Leukoencephalopathy with involvement of the thalamus and brainstem and high lactate (thalamus and brainstem Leukoencephalopathy With Involvement and high lactate) - Gen EARS2

Leukoencephalopathy with involvement of the thalamus and brainstem and elevated lactate (LTBL) is a process that affects the brain. This process is one of a group of genetic disorders called the leukodystrophies, characterized by abnormalities of the nervous system white matter. White matter consists of nerve fibers covered by myelin, which insulates nerve fibers and promotes rapid transmission of nerve impulses.

In particular, the LTBL is characterized by various changes in the brain that can be seen by MRI. These abnormalities usually involve the white matter in the cerebrum and cerebellum, but also may be in other regions of the brain, including the brainstem. Affected brain regions include the thalamus, midbrain, pons and medulla. In addition, affected individuals in a reduction of the corpus callosum may occur. Individuals most affected, have high concentrations of lactate in the brain and other parts of the body.

The severity of the disease can be variable. Individuals with mild disease usually develop signs and symptoms after 6 months of age. In these individuals psychomotor regression, spasticity and extreme irritability, and some people with mild LTBL often develop seizures. However, after 2 years of age, signs and symptoms of the disease improve: affected children recover some psychomotor skills, seizures are reduced or disappear, and lactate concentrations decrease.

For its part, individuals with severe disease manifest characteristics that begin shortly after birth. These children often have psychomotor retardation, hypotonia, dystonia, muscle spasticity and seizures. Some individuals have lactic acidosis, which can cause serious respiratory problems and an abnormal heart rhythm. Liver failure occurs in some newborns severely affected. In severe cases, signs and symptoms do not improve and can be potentially fatal.

This process is due to mutations in the gene EARS2 (glutamyl-tRNA synthetase 2, mitochondrial), located on the short arm of chromosome 16 (16p12.2), encoding glutamyl tRNA synthetase mitochondrial enzyme. This enzyme is important in protein synthesis in mitochondria. Although increased protein synthesis occurs in the cytoplasm, some proteins are synthesized in the mitochondria. During protein synthesis, either mitochondria or cytoplasm, tRNA helps assemble amino acids in a protein chain form. Each tRNA carries a specific amino acid to the growing chain. The aminoacyl-tRNA synthetases enzymes including mitochondrial tRNA synthetase glutamyl contribute to add a particular tRNA with a specific amino acid. Specifically, glutamyl-tRNA synthetase mitochondrial binds the amino acid glutamate to correct tRNA, which helps ensure that glutamate is added at the appropriate place in the mitochondrial protein.

They have been described at least 23 mutations in the gene in individuals with EARS2 leukoencephalopathy with involvement of the thalamus and brainstem and high lactate (LTBL). These genetic changes are likely to reduce the amount of glutamyl-tRNA synthetase mitochondrial. It is believed that a deficiency of this protein inhibits the normal formation of new proteins in the mitochondria. Although some authors suggest that an alteration in the constitution of proteins disrupts mitochondrial energy production, it is not clear exactly how genetic mutations lead to EARS2 features LTBL.

This disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with leukoencephalopathy with involvement of the thalamus and the brainstem and high lactate (LTBL), by complete PCR amplification of exons EARS2 gene, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).