Leukoencephalopathy with Brainstem and Spinal cord involvement and Lactate elevation (LBSL) is a rare type of leukodystrophy, which is a group of inherited neurological disorders affecting the white matter in the central nervous system [1]. LBSL results in neurologic symptoms affecting coordination, balance, sensation, and muscle movement. Onset can occur in infancy, childhood, or adulthood, and the progression and disease severity increase with earlier onset of symptoms. The disease is very rare. The carrier rate, or the proportion of the population that carries a single recessive pathogenic mutation, is low [2]. However, the carrier rate in Finland has been reported to be 1:95 and 1:380 for specific DARS2 mutations [2, 3].
LBSL is most commonly caused by autosomal recessive mutations in the DARS2 gene. DARS2 encodes for mitochondrial aspartyl-tRNA synthetase (mtAspRS) [2, 4]. mtAspRS is responsible for matching the amino acid aspartate to its corresponding transfer RNA in the mitochondria, which can then be used to build important proteins for mitochondrial function. Prior studies have shown that LBSL patients show decreased mtAspRS activity [4, 5]. Because LBSL is a recessive disease, it is common for LBSL patients to have two pathogenic mutations—one from each parent—in the DARS2 gene. These mutations can be located in different parts of the DARS2 gene (referred to as compound heterozygous mutations) or the same pathogenic mutation inherited from both parents (referred to as homozygous mutations) [2].
Patients with LBSL have a broad range of symptoms, and more research is needed to better understand specific symptoms associated with specific mutations in DARS2. The primary symptoms of LBSL are ataxia (problems with coordination, balance, and muscle movement), spasticity (abnormal stiffening or tightening of), and dorsal column dysfunction (loss of sense of position and vibration sense). These symptoms are slowly progressive, and the legs are typically more affected than the arms. The deterioration of motor skills typically manifests in childhood or adolescence, though it has been observed in infancy and adulthood. Over time, affected individuals may develop speech problems called dysarthria. Microcephaly, or a smaller than normal head, occurs in affected individuals who have onset before birth or in early infancy. Other potential symptoms include sensory loss or distal weakness caused by axonal periphery neuropathy, epilepsy, learning disabilities, slow cognitive decline, and decreased responsiveness, neurologic deterioration, and fever after minor head trauma [2].
To determine if your loved one has LBSL, your healthcare provider may perform magnetic resonance imaging (MRI) to check for characteristic abnormalities in the brain and spinal cord. Major criteria used to diagnose the disease include abnormal white matter signal abnormalities in the cerebral white matter, spinal cord, and brain stem or loss of brain cells and connection called brain atrophy [2, 4]. Other signal abnormalities in the brain MRI may serve as supportive criteria in the diagnosis. Your healthcare provider may also perform molecular genetic testing to search for pathogenic variants of the DARS2 gene. If molecular genetic testing is inconclusive, your healthcare provider may refer you to a specialty center that can conduct an assay on MtAspRS activity in lymphoblasts or other mitochondrial-specific function testing [2].
Like most mitochondrial diseases, LBSL does not have a cure at the moment, and treatments are focused on managing symptoms, including:
- Physical therapy for spasticity
- Occupational therapy for coordination and fine motor control
- Anti-seizure medication for epilepsy
- Speech therapy for dysarthria
- Individualized education plan for intellectual disability
- Social work and care coordination to support families
Routine surveillance for neurological symptoms and developmental progress is recommended. As LBSL is an autosomal recessive disorder, genetic counseling may be recommended for the family [2].
If you have other forms of mitochondrial disease — or are still on your diagnostic journey and suspect mito, we encourage you to reach out to UMDF’s support team at (888) 900-6486 or support@umdf.org.
- Get Support
Connect with our Support & Education Team online, via email at support@umdf.org or phone at (888) 900-6486.
- Check our clinical trials finder
Use our Clinical Trials Finder tool to see if you qualify for any clinical trials.
- Join our patient registry, mitoSHARE
We are actively recruiting LBSL families to participate in our patient registry, mitoSHARE. Patient registries like mitoSHARE are an integral part in charting a course toward treatments and cures for LBSL and other mitochondrial diseases. There are currently over 30 active mitochondrial disease clinical trials. Next generation patient registries like mitoSHARE are an integral part of expanding that number.
- Become an advocate
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- Join the conversation online
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- Get involved
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UMDF is helping chart a path toward treatments and eventual cure of mitochondrial diseases like LBSL through:
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- Research & Funding: UMDF has provided more than $18 million in research funding to find treatments for diseases like LBSL. UMDF advocacy has helped secure an additional $80 million in federal funding via the Department of Defense and National Institutes of Health.
- Data: Over two decades ago, UMDF pioneered patient registries for the mitochondrial disease community. Today, our next generation patient registry, mitoSHARE, is helping chart a path toward the treatment and eventual cure of mitochondrial diseases.
- Patient Support: Thousands of families just like you depend upon UMDF for support and education on diseases like LBSL. Attendance at our support meetings annually tops 5,000, including disease specific support meetings for families.
- Clinician Support: To help educate clinicians on diseases like LBSL, we feature monthly Bench to Bedside clinician seminars, host the annual Mitochondrial Medicine Symposium, support the Mitochondrial Care Network, and educate clinicians on our Mito U platform.
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UMDF is here to help. Contact the Support Line at (888) 900-6486 weekdays from 8:00am to 5:00pm EST to connect with our Patient Concierge. Or, via email contact support@umdf.org.
- National Institute of Neurological Disorders and Stroke. Leukodystrophy.
- Engelen et al., 2010 (last updated 2021). Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation.
- Isohanni et al. 2010. DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis.
- Scheper et al., 2007. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.
- van Berge et al., 2014. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy.