Rare Pulmonology News

Disease Profile

Leukoencephalopathy with thalamus and brainstem involvement and high lactate

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

#N/A

ICD-10

#N/A

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Combined oxidative phosphorylation defect type 12; Combined oxidative phosphorylation deficiency 12; COXPD12;

Categories

Congenital and Genetic Diseases; Nervous System Diseases

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]

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.

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

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

    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.

      References

      1. Combined oxidative phosphorylation deficiency 12. OMIM. December, 2013; https://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.