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Phenotypic spectrum of DARS2 mutations
Journal of the Neurological Sciences 376 (2017) 117–118
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Phenotypic spectrum of DARS2 mutations Keywords: DARS2 LBSL Leucoencephalopathy Spasticity Ataxia Compound heterozygote Lactic acidosis
phenotype include exercise-induced ataxia, organic psychosyndrome, absence of cerebral lactic acidosis, optic atrophy, hypoacusis, ptosis, diplopia, creatin-kinase(CK)-elevation, muscle weakness, muscle wasting, muscle cramps, polyneuropathy, anemia, and nephrolithiasis (Table 1). Whether Table 1 Phenotype spectrum of DARS2 mutations (only features in addition to the classical manifestations such as ataxia, spasticity, epilepsy, leucoencephalopathy, brain lactic acidosis, dorsal column dysfunction, and spastic bladder with urge incontinence are presented). Mutation NOP Non-classical features
With interest we read the article by Lan et al. about a 35yo female with leucoencephalopathy, brainstem and spinal cord involvement, and lactate elevation (LBSL) due to a compound heterozygous mutation (known point mutation plus novel deletion of exon 12) in the DARS2 gene, manifesting as impaired balance since teenage, unsteady gait since age 20 y, and weakness, spasticity, and sensory dysfunction of the lower-limbs since age 20 y [1]. It is the only case of spastic paraparesis in the absence of other neurological deficits due to a DARS2 mutation. We have the following comments and concerns. Spastic paraparesis as a manifestation of a DARS2 gene mutation is not unique but has been previously reported in at least 17 LBSL patients (Table 1). Already in the first report about eight patients with LBSL, van der Knaap et al. described predominance of clinical manifestations in the lower limbs [2]. The three patients described by Martikainen et al. had lower limb paraparesis, complained about muscle cramps, and had polyneuropathy [3]. The patient described by Huang et al. presented with ataxia and spasticity predominantly of the lower limbs [4]. The two patients described by Tzoulis et al. presented with predominant lower-limb weakness, spasticity and wasting of the lower limb muscles [5]. In the majority of the cases LBSL is due to compound heterozygous DARS2 mutations. However, at least seven LBSL patients with homozygous DARS2 mutations have been reported (Table 1). Since the father carried the exon 12 deletion and the mother the point mutation, and their sibs either of the two except for the index case, it would be interesting to know if any of those carrying a single DARS2 mutation also manifested clinically. Usually, however, probands carrying only a single DARS2 mutation do not manifest clinically. Patients carrying homozygous mutations do not necessarily die intrauterinely but may present with a similar phenotype as patients carrying a compound heterozygous mutation. Whether the outcome of patients carrying a homozygous DARS2 mutation is worse compared to patients carrying a compound heterozygous DARS2 mutation has not been investigated. Since the initial description of the DARS2 phenotype, manifesting with ataxia, spasticity, cognitive impairment, leucoencephalopathy, seizures, posterior column affection, sphincter dysfunction with urge incontinence, and cerebral lactic acidosis (classical phenotype) [2], it has been shown that the phenotypic spectrum is much broader than anticipated (Table 1) [6]. Phenotypic features in addition to the classical
http://dx.doi.org/10.1016/j.jns.2017.03.006 0022-510X/© 2017 Elsevier B.V. All rights reserved.
