scholarly journals Leucoencephalopathy with brain stem and spinal cord involvement and lactate elevation: a novel mutation in the DARS2 gene

2019 ◽  
Vol 12 (1) ◽  
pp. bcr-2018-227755 ◽  
Author(s):  
Anudeep Yelam ◽  
Elanagan Nagarajan ◽  
Miguel Chuquilin ◽  
Raghav Govindarajan
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Brain Stem ◽  
Autosomal Recessive ◽  
Novel Mutation ◽  
Trna Synthetase ◽  
Dorsal Column ◽  
Clinical Findings ◽  
Cerebral White Matter ◽  
Spinal Cord Involvement

Leucoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a very rare autosomal recessive, slowly progressive neurological disorder characterised by distinctive clinical findings including cerebellar, pyramidal and dorsal column dysfunction. This is caused by a mutation in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase. MRI shows distinctive abnormalities in the cerebral white matter and specific brain stem and spinal cord tracts. Here, we present a case of LBSL, with a novel c.1192-2A>G mutation.

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA

2012 ◽  
Vol 441 (3) ◽  
pp. 955-962 ◽  
Author(s):  
Laura van Berge ◽  
Stephanie Dooves ◽  
Carola G.M. van Berkel ◽  
Emiel Polder ◽  
Marjo S. van der Knaap ◽  
...  
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Brain Stem ◽  
Cell Lines ◽  
Trna Synthetase ◽  
Neural Cell ◽  
Cell Type ◽  
White Matter Tracts ◽  
Spinal Cord Involvement ◽  
Neural Cell Lines

LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) is an autosomal recessive white matter disorder with slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction. Magnetic resonance imaging shows characteristic abnormalities in the cerebral white matter and specific brain stem and spinal cord tracts. LBSL is caused by mutations in the gene DARS2, which encodes mtAspRS (mitochondrial aspartyl-tRNA synthetase). The selective involvement of specific white matter tracts in LBSL is striking since this protein is ubiquitously expressed. Almost all LBSL patients have one mutation in intron 2 of DARS2, affecting the splicing of the third exon. Using a splicing reporter construct, we find cell-type-specific differences in the sensitivity to these mutations: the mutations have a larger effect on exon 3 exclusion in neural cell lines, especially neuronal cell lines, than in non-neural cell lines. Furthermore, correct inclusion of exon 3 in the normal mtAspRS mRNA occurs less efficiently in neural cells than in other cell types, and this effect is again most pronounced in neuronal cells. The combined result of these two effects may explain the selective vulnerability of specific white matter tracts in LBSL patients.

scholarly journals Leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate: report of three brazilian patients

2007 ◽  
Vol 65 (2b) ◽  
pp. 506-511 ◽  
Author(s):  
Daniel Gurgel Fernandes Távora ◽  
Mauro Nakayama ◽  
Rômulo Lopes Gama ◽  
Thereza Cristina de Lara Alvim ◽  
Dalton Portugal ◽  
...  
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Magnetic Resonance ◽  
Autosomal Recessive Disorder ◽  
Dorsal Column ◽  
Resonance Spectroscopy ◽  
Motor Neuropathy ◽  
Spinal Cord Involvement ◽  
Spinal Cord Dorsal ◽  
Magnetic Resonance Imaging Mri

A novel leukoencephalopathy was recently identified based on magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (¹H-MRS) findings. Leukoencephalopathy with brainstem and spinal cord involvement and high lactate (LBSL) is an autosomal recessive disorder characterized by early onset of symptoms and slowly progressive cerebellar, pyramidal and spinal cord dorsal column dysfunction. MRI and ¹H-MRS typically show abnormalities within cerebral and cerebellar white matter, a characteristic involvement of brainstem and spinal cord tracts and elevated lactate in the abnormal white matter. We present three cases with characteristic clinical and neuroimaging findings of this disorder. Some additional unique findings of our patients are discussed, like distal motor neuropathy and elevated creatine kinase in the serum.

Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

2007 ◽  
Vol 39 (4) ◽  
pp. 534-539 ◽  
Author(s):  
Gert C Scheper ◽  
Thom van der Klok ◽  
Rob J van Andel ◽  
Carola G M van Berkel ◽  
Marie Sissler ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Brain Stem ◽  
Trna Synthetase ◽  
Synthetase Deficiency ◽  
Spinal Cord Involvement

Leukoencephalopathy With Brain Stem and Spinal Cord Involvement and High Lactate: A Genetically Proven Case Without Elevated White Matter Lactate

2011 ◽  
Vol 26 (6) ◽  
pp. 773-776 ◽  
Author(s):  
Suvasini Sharma ◽  
Naveen Sankhyan ◽  
Atin Kumar ◽  
Gert C. Scheper ◽  
Marjo S. van der Knaap ◽  
...  
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Brain Stem ◽  
Spinal Cord Involvement ◽  
Proven Case ◽  
High Lactate

Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways

2013 ◽  
Vol 450 (2) ◽  
pp. 345-350 ◽  
Author(s):  
Laura van Berge ◽  
Josta Kevenaar ◽  
Emiel Polder ◽  
Agnès Gaudry ◽  
Catherine Florentz ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Enzyme Activity ◽  
Catalytic Activity ◽  
White Matter ◽  
Autosomal Recessive ◽  
Trna Synthetase ◽  
Compound Heterozygous ◽  
Small Contribution ◽  
Missense Mutations ◽  
White Matter Disorder

The autosomal recessive white matter disorder LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) is caused by mutations in DARS2, coding for mtAspRS (mitochondrial aspartyl-tRNA synthetase). Generally, patients are compound heterozygous for mutations in DARS2. Many different mutations have been identified in patients, including several missense mutations. In the present study, we have examined the effects of missense mutations found in LBSL patients on the expression, enzyme activity, localization and dimerization of mtAspRS, which is important for understanding the cellular defect underlying the pathogenesis of the disease. Nine different missense mutations were analysed and were shown to have various effects on mtAspRS properties. Several mutations have a direct effect on the catalytic activity of the enzyme; others have an effect on protein expression or dimerization. Most mutations have a clear impact on at least one of the properties of mtAspRS studied, probably resulting in a small contribution of the missense variants to the mitochondrial aspartylation activity in the cell.

Leukoencephalopathy With Brain Stem and Spinal Cord Involvement and Lactate Elevation (LBSL)

2020 ◽  
Vol 25 (5) ◽  
pp. 144-147
Author(s):  
Isil Yazici Gencdal ◽  
Alp Dincer ◽  
Oguzhan Obuz ◽  
Zuhal Yapici
Keyword(s):  
Spinal Cord ◽  
Brain Stem ◽  
Spinal Cord Involvement
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