NW et al (2001) Adult-onset Leukoencephalopathy with vanishing white matter presenting with dementia. Ann Neurol 50:665–668. https://doi.org/10.1002/ana.1259

    Article  CAS  PubMed  Google Scholar 

  5. Biancheri R, Rossi A, Di Rocco M et al (2003) Leukoencephalopathy with vanishing white matter: an adult onset case. Neurology 61:1818–1819. https://doi.org/10.1212/01.wnl.0000098994.35677.3c

    Article  CAS  PubMed  Google Scholar 

  6. Ohtake H, Shimohata T, Terajima K et al (2004) Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5. Neurology 62:1601–1603. https://doi.org/10.1212/01.wnl.0000123117.11264.0e

    Article  CAS  PubMed  Google Scholar 

  7. van der Knaap MS, Leegwater PAJ, van Berkel CGM et al (2004) Arg113His mutation in eIF2Bepsilon as cause of leukoencephalopathy in adults. Neurology 62:1598–1600. https://doi.org/10.1212/01.wnl.0000123118.86746.fc

    Article  PubMed  Google Scholar 

  8. Labauge P, Horzinski L, Ayrignac X et al (2009) Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases. Brain 132:2161–2169. https://doi.org/10.1093/brain/awp171

    Article  PubMed  Google Scholar 

  9. Ghezzi L, Scarpini E, Rango M et al (2012) A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation. Neurology 79:2077–2078. https://doi.org/10.1212/WNL.0b013e3182749edc

    Article  PubMed  Google Scholar 

  10. La Piana R, Vanderver A, van der Knaap M et al (2012) Adult-onset vanishing white matter disease due to a novel EIF2B3 mutation. Arch Neurol 69:765–768. https://doi.org/10.1001/archneurol.2011.1942

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hamilton EMC, van der Lei HDW, Vermeulen G et al (2018) Natural history of vanishing white matter. Ann Neurol 84:274–288. https://doi.org/10.1002/ana.25287

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ren Y, Yu X, Chen B et al (2022) Genotypic and phenotypic characteristics of juvenile/adult onset vanishing white matter: a series of 14 Chinese patients. Neurol Sci 43:4961–4977. https://doi.org/10.1007/s10072-022-06011-0

    Article  PubMed  Google Scholar 

  13. Tomás J, Gouveia A, Galego O et al (2015) Vanishing white matter disease: clinical and imaging description of seven adult patients. Sinapse 15:13

    Google Scholar 

  14. Di Bella D, Magri S, Benzoni C et al (2021) Hypomyelinating leukodystrophies in adults: clinical and genetic features. Eur J Neurol 28:934–944. https://doi.org/10.1111/ene.14646

    Article  PubMed  Google Scholar 

  15. Synofzik M, Smets K, Mallaret M et al (2016) SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study. Brain 139:1378–1393. https://doi.org/10.1093/brain/aww079

    Article  PubMed  PubMed Central  Google Scholar 

  16. Klambauer G, Schwarzbauer K, Mayr A et al (2012) cn.MOPS: mixture of Poissons for discovering copy number variations in next-generation sequencing data with a low false discovery rate. Nucleic Acids Res 40:e69. https://doi.org/10.1093/nar/gks003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  18. Shimada S, Miya K, Oda N et al (2012) An unmasked mutation of EIF2B2 due to submicroscopic deletion of 14q24.3 in a patient with vanishing white matter disease. Am J Med Genet A 158A:1771–1777. https://doi.org/10.1002/ajmg.a.35431

    Article  CAS  PubMed  Google Scholar 

  19. Ramaswamy V, Chan AK, Kolski HK (2006) Vanishing white matter disease with periodic (paroxysmal) hemiparesis. Pediatr Neurol 35:65–68. https://doi.org/10.1016/j.pediatrneurol.2005.12.014

    Article  PubMed  Google Scholar 

  20. Trevisan L, Grazzini M, Cianflone A et al (2021) An eleven-year history of Vanishing White Matter Disease in an adult patient with no cognitive decline and EIF2B5 mutations. A case report. Neurocase 27:452–456. https://doi.org/10.1080/13554794.2021.1999984

    Article  PubMed  Google Scholar 

  21. Mochel F, Schiffmann R, Steenweg ME et al (2012) Adult polyglucosan body disease: natural history and key magnetic resonance imaging findings. Ann Neurol 72:433–441. https://doi.org/10.1002/ana.23598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Finnsson J, Sundblom J, Dahl N et al (2015) LMNB1-related autosomal-dominant leukodystrophy: clinical and radiological course. Ann Neurol 78:412–425. https://doi.org/10.1002/ana.24452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rouaud T, Labauge P, Tournier Lasserve E et al (2010) Acute urinary retention due to a novel collagen COL4A1 mutation. Neurology 75:747–749. https://doi.org/10.1212/WNL.0b013e3181eee440

