Diagram of normal neuron showing myelin covering axon without damage (myelin sheath is in light blue).<unk>  (LENAS) is believed to occur when presence of white matter degeneration and axonal<unk>  are seen with a brain biopsy or an MRI. White matter consists of nerve fibers (axons) covered by a substance called myelin that insulates and protects them. The axons extend from nerve cells (neurons) and transmit nerve impulses throughout the body. The result of<unk>  in the brain leads to this significant decline of functioning that progressively worsens the brain function and leads to varied symptoms. However, why this occurs is still not entirely understood, thus more research is continuously being done to this day. There have been identifiable genetic differences that are better understood. This disease is inherited while following an autosomal dominant pattern. Genetic Etiology There are identifiable genetic causes that are better understood with this disease. LENAS is caused by a mutation in a gene, specifically the CSF1R gene. This mutation changes protein receptors on the gene which normally plays a role in important cell signaling pathways; however, this altercation inhibits the regular function. Normal Function of CSF1R Gene The colony stimulating factor 1 receptor (CSFR1) gene regularly functions by giving instructions for making a protein termed the colony stimulating factor 1 receptor (CSF-1 receptor). Proteins in general attach (bind) to their specific receptor which "turns on" (activates) to stimulate a cascade of cellular signaling pathways crucial for cell function to occur. These events occur with the specific CSF-1 protein. As it binds and is activated, it allows for important cellular processes to occur which include cell growth, division, and maturation of cells to in turn take on specific functions. Visual representation of what occurs due to a missense mutation like in a mutated CSF1R gene seen in LENAS Glial cells, located in the brain, are responsible for protection and maintenance of neurons. In a healthy brain, the membrane of glial cells are abundant with the CSF-1 receptor gene and is also thought to be an important player in the proliferation and differentiation of these cells. Mutated CSF1R Gene There are several types of mutations that occur in genes. The majority of CSF1R genetic mutations in LENAS occur due to a type of mutation which is called a missense mutation. Missense mutations occur when there is a change in a single amino acid of a protein. This single change can result in problems with functions of the protein, like the CSF-1 receptor. The kinase domain, which is the region of CSF-1 receptor where the mutation occurs, is altered and thus the normal function that activates other proteins is compromised and cannot stimulate cell signaling pathways properly. Although this is the primary type of mutation in LENAS, other types may occur as well but it is not as well understood for this disease. This genetic mutation is related to LENAS and said to be the main cause but how these lead to damage in the white matter and associated symptoms (cognitive and movement impairment symptoms) is still not fully clear. Inheritance LENAS is inherited in an autosomal dominant pattern. This means that one copy of the mutated gene in each cell is sufficient to cause the disorder. If one parent who is unaffected and one parent who is affected with LENAS give birth to four children, at least two of the four will become affected and have the disorder because the affected parent would pass on the one copy of the gene. In most cases, an affected person does inherit the mutation from one affected parent but not all cases. There have been very few reports of cases that result from new mutations have been seen as well as cases in which there has been no history of LENAS. These few reports are not as concrete or well understood yet and further studies should be conducted.
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