Abstract
Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) is clinically characterized by progressive pyramidal and cerebellar dysfunction, dorsal column dysfunction and sometimes with axonal neuropathy. Magnetic resonance imaging of brain and the spinal cord reveals characteristic findings. LBSL is caused by mutations in the DARS2 gene that encodes the mitochondrial aspartyl-tRNA synthetase. The presentation and clinical course of LBSL is not uniform, and there is lack of longitudinal data on these patients. In addition, the existing data on the prevalence and characteristics of cognitive abnormalities in patients with LBSL are scarce and somewhat conflicting. Here we report long-term data of neurological and cognitive functioning in three non-related adult patients with LBSL. Cognitive impairment seems to be common among patients with LBSL and DARS2 mutations. The cognitive profile in LBSL shares similarities with that reported in multiple sclerosis, as information-processing speed and working memory are especially affected. In addition, our results and the previously reported carrier frequencies of common pathogenic DARS2 mutations suggest that LBSL may be underdiagnosed in the population.
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van der Knaap MS, van der Voorn P, Barkhof F, Van Coster R, Krägeloh-Mann I, Feigenbaum A, Blaser S, Vles JS, Rieckmann P, Pouwels PJ (2003) A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol 53:252–258
Serkov SV, Pronin IN, Bykova OV, Maslova OI, Arutyunov NV, Muravina TI, Kornienko VN, Fadeeva LM, Marks H, Bönnemann C, Schiffmann R, van der Knaap MS (2004) Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate. Neuropediatrics 35:1–5
Linnankivi T, Lundbom N, Autti T, Häkkinen AM, Koillinen H, Kuusi T, Lönnqvist T, Sainio K, Valanne L, Aärimaa T, Pihko H (2004) Five new cases of a recently described leukoencephalopathy with high brain lactate. Neurology 63:688–692
Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, Muravina TI, Serkov SV, Uziel G, Bugiani M, Schiffmann R, Krägeloh-Mann I, Smeitink JA, Florentz C, Van Coster R, Pronk JC, van der Knaap MS (2007) Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 39:534–539
Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081. doi:10.1038/nprot.2009.86
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. doi:10.1038/nmeth0410-248
Wechsler D (1999) WISC-III Käsikirja [Wechsler Intelligence Scale for Children-III, Finnish version], 3rd edn. Psykologien Kustannus Oy, Helsinki
Wechsler D (2005) WAIS-III Käsikirja [Wechsler Adult Intelligence Scale-III, Finnish version], 3rd edn. Psykologien Kustannus Oy, Helsinki
Wechsler D (2007) WMS-III Käsikirja [Wechsler Memory Scale-III, Finnish version], 3rd edn. Psykologien Kustannus Oy, Helsinki
Lezak MD, Howieson DB, Loring DW (2004) Neuropsychological assessment, 4th edn. Oxford University Press, New York, pp 265–374
Yamashita S, Miyake N, Matsumoto N, Osaka H, Iai M, Aida N, Tanaka Y (2013) Neuropathology of leukoencephalopathy with brainstem and spinal cord involvement and high lactate caused by a homozygous mutation of DARS2. Brain Dev 35:312–316
Isohanni P, Linnankivi T, Buzkova J, Lönnqvist T, Pihko H, Valanne L, Tienari PJ, Elovaara I, Pirttilä T, Reunanen M, Koivisto K, Marjavaara S, Suomalainen A (2010) DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis. J Med Genet 47:66–70
van Berge L, Dooves S, van Berkel CG, Polder E, van der Knaap MS, Scheper GC (2012) Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA. Biochem J 441:955–962
Statistics Finland website. http://www.stat.fi/tup/suoluk/suoluk_vaesto_en.html. Accessed 11 Mar 2013
Steenweg ME, van Berge L, van Berkel CG, de Coo IF, Temple IK, Brockmann K, Mendonça CI, Vojta S, Kolk A, Peck D, Carr L, Uziel G, Feigenbaum A, Blaser S, Scheper GC, van der Knaap MS (2012) Early-onset LBSL: how severe does it get? Neuropediatrics 43:332–338
Labauge P, Dorboz I, Eymard-Pierre E, Dereeper O, Boespflug-Tanguy O (2011) Clinically asymptomatic adult patient with extensive LBSL MRI pattern and DARS2 mutations. J Neurol 258:335–337
Tzoulis C, Tran GT, Gjerde IO, Aasly J, Neckelmann G, Rydland J, Varga V, Wadel-Andersen P, Bindoff LA (2012) Leukoencephalopathy with brainstem and spinal cord involvement caused by a novel mutation in the DARS2 gene. J Neurol 259:292–296
Tillema JM, Renaud DL (2012) Leukoencephalopathies in adulthood. Semin Neurol 32:85–94
Moore SA, Kumar N, Gavrilova RH (2012) Leukoencephalopathy with brain stem and spinal cord involvement (and high lactate): raising the bar for diagnosis. J Neurol 259:2494–2497. doi:10.1007/s00415-012-6596-1
Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F (1991) Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology 41:692–696
Amato MP, Ponziani G, Siracusa G, Sorbi S (2001) Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol 58:1602–1606
Lengenfelder J, Bryant D, Diamond BJ, Kalmar JH, Moore NB, DeLuca J (2006) Processing speed interacts with working memory efficiency in multiple sclerosis. Arch Clin Neuropsychol 21:229–238
Hoffmann S, Tittgemeyer M, von Cramon DY (2007) Cognitive impairment in multiple sclerosis. Curr Opin Neurol 20:275–280
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High standard of ethics according to the WMA Declaration of Helsinki was applied in all clinical work and investigations described in this manuscript.
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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 260, 2078–2083 (2013). https://doi.org/10.1007/s00415-013-6940-0
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DOI: https://doi.org/10.1007/s00415-013-6940-0