Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation

Disease Overview

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a rare disorder characterized by a range of neurological issues. Affected individuals have disease of the white matter of the brain (leukoencephalopathy). White matter forms what is known as the myelin sheath, which is the protective covering of the nerve fibers. Without white matter, the signals between nerve cells cannot be transmitted properly. Lactate is a metabolite found in the brain and its exact role in the brain is not fully understood but it may help to supply energy to nerve cells. Lactate is elevated in most people with LBSL. Signs and symptoms of LBSL may include spasticity, weakness and progressive cerebellar ataxia. Spasticity is stiffness of the muscles, which leads to progressive difficulty with walking and in some people, to the inability to walk. Cerebellar ataxia refers to the difficulty with coordinating voluntary movements, which can lead a variety of issues including poor manual coordination, difficulty with fine motor tasks and unsteadiness when walking. LBSL is caused by a change (variant) in the DARS2 gene. There is no cure yet. Treatment is aimed at the specific symptoms that are present.

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Synonyms

• LBSL
• mitochondrial aspartyl-tRNA synthetase deficiency
• leukoencephalopathy with brain stem and spinal cord involvement-lactate elevation syndrome
• leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
• mitochondrial aspartyl-tRNA synthetase deficiency

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Signs & Symptoms

Although researchers have been able to establish some characteristic or “core” symptoms that define LBSL, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the fact that many combinations of DARS2 gene variants can cause this disorder make it difficult to know all the associated symptoms and prognosis. Therefore, it is important to note that affected people may not have all the symptoms discussed below. Affected individuals or parents of affected children should talk to their doctor about their specific case, associated symptoms and overall prognosis.

LBSL is best thought of as a spectrum of disease. It can cause symptoms that develop before birth (neonatally) with severe complications in infancy. Often, newborns or infants who develop symptoms early in infancy die within the first couple of years of life. On the other hand, some affected people may not develop noticeable symptoms until school age or adulthood, and these symptoms may remain mild for many years. LBSL usually develops slowly over years, except in the more severe cases.

People with childhood onset may have the following symptoms:

• Normal early development
• Progressive difficulty walking, resulting in the need for assistance to walk, including the need for a wheelchair by teenage years or later in adulthood in some people
• Onset, progression and severity vary from person to person
• Some people may have mild balance problems in their teens that result in difficulty walking (gait disturbance)

Most people with adult onset of LBSL do not become reliant on a wheelchair.

The most common symptoms are:

• Stiffness of muscles (spasticity)
• Difficulty coordinating walking and executing fine motor skills (cerebellar ataxia)

Additional symptoms that can occur include:

• Problems sensing the position of the arms and legs, especially the legs
• Seizures
• Difficulty speaking (dysarthria)
• Hand tremors
• Rapid, involuntary eye movements (nystagmus)
• Decline in cognitive skills, although most affected individuals have normal intellectual abilities
• Learning disabilities
• Peripheral neuropathy, a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged and may result in tingling, burning, numbness and stabbing pain in the affected extremities

People with LBSL may be at risk for severe complications following minor head trauma. Minor head trauma can cause loss of consciousness, fever and neurological decline.

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Causes

LBSL is caused by changes (variants) in the DARS2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When gene variants occur, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain and spinal cord.

The DARS2 gene produces an enzyme called mitochondrial aspartyl-tRNA synthetase. Enzymes are specialized proteins that act to bring about biochemical reactions. The mitochondrial aspartyl-tRNA synthetase enzyme acts to combine the amino acid aspartic acid with mitochondrial proteins. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through respiratory chain enzymes, which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. Because of variants in the DARS2 gene, there is insufficient production of functional mitochondrial aspartyl-tRNA synthetase, which impacts the binding of aspartic acid to mitochondrial proteins. How these changes ultimately lead to the signs and symptoms of LBSL is not fully understood.

Inheritance

LBSL follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Nearly all people with LBSL are compound heterozygous for two DARS2 variants which means they have inherited two different DARS2 variants.

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Affected populations

LBSL is an extremely rare disorder that was first reported in the medical literature in 2002. According to Cure LBSL, as of April 2018, there are about 100 people worldwide who have been diagnosed with LBSL. Because rare diseases like LBSL often go undiagnosed or misdiagnosed, it is difficult to determine the true frequency in the general population.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of LBSL. Comparisons may be useful for a differential diagnosis.

Mitochondrial diseases are a group of rare genetic disorders. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through the respiratory chain enzymes (complexes I-V) which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial diseases. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body.

The spinocerebellar ataxias (SCA) are a group of genetic neurological disorders characterized by difficulty controlling and coordinating voluntary movements (ataxia) due to degenerative changes in the brain and spinal cord (spinocerebellar). Ataxia can lead to an awkward, uncoordinated walk (gait) often accompanied by poor eye-hand coordination, clumsiness, visual problems and abnormal speech (dysarthria).

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Diagnosis

A diagnosis of LBSL is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including genetic testing to determine mutations in the DARS2 gene.

Clinical Testing and Workup
Distinctive findings can be found on a specialized imaging technique called magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Specifically, there are distinctive changes on MRIs of certain areas of the brain or spinal cord that can be used to diagnose LBSL.

