RARE DISEASE
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
Synonyms: LBSL, Leukoencephalopathy with brain stem and spinal cord involvement-lactate elevation syndrome
Synonyms: LBSL, Leukoencephalopathy with brain stem and spinal cord involvement-lactate elevation syndrome
Synonyms: LBSL, Leukoencephalopathy with brain stem and spinal cord involvement-lactate elevation syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Leukoencephalopathy with brainstem and spinal cord involvement-high lactate syndrome (LBSL) is a rare autosomal recessive disorder caused by DARS2 gene mutations, impairing mitochondrial aspartyl-tRNA synthetase function. It manifests as progressive white matter degeneration affecting pyramidal, cerebellar, and dorsal column pathways, with spasticity, ataxia, and sensory deficits [1][5][11]. Diagnosis relies on characteristic MRI findings (brainstem, spinal cord tracts, and cerebral white matter involvement) and elevated lactate on MRS [2][11]. No disease-modifying therapies exist; management focuses on symptom relief and supportive care [3][5].
Burden
Progressive motor decline leads to wheelchair dependency in ≥50% by adulthood [11][19].
Cognitive impairment occurs in 30–40%, while complications (e.g., respiratory infections, trauma-triggered deterioration) increase morbidity [1][9][11].
Life expectancy varies, with severe early-onset cases showing higher mortality [9][13].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
12 drug discovery papers about Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
12 drug discovery papers about Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-29 | Vocal Cord Paresis and Neuropathic Pain in Infantile Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation: A Case Report.
Mutations in the aspartyl-tRNA synthetase 2 (DARS2) gene cause the rare disease leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). Mitochondrial dysfunction leads to characteristic abnormalities in cerebral white matter, brainstem, and spinal cord. Symptoms usually present in childhood and progress slowly, but a more severe infantile form exists, often with rapid deterioration. We present a young Norwegian boy with hypotonia, areflexia, obesity, and vocal cord paresis, as well as extreme pain and swift disease progression. He had two DARS2 variants, which, through functional analyses, were confirmed as causative. He was treated with high doses of ketamine that allowed for effective pain relief and lenient palliative care. This patient had an aggressive form of LBSL, and we propose a genotype-phenotype relationship as well as suggestions for suitable palliative care.
2025-04-05 | Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms.
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene DARS2, which compromises mitochondrial protein translation. The typical presentation is juvenile in onset with gradually progressive spasticity and ataxia. Only palliative treatment is available for LBSL individuals. Here we showed that the use of the Food and Drug Administration-approved heme precursors, aminolevulinate plus ferrous iron (ALA/Fe), can result in a novel pharmacological treatment that increases energy status in DARS2 deficient cells. The marked mitochondrial and antioxidant deficiencies observed in fibroblasts from two LBSL-affected brothers, harboring intron-2 (c.228-17C > G) and intron-5 (c.492 + 2 T > C) DARS2 mutations, were rescued by ALA/Fe exposure, and the use of dexamethasone, a known Nrf-2 inhibitor, blocked the positive effects of ALA/Fe. Altogether, this study showed that fibroblasts can be used as a biological system to identify potential new treatments for LBSL that can reduce morbidity and mortality, and that the activation of Nrf-2-mediated cytoprotection can be targeted for the treatment of LBSL and other mitochondrial diseases.
2020-08-14 | Modern views of brainstem and spinal cord leukoencephalopathy with increased lactate content
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.
