Modern views of brainstem and spinal cord leukoencephalopathy with increased lactate content
https://doi.org/10.25207/1608-6228-2020-27-4-149-160
Abstract
The review considers modern evidence on a rare genetic disease, leukoencephalopathy of brainstem and spinal cord associated with elevated lactate content. The research history of the disease is described. The epidemiology of the disease prevalence in a population is described. Emphasis is placed on aetiology of leukoencephalopathy and peculiar genetic and pathomorphological changes associated with a DARS2 gene mutation leading to mitochondrial aspartyl-tRNA synthetase deficiency. The review details the clinical picture, manifestations specific in various age groups and identifies diseases with similar clinical symptoms and morbid changes that require differential diagnosis. Modern relevant diagnostic approaches are outlined based primarily on neuroimaging techniques. The major neuroimaging approach to leukoencephalopathy is magnetic resonance imaging that allows detection of disease-specific lesion patterns in the brainstem and spinal cord. Magnetic resonance spectrometry is used in turn to detect a usually higher lactate content in the affected white matter of the brain. Definitive diagnosis is based on detection of the marker DARS2 mutation in patients with characteristic clinical picture and MRI signatures in the brain and spinal cord. The review describes contemporary treatment strategies utilising pathogenetic effects to potentially contain the disease. However, its genetic determination renders symptomatic therapy yet a common treatment.
About the Authors
A. Yu. Ryabchenko
Orenburg State Medical University
Russian Federation
Russian Federation
Aleksandr Yu. Ryabchenko — Cand. Sci. (Med.), Assoc. Prof., Chair of Neurology and Medical Genetics
Sovetskaya str., 6, Orenburg, 460000
tel.: +7 (912) 849-78-66
A. E. Gubina
Orenburg State Medical University
Russian Federation
Russian Federation
Anastasia Е. Gubina — Clinical Resident, Chair of Clinical Medicine
Sovetskaya str., 6, Orenburg, 460000
References
1. Werner R., Daum E., Felber S., Wöhrle J.C. Leukoencephalopathy with brain stem and spinal cord involvement and not always lactate elevation. Clin. Neuroradiol. 2018; 28(3): 451–453. DOI: 10.1007/s00062-017-0647-z
2. van Berge L., Hamilton E.M., Linnankivi T., Uziel G., Steenweg M.E., Isohanni P., et al., LBSL Research Group. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy. Brain. 2014; 137(Pt 4): 1019–1029. DOI: 10.1093/brain/awu026
3. Wong L.С. Mitochondrial syndromes with leukoencephalopathies. Semin. Neurol. 2012; 32(1): 55–61. DOI: 10.1055/s-0032-1306387
4. Ardissone A., Tonduti D., Legati A., Lamantea E., Barone R., Dorboz I., et al. KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature. Orphanet. J. Rare. Dis. 2018;13(1):45. DOI: 10.1186/s13023-018-0788-4
5. Lebre A.S., Rio M., Faivre d’Arcier L., Vernerey D., Landrieu P., Slama A., et al. A common pattern of brain MRI imaging in mitochondrial diseases with complex I deficiency. J. Med. Genet. 2011;48(1):16–23. DOI: 10.1136/jmg.2010.079624
6. Finsterer J., Zarrouk-Mahjoub S. Involvement of the spinal cord in mitochondrial disorders. J. Neurosci. Rural. Pract. 2018; 9(2): 245–251. DOI: 10.4103/jnrp.jnrp_446_17
7. Yelam A., Nagarajan E., Chuquilin M., Govindarajan R. Leucoencephalopathy with brain stem and spinal cord involvement and lactate elevation: a novel mutation in the DARS2 gene. BMJ Case Rep. 2019; 12(1): bcr2018–227755. DOI: 10.1136/bcr-2018-227755
8. Sissler M., González-Serrano L.E., Westhof E. Recent Advances in Mitochondrial Aminoacyl-tRNASynthetases and Disease. Trends. Mol. Med. 2017; 23(8): 693–708. DOI: 10.1016/j.molmed.2017.06.002
9. Zhang J., Liu M., Zhou L., Zhang Z.B., Wang J.M., Jiang Y.W., Wu Y. DARS mutations responsible for hypomyelination with brain stem and spinal cord involvement and leg spasticity: report of two cases and review of literature. Zhonghua. Er. Ke. Za. Zhi. 2018; 56(3): 211–215. DOI: 10.3760/cma.j.issn.0578-1310.2018.03.011
10. van Berge L., Dooves S., van Berkel C.G.M., Polder E., van der Knaap M.S., Scheper G.C. Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA. Biochem. J. 2012; 441(3): 955–962. DOI: 10.1042/BJ20110795
11. Synofzik M., Schicks J., Lindig T., Biskup S., Schmidt T., Hansel J., et al. Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation. J. Med. Genet. 2011; 48(10): 713–715. DOI: 10.1136/jmg.2011.090282
12. Nikolayeva E.A., Kozina A.A., Yablonskaya M.I., Kharabadze M.N., Mamedov I.S., Zolkina I.V., Novikov P.V. Leukoencephalopathy with predominant brainstem and spinal cord involvement and lactate elevation. Rossiiskii Vestnik Perinatologiii Pediatrii. 2013; 58(5): 54–58 (In Russ., English abstract).
