Leukoencephalopathy with involvement of brainstem and spinal cord and elevated lactate (Leukoencephalopathy With brainstem and spinal cord and lactate elevation Involvement) - Gen DARS2.
Leukoencephalopathy with involvement of the brainstem and spinal cord and elevated lactate (LBSL) is a progressive disease that affects the brain and spinal cord. The most affected people begin to develop movement problems during childhood or adolescence. However, in some people, these problems do not develop until adulthood.
Signs and symptoms associated with this disease may include spasticity, ataxia and loss of ability to detect the position of the extremities or vibrations with their limbs. These problems affect movement and sensation to the legs more than the arms, making it difficult to walk. The most affected people eventually require wheelchair in adolescence, although age may vary. Other signs and symptoms may include epilepsy, dysarthria, mild learning disabilities and impaired mental function. Some people affected are particularly vulnerable to serious complications following minor trauma to the head, which can cause loss of consciousness, other reversible neurological problems and fever. By MRI can be seen characteristic abnormalities involving particular parts of the cerebral white matter and specific regions within the brain stem and spinal cord, particularly the pyramidal tract and the dorsal column. In addition, most affected individuals have a high concentration of lactate in the cerebral white matter, which is identified by magnetic resonance spectroscopy (MRS).
This process is due to mutations in the gene DARS2, located on the long arm of chromosome 1 (1q25.1). This gene encodes an enzyme called mitochondrial tRNA synthetase aspartyl. This enzyme is important in protein synthesis in mitochondria. While most protein synthesis occurs in the cytoplasm, some proteins are synthesized in the mitochondria. During protein synthesis, either in the cytoplasm or mitochondria, transfer RNA (tRNA) placed amino acids to form the protein. Each tRNA carries a specific amino acid to the growing chain. Aspartyl-tRNA synthetase mitochondrial plays its role colocandoel amino acid aspartic acid at the appropriate place in mitochondrial proteins.
They have identified at least 25 DARS2 gene mutations in people with leukoencephalopathy with involvement of brainstem and spinal cord and elevated lactate (LBSL). The most common mutation alters the way in which the genetic information encoding plans aspartyl tRNA synthetase enzyme mitochondrial. Most copies are incorrectly, which prevents the enzyme is encoded. However, some specimens are properly and a small amount of normal enzyme is encoded. Other mutations change individual amino acids in the enzyme. This type of mutation results in a decreased activity of the mitochondrial enzyme aspartyl-tRNA synthetase. With reduced activity, the enzyme has difficulty adding aspartic acid the tRNA molecule, which hinders the addition of this amino acid to mitochondrial proteins. However, it is unclear how genetic mutations result in signs and symptoms of LBSL, and is not understood why a reduced activity aspartyl tRNA synthetase mitochondrial specifically affects parts of the brain and spinal cord.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. In this condition, each copy of the gene carries a different mutation (compound heterozygous mutations). 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 brainstem and spinal cord and elevated lactate (LBSL), by complete PCR amplification of exons DARS2 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).