leukoencephalopathy with vanishing white matter

Leukoencephalopathy with vanishing white matter (VWM) is a hereditary disorder that damages the brain’s white matter, the tissue responsible for rapid signal transmission within the central nervous system. The condition results from pathogenic variants in any of six genes—EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5, or AARS2—whose proteins help regulate cellular protein synthesis and stress responses. Symptoms most often begin between two and five years of age, although onset can range from infancy to adulthood. Because formal prevalence studies are lacking, the condition is considered uncommon worldwide. Both boys and girls can be affected, and some females additionally develop premature ovarian insufficiency.

Early signs are usually neurological, with children developing an unsteady gait, limb and truncal ataxia, spasticity, and exaggerated reflexes. Episodes of rapid decline are common after fever, minor head trauma, or other stresses, often leading to sudden losses in motor or cognitive abilities. Over time many individuals experience progressive neurologic deterioration that can include seizures, worsening balance problems, and optic atrophy that affects vision. In a subset of females, premature ovarian insufficiency causes menstrual irregularities or infertility, highlighting that the disorder can affect more than the nervous system. Less common features reported in some people are migraines, dysphagia, growth delay, and pancreatitis. Not all individuals experience all features, and severity varies considerably from person to person.

VWM is caused by autosomal recessive variants in EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5, or AARS2. These genes encode proteins crucial for initiating protein synthesis and helping cells cope with physiologic stress, roles that are especially important in the brain’s white matter. A child must inherit one non-working copy of an affected gene from each parent to develop the condition. Parents who each carry a single pathogenic variant are typically healthy but have a 25 percent chance with each pregnancy of having a child with VWM. The condition may be more common in families where parents share a common ancestor, because both may carry the same rare variant. Even within the same family the age of onset and symptom severity can differ markedly, reflecting variable expressivity. Genetic counseling is recommended for families seeking information about carrier testing and family planning.

Currently, management centers on supportive care tailored to each person’s needs. Physical, occupational, and speech therapies aim to preserve motor skills and communication, while medications may be prescribed to control seizures or muscle spasticity. Because infections and head trauma can trigger rapid neurologic decline, prompt treatment of fever and careful avoidance of head injuries are emphasized. Regular surveillance is an essential part of long-term care, including periodic neurological evaluations, brain imaging when clinically indicated, and hormonal monitoring in females at risk for ovarian insufficiency. Most families benefit from care coordinated by a multidisciplinary team that may include neurology, rehabilitation medicine, endocrinology, and genetics specialists. Patients should discuss individualized management plans and emerging research options with their healthcare team.

The clinical course of VWM is highly variable. Many children experience periods of relative stability punctuated by sudden neurologic setbacks after illness or injury, while others have a more gradual progression. Long-term outcomes depend on the age at onset, frequency and severity of stress-related episodes, and access to specialized supportive care. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with neurologists and genetic counselors familiar with leukodystrophies, as well as patient support networks, for up-to-date information and shared experience.

Several clinical trials are currently investigating new treatments aimed at modifying the disease course or protecting white-matter cells. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility and potential benefits or risks of participation.