13. Lan M.Y., Chang Y.Y., Yeh T.H., Lin T.K., Lu C.S. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) with a novel DARS2 mutation and isolated progressive spastic paraparesis. J. Neurol. Sci. 2017; 372: 229–231. DOI: 10.1016/j.jns.2016.11.058
14. van Berge L., Doovestephanie S., van Berkel C.G.M., Polder E., van der Knaap M.S., Scheper G.C. Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA. Biochem. J. 2012; 441(3): 955–962. DOI: 10.1042/BJ20110795
15. Kassem H., Wafaie A., Abdelfattah S., Farid T. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL): assessment of the involved white matter tracts by MRI. Eur. J. Radiol. 2014;83(1):191–196. DOI: 10.1016/j.ejrad.2013.09.023
16. Shimojima K., Higashiguchi T., Kishimoto K., Miyatake S., Miyake N., Takanashi J.I., et al. A Novel DARS2 mutation in a japanese patient with leukoencephalopathy with brainstem and spinal cord involvement but no lactate elevation. Hum. Genome. Var. 2017; 4: 17051. DOI: 10.1038/hgv.2017.51
17. Steenweg M.E., Ghezzi D., Haack T., Abbink T.E.M., Martinelli D., van Berkel C.G.M., et al. Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘LTBL’ caused by EARS2 mutations. Brain. 2012;135(Pt 5): 1387–1394. DOI: 10.1093/brain/aws070
18. Moore S.A., Kumar N., Gavrilova R.H. Leukoencephalopathy with brain stem and spinal cord involvement (and high lactate): raising the bar for diagnosis. J. Neurol. 2012; 259(11): 2494–2497. DOI: 10.1007/s00415-012-6596-1
19. Çavuşoğlu D., Olgaç-Dündar N., Öztekin Ö., Özdemir T.R., Arıcan P., Gençpınar P. The first pediatric case of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) from Turkey.Turk. J. Pediatr. 2018; 60(2): 216–220x. DOI: 10.24953/turkjped.2018.02.018
20. Yahia A., Elsayed L., Babai A., Salih M.A., ElSadig S.M., Amin M., et al. Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report. BMC Neurol. 2018; 18(1): 175. DOI: 10.1186/s12883-0181180-7
21. Yamashita S., Miyake N., Matsumoto N., Osaka H., Iai M., Aida N., Tanaka Y. Neuropathology of leukoencephalopathy with brainstem and spinal cord involvement and high lactate caused by a homozygous mutation of DARS2. Brain. Dev. 2013; 35(4): 312–316. DOI: 10.1016/j.braindev.2012.05.00
22. Mierzewska H., van der Knaap M.S., Scheper G.C., Bekiesinska-Figatowska M., Szczepanik E., Jurkiewicz E. Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation in the first Polish patient. Brain. Dev. 2011; 33(9): 713–717. DOI: 10.1016/j.braindev.2010.12.00
23. Kolesnikova Y.P., Kuzenkova L.M., Savostyanov K.V., Globa O.V., Podkletnova T.V. Clinical Cases of Leukoencephalopathy with Predominant Lesion of the Brain Stem, Spinal Cord and High Blood Lactate in the MR Spectroscopy (Mitochondrial Aspartyl-tRNASynthetase Deficiency). Current Pediatrics. 2015; 14(6): 724–731 (In Russ., English abstract). DOI: 10.15690/vsp.v14i6.1483
24. Moore D.R., Areta J., Coffey V.G., Stellingwerff T., Phillips S.M., Burke L.M., et al. Daytime pattern of post-exercise protein intake affects whole-body protein turnover in resistance-trained males. Nutr. Metab. (Lond.). 2012; 9(1): 91. DOI: 10.1186/1743-7075-9-91
