What is vanishing white matter syndrome?

Vanishing White Matter Syndrome

Vanishing white matter (VWM) syndrome is a rare autosomal recessive leukodystrophy caused by mutations in the EIF2B1-EIF2B5 genes, characterized by progressive white matter rarefaction with replacement by cerebrospinal fluid, chronic neurologic deterioration punctuated by stress-provoked episodes of rapid decline, and a clinical presentation dominated by cerebellar ataxia and spasticity with relatively preserved cognition. 1, 2

Genetic Basis and Pathophysiology

• VWM results from recessive mutations in genes EIF2B1 through EIF2B5, which encode the five subunits of eukaryotic initiation factor 2B (eIF2B), essential for translating mRNAs into proteins 1, 3

• The EIF2B5 gene is most frequently mutated, with specific mutations like p.Arg113His recurrently associated with adult-onset disease 2, 4

• The eIF2B complex serves as a principal regulator of the integrated stress response (ISR), and deregulation of this pathway is central to VWM pathology 1

• The mutation leads to dysregulation of cellular stress responses, which particularly disrupts myelination and affects oligodendrocytes and astrocytes while sparing neurons 5

Clinical Presentation and Disease Course

Age of Onset and Phenotypic Spectrum

• Disease onset spans from the antenatal period through senescence, with age at onset predicting disease evolution for early-onset patients but remaining unpredictable for later-onset cases 1

• Infantile and early childhood onset consistently produces severe disease with rapid neurologic decline and often early death 1

• Adult-onset forms present with slower progression and highly variable disease courses, with onset documented as late as age 42 years 2

• Significant intra-familial phenotypic variability occurs, even among siblings with identical mutations, suggesting external precipitating factors contribute to clinical differences 2

Neurological Features

• Cerebellar ataxia and spasticity dominate the neurological presentation, with relatively preserved mental abilities in most cases 2, 3

• Variable optic atrophy may occur as part of the clinical spectrum 3

• Adult-onset cases may present with atypical features including transient aphasia with complete recovery, abusive behavior, emotional lability, and motor incoordination 4, 5

• Cognitive decline is not universal, with documented cases showing no cognitive deterioration over eleven years of disease 4

Disease Progression Pattern

• The course follows chronic progressive neurological deterioration with intermittent episodes of acute regression 3

• Stress-provoked episodes of rapid decline are pathognomonic, triggered by febrile illnesses, head trauma, sudden fright, acute psychological stress, or infection 1, 2, 5

• These acute deteriorations represent a key diagnostic feature distinguishing VWM from other white matter disorders 1

Diagnostic Approach

Neuroimaging Findings

• Brain MRI shows diffuse abnormal signal of cerebral white matter with progressive rarefaction and replacement by cerebrospinal fluid 2, 3

• Cystic degeneration of white matter is characteristic, creating the "vanishing" appearance that gives the disease its name 2

• Relative sparing of subcortical U-fibers is typical, helping distinguish VWM from other leukoencephalopathies 4

• Diffuse leukoencephalopathy on MRI represents a key diagnostic step alongside clinical picture and gene sequencing 3

Genetic Testing

• Molecular diagnosis requires sequencing of all five EIF2B genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) 3

• Identification of biallelic pathogenic variants confirms the diagnosis in the appropriate clinical and radiological context 1

• Genotype-phenotype correlations exist, with specific mutations like p.Arg113His in EIF2B5 associated with adult-onset disease 2

Management Considerations

Current Treatment Limitations

• Only symptomatic care is currently offered, as no disease-modifying therapies are approved 1

• Prevention of stressors that could provoke acute deteriorations represents the primary management strategy 1

Emerging Therapeutic Approaches

• Targeting components of the ISR has proven beneficial in mutant VWM mouse models, with several drugs now in clinical development 1

• Clinical trials face considerable challenges including low numbers of known patients, unpredictable disease course for post-early-childhood onset, absence of intermediate biomarkers, and novel first-in-human molecular targets 1

Clinical Pitfalls and Diagnostic Challenges

• VWM is likely underdiagnosed, particularly in adults, as the classic childhood presentation may bias clinicians against considering this diagnosis in older patients 1

• The highly variable disease course in adult-onset cases complicates prognostication and clinical trial design 1

• External precipitating factors significantly influence phenotypic expression, making it difficult to predict individual disease trajectories even within families 2