    Article  CAS  PubMed  Google Scholar 

  24. Potic A, Popovic V, Ostojic J et al (2015) Neurogenic bladder and neuroendocrine abnormalities in Pol III-related leukodystrophy. BMC Neurol 15:22. https://doi.org/10.1186/s12883-015-0283-7

    Article  PubMed  PubMed Central  Google Scholar 

  25. Nakamura M, Ueki S, Kubo M et al (2018) Two cases of sporadic adult-onset neuronal intranuclear inclusion disease preceded by urinary disturbance for many years. J Neurol Sci 392:89–93. https://doi.org/10.1016/j.jns.2018.07.012

    Article  PubMed  Google Scholar 

  26. van der Lei HDW, van Berkel CGM, van Wieringen WN et al (2010) Genotype-phenotype correlation in vanishing white matter disease. Neurology 75:1555–1559. https://doi.org/10.1212/WNL.0b013e3181f962ae

    Article  PubMed  Google Scholar 

  27. Ayrignac X, Boutiere C, Carra-Dalliere C, Labauge P (2016) Posterior fossa involvement in the diagnosis of adult-onset inherited leukoencephalopathies. J Neurol 263:2361–2368. https://doi.org/10.1007/s00415-016-8131-2

    Article  CAS  PubMed  Google Scholar 

  28. Stellingwerff MD, Al-Saady ML, van de Brug T et al (2021) MRI natural history of the leukodystrophy vanishing white matter. Radiology 300:671–680. https://doi.org/10.1148/radiol.2021210110

    Article  PubMed  Google Scholar 

  29. Fogli A, Schiffmann R, Bertini E et al (2004) The effect of genotype on the natural history of eIF2B-related leukodystrophies. Neurology 62:1509–1517. https://doi.org/10.1212/01.wnl.0000123259.67815.db

    Article  CAS  PubMed  Google Scholar 

  30. Zhang H, Dai L, Chen N et al (2015) Fifteen novel EIF2B1–5 mutations identified in Chinese children with leukoencephalopathy with vanishing white matter and a long term follow-up. PLoS ONE 10:e0118001. https://doi.org/10.1371/journal.pone.0118001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. van der Lei HDW, Steenweg ME, Bugiani M et al (2012) Restricted diffusion in vanishing white matter. Arch Neurol 69:723–727. https://doi.org/10.1001/archneurol.2011.1658

    Article  PubMed  Google Scholar 

  32. Fornasa F (2011) Diffusion-weighted magnetic resonance imaging: what makes water run fast or slow? J Clin Imaging Sci 1:27. https://doi.org/10.4103/2156-7514.81294

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bonomini F, Rezzani R (2010) Aquaporin and blood brain barrier. Curr Neuropharmacol 8:92–96. https://doi.org/10.2174/157015910791233132

    Article  CAS  PubMed  Google Scholar 

  34. Marom L, Ulitsky I, Cabilly Y et al (2011) A point mutation in translation initiation factor eIF2B leads to function- and time-specific changes in brain gene expression. PLoS ONE 6:e26992. https://doi.org/10.1371/journal.pone.0026992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Leferink PS, Dooves S, Hillen AEJ et al (2019) Astrocyte subtype vulnerability in stem cell models of vanishing white matter. Ann Neurol 86:780–792. https://doi.org/10.1002/ana.25585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Salsano E, Marotta G, Manfredi V et al (2014) Brain fluorodeoxyglucose PET in adrenoleukodystrophy. Neurology 83:981–989. https://doi.org/10.1212/WNL.0000000000000770

    Article  CAS  PubMed  Google Scholar 

  37. Finnsson J, Lubberink M, Savitcheva I et al (2019) Glucose metabolism in the brain in LMNB1-related autosomal dominant leukodystrophy. Acta Neurol Scand 139:135–142. https://doi.org/10.1111/ane.13024

    Article  CAS  PubMed  Google Scholar 

  38. van der Knaap MS, Valk J (2005) Leukoencephalopathy with vanishing white matter. Magnetic resonance of myelination and myelin disorders. Springer, Berlin, pp 481–495

    Chapter  Google Scholar 

  39. Dooves S, Bugiani M, Postma NL et al (2016) Astrocytes are central in the pathomechanisms of vanishing white matter. J Clin Invest 126:1512–1524. https://doi.org/10.1172/JCI83908

    Article  PubMed  PubMed Central  Google Scholar 

  40. van der Knaap MS, Bugiani M (2017) Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol 134:351–382. https://doi.org/10.1007/s00401-017-1739-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Audo I, Robson AG, Holder GE, Moore AT (2008) The negative ERG: clinical phenotypes and disease mechanisms of inner retinal dysfunction. Surv Ophthalmol 53:16–40. https://doi.org/10.1016/j.survophthal.2007.10.010