25. Steenweg M.E., van Berge L., van Berkel C.G., de Coo I.F., Temple I.K., Brockmann K., et al. Early-onset LBSL: how severe does it get? Neuropediatrics. 2012; 43(6): 332–338. DOI: 10.1055/s-0032-1329395
26. Finsterer J., Zarrouk-Mahjoub S. Involvement of the Spinal Cord in Mitochondrial Disorders. J. Neurosci. Rural. Pract. 2018; 9(2): 245–251. DOI: 10.4103/jnrp.jnrp_446_17
27. Tzoulis C., Tran G.T., Coxhead J., Bertelsen B., Lilleng P.K., Balafkan N., et al. Molecular pathogenesis of polymerase γ-related neurodegeneration. Ann. Neurol. 2014; 76(1): 66–81. DOI: 10.1002/ana.24185
28. van der Knaap M.S., Hamilton E.M., van Berge L. Reply: DARS2 gene clinical spectrum: new ideas regarding an underdiagnosed leukoencephalopathy. Brain. 2014; 137(Pt 7): e290. DOI: 10.1093/brain/awu135
29. Labauge P., Dorboz I., Eymard-Pierre E., Dereeper O., Boespflug-Tanguy O. Clinically asymptomatic adult patient with extensive LBSL MRI pattern and DARS2 mutations. J. Neurol. 2011; 258: 335–337. DOI: 10.1007/s00415-010-5755-5
30. Cheng F.B., Shen P.P., Zhou H.W., Meng H.M., Yang Y., Feng J.C. Adult-onset leukoencephalopathy with brain stem and spinal cord involvement in Chinese Han population: a case report and literature review. Neurol. India. 2013; 61(2): 161–163. DOI: 10.4103/0028-3886
31. Karpova M.I., Vasilenko A.F., Korotkova D.G., Kochetkov I.V., Shestakova M.V., Buyanova G.V., Zaripova Z.Z. Late-onset leukoencephalopathy with predominant damage to the brain stem, spinal cord and increased lactate (clinical observations). Neuromuscular Diseases. 2019; 9(3): 32–39 (In Russ., English abstract). DOI: 10.17650/2222-8721-2019-9-3-32-39
32. Taft R.J., Vanderver A., Leventer R.J., Damiani S.A., Simons C., Grimmond S.M., et al. Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. Am. J. Hum. Genet. 2013; 92(5): 774–780. DOI: 10.1016/j.ajhg.2013.04.006
33. Tylki-Szymanska A., Jurkiewicz E., Zakharova E.Y., Bobek-Billewicz B. Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation: high outcome variation between two siblings. Neuropediatrics. 2014; 45(3): 188–191. DOI: 10.1055/s-0033-1364105
34. Schicks J., Schöls L., Synofzik M., Van Der Knaap M.S. Teaching neuroimages: MRI guides genetics: Leucoencephalophaty with brainstem and spinal cord involvement. Neurology. 2013; 80 (16): 176–177. DOI: 10.1212/WNL.0b013e31828cf846.
35. Wolf N.I., Toro C., Kister I., Latif K.A., Leventer R., Pizzino A., et al. DARS-associated leukoencephalopathy can mimic a steroid-responsive neuroinflammatory disorder. Neurology. 2015; 84(3): 226–230. DOI: 10.1212/WNL.0000000000001157
36. Martikainen M.H., Ellfolk U., Majamaa K. Impaired information-processing speed and working memory in leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) and DARS2 mutations: a report of three adult patients. J. Neurol. 2013; 260(8): 2078–2083. DOI: 10.1007/s00415-0136940-0
Review
For citations:
Ryabchenko A.Yu., Gubina A.E. Modern views of brainstem and spinal cord leukoencephalopathy with increased lactate content. Kuban Scientific Medical Bulletin. 2020;27(4):149-160. (In Russ.) https://doi.org/10.25207/1608-6228-2020-27-4-149-160
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