Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is a disorder that affects the brain. LTBL is one of a group of genetic disorders called leukodystrophies, which feature abnormalities of the nervous system's white matter. White matter consists of nerve fibers covered by a fatty substance, called myelin, that insulates nerve fibers and promotes the rapid transmission of nerve impulses.

LTBL is characterized by distinct changes in the brain, which can be seen using magnetic resonance imaging (MRI). These abnormalities typically involve white matter in regions of the brain known as the cerebrum and cerebellum. Abnormalities can also be seen in other regions of the brain, including the brainstem, which is the part that connects to the spinal cord. Affected brain regions include the thalamus, midbrain, pons, and medulla oblongata. Thinning of the tissue that connects the left and right halves of the brain (the corpus callosum) also occurs in people with LTBL. In addition, most affected individuals have a high level of a substance called lactate in the brain and elsewhere in the body.

The severity of the condition varies. Mildly affected individuals usually develop signs and symptoms after the age of 6 months. Loss of mental and movement abilities (psychomotor regression), muscle stiffness (spasticity), and extreme irritability are common, and some people with mild LTBL develop seizures. However, after age 2, the signs and symptoms of the condition improve: affected children regain some psychomotor abilities, seizures are reduced or disappear, MRI results become more normal, and lactate levels drop.

Severely affected individuals have features that begin soon after birth. These infants typically have delayed development of mental and movement abilities (psychomotor delay), weak muscle tone (hypotonia), involuntary muscle tensing (dystonia), muscle spasticity, and seizures. Some have extremely high levels of lactate (lactic acidosis), which can cause serious breathing problems and an abnormal heartbeat. Liver failure occurs in some severely affected infants. In severe cases, the signs and symptoms do not improve and can be life-threatening. In some people with LTBL, the features fall between mild and severe.

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.

There are basically two forms of the disease based on severity of symptoms and age of onset:

• 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. 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. It is inherited in an autosomal recessive pattern. There is still no cure for this disease. Treatment is typically supportive based on presenting symptoms.

LTBL is caused by mutations in the EARS2 gene, which provides instructions for making an enzyme called mitochondrial glutamyl-tRNA synthetase. This enzyme is important in the production (synthesis) of proteins in cellular structures called mitochondria, the energy-producing centers in cells. While most protein synthesis occurs in the fluid surrounding the cell nucleus (cytoplasm), some proteins are synthesized in the mitochondria.

During protein synthesis, in either the mitochondria or the cytoplasm, building blocks called amino acids are connected together in a specific order, creating a chain of amino acids that forms the protein. Mitochondrial glutamyl-tRNA synthetase plays a role in adding the amino acid glutamate at the proper place in mitochondrial proteins.

Mutations in the EARS2 gene likely reduce the amount of mitochondrial aspartyl-tRNA synthetase protein, which hinders the addition of glutamate to mitochondrial proteins. Researchers speculate that impaired protein assembly disrupts mitochondrial energy production. However, it is unclear how a reduction of mitochondrial aspartyl-tRNA synthetase specifically affects certain brain regions, causing LTBL.

Normal Function

The EARS2 gene provides instructions for making an enzyme called mitochondrial glutamyl-tRNA synthetase. This enzyme is important in the production (synthesis) of proteins in cellular structures called mitochondria, the energy-producing centers in cells. While most protein synthesis occurs in the fluid surrounding the cell nucleus (cytoplasm), some proteins are synthesized in the mitochondria.

During protein synthesis, in either the mitochondria or the cytoplasm, a type of RNA called transfer RNA (tRNA) helps assemble protein building blocks called amino acids into a chain that forms the protein. Each tRNA carries a specific amino acid to the growing chain. Enzymes called aminoacyl-tRNA synthetases, including mitochondrial glutamyl-tRNA synthetase, attach a particular amino acid to a specific tRNA. Mitochondrial glutamyl-tRNA synthetase attaches the amino acid glutamate to the correct tRNA, which helps ensure that glutamate is added at the proper place in the mitochondrial protein.

Health Conditions Related to Genetic Changes

Leukoencephalopathy with thalamus and brainstem involvement and high lactate

At least 23 mutations in the EARS2 gene have been found in individuals with leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL), a condition characterized by abnormalities in certain brain regions, including the thalamus and the brainstem (the part of the brain that connects to the spinal cord), and a high level of a substance called lactate in the brain and elsewhere in the body. Affected individuals typically have problems with thinking and motor abilities and with controlling muscle function.

The EARS2 gene mutations involved in LTBL likely reduce the amount of mitochondrial glutamyl-tRNA synthetase. A shortage of this protein is thought to prevent the normal assembly of new proteins within mitochondria. Researchers speculate that impaired protein assembly disrupts mitochondrial energy production. However, it is unclear exactly how EARS2 gene mutations lead to the features of LTBL.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Other Names for This Gene

• COXPD12
• gluRS
• glutamate tRNA ligase 2, mitochondrial
• glutamate--tRNA ligase
• KIAA1970
• MSE1

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

LTBL is a rare condition. While its prevalence is unknown, at least 19 cases have been described in the medical literature.