2017-08-02 | DARS2 protects against neuroinflammation and apoptotic neuronal loss, but is dispensable for myelin producing cells
Although mitochondria are ubiquitous, each mitochondrial disease has surprisingly distinctly different pattern of tissue and organ involvement. Congruently, mutations in genes encoding for different mitochondrial tRNA synthetases result in the development of a very flamboyant group of diseases. Mutations in some of these genes, including aspartyl-tRNA synthetase (DARS2), lead to the onset of a white matter disease—leukoencephalopathy with brainstem and spinal cord involvement, and lactate elevation (LBSL) characterized by progressive spastic ataxia and characteristic leukoencephalopathy signature with multiple long-tract involvements. Puzzled by the white matter disease phenotypes caused by DARS2 deficiency when numerous other mutations in the genes encoding proteins involved in mitochondrial translation have a detrimental effect predominantly on neurons, we generated transgenic mice in which DARS2 was specifically depleted in forebrain-hippocampal neurons or myelin-producing cells. Our results now provide the first evidence that loss of DARS2 in adult neurons leads to strong mitochondrial dysfunction and progressive loss of cells. In contrast, myelin-producing cells seem to be resistant to cell death induced by DARS2 depletion despite robust respiratory chain deficiency arguing that LBSL might originate from the primary neuronal and axonal defect. Remarkably, our results also suggest a role for early neuroinflammation in the disease progression, highlighting the possibility for therapeutic interventions of this process.
2014-02-24 | Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is a disorder caused by recessive mutations in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. Recent observations indicate that the phenotypic range of the disease is much wider than initially thought. Currently, no treatment is available. The aims of our study were (i) to explore a possible genotype-phenotype correlation; and (ii) to identify potential therapeutic agents that modulate the splice site mutations in intron 2 of DARS2, present in almost all patients. A cross-sectional observational study was performed in 78 patients with two DARS2 mutations in the Amsterdam and Helsinki databases up to December 2012. Clinical information was collected via questionnaires. An inventory was made of the DARS2 mutations in these patients and those previously published. An assay was developed to assess mitochondrial aspartyl-tRNA synthetase enzyme activity in cells. Using a fluorescence reporter system we screened for drugs that modulate DARS2 splicing. Clinical information of 66 patients was obtained. The clinical severity varied from infantile onset, rapidly fatal disease to adult onset, slow and mild disease. The most common phenotype was characterized by childhood onset and slow neurological deterioration. Full wheelchair dependency was rare and usually began in adulthood. In total, 60 different DARS2 mutations were identified, 13 of which have not been reported before. Except for 4 of 42 cases published by others, all patients were compound heterozygous. Ninety-four per cent of the patients had a splice site mutation in intron 2. The groups of patients sharing the same two mutations were too small for formal assessment of genotype-phenotype correlation. However, some combinations of mutations were consistently associated with a mild phenotype. The mitochondrial aspartyl-tRNA synthetase activity was strongly reduced in patient cells. Among the compounds screened, cantharidin was identified as the most potent modulator of DARS2 splicing. In conclusion, the phenotypic spectrum of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is wide, but most often the disease has a relatively slow and mild course. The available evidence suggests that the genotype influences the phenotype, but because of the high number of private mutations, larger numbers of patients are necessary to confirm this. The activity of mitochondrial aspartyl-tRNA synthetase is significantly reduced in patient cells. A compound screen established a 'proof of principle' that the splice site mutation can be influenced. This finding is promising for future therapeutic strategies.
gene therapies
2025-09-15 | AAV9-DARS2 Gene Therapy Rescues Phenotype in Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation Patient Cells and Neuronal Dars2 Deficient Mice.
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare, autosomal recessive disorder caused by variants in the gene DARS2. DARS2 is an essential and ubiquitously expressed enzyme that catalyzes the attachment of aspartate to its cognate tRNA for mitochondrial protein translation. LBSL is clinically characterized by progressive spasticity, ataxia, and dorsal column dysfunction, and is considered a primary axonopathy with secondary demyelination. Herein, we tested the efficacy of gene supplementation, using adeno-associated virus, serotype 9 (AAV9)-DARS2 in LBSL patient cells, as well as in an LBSL mouse phenolog in which Dars2 was deleted in CamKIIα-expressing neurons of the hippocampus and cortex. In vitro, patient neurons treated with AAV9-DARS2 showed increased gene expression of the gene mirrored by improved mitochondrial function, axonal growth, and reduced lactate release, despite variation in impairment across lines. Knockout mice showed improved behavior and reduced cortical neurodegeneration 6 months after a single intracerebroventricular injection of AAV9-DARS2. Together, this work provides proof-of-concept data that gene supplementation can improve cell function and survival for an extended period of time. AAV9 therapy has proven especially useful for loss of function monogenetic disorders, and these data may support further investigation into therapies for LBSL. ANN NEUROL 2026;99:59-72.
