What are the other Names for this Condition? (Also known as/Synonyms)

• Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter (CACH/VWM)
• Cree Leukoencehalopathy
• Vanishing White Matter Leukodystrophy

What is Leukoencephalopathy with Vanishing White Matter? (Definition/Background Information)

• Leukoencephalopathy with Vanishing White Matter is a progressive disorder that mainly affects the central nervous system (CNS)
• This disorder causes deterioration of white matter, which consists of nerve fibers covered by myelin (the substance that protects the nerves)
• Most affected people begin to have signs and symptoms during childhood, but symptoms may first become apparent anywhere from before birth to adulthood
• Symptoms may include difficulty coordinating movements (ataxia); muscle stiffness (spasticity); and optic atrophy
• Symptoms may worsen rapidly with episodes of fever, after head trauma, or with other stresses on the body
• This disorder may be caused by mutations in any of 5 genes and is inherited in an autosomal recessive manner
• There is no specific treatment, and prognosis seems to correlate with the age of onset, the earliest forms being more severe

(Source: Leukoencephalopathy with Vanishing White Matter; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Leukoencephalopathy with Vanishing White Matter? (Age and Sex Distribution)

• Leukoencephalopathy with Vanishing White Matter is a rare congenital disorder
• The presentation of symptoms may occur at birth, in childhood (mostly), or even later during adulthood
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Leukoencephalopathy with Vanishing White Matter? (Predisposing Factors)

• A positive family history may be an important risk factor, since Leukoencephalopathy with Vanishing White Matter is an inherited condition
• Currently, no other risk factors have been clearly identified for the syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Leukoencephalopathy with Vanishing White Matter? (Etiology)

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

(Source: Leukoencephalopathy with Vanishing White Matter; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Leukoencephalopathy with Vanishing White Matter?

The signs and symptoms of Leukoencephalopathy with Vanishing White Matter may include:

• Cerebral hypomyelination
• Cessation of head growth
• CNS demyelination
• Decreased serum progesterone
• Delusions
• Developmental regression
• Dysarthria
• Emotional lability
• Lethargy
• Leukoencephalopathy
• Memory impairment
• Muscular hypotonia
• Optic atrophy
• Personality changes
• Premature ovarian insufficiency
• Primary gonadal insufficiency
• Secondary amenorrhea
• Seizures
• Spasticity
• Unsteady gait

Frequently present symptoms in 30-79% of the cases: Macrocephaly

Occasionally present symptoms in 5-29% of the cases: Blindness

(Source: Leukoencephalopathy with Vanishing White Matter; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Leukoencephalopathy with Vanishing White Matter Diagnosed?

Leukoencephalopathy with Vanishing White Matter is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Leukoencephalopathy with Vanishing White Matter?

The complications of Leukoencephalopathy with Vanishing White Matter may include:

• Severely affected quality of life
• Severe neurological impairment
• Infertility

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Leukoencephalopathy with Vanishing White Matter Treated?

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

(Source: Leukoencephalopathy with Vanishing White Matter; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Leukoencephalopathy with Vanishing White Matter be Prevented?

Currently, Leukoencephalopathy with Vanishing White Matter may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Leukoencephalopathy with Vanishing White Matter? (Outcomes/Resolutions)

• There is no specific treatment for Leukoencephalopathy with Vanishing White Matter, and the prognosis seems to correlate with the age of onset, the earliest forms being more severe

(Source: Leukoencephalopathy with Vanishing White Matter; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Leukoencephalopathy with Vanishing White Matter:

Leukoencephalopathy with Vanishing White Matter is also known by the following names:

• CACH Syndrome
• CACH/VWM Syndrome
• Childhood Ataxia with Diffuse Central Nervous System Hypomyelination
• Myelinosis Centralis Diffusa
• Vanishing White Matter Disease

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/