Leukoencephalopathy with vanishing white matter

Synonyms

5

Overview

Leukoencephalopathy with vanishing white matter is a progressive disorder that mainly affects the brain and spinal cord (central nervous system). This disorder causes deterioration of the central nervous system's white matter, which consists of nerve fibers covered by myelin. Myelin is the fatty substance that insulates and protects nerves.

In most cases, people with leukoencephalopathy with vanishing white matter show no signs or symptoms of the disorder at birth. Affected children may have slightly delayed development of motor skills such as crawling or walking. During early childhood, most affected individuals begin to develop motor symptoms, including abnormal muscle stiffness (spasticity) and difficulty with coordinating movements (ataxia). There may also be some deterioration of mental functioning, but this is not usually as pronounced as the motor symptoms. Some affected females may have abnormal development of the ovaries (ovarian dysgenesis). Specific changes in the brain as seen using magnetic resonance imaging (MRI) are characteristic of leukoencephalopathy with vanishing white matter, and may be visible before the onset of symptoms.

While childhood onset is the most common form of leukoencephalopathy with vanishing white matter, some severe forms are apparent at birth. A severe, early-onset form seen among the Cree and Chippewayan populations of Quebec and Manitoba is called Cree leukoencephalopathy. Milder forms may not become evident until adolescence or adulthood, when behavioral or psychiatric problems may be the first signs of the disease. Some females with milder forms ofleukoencephalopathy with vanishing white matter who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.

Progression of leukoencephalopathy with vanishing white matter is generally uneven, with periods of relative stability interrupted by episodes of rapid decline. People with this disorder are particularly vulnerable to stresses such as infection, mild head trauma or other injury, or even extreme fright. These stresses may trigger the first symptoms of the condition or worsen existing symptoms, and can cause affected individuals to become lethargic or comatose.

 

Symptoms

Onset usually occurs in childhood, however some adult cases have been found. Generally, physicians look for the symptoms in children. Symptoms include cerebellar ataxia, spasticity, optic atrophy, epilepsy, loss of motor functions, irritability, vomiting, coma, and even fever has been tied to VWM. The neurological disorders and symptoms which occur with VWM are not specific to countries; they are the same all over the world. Neurological abnormalities may not always be present in those who experience onset as adults. Symptoms generally appear in young children or infants who were previously developing fairly normally.

Causes

This disorder may be caused by mutations in any of 5 genes and is inherited in an autosomal recessive manner, 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.

Leukoencephalopathy with vanishing white matter is a genetic condition caused by mutations in any of 5 genes - EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5. These genes give the body instructions to make the five parts (subunits) of a protein called eIF2B. This protein helps regulate overall production of protein in cells (protein synthesis). Proper regulation of protein synthesis ensures that the correct levels of protein are available for cells to cope with changing conditions and stress.

Mutations in any of these 5 genes results in partial loss of eIF2B function, making it more difficult for cells to regulate protein synthesis and deal with changing conditions and stress. Researchers believe that cells in the white matter may be particularly affected by an abnormal response to stress, thus causing the signs and symptoms of this condition.

Approximately 90% of affected people have been found to have mutations in one of these 5 genes. Approximately 10% of families who have been diagnosed by MRI and clinical features do not have an identifiable mutation, suggesting that additional genes may also be responsible for the condition.

Leukoencephalopathy with vanishing white matter is inherited in an autosomal recessive manner. This means that a person must have a mutation in both copies of the responsible gene to be affected. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not have signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) chance to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Diagnosis

Most diagnosis occurs in the early years of life around 2 to 6 years old. There have been cases in which onset and diagnosis have occurred late into adulthood. Those with onset at this time have different signs, particularly the lack of cognitive deterioration. Overall, detection of adult forms of VWM is difficult as MRI was not a common tool when they were diagnosed. Common signs to look for include chronic progressive neurological deterioration with cerebellar ataxia, spasticity, mental decline, decline of vision, mild epilepsy, hand tremor, the ability to chew and swallow food becomes difficult, rapid deterioration and fibrile infections following head trauma or fright, loss of motor functions, irritability, behavioural changes, vomiting, and even coma. Those who go into coma, if they do come out usually die within a few years. The diagnosis can be difficult if the physician does not take an MRI.

Prognosis

The prognosis of CACH syndrome usually refers to the likely outcome of CACH syndrome. The prognosis of CACH syndrome may include the duration of CACH syndrome, chances of complications of CACH syndrome, probable outcomes, prospects for recovery, recovery period for CACH syndrome, survival rates, death rates, and other outcome possibilities in the overall prognosis of CACH syndrome. Naturally, such forecast issues are by their nature unpredictable.

Treatment

There is no specific treatment, and prognosis seems to correlate with the age of onset, the earliest forms being more severe. Treatment for leukoencephalopathy with vanishing white matter is supportive, aiming to alleviate symptoms. Management may include physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia); and anti-seizure medications for seizures.

Infections and fevers should be prevented when possible through the use of vaccinations; low-dose maintenance antibiotics during winter months; antibiotics for minor infections; and antipyretics (fever-reducing medications) for fever. For children, wearing a helmet outside can help minimize the effects of head trauma. Contact sports, head trauma, and stressful situations (including high body temperature) should be avoided.

Resources

• NIH
• Genetics Home Reference