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|Year : 2013 | Volume
| Issue : 2 | Page : 161-163
Adult-onset leukoencephalopathy with brain stem and spinal cord involvement in Chinese Han population: A case report and literature review
Fu-Bo Cheng1, Ping-Ping Shen1, Hong-Wei Zhou2, Hong-Mei Meng1, Yu Yang1, Jia-Chun Feng1
1 Department of Neurology, The First Affiliated Hospital of Jilin University, Changchun, Jilin Province, 130021, P. R. China
2 Department of Radiology, The First Affiliated Hospital of Jilin University, Changchun, Jilin Province, 130021, P. R. China
|Date of Submission||28-Dec-2012|
|Date of Decision||28-Dec-2012|
|Date of Acceptance||17-Mar-2013|
|Date of Web Publication||29-Apr-2013|
Department of Neurology, The First Affiliated Hospital of Jilin University, Xinmin Street 71, Changchun, Jilin Province, 130021
P. R. China
Source of Support: None, Conflict of Interest: None
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a recently described disorder with an autosomal recessive mode of inheritance. We report a case of rare adult-onset LBSL with typical magnetic resonance imaging (MRI) features. The DARS2 gene mutation analysis has identified a c. 228-20_21delTTinsC (p.R76SfsX5) mutation and a c. 850G > A (p. 284E > K) mutation. With glucocorticosteroid treatment the patient has had improvement in bladder symptoms. This is the first reported adult-onset LBSL case in the Chinese Han population. A review of the literature suggests that brain lactate elevation in adult-onset LBSL is lower than early-onset cases (P < 0.01), and early-onset cases show mild intelligence and cognition decline. These observations suggest that age of onset and brain lactate levels probably influence the prognosis of LBSL.
Keywords: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, Adult-onset, early-onset, lactate level, proton magnetic resonance spectroscopy
|How to cite this article:|
Cheng FB, Shen PP, Zhou HW, Meng HM, Yang Y, Feng JC. Adult-onset leukoencephalopathy with brain stem and spinal cord involvement in Chinese Han population: A case report and literature review. Neurol India 2013;61:161-3
|How to cite this URL:|
Cheng FB, Shen PP, Zhou HW, Meng HM, Yang Y, Feng JC. Adult-onset leukoencephalopathy with brain stem and spinal cord involvement in Chinese Han population: A case report and literature review. Neurol India [serial online] 2013 [cited 2021 Sep 28];61:161-3. Available from: https://www.neurologyindia.com/text.asp?2013/61/2/161/111123
| » Introduction|| |
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare, automsomal recessive neurological disorder caused by a mutation in the gene encoding a mitochondrial aspartyl-tRNA synthetase, DARS2.  Although many cases of LBSL have been reported, only a few have been documented with full clinical details.  LBSL can be asymptomatic or have a relapsing and remitting course; and often the diagnosis may be missed. , The diagnosis mainly relies on the clinical features and highly characteristic neuroimaging features. The typical MRI features include heterogeneous cerebral white matter abnormalities accompanied by a selective involvement of the brainstem and spinal cord tracts.  Most often the disease onset is in early childhood or adolescence, , rarely can it be an adult onset. , However, the differences between early-onset and adult-onset LBSL have not been well characterized. We report the first adult-onset LBSL case in the Chinese Han population. The published literature has been reviewed to identify the clinical and MRS differences between early-onset and adult-onset LBSL.
| » Case Report|| |
A 39-year-old Chinese Han male presented with diplopia, gait disorder, and progressive lower extremity weakness. At the age of 20 years, he first noted diplopia, weakness of both the lower extremities, and unsteady gait. The diagnosis at that time was multiple sclerosis (MS). At the age of 38 years he could not walk independently and developed spastic bladder symptoms. He was a product of consanguineous parentage. His developmental and medical histories were unremarkable. The family history for any neurological illness was negative. The neurological examination revealed spontaneous nystagmus, spasticity in the lower limbs, ataxia, and hyperreflexia in all the four limbs, with ankle clonus and bilateral extensor plantar response. Sensory testing revealed a distal symmetrical decrease in position and vibration sense.
Blood chemistry, serum ammonia, serum creatine kinase, thyroid function, antinuclear antibodies, blood lactate, serum copper, serum caeruloplasmin, and cerebrospinal fluid testing including CSF protein, IgG level, IgG index, and IgG synthesis were all normal. An MRI (3.0 Tesla) of the brain revealed non-enhancing lesions, hypointense on T1-weighted and hyperintense on T2-weight images. The image characteristics were consistent with the typical LBSL [Figure 1]a-e. Repeated MRS with short and long echo time showed a mild decrease of N-acetylaspartate, an increase of choline levels, and normal lactate levels [Figure 1]a-d.