Some publications suggest that proton magnetic resonance spectroscopy be used to detect lactate, which is elevated in abnormal white matter sections in most but not all affected individuals. This noninvasive test is a specialized imaging technique that allows physicians to assessed changes in brain biochemistry. However, because not every patient shows elevated lactate levels, LBSL should be suspected if characteristic MRI findings are present whether lactate levels are elevated or not.

Molecular genetic testing can confirm a diagnosis of LBSL. Molecular genetic testing can detect abnormal variations in the DARS2 gene, but is available only as a diagnostic service at specialized laboratories.

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Standard Therapies

There is no cure for LBSL. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, specialists in diagnosing and treating disorders of the brain and central nervous system in children (neurologists), physical therapists, geneticists, social workers and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well.

Genetic counseling is recommended for affected individuals and their families.

There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or a small series of reports. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with LBSL.

Affected individuals may benefit from physical therapy and rehabilitation, which can improve motor function. Speech therapy can help individuals with dysarthria. Additional medical, social and/or vocation services including special remedial education may be necessary. Anti-seizure medications, called anti-convulsants or anti-epileptics, may be prescribed for seizures.

LBSL is usually a slowly progressive disorder and follow-up MRIs every few years are recommended.

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Clinical Trials and Studies

Some researchers have found that treatment with a combination of aminolevulinic acid (ALA) and iron (Fe) helped restore energy levels and reduce this stress. This effect was driven by activation of Nrf-2, a protein that acts as the master regulator of the cell’s antioxidant defenses and, when activated, turns on genes that protect cells from oxidative stress and improve mitochondrial function. Because ALA and iron are already FDA-approved for other conditions, this approach could move toward clinical use more quickly than development of a new drug. While more research is needed, these findings suggest ALA/Fe may offer a meaningful step forward in treating LBSL by improving the core cellular problems driving the disease.

There is progress toward gene‑replacement therapy. Researchers have reported that gene transfer in preclinical models has altered disease trajectory, and a human‑ready vector is in development, pending safety testing across species. A natural history clinical trial aimed at quantifying LBSL progression is underway, which may help validate clinical outcome measures and therapeutic endpoints. Patient‑led initiatives and research consortia (e.g., Cure LBSL, LBSL Global Research Consortium) continue expanding registry data, variant curation, and collaboration to accelerate understanding and eventual treatment trials.

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Huang WL, Eichwald T, Stover A, et al. Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms. Biochim Biophys Acta Mol Basis Dis. 2025;1871(5):167824. doi:10.1016/j.bbadis.2025.167824

Guang S, O’Brien B, Fine AS, Ying M, Fatemi A, Nemeth C. Mutations in DARS2 result in global dysregulation of mRNA metabolism and splicing. Preprint. Res Sq. 2023;rs.3.rs-2603446. Published 2023 Feb 27. doi:10.21203/rs.3.rs-2603446/v1

Shimojima K, Higashiguchi T, Kishimoto K, et al. A novel DARS2 mutation in a Japanese patient with leukoencephalopathy with brainstem and spinal cord involvement but no lactate elevation. Hum Genome Var. 2017;4:17051. https://www.ncbi.nlm.nih.gov/pubmed/29138691

Rathmore G, Star L, Larsen P, Rizzo W. Novel mutation of DARS2 gene leads to a rare and aggressive presentation of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). Neurology. 2017;88 (16 Supplement).

Navarro Vazquez I, Maestre Martinez L, Lozano Setien E, Menor Serrano F. Leucoencephalopathy with brain stem and spinal cord involvement and lactate elevation: report of two new cases. An Pediatr (Barc). 2016;84:291-293. https://www.ncbi.nlm.nih.gov/pubmed/26320665

Van Berge L, Hamilton EM, Linnankivi T, et al. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy. Brain. 2014;137:1019-1029. https://www.ncbi.nlm.nih.gov/pubmed/24566671

Schicks J, Schols L, van der Knaap MS, Synofzik M. Teaching NeuroImages: MRI guides genetics: leukoencephalopathy with brainstem and spinal cord involvement (LBSL). Neurology. 2013;80:e176-177. https://www.ncbi.nlm.nih.gov/pubmed/23589646

Tzoulis C, Tran GT, Gjerde IO, et al. Leukoencephalopathy with brainstem and spinal cord involvement caused by a novel mutation in the DARS2 gene. J Neuol. 2012;259:292-296. https://www.ncbi.nlm.nih.gov/pubmed/21792730

Mierzewska H, van der Knaap MS, Scheper GC, et al. Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation in the first Polish patient. Brain Dev. 2011;33:713-717. https://www.ncbi.nlm.nih.gov/pubmed/21277128

Tavora DG, Nakayama M, Gama RL, et al. Leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate: report of three Brazilian patients. Arq Neuropsiquiatr. 2007;65:506-511.

INTERNET

Engelen M, Abbink TEM, Salomons GS, et al. Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation. 2010 May 25 [Updated 2021 Feb 18]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK43417/  Accessed August 5, 2025.

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