National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Leukoencephalopathy with thalamus and brainstem involvement and high lactate


Other Names:
Combined oxidative phosphorylation defect type 12; Combined oxidative phosphorylation deficiency 12; COXPD12; Combined oxidative phosphorylation defect type 12; Combined oxidative phosphorylation deficiency 12; COXPD12; LTBL; Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome See More
Categories:
This disease is grouped under:
Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is a rare disorder that affects the brain. It is part of a group of disorders known as leukodystrophies. Leukodystrophies are diseases that affect the white matter of the brain. The white matter contains nerve fibers (axons), surrounded by a type of sheath or covering called myelin (a fatty, white colored substance) that allows the transmission of impulses or communication among brain cells (neurons). 

LTBL is characterized by changes in specific parts of the brain including the cerebellum, thalamus and brainstem. These changes can be seen by brain imaging exams (MRI). High levels of lactate in the blood and in the cerebral spinal fluid are also seen.[1][2][3]

There are basically two forms of the disease based on severity of symptoms and age of onset: [2][3][4][5] 
  • A mild disease, with onset around 6 months of age, characterized by the loss of acquired skills (psychomotor regression), muscle stiffness (spasticity), irritability and seizures. These symptoms often improve during the toddler years. 
  • A severe disease with symptoms that start in newborns and include brain and liver problems. Symptoms generally do not improve with age. 
LTBL is caused by changes (mutations) in the EARS2 gene.[1][2] Mutations in this gene decrease the amount of a specific mitochondrial enzyme needed for proper mitochondrial function (mitochondria are cell structures that convert the energy from food into a form that cells can use), and therefore, LTBL is also considered a type of mitochondrial disorder.[6] It is inherited in an autosomal recessive pattern.[2] There is still no cure for this disease. Treatment is typically supportive based on presenting symptoms.[7]
Last updated: 10/17/2017

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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Medical Terms Other Names
Learn More:
HPO ID
5%-29% of people have these symptoms
Cholestasis
Slowed or blocked flow of bile from liver
0001396
Cleft palate
Cleft roof of mouth
0000175
Hepatomegaly
Enlarged liver
0002240
Macrovesicular hepatic steatosis 0001403
Percent of people who have these symptoms is not available through HPO
Absent speech
Absent speech development
Lack of language development
Lack of speech
No speech development
No speech or language development
Nonverbal
[ more ] 		0001344
Autosomal recessive inheritance 0000007
Bradykinesia
Slow movements
Slowness of movements
[ more ] 		0002067
Decreased activity of mitochondrial complex I 0011923
Decreased activity of mitochondrial complex III 0011924
Decreased activity of mitochondrial complex IV 0008347
Developmental regression
Loss of developmental milestones
Mental deterioration in childhood
[ more ] 		0002376
Dysplastic corpus callosum 0006989
Dystonia 0001332
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
Global developmental delay 0001263
Hypoplasia of the corpus callosum
Underdevelopment of part of brain called corpus callosum
0002079
Increased serum lactate 0002151
Infantile onset
Onset in first year of life
Onset in infancy
[ more ] 		0003593
Lactic acidosis
Increased lactate in body
0003128
Leukoencephalopathy 0002352
Neonatal hypotonia
Low muscle tone, in neonatal onset
0001319
Ophthalmoplegia
Eye muscle paralysis
0000602
Ptosis
Drooping upper eyelid
0000508
Ragged-red muscle fibers 0003200
Seizure 0001250
Spastic tetraparesis 0001285
Visual impairment
Impaired vision
Loss of eyesight
Poor vision
[ more ] 		0000505
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Last updated: 7/1/2020

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

In-Depth Information

  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

  1. Combined oxidative phosphorylation deficiency 12. OMIM. December, 2013; http://www.omim.org/entry/614924.
  2. Leukoencephalopathy with thalamus and brainstem involvement and high lactate.. Genetics Home Reference (GHR). September 2016; https://ghr.nlm.nih.gov/condition/leukoencephalopathy-with-thalamus-and-brainstem-involvement-and-high-lactate#.
  3. 3. Steenweg ME, Ghezzi D, Haack T, Abbink TE, Martinelli D, van Berkel CG, Bley A, Diogo L, Grillo E, Te Water Naudé J, Strom TM, Bertini E, Prokisch H, van der Knaap MS, Zeviani M.. Leukoencephalopathy with thalamus and brainstem involvement and high lactate 'LTBL' caused by EARS2 mutations.. Brain.. May, 2012; 135(Pt 5):1387-94. https://www.ncbi.nlm.nih.gov/pubmed/22492562.
  4. Sellars EA, Balmakund T, Bosanko K, Nichols BL, Kahler SG, Zarate YA. Severe Metabolic Acidosis and Hepatopathy due to Leukoencephalopathy with Thalamus and Brainstem Involvement and High Lactate.. Neuropediatrics. 2017; 48(2):108-110. https://www.ncbi.nlm.nih.gov/pubmed/?term=Severe+Metabolic+Acidosis+and+Hepatopathy+due+to+Leukoencephalopathy+with+Thalamus+and+Brainstem+Involvement+and+High+Lactate.
  5. Kevelam SH, Klouwer FC, Fock JM, Salomons GS, Bugiani M, van der Knaap MS. Absent Thalami Caused by a Homozygous EARS2 Mutation: Expanding Disease Spectrum of LTBL. Neuropediatrics. Jan, 2016; 47(1):64-7. https://www.ncbi.nlm.nih.gov/pubmed/?term=Absent+Thalami+Caused+by+a+Homozygous+EARS2+Mutation%3A+Expanding+Disease+Spectrum+of+LTBL.
  6. Wong LJ. Mitochondrial syndromes with leukoencephalopathies. Semin Neurol. 2012; 32(1):55-61. https://www.ncbi.nlm.nih.gov/pubmed/22422207.
  7. Vanderver A, Tonduti D, Schiffmann R, et al. Leukodystrophy Overview. GeneReviews. . February 6, 2014; https://www.ncbi.nlm.nih.gov/books/NBK184570.