|Figure 1: MRI findings in our patient. (a) Axial T2 image showing high signal in the posterior limb of the internal capsule and white matter. (b) Axial T2 image showing high signal in the inferior cerebellar peduncle and pyramids in the medulla oblongata. (c) Axial T2 image through the medulla oblongata showing high signal in the pyramidal decussation. (d) Single voxel MR spectroscopy of the affected white matter revealed decreased N-acetylaspartate (NAA) and increased choline levels (Cho), but no lactate increase. (e) Sagittal T2 image of the spine showing high signal along the dorsal column of the cord (black arrows)|
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The mutation screen of the DARS2 gene revealed compound heterozygous mutations, a c. 228-20_ 21delTTinsC (p.R76SfsX5) mutation located in the stretch of C residues just upstream of exon 3 and a novel missense mutation c. 850G > A (p. 284E > K) located in exon 10. His mother carried the c. 228-20_21delTTinsC mutation, while his father carried the c. 850G > A mutation. The patient was diagnosed as LBSL, and treated with high-dose glucocorticosteroid. One month later, he had improvement in bladder symptoms, but not in other symptoms.
| » Discussion|| |
Many cases of LBSL from different ethnic backgrounds have been reported. ,,,,,,,, In our patient the clinical symptom and MRI features were consistent with typical LBSL and the genetic mutation screen confirmed the diagnosis.  Our patient had adult-onset LBSL, with age of onset at 20 years. In this patient, we identified a common mutation (c. 228-20_21delTTinsC) and a novel DARS2 mutation (c. 850G > A p. 284E > K). This novel mutation was not found in a panel of 200 chromosomes of the control subjects of Chinese origin. This patient had partial symptomatic improvement in bladder symptoms with treatment of glucocorticosteroid.
In 2007, Scheper et al.,  have reported that mutations in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase, are responsible for LBSL. To date, more than fifty cases have been reported in different ethnic populations  [Table 1]. LBSL is a rare autosomal recessive hereditary disease. Most of these patients have compound heterozygous mutation. ,,,,,,,, Different types of mutations have been found in DARS2, that is, deletions, nonsense, and splice site mutations, leading to major alterations at the protein level, as also missense mutations. The most common pathogenic mutation in the DARS2 gene is a heterozygous variant of c. 228-20_21delTTinsC, which shifts the open-reading frame, leading to premature termination of translation (p.R76SfsX5).  The other variants can be located in the region of the whole genome. In our patient, we found a novel mutation located in exon 10 of the gene (c. 850G > A), which led to a change of the acidic amino acid (glutamine) to basic amino acid (lysine), which might suggest that this novel mutation is pathogenic.
|Table 1: The clinical and MRS data of the patients with early-onset and adult-onset LBSL (including the present case)|
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On comparing the clinical and MRS data of early-onset (onset age < 18 years) and adult-onset (onset age ≥ 18 years) LBSL cases, we found that early-onset cases usually have severe clinical disease including intelligence and cognition decline [Table 1]. We also found that the brain lactate level was higher in most of the early-onset cases (73.7%) than the adult-onset cases (12.5%) (P < 0.01). These observations suggested that the age of onset of the disease and the brain lactate level probably influenced the prognosis of LBSL. However, further long-term prospective studies are needed to confirm these observations. Furthermore, some researchers proposed that the lactate elevation was related to the advanced stage of disease. 
| » Acknowledgment|| |
The authors would like to thank the patients for their participation in the study.
| » References|| |
|1.||Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 2007;39:534-9. |
|2.||Tzoulis C, Tran GT, Gjerde IO, Aasly J, Neckelmann G, Rydland J, et al. Leukoencephalopathy with brainstem and spinal cord involvement caused by a novel mutation in the DARS2 gene. J Neurol 2012;259:292-6. |
|3.||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;258:335-7. |
|4.||Isohanni P, Linnankivi T, Buzkova J, Lönnqvist T, Pihko H, Valanne L, et al. DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis. J Med Genet 2010;47:66-70. |
|5.||Miyake N, Yamashita S, Kurosawa K, Miyatake S, Tsurusaki Y, Doi H, et al. A novel homozygous mutation of DARS2 may cause a severe LBSL variant. Clin Genet 2011;80:293-6. |
|6.||Petzold GC, Bohner G, Klingebiel R, Amberger N, van der Knaap MS, Zschenderlein R. Adult onset leucoencephalopathy with brain stem and spinal cord involvement and normal lactate. J Neurol Neurosurg Psychiatry 2006;77:889-91. |
|7.||Moore SA, Kumar N, Gavrilova RH. Leukoencephalopathy with brain stem and spinal cord involvement (and high lactate): Raising the bar for diagnosis. J Neurol 2012;259:2494-7. |
|8.||Van der Knaap MS, van der Voorn P, Barkhof F, Van Coster R, Krägeloh-Mann I, Feigenbaum A, et al. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol 2003;53:252-8. |
|9.||Sen A, Wattamwar PR, Thomas B, Nair M. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: A rare white matter disease with characteristic magnetic resonance imaging findings. Neurol India 2010;58:958-60. |
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