    Article  PubMed  Google Scholar 

  42. Imam I, Brown J, Lee P et al (2011) Ovarioleukodystrophy: report of a case with the c.338G>A (p.Arg113His) mutation on exon 3 and the c.896G>A (p.Arg299His) mutation on exon 7 of the EIF2B5 gene. BMJ Case Rep 2011:bcr1120103552. https://doi.org/10.1136/bcr.11.2010.3552

    Article  PubMed  PubMed Central  Google Scholar 

  43. Fogli A, Schiffmann R, Hugendubler L et al (2004) Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. Eur J Hum Genet 12:561–566. https://doi.org/10.1038/sj.ejhg.5201189

    Article  CAS  PubMed  Google Scholar 

  44. Mazziotta JC, Phelps ME, Carson RE, Kuhl DE (1982) Tomographic mapping of human cerebral metabolism: sensory deprivation. Ann Neurol 12:435–444. https://doi.org/10.1002/ana.410120505

    Article  CAS  PubMed  Google Scholar 

  45. Spetsieris PG, Moeller JR, Dhawan V et al (1995) Visualizing the evolution of abnormal metabolic networks in the brain using PET. Comput Med Imaging Graph 19:295–306. https://doi.org/10.1016/0895-6111(95)00011-e

    Article  CAS  PubMed  Google Scholar 

  46. McCulloch DL, Marmor MF, Brigell MG et al (2015) ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol 130:1–12. https://doi.org/10.1007/s10633-014-9473-7

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank Seren Hawksworth for help with English.

Funding

The study was funded by the Italian Ministry of Health (Grants RF-2018-12367768 and Progetto Rete IDEA “BIaNCA” to F.T., GR-2016-02363337 to S.M., RF-2016-02361285 to C.G., “Ricerca Corrente” to E.S.) and Fondazione Regionale per la Ricerca Biomedica (FRRB grant Care4NeuroRare CP_20/2018 to F.T.).

Author information

Author notes

  1. Chiara Benzoni, Marco Moscatelli, Daniela Di Bella and Ettore Salsano contributed equally to the manuscript.

Authors and Affiliations

  1. Unit of Rare Neurological Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy

    Chiara Benzoni, Davide Pareyson & Ettore Salsano

  2. Unit of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Marco Moscatelli

  3. Neuroimaging Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy

    Laura Farina

  4. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Stefania Magri, Cinzia Gellera, Franco Taroni & Daniela Di Bella

  5. Unit of Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Claudia Ciano, Vidmer Scaioli & Sara Alverà

  6. Neuro-Ophthalmology Center and Ocular Electrophysiology Laboratory, Istituto Auxologico Italiano IRCCS Capitanio Hospital, Milan, Italy

    Gabriella Cammarata & Stefania Bianchi-Marzoli

  7. Department of Nuclear Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    Massimo Castellani, Felicia Margherita Zito & Giorgio Marotta

  8. Unit of Neuropsychology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Sylvie Piacentini

  9. ULSS6 Euganea Camposampiero, Padua, Italy

    Alberto Villacara

  10. Unit of Neuromuscular Diseases and Neuroimmunology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Renato Mantegazza

  11. Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

    João Durães, Ana Gouveia, Anabela Matos & Maria do Carmo Macário

Authors
  1. Chiara Benzoni
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  2. Marco Moscatelli
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  3. Laura Farina
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  4. Stefania Magri
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  5. Claudia Ciano
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  6. Vidmer Scaioli
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  7. Sara Alverà
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  8. Gabriella Cammarata
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  9. Stefania Bianchi-Marzoli
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  24. Ettore Salsano
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Contributions

Conceptualization MdCM, ES; methodology: DDB, ES; formal analysis and investigation: CB, MM, LF, SM, CC, VS, SA, GC, SBM, MC, FMZ, GM, SP, AV, RM, JD, AG, AM, DP, DDB, ES; writing—original draft preparation: CB, MM, LF, SM, CC, VS, GC, SBM, SP, AG, DDB, ES; writing—review and editing: CB, MM, LF, RM, CG, JD, AM, MdCM, DP, FT, DDB, ES; funding acquisition: CG, FT; resources: AV, RM, CG, JD, AG, AM, FT; supervision: MdCM, DDB, ES.

Corresponding author

Correspondence to Ettore Salsano.

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There are no competing financial or non-financial interests to report.

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The authors confirm to have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines; the study is in accordance with the ethical standards of our institution and with the 1964 Helsinki Declaration and its later amendments.

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Written informed consent to the submission of the case reports to the journal was obtained from the patients.

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Benzoni, C., Moscatelli, M., Farina, L. et al. Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients. J Neurol 270, 4219–4234 (2023). https://doi.org/10.1007/s00415-023-11762-7

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  • DOI: https://doi.org/10.1007/s00415-023-11762-7

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