CH
1
Normal brain lactate Deterioration during infection, recovery after treatment
HZ
1
CH
2
LLP
nm
16
None
HZ, CH
66
None
CH
1
Cramps, nephrolithiasis, PNP
HZ
3
PNP
CH
3
PNP, weakness, cramps, LLP
CH CH CH
1 1 1
CH
2
Diplopia, improvement upon steroids Impaired fine motor skills LLP (without weakness) Normal brain lactate, ptosis, optic atrophy, LLP
Nm
8
Nm
HZ
1
Exercise induced ataxia
CH HZ
1 1
Normal brain lactate Tremor, weakness, wasting, contractures
HZ
1
None
CH
2
None
Nm Nm CH
1 1 8
Deafness, anemia Normal brain lactate PNP
Nm
31
PNP, OPS
CH Nm
1 3
None Depressed tendon reflexes, CK-elevation
Nm
38
Nm
Nm Nm
1 2
Normal brain lactate Normal brain lactate, LLP
Nm
5
Tremor
Nm
5
None
Nm
8
LLP
Reference Lan et al. (2017) [1] Köhler et al. (2015) [7] Tylki-Szymanska et al. (2014) [8] Kassem et al. (2014) [9] van Berge et al. (2014) [10] Alibas et al. (2014) [11] Yamashita et al. (2013) [12] Martikainen et al. (2013) [3] Cheng et al. (2013) [13] Schicks et al. (2013) [14] Huang et al. (2012) [4] Tzoulis et al. (2012) [5] Steenweg et al. (2011) [15] Synofzik et al. (2011) [16] Sharma et al. (2011) [17] Miyake et al. (2011) [18] Mierzewska et al. (2011) [19] Labauge et al. (2007) [20] Orcesi et al. (2011) [21] Lin et al. (2010) [22] Isohanni et al. (2010) [23] Mikhailova et al. (2009) [24] Uluc et al. (2008) [25] Távora et al. (2007) [26] Scheper et al. (2007) [27] Labauge et al. (2007) [20] Petzold et al. (2006) [28] Linnankivi et al. (2004) [29] Serkov et al. (2004) [30] Van der Knaap et al. (2003) [2]
NOP: number of patients, LE: leucoencephalopathy, ATX: cerebellar ataxia, SP: spasticity, CI: cognitive impairment, DCD: dorsal column dysfunction, PNP: polyneuropathy, LA: cerebral lactic acidosis, HZ: homozygote, CH: compound heterozygote, OPS: organic psychosyndrome, LLP: lower-limb predominance of weakness and spasticity, nm: not mentioned.
118
Letter to the Editor
steroids should be routinely given to LBSL patients is unknown but at least in one patient, so far reported, steroids had a beneficial effect (Table 1). Overall, this interesting case confirms previous findings, that the lower limbs may be exclusively or predominantly affected in LBSL. The case provides evidence that the phenotypic spectrum of DARS2 mutations is broader than so far anticipated. Furthermore, in cases in which only a single DARS2 mutation is detected by sequencing, exon deletions of the DARS2 gene should be excluded. Conflicts of interest There are no conflicts of interest. Funding No funding was received Author contribution JF: design, literature search, discussion, frist draft, SZ-M: literature search, discussion, critical comments. References [1] M.Y. Lan, Y.Y. Chang, T.H. Yeh, T.K. Lin, C.S. Lu, Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) with a novel DARS2 mutation and isolated progressive spastic paraparesis, J. Neurol. Sci. 372 (2017 Jan 15) 229–231. [2] M.S. van der Knaap, P. van der Voorn, F. Barkhof, R. Van Coster, I. Krägeloh-Mann, A. Feigenbaum, S. Blaser, J.S. Vles, P. Rieckmann, P.J. Pouwels, A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate, Ann. Neurol. 53 (2003) 252–258. [3] M.H. Martikainen, U. Ellfolk, K. Majamaa, 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 (2013) 2078–2083. [4] Q.H. Huang, J.X. Xiao, J.M. Wang, Y.W. Jiang, Y. Wu, Clinical and genetic analysis of a family with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, Zhonghua Er Ke Za Zhi 50 (2012) 50–55. [5] C. Tzoulis, G.T. Tran, I.O. Gjerde, J. Aasly, G. Neckelmann, J. Rydland, V. Varga, P. Wadel-Andersen, L.A. Bindoff, Leukoencephalopathy with brainstem and spinal cord involvement caused by a novel mutation in the DARS2 gene, J. Neurol. 