2023-12-21 | Leukoencephalopathy with Brain stem and Spinal cord involvement and Lactate elevation (LBSL): Report of a new family and a novel DARS2 mutation.
LBSL is a mitochondrial disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene DARS2, resulting in a distinctive pattern on brain magnetic resonance imaging (MRI) and spectroscopy. Clinical presentation varies from severe infantile to chronic, slowly progressive neuronal deterioration in adolescents or adults. Most individuals with LBSL are compound heterozygous for one splicing defect in an intron 2 mutational hotspot and a second defect that could be a missense, non-sense, or splice site mutation or deletion resulting in decreased expression of the full-length protein. To present a new family with two affected members with LBSL and report a novel DARS2 mutation. An 8-year-old boy (Patient 1) was referred due to headaches and abnormal MRI, suggestive of LBSL. Genetic testing revealed a previously reported c.492 + 2 T > C mutation in the DARS2 gene. Sanger sequencing uncovered a novel variant c.228-17C > G in the intron 2 hotspot. Family studies found the same genetic changes in an asymptomatic 4-year-old younger brother (Patient 2), who was found on follow-up to have an abnormal MRI. mRNA extracted from patients' fibroblasts showed that the c.228-17C > G mutation caused skipping of exon 3 resulting in lower DARS2 mRNA level. Complete absence of DARS2 protein was also found in both patients. We present a new family with two children affected with LBSL and describe a novel mutation in the DARS2 intron 2 hotspot. Despite findings of extensive white matter disease in the brain and spine, the proband in this family presented only with headaches, while the younger sibling, who also had extensive white matter changes, was asymptomatic. Our in-vitro results confirmed skipping of exon 3 in patients and family members carrying the intron 2 variant, which is consistent with previous reported mutations in intron 2 hotspots. DARS2 mRNA and protein levels were also reduced in both patients, further supporting the pathogenicity of the novel variant.
oligonucleotides
2024-04-09 | In-vitro Efficacy and In-vivo Biodistribution Studies of an Antisense Oligonucleotide Targeting Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (S37.010)
This study aimed to explore the efficacy of antisense oligonucleotides (ASOs) to modify DARS2 gene expression in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL).
small molecules
2026-06-29 | Vocal Cord Paresis and Neuropathic Pain in Infantile Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation: A Case Report.
Mutations in the aspartyl-tRNA synthetase 2 (DARS2) gene cause the rare disease leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). Mitochondrial dysfunction leads to characteristic abnormalities in cerebral white matter, brainstem, and spinal cord. Symptoms usually present in childhood and progress slowly, but a more severe infantile form exists, often with rapid deterioration. We present a young Norwegian boy with hypotonia, areflexia, obesity, and vocal cord paresis, as well as extreme pain and swift disease progression. He had two DARS2 variants, which, through functional analyses, were confirmed as causative. He was treated with high doses of ketamine that allowed for effective pain relief and lenient palliative care. This patient had an aggressive form of LBSL, and we propose a genotype-phenotype relationship as well as suggestions for suitable palliative care.
2025-04-05 | Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms.
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene DARS2, which compromises mitochondrial protein translation. The typical presentation is juvenile in onset with gradually progressive spasticity and ataxia. Only palliative treatment is available for LBSL individuals. Here we showed that the use of the Food and Drug Administration-approved heme precursors, aminolevulinate plus ferrous iron (ALA/Fe), can result in a novel pharmacological treatment that increases energy status in DARS2 deficient cells. The marked mitochondrial and antioxidant deficiencies observed in fibroblasts from two LBSL-affected brothers, harboring intron-2 (c.228-17C > G) and intron-5 (c.492 + 2 T > C) DARS2 mutations, were rescued by ALA/Fe exposure, and the use of dexamethasone, a known Nrf-2 inhibitor, blocked the positive effects of ALA/Fe. Altogether, this study showed that fibroblasts can be used as a biological system to identify potential new treatments for LBSL that can reduce morbidity and mortality, and that the activation of Nrf-2-mediated cytoprotection can be targeted for the treatment of LBSL and other mitochondrial diseases.
2020-08-14 | Modern views of brainstem and spinal cord leukoencephalopathy with increased lactate content
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.
2017-08-02 | DARS2 protects against neuroinflammation and apoptotic neuronal loss, but is dispensable for myelin producing cells
Although mitochondria are ubiquitous, each mitochondrial disease has surprisingly distinctly different pattern of tissue and organ involvement. Congruently, mutations in genes encoding for different mitochondrial tRNA synthetases result in the development of a very flamboyant group of diseases. Mutations in some of these genes, including aspartyl-tRNA synthetase (DARS2), lead to the onset of a white matter disease—leukoencephalopathy with brainstem and spinal cord involvement, and lactate elevation (LBSL) characterized by progressive spastic ataxia and characteristic leukoencephalopathy signature with multiple long-tract involvements. Puzzled by the white matter disease phenotypes caused by DARS2 deficiency when numerous other mutations in the genes encoding proteins involved in mitochondrial translation have a detrimental effect predominantly on neurons, we generated transgenic mice in which DARS2 was specifically depleted in forebrain-hippocampal neurons or myelin-producing cells. Our results now provide the first evidence that loss of DARS2 in adult neurons leads to strong mitochondrial dysfunction and progressive loss of cells. In contrast, myelin-producing cells seem to be resistant to cell death induced by DARS2 depletion despite robust respiratory chain deficiency arguing that LBSL might originate from the primary neuronal and axonal defect. Remarkably, our results also suggest a role for early neuroinflammation in the disease progression, highlighting the possibility for therapeutic interventions of this process.
2014-02-24 | Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is a disorder caused by recessive mutations in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. Recent observations indicate that the phenotypic range of the disease is much wider than initially thought. Currently, no treatment is available. The aims of our study were (i) to explore a possible genotype-phenotype correlation; and (ii) to identify potential therapeutic agents that modulate the splice site mutations in intron 2 of DARS2, present in almost all patients. A cross-sectional observational study was performed in 78 patients with two DARS2 mutations in the Amsterdam and Helsinki databases up to December 2012. Clinical information was collected via questionnaires. An inventory was made of the DARS2 mutations in these patients and those previously published. An assay was developed to assess mitochondrial aspartyl-tRNA synthetase enzyme activity in cells. Using a fluorescence reporter system we screened for drugs that modulate DARS2 splicing. Clinical information of 66 patients was obtained. The clinical severity varied from infantile onset, rapidly fatal disease to adult onset, slow and mild disease. The most common phenotype was characterized by childhood onset and slow neurological deterioration. Full wheelchair dependency was rare and usually began in adulthood. In total, 60 different DARS2 mutations were identified, 13 of which have not been reported before. Except for 4 of 42 cases published by others, all patients were compound heterozygous. Ninety-four per cent of the patients had a splice site mutation in intron 2. The groups of patients sharing the same two mutations were too small for formal assessment of genotype-phenotype correlation. However, some combinations of mutations were consistently associated with a mild phenotype. The mitochondrial aspartyl-tRNA synthetase activity was strongly reduced in patient cells. Among the compounds screened, cantharidin was identified as the most potent modulator of DARS2 splicing. In conclusion, the phenotypic spectrum of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is wide, but most often the disease has a relatively slow and mild course. The available evidence suggests that the genotype influences the phenotype, but because of the high number of private mutations, larger numbers of patients are necessary to confirm this. The activity of mitochondrial aspartyl-tRNA synthetase is significantly reduced in patient cells. A compound screen established a 'proof of principle' that the splice site mutation can be influenced. This finding is promising for future therapeutic strategies.
gene therapies
2025-09-15 | AAV9-DARS2 Gene Therapy Rescues Phenotype in Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation Patient Cells and Neuronal Dars2 Deficient Mice.
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare, autosomal recessive disorder caused by variants in the gene DARS2. DARS2 is an essential and ubiquitously expressed enzyme that catalyzes the attachment of aspartate to its cognate tRNA for mitochondrial protein translation. LBSL is clinically characterized by progressive spasticity, ataxia, and dorsal column dysfunction, and is considered a primary axonopathy with secondary demyelination. Herein, we tested the efficacy of gene supplementation, using adeno-associated virus, serotype 9 (AAV9)-DARS2 in LBSL patient cells, as well as in an LBSL mouse phenolog in which Dars2 was deleted in CamKIIα-expressing neurons of the hippocampus and cortex. In vitro, patient neurons treated with AAV9-DARS2 showed increased gene expression of the gene mirrored by improved mitochondrial function, axonal growth, and reduced lactate release, despite variation in impairment across lines. Knockout mice showed improved behavior and reduced cortical neurodegeneration 6 months after a single intracerebroventricular injection of AAV9-DARS2. Together, this work provides proof-of-concept data that gene supplementation can improve cell function and survival for an extended period of time. AAV9 therapy has proven especially useful for loss of function monogenetic disorders, and these data may support further investigation into therapies for LBSL. ANN NEUROL 2026;99:59-72.
2023-12-21 | Leukoencephalopathy with Brain stem and Spinal cord involvement and Lactate elevation (LBSL): Report of a new family and a novel DARS2 mutation.
LBSL is a mitochondrial disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene DARS2, resulting in a distinctive pattern on brain magnetic resonance imaging (MRI) and spectroscopy. Clinical presentation varies from severe infantile to chronic, slowly progressive neuronal deterioration in adolescents or adults. Most individuals with LBSL are compound heterozygous for one splicing defect in an intron 2 mutational hotspot and a second defect that could be a missense, non-sense, or splice site mutation or deletion resulting in decreased expression of the full-length protein. To present a new family with two affected members with LBSL and report a novel DARS2 mutation. An 8-year-old boy (Patient 1) was referred due to headaches and abnormal MRI, suggestive of LBSL. Genetic testing revealed a previously reported c.492 + 2 T > C mutation in the DARS2 gene. Sanger sequencing uncovered a novel variant c.228-17C > G in the intron 2 hotspot. Family studies found the same genetic changes in an asymptomatic 4-year-old younger brother (Patient 2), who was found on follow-up to have an abnormal MRI. mRNA extracted from patients' fibroblasts showed that the c.228-17C > G mutation caused skipping of exon 3 resulting in lower DARS2 mRNA level. Complete absence of DARS2 protein was also found in both patients. We present a new family with two children affected with LBSL and describe a novel mutation in the DARS2 intron 2 hotspot. Despite findings of extensive white matter disease in the brain and spine, the proband in this family presented only with headaches, while the younger sibling, who also had extensive white matter changes, was asymptomatic. Our in-vitro results confirmed skipping of exon 3 in patients and family members carrying the intron 2 variant, which is consistent with previous reported mutations in intron 2 hotspots. DARS2 mRNA and protein levels were also reduced in both patients, further supporting the pathogenicity of the novel variant.
oligonucleotides
2024-04-09 | In-vitro Efficacy and In-vivo Biodistribution Studies of an Antisense Oligonucleotide Targeting Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (S37.010)
This study aimed to explore the efficacy of antisense oligonucleotides (ASOs) to modify DARS2 gene expression in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL).
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.