August 13, 2018
Years published: 2018
NORD gratefully acknowledges Amena Smith MD, PhD, Neurodevelopmental Medicine Department, The Kennedy Krieger Institute, and A Cure for Ellie, for assistance in the preparation of this report.
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; it’s exact role in the brain is not fully understood but it may help to supply energy to nerve cells. Lactate is elevated in most individuals with LBSL. Affected individuals exhibit a variety of symptoms including spasticity, weakness and progressive cerebellar ataxia. Spasticity is stiffness of the muscles, which leads to progressive difficulty with walking and for some, loss of the ability to walk. Cerebellar ataxia is 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 an abnormal variant (mutation) in the DARS2 gene. There is no cure and treatment is aimed at the specific symptoms that are present.
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 mutation types can produce this disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team 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 pass away within the first couple years of life. Conversely, some individuals may not develop noticeable symptoms until school age or adulthood and these symptoms may remain mild for many years. Except for the most severe form, LBSL usually develops slowly over years.
In most individuals with childhood onset of this disorder, initial development is normal. Most children will walk within a normal age range, but many will require assistance to walk by their teen-age years, their 20s, or later in adulthood. Some will require the use of a wheelchair. The onset, progression and severity will vary. Some individuals may have mild balance problems in their teens that become difficulties with walking (gait disturbance). Most individuals with adult onset of the disorder do not become reliant on a wheelchair.
The most common symptoms experienced in LBSL are spasticity, or stiffness of the muscles, and cerebellar ataxia, which is difficulty coordinating walking and executing fine motor skills. Affected individuals may also have problems sensing the position of their arms and legs. The legs tend to be more severely affected than the arms. Additional symptoms that can occur include seizures, difficulty speaking (dysarthria), hand tremors, rapid, involuntary eye movements (nystagmus), and a decline in cognitive skills, although most affected individuals have normal intellectual abilities. Some children may experience learning disabilities. Sometimes, peripheral neuropathy develops. This 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. Those affected may experience tingling, burning, numbness, and stabbing pain in the affected extremities.
Individuals 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.
LBSL is caused by an abnormal variant on in the DARS2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain and spinal cord.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits the same abnormal gene for the same trait from each parent. Nearly all individuals with LBSL are compound heterozygous for two DARS2 mutations, which means they have actually inherited 2 different autosomal recessive mutations that have the combined effect of causing disease.
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 the mutations affecting 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.
LBSL is an extremely rare disorder that was first reported in the medical literature in 2002. According to the nonprofit organization, A Cure for Ellie, as of April 2018, there are about 100 individuals worldwide who have been identified with the disorder. Because rare diseases like LBSL often go undiagnosed or misdiagnosed, it is difficult to determine the true frequency in the general population.
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.
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 disorder 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 may be of benefit 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 is recommended.
As of July 2018, there is a natural history study being conducted by physicians at the Kennedy Krieger Institute, a medical institution in Baltimore, Maryland. A natural history study is a study that follows a group of people with a disorder or at risk of developing a disorder. A natural history study collects lots of different types of health information including about how a disorder progresses, what symptoms are most common or less common, how the disorder differs among different age groups, etc. This information helps researchers better understand a disorder and, hopefully, will lead to ideas for better, more effective treatments. The natural history study for LBSL is listed on clinicaltrials.gov (see next paragraph), or can be reached at the nonprofit website, A Cure for Ellie: http://acureforellie.org/clinical-trial/.
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
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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.
Genetics Home Reference. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation. August 2011. Available at: https://ghr.nlm.nih.gov/condition/leukoencephalopathy-with-brainstem-and-spinal-cord-involvement-and-lactate-elevation Accessed April 18, 2018.
van der Knaap MS, Salomons GA. Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. 2010 May 25 [Updated 2015 Feb 12]. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Internet. Seattle, WA: University of Washington, Seattle; 1993-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK43417/ Accessed April 18, 2018.
A Cure for Ellie website. What is LBSL? 2018. Available at: http://acureforellie.org/what-is-lbsl/ Accessed April 18, 2018.
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