259 (2012) 292–296. [6] W.B. Pinto, P.V. de Souza, DARS2 gene clinical spectrum: new ideas regarding an underdiagnosed leukoencephalopathy, Brain 137 (2014) e289. [7] C. Köhler, C. Heyer, S. Hoffjan, S. Stemmler, T. Lücke, C. Thiels, A. Kohlschütter, U. Löbel, R. Horvath, S. Kleinle, A. Benet-Pages, A. Abicht, Early-onset leukoencephalopathy due to a homozygous missense mutation in the DARS2 gene, Mol. Cell. Probes 29 (2015) 319–322. [8] A. Tylki-Szymanska, E. Jurkiewicz, E.Y. Zakharova, B. Bobek-Billewicz, Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation: high outcome variation between two siblings, Neuropediatrics 45 (2014) 188–191. [9] H. Kassem, A. Wafaie, S. Abdelfattah, T. Farid, Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL): assessment of the involved white matter tracts by MRI, Eur. J. Radiol. 83 (2014) 191–196. [10] L. van Berge, E.M. Hamilton, T. Linnankivi, G. Uziel, M.E. Steenweg, P. Isohanni, N.I. Wolf, I. Krägeloh-Mann, N.J. Brautaset, P.I. Andrews, B.A. de Jong, M. Al Ghamdi, W.N. van Wieringen, B.A. Tannous, E. Hulleman, T. Würdinger, C.G. van Berkel, E. Polder, T.E. Abbink, E.A. Struys, G.C. Scheper, M.S. van der Knaap, LBSL Research Group, Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy, Brain 137 (2014) 1019–1029. [11] H. Alibas, P.K. Koytak, G. Ekinci, K. Uluc, A case with leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) with Its Characteristic Clinical and Neuroimaging Findings, Clin. Neuroradiol. 24 (2014) 297–300. [12] S. Yamashita, N. Miyake, N. Matsumoto, H. Osaka, M. Iai, N. Aida, Y. Tanaka, Neuropathology of leukoencephalopathy with brainstem and spinal cord involvement and high lactate caused by a homozygous mutation of DARS2, Brain Dev 35 (2013) 312–316. [13] F.B. Cheng, P.P. Shen, H.W. Zhou, H.M. Meng, Y. Yang, J.C. Feng, Adult-onset leukoencephalopathy with brain stem and spinal cord involvement in Chinese Han population: a case report and literature review, Neurol. India 61 (2013) 161–163.
[14] J. Schicks, L. Schöls, M.S. van der Knaap, M. Synofzik, Teaching NeuroImages: MRI guides genetics: leukoencephalopathy with brainstem and spinal cord involvement (LBSL), Neurology 80 (2013) e176–e177. [15] M.E. Steenweg, P.J. Pouwels, N.I. Wolf, W.N. van Wieringen, F. Barkhof, M.S. van der Knaap, Leucoencephalopathy with brainstem and spinal cord involvement and high lactate: quantitative magnetic resonance imaging, Brain 134 (2011) 3333–3341. [16] M. Synofzik, J. Schicks, T. Lindig, S. Biskup, T. Schmidt, J. Hansel, F. Lehmann-Horn, L. Schöls, Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation, J. Med. Genet. 48 (2011) 713–715. [17] S. Sharma, N. Sankhyan, A. Kumar, G.C. Scheper, M.S. van der Knaap, S. Gulati, Leukoencephalopathy with brain stem and spinal cord involvement and high lactate: a genetically proven case without elevated white matter lactate, J. Child Neurol. 26 (2011) 773–776. [18] N. Miyake, S. Yamashita, K. Kurosawa, S. Miyatake, Y. Tsurusaki, H. Doi, H. Saitsu, N. Matsumoto, A novel homozygous mutation of DARS2 may cause a severe LBSL variant, Clin. Genet 80 (2011) 293–296. [19] H. Mierzewska, M.S. van der Knaap, G.C. Scheper, M. Bekiesinska-Figatowska, E. Szczepanik, E. Jurkiewicz, Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation in the first Polish patient, Brain Dev. 33 (2011) 713–717. [20] P. Labauge, E. Roullet, O. Boespflug-Tanguy, F. Nicoli, Y. Le Fur, P.J. Cozzone, D. Ducreux, D. Rodriguez, Familial, adult onset form of leukoencephalopathy with brain stem and spinal cord involvement: inconstant high brain lactate and very slow disease progression, Eur. Neurol. 58 (2007) 59–61. [21] S. Orcesi, R. La Piana, C. Uggetti, D. Tonduti, A. Pichiecchio, M. Pasin, G. Viselner, G.P. Comi, R. Del Bo, D. Ronchi, S. Bastianello, U. Balottin, Spinal cord calcification in an early-onset progressive leukoencephalopathy, J. Child Neurol. 26 (2011) 876–880. [22] J. Lin, E. Chiconelli Faria, A.J. Da Rocha, M. Rodrigues Masruha, L.C. Pereira Vilanova, G.C. Scheper, M.S. Van der Knaap, Leukoencephalopathy with brainstem and spinal cord involvement and normal lactate: a new mutation in the DARS2 gene, J. Child Neurol. 