Vanishing white matter disease

INTRODUCTION AND TERMINOLOGY — Vanishing white matter (VWM) is also known as leukoencephalopathy with vanishing white matter disease, childhood ataxia with central nervous system hypomyelination (CACH), and myelinopathia centralis diffusa. VWM disease is a chronic and progressive white matter disorder (leukodystrophy) characterized by a variable phenotype, typically with prominent ataxia and spasticity in the classic form. VWM is often exacerbated by infection, head trauma, or other stresses.

Scattered neuropathologic case reports beginning in the 1960s were the earliest descriptions of the disease [1-8]. However, VWM was not recognized as a clinical syndrome until the 1990s [9-11]. Later studies have revealed the genetic underpinnings and the phenotypic variability of VWM. (See 'Genetics' below and 'Clinical features' below.)

This review will use the term "vanishing white matter" (VWM) for this condition. Other heritable leukodystrophies and leukoencephalopathies are discussed separately:

●Alexander disease (see "Alexander disease")

●Canavan disease (see "Aspartoacylase deficiency (Canavan disease)")

●Cerebrotendinous xanthomatosis (see "Cerebrotendinous xanthomatosis")

●Globoid cell leukodystrophy (Krabbe) (see "Krabbe disease")

●Metachromatic leukodystrophy (see "Metachromatic leukodystrophy")

●Pelizaeus Merzbacher disease (see "Pelizaeus-Merzbacher disease")

●Sjögren-Larsson syndrome (see "Sjögren-Larsson syndrome")

●X-linked adrenoleukodystrophy (see "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy")

PATHOGENESIS

Genetics — Inheritance of VWM disease is autosomal recessive. Pathogenic variants in any of the five genes that encode subunits of the eukaryotic translation initiation factor 2B (eIF2B) are the cause of VWM and its phenotypic variants [12,13].

The eIF2B protein complex is composed of five different subunits (eIF2B-alpha, eIF2B-beta, eIF2B-gamma, eIF2B-delta, and eIF2B-epsilon). The genes corresponding to these subunits are named EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5 and are located on chromosomes 12q24.3, 14q24, 1p34.1, 2p23.3, and 3q27, respectively.

More than 120 pathogenic variants of EIF2B genes have been reported [14]. Pathogenic variants in the EIF2B5 gene account for more than one-half of cases [14,15].

Most of the disease variants in any one of the five causative genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) are hypomorphic, causing partial loss of function of eIF2B guanine nucleotide exchange factor (GEF) activity [16-18]. Some variants, including some associated with severe disease, cause little or no decrease in eIF2B activity, and some cause an increase in GEF activity.

eIF2B function — eIF2B is a eukaryotic initiation factor involved in the translation of messenger ribonucleic acid (mRNA) to polypeptides. A general discussion of translation is found separately. (See "Basic genetics concepts: DNA regulation and gene expression".)

The biochemical function of the eIF2B protein complex is via initiation of protein synthesis and activation of the initiation factor eIF2 (eukaryotic initiation factor 2) [12,19]. In this role, eIF2B catalyzes the exchange of guanosine diphosphate (GDP), which is bound to inactive eIF2, for guanosine triphosphate (GTP). Activated eIF2-GTP delivers the initiator methionyl-transfer RNA (Met-tRNA) to the small ribosomal subunits. Upon recognition of the start codon of the ribonