Leukoencephalopathy with thalamus and brainstem involvement and high lactate

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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:

Congenital and Genetic Diseases; Nervous System Diseases

This disease is grouped under:

Combined oxidative phosphorylation deficiency

Summary Summary

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

Symptoms Symptoms

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: 1/1/2021

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Find a Specialist Find a Specialist

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

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Organizations Organizations

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 Providing General Support

Alex The Leukodystrophy Charity (Alex TLC)
45 Peckham High Street
London, SE15 5EB United Kingdom
Telephone: 020 7701 4388
E-mail: info@alextlc.org
Website: https://www.alextlc.org

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Learn More Learn More

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.

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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.

Have a question? Contact a GARD Information Specialist.

References References

Combined oxidative phosphorylation deficiency 12. OMIM. December, 2013; http://www.omim.org/entry/614924.
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. 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.
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.
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.
Wong LJ. Mitochondrial syndromes with leukoencephalopathies. Semin Neurol. 2012; 32(1):55-61. https://www.ncbi.nlm.nih.gov/pubmed/22422207.
Vanderver A, Tonduti D, Schiffmann R, et al. Leukodystrophy Overview. GeneReviews. . February 6, 2014; https://www.ncbi.nlm.nih.gov/books/NBK184570.