25 (2010) 1425–1428. [23] P. Isohanni, T. Linnankivi, J. Buzkova, T. Lönnqvist, H. Pihko, L. Valanne, P.J. Tienari, I. Elovaara, T. Pirttilä, M. Reunanen, K. Koivisto, S. Marjavaara, A. Suomalainen, DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis, J. Med. Genet. 47 (2010) 66–70. [24] S.V. Mikhailova, EIu Zakharova, A.V. Banin, A.A. Demushkina, A.S. Petrukhin, Clinical and molecular genetic diagnosis of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation in children, Zh. Nevrol. Psikhiatr. Im. S S Korsakova 109 (2009) 16–22. [25] K. Uluc, O. Baskan, K.A. Yildirim, S. Ozsahin, M. Koseoglu, B. Isak, G.C. Scheper, D.I. Gunal, M.S. van der Knaap, Leukoencephalopathy with brain stem and spinal cord involvement and high lactate: a genetically proven case with distinct MRI findings, J. Neurol. Sci. 273 (2008) 118–122. [26] D.G. Távora, M. Nakayama, R.L. Gama, T.C. Alvim, D. Portugal, E.A. Comerlato, Leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate: report of three Brazilian patients, Arq. Neuropsiquiatr. 65 (2007) 506–511. [27] G.C. Scheper, T. van der Klok, R.J. van Andel, C.G. van Berkel, M. Sissler, J. Smet, T.I. Muravina, S.V. Serkov, G. Uziel, M. Bugiani, R. Schiffmann, I. Krägeloh-Mann, J.A. Smeitink, C. Florentz, R. Van Coster, J.C. Pronk, M.S. van der Knaap, Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, Nat. Genet. 39 (2007) 534–539. [28] G.C. Petzold, G. Bohner, R. Klingebiel, N. Amberger, M.S. van der Knaap, R. Zschenderlein, Adult onset leucoencephalopathy with brain stem and spinal cord involvement and normal lactate, J. Neurol. Neurosurg. Psychiatry 77 (2006) 889–891. [29] T. Linnankivi, N. Lundbom, T. Autti, A.M. Häkkinen, H. Koillinen, T. Kuusi, T. Lönnqvist, K. Sainio, L. Valanne, T. Aärimaa, H. Pihko, Five new cases of a recently described leukoencephalopathy with high brain lactate, Neurology 63 (2004) 688–692. [30] S.V. Serkov, I.N. Pronin, O.V. Bykova, O.I. Maslova, N.V. Arutyunov, T.I. Muravina, V.N. Kornienko, L.M. Fadeeva, H. Marks, C. Bönnemann, R. Schiffmann, M.S. van der Knaap, Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate, Neuropediatrics 35 (2004) 1–5.
Josef Finsterer1 Krankenanstalt Rudolfstiftung, Vienna, Austria Corresponding author at: Postfach 20, 1180 Vienna, Austria. E-mail address: fifi[email protected]. Sinda Zarrouk-Mahjoub1 University of Tunis El Manar, Genomics Platform, Pasteur Institute of Tunis, Tunisia 3 February 2017 Available online 9 March 2017
1
Both authors contributed equally.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Phenotypic spectrum of DARS2 mutations Keywords: DARS2 LBSL Leucoencephalopathy Spasticity Ataxia Compound heterozygote Lactic acidosis
phenotype include exercise-induced ataxia, organic psychosyndrome, absence of cerebral lactic acidosis, optic atrophy, hypoacusis, ptosis, diplopia, creatin-kinase(CK)-elevation, muscle weakness, muscle wasting, muscle cramps, polyneuropathy, anemia, and nephrolithiasis (Table 1). Whether Table 1 Phenotype spectrum of DARS2 mutations (only features in addition to the classical manifestations such as ataxia, spasticity, epilepsy, leucoencephalopathy, brain lactic acidosis, dorsal column dysfunction, and spastic bladder with urge incontinence are presented). Mutation NOP Non-classical features
With interest we read the article by Lan et al. about a 35yo female with leucoencephalopathy, brainstem and spinal cord involvement, and lactate elevation (LBSL) due to a compound heterozygous mutation (known point mutation plus novel deletion of exon 12) in the DARS2 gene, manifesting as impaired balance since teenage, unsteady gait since age 20 y, and weakness, spasticity, and sensory dysfunction of the lower-limbs since age 20 y [1]. It is the only case of spastic paraparesis in the absence of other neurological deficits due to a DARS2 mutation. We have the following comments and concerns. Spastic paraparesis as a manifestation of a DARS2 gene mutation is not unique but has been previously reported in at least 17 LBSL patients (Table 1). Already in the first report about eight patients with LBSL, van der Knaap et al. described predominance of clinical manifestations in the lower limbs [2]. The three patients described by Martikainen et al. had lower limb paraparesis, complained about muscle cramps, and had polyneuropathy [3]. The patient described by Huang et al. presented with ataxia and spasticity predominantly of the lower limbs [4]. The two patients described by Tzoulis et al. presented with predominant lower-limb weakness, spasticity and wasting of the lower limb muscles [5]. In the majority of the cases LBSL is due to compound heterozygous DARS2 mutations. However, at least seven LBSL patients with homozygous DARS2 mutations have been reported (Table 1). Since the father carried the exon 12 deletion and the mother the point mutation, and their sibs either of the two except for the index case, it would be interesting to know if any of those carrying a single DARS2 mutation also manifested clinically. Usually, however, probands carrying only a single DARS2 mutation do not manifest clinically. Patients carrying homozygous mutations do not necessarily die intrauterinely but may present with a similar phenotype as patients carrying a compound heterozygous mutation. Whether the outcome of patients carrying a homozygous DARS2 mutation is worse compared to patients carrying a compound heterozygous DARS2 mutation has not been investigated. Since the initial description of the DARS2 phenotype, manifesting with ataxia, spasticity, cognitive impairment, leucoencephalopathy, seizures, posterior column affection, sphincter dysfunction with urge incontinence, and cerebral lactic acidosis (classical phenotype) [2], it has been shown that the phenotypic spectrum is much broader than anticipated (Table 1) [6]. Phenotypic features in addition to the classical
http://dx.doi.org/10.1016/j.jns.2017.03.006 0022-510X/© 2017 Elsevier B.V. All rights reserved.
CH
1
Normal brain lactate Deterioration during infection, recovery after treatment
HZ
1
CH
2
LLP
nm
16
None
HZ, CH
66
None
CH
1
Cramps, nephrolithiasis, PNP
HZ
3
PNP
CH
3
PNP, weakness, cramps, LLP
CH CH CH
1 1 1
CH
2
Diplopia, improvement upon steroids Impaired fine motor skills LLP (without weakness) Normal brain lactate, ptosis, optic atrophy, LLP
Nm
8
Nm
HZ
1
Exercise induced ataxia
CH HZ
1 1
Normal brain lactate Tremor, weakness, wasting, contractures
HZ
1
None
CH
2
None
Nm Nm CH
1 1 8
Deafness, anemia Normal brain lactate PNP
Nm
31
PNP, OPS
CH Nm
1 3
None Depressed tendon reflexes, CK-elevation
Nm
38
Nm
Nm Nm
1 2
Normal brain lactate Normal brain lactate, LLP
Nm
5
Tremor
Nm
5
None
Nm
8
LLP
Reference Lan et al. (2017) [1] Köhler et al. (2015) [7] Tylki-Szymanska et al. (2014) [8] Kassem et al. (2014) [9] van Berge et al. (2014) [10] Alibas et al. (2014) [11] Yamashita et al. (2013) [12] Martikainen et al. (2013) [3] Cheng et al. (2013) [13] Schicks et al. (2013) [14] Huang et al. (2012) [4] Tzoulis et al. (2012) [5] Steenweg et al. (2011) [15] Synofzik et al. (2011) [16] Sharma et al. (2011) [17] Miyake et al. (2011) [18] Mierzewska et al. (2011) [19] Labauge et al. (2007) [20] Orcesi et al. (2011) [21] Lin et al. (2010) [22] Isohanni et al. (2010) [23] Mikhailova et al. (2009) [24] Uluc et al. (2008) [25] Távora et al. (2007) [26] Scheper et al. (2007) [27] Labauge et al. (2007) [20] Petzold et al. (2006) [28] Linnankivi et al. (2004) [29] Serkov et al. (2004) [30] Van der Knaap et al. (2003) [2]
NOP: number of patients, LE: leucoencephalopathy, ATX: cerebellar ataxia, SP: spasticity, CI: cognitive impairment, DCD: dorsal column dysfunction, PNP: polyneuropathy, LA: cerebral lactic acidosis, HZ: homozygote, CH: compound heterozygote, OPS: organic psychosyndrome, LLP: lower-limb predominance of weakness and spasticity, nm: not mentioned.
