What is Vanishing White Matter Leukodystrophy?

VWM, also know as CACH (Childhood Ataxia with Central nervous system Hypomyelinization) is one of several types of Leukodystrophy. Leukodystrophy is a disorder that primarily affects the white matter of the central nervous system and is characterized by progressive breakdown and loss of white matter. Each type of Leukodystrophy is caused by a different inherited genetic defect.  For example, VWM is the result of a defect in an eIF2B related gene.

What is White Matter?

The human brain consists of gray matter and white matter. Grey matter is made up of neuronal cell bodies, and includes regions of the brain involved in muscle control, sensory perception such as seeing and hearing, memory, emotions, and speech.

 

White matter is the tissue through which messages pass between different areas of gray matter within the nervous system. Using a computer network as an analogy, the gray matter can be thought of as the actual computers themselves, whereas the white matter represents the network cables connecting the computers together. White matter has two primary components: The nerve fibers (axons) and the myelin sheath that surrounds the nerve fibers. The white matter gets its color from the myelin sheath that surrounds the nerve fibers.

 

The myelin sheath has two functions: the insulation and acceleration of impulse conduction through the nerve fibers. Insulation is important for the prevention of short-circuits. Through its special construction, myelin also accelerates the propagation of impulses along nerve fibers.

Myelin is an essential part of the white matter. When the myelin sheath is damaged or disappears, the conduction of impulses along nerve fibers slows down or fails completely. Consequently, brain functions become hampered or may be lost.

 


VWM Genetics

VWM is an inherited disease with an autosomal recessive mode of inheritance. An autosomal recessive disorder means two copies of an abnormal gene must be present in order for the disease to develop. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers) Two unaffected people, or carriers, have a 25% chance with each pregnancy of having a child together that is affected by the disorder. Each child would have a 50% chance of inheriting just one abnormal gene, which would make the child a carrier.

The function of eIF2B

VWM is the result of mutations in any of the 5 genes encoding subunits of the translation initiation factor eIF2B. The genes are identified as eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5

 

eIF2B is a factor that is essential in the production of all proteins in the body. DNA is transcribed into RNA; RNA is translated into proteins. eIF2B plays an essential role in the initiation of translation of all proteins. It is also important in the regulation of protein synthesis. In conditions of stress, such as fever, proteins may coagulate. One of the defense mechanisms of the cell is to decrease the production of proteins to prevent this abnormal coagulation of proteins. In febrile conditions, eIF2B may be the most important factor to decrease protein production.

 

It is difficult to understand why the patients only have a brain disease and why other organs are not involved. It may be that the structures most sensitive to the detrimental effects of protein plugs along the axons, the very long and very thin extensions of neurons. The research goes on. 

Clinical Symptoms of VWM

Usually, the early development of patients with VWM is normal. The first clear signs of the disease typically occur in infancy or early-childhood, but can present in late-childhood, adolescence or even adulthood.

 

The course of the disease is chronic and progressive with additional episodes of more rapid and severe deterioration. These episodes are precipitated by infections with fever and/or minor head trauma. 

 

The motor signs consist of cerebellar ataxia and variable spasticity. Decreased vision due to optic atrophy occurs in some patients. The mental capacities are relatively preserved. The severity of the disease is highly variable. Some patients die within a couple of months while other patients only become wheelchair-dependent after many years of disease progression. The typical lifespan after diagnosis is ten years.

 

There is no current treatment for VWM, we are only able to treat some symptoms as they present. However, current research offers hope for better treatment and perhaps a cure... please support VWM research and donate now!

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