leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (LBSL) is a very rare inherited leukodystrophy that primarily affects the brain’s white matter, spinal cord, and cerebellum. The condition is caused by pathogenic variants in the DARS2 gene, which encodes the mitochondrial aspartyl-tRNA synthetase needed for normal energy production in nerve cells. Symptoms often begin in childhood or adolescence, though onset can range from infancy to adulthood, and both males and females are affected equally. Worldwide, fewer than one in a million people are thought to live with LBSL. Progressive problems with movement and balance are typical, but the severity and specific symptoms vary widely between individuals.

Early signs frequently include clumsiness, an unsteady gait, or difficulty running that draw attention to a neurological problem. Over time many individuals develop progressive cerebellar ataxia, leg stiffness (spasticity), and distal muscle weakness, reflecting combined involvement of the cerebellum, pyramidal tracts, and spinal dorsal columns. Speech may become slow or slurred, and some people notice reduced vibration or position sense in the feet. Characteristic MRI findings show symmetrical abnormalities of the brainstem, cerebellar tracts, and spinal cord, while magnetic resonance spectroscopy or cerebrospinal fluid studies may reveal elevated lactate in the affected white matter. Cognitive impairment or specific learning disabilities occur in a minority of individuals and are usually mild, but they highlight that LBSL can affect cognitive as well as motor pathways. Not all individuals experience all features, and severity varies considerably.

LBSL results from inheriting damaging variants in both copies of the DARS2 gene. The DARS2 protein helps mitochondria attach the amino acid aspartate to its transfer RNA, a critical step in mitochondrial protein synthesis. When the enzyme does not function properly, cells with high energy needs—particularly those that make or maintain myelin in the brain and spinal cord—are most affected. The disorder follows an autosomal recessive inheritance pattern, meaning an individual must receive one altered gene from each parent to develop symptoms. Parents who each carry one altered DARS2 gene (carriers) are typically healthy but have a 25 percent chance with each pregnancy to have a child with LBSL. Because both parents must carry the same rare variant, the condition can be more common when parents share a common ancestor. Genetic counseling is recommended for affected individuals and at-risk relatives to discuss carrier testing, family planning options, and implications for future pregnancies.

Currently, management focuses on supportive care and symptom management. Physical and occupational therapy help maintain mobility, improve balance, and address spasticity, while speech therapy can support communication when dysarthria is present. Spasticity may also be managed with oral medications or targeted interventions recommended by a neurologist. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious; periodic neurological examinations, assessment of walking ability, and follow-up imaging are commonly employed. A multidisciplinary team—often including neurologists, rehabilitation specialists, physiatrists, and genetic counselors—coordinates care and tailors interventions to individual needs. Patients should discuss all treatment options with their healthcare team to determine which approaches are most appropriate for their situation.

LBSL is typically slowly progressive. Many individuals remain able to walk into adolescence or adulthood, although some eventually need mobility aids or may lose independent ambulation. Cognitive functions are often preserved or only mildly affected, and life expectancy can be near normal, particularly with attentive supportive care, though long-term data are limited. Outcomes vary depending on the age at symptom onset, the rate of progression, and access to specialized care and rehabilitation services. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with neurologists and rehabilitation specialists experienced in leukodystrophies, participate in patient registries, and seek genetic counseling for ongoing support and future planning.

Clinical trials are underway exploring new treatment approaches and strategies to better understand the natural history of LBSL. Individuals interested in research participation can search ClinicalTrials.gov or consult their care team about eligibility.