118
Letter to the Editor
steroids should be routinely given to LBSL patients is unknown but at least in one patient, so far reported, steroids had a beneficial effect (Table 1). Overall, this interesting case confirms previous findings, that the lower limbs may be exclusively or predominantly affected in LBSL. The case provides evidence that the phenotypic spectrum of DARS2 mutations is broader than so far anticipated. Furthermore, in cases in which only a single DARS2 mutation is detected by sequencing, exon deletions of the DARS2 gene should be excluded. Conflicts of interest There are no conflicts of interest. Funding No funding was received Author contribution JF: design, literature search, discussion, frist draft, SZ-M: literature search, discussion, critical comments. References [1] M.Y. Lan, Y.Y. Chang, T.H. Yeh, T.K. Lin, C.S. Lu, Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) with a novel DARS2 mutation and isolated progressive spastic paraparesis, J. Neurol. Sci. 372 (2017 Jan 15) 229–231. [2] M.S. van der Knaap, P. van der Voorn, F. Barkhof, R. Van Coster, I. Krägeloh-Mann, A. Feigenbaum, S. Blaser, J.S. Vles, P. Rieckmann, P.J. Pouwels, A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate, Ann. Neurol. 53 (2003) 252–258. [3] M.H. Martikainen, U. Ellfolk, K. Majamaa, 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 (2013) 2078–2083. [4] Q.H. Huang, J.X. Xiao, J.M. Wang, Y.W. Jiang, Y. Wu, Clinical and genetic analysis of a family with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, Zhonghua Er Ke Za Zhi 50 (2012) 50–55. [5] C. Tzoulis, G.T. Tran, I.O. Gjerde, J. Aasly, G. Neckelmann, J. Rydland, V. Varga, P. Wadel-Andersen, L.A. Bindoff, Leukoencephalopathy with brainstem and spinal cord involvement caused by a novel mutation in the DARS2 gene, J. Neurol. 259 (2012) 292–296. [6] W.B. Pinto, P.V. de Souza, DARS2 gene clinical spectrum: new ideas regarding an underdiagnosed leukoencephalopathy, Brain 137 (2014) e289. [7] C. Köhler, C. Heyer, S. Hoffjan, S. Stemmler, T. Lücke, C. Thiels, A. Kohlschütter, U. Löbel, R. Horvath, S. Kleinle, A. Benet-Pages, A. Abicht, Early-onset leukoencephalopathy due to a homozygous missense mutation in the DARS2 gene, Mol. Cell. Probes 29 (2015) 319–322. [8] A. Tylki-Szymanska, E. Jurkiewicz, E.Y. Zakharova, B. Bobek-Billewicz, Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation: high outcome variation between two siblings, Neuropediatrics 45 (2014) 188–191. [9] H. Kassem, A. Wafaie, S. Abdelfattah, T. Farid, Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL): assessment of the involved white matter tracts by MRI, Eur. J. Radiol. 83 (2014) 191–196. [10] L. van Berge, E.M. Hamilton, T. Linnankivi, G. Uziel, M.E. Steenweg, P. Isohanni, N.I. Wolf, I. Krägeloh-Mann, N.J. Brautaset, P.I. Andrews, B.A. de Jong, M. Al Ghamdi, W.N. van Wieringen, B.A. Tannous, E. Hulleman, T. Würdinger, C.G. van Berkel, E. Polder, T.E. Abbink, E.A. Struys, G.C. Scheper, M.S. van der Knaap, LBSL Research Group, Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy, Brain 137 (2014) 1019–1029. [11] H. Alibas, P.K. Koytak, G. Ekinci, K. Uluc, A case with leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) with Its Characteristic Clinical and Neuroimaging Findings, Clin. Neuroradiol. 24 (2014) 297–300. [12] S. Yamashita, N. Miyake, N. Matsumoto, H. Osaka, M. Iai, N. Aida, Y. Tanaka, Neuropathology of leukoencephalopathy with brainstem and spinal cord involvement and high lactate caused by a homozygous mutation of DARS2, Brain Dev 35 (2013) 312–316. [13] F.B. Cheng, P.P. Shen, H.W. Zhou, H.M. Meng, Y. Yang, J.C. Feng, Adult-onset leukoencephalopathy with brain stem and spinal cord involvement in Chinese Han population: a case report and literature review, Neurol. India 61 (2013) 161–163.
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Josef Finsterer1 Krankenanstalt Rudolfstiftung, Vienna, Austria Corresponding author at: Postfach 20, 1180 Vienna, Austria. E-mail address: fifi[email protected]. Sinda Zarrouk-Mahjoub1 University of Tunis El Manar, Genomics Platform, Pasteur Institute of Tunis, Tunisia 3 February 2017 Available online 9 March 2017
1
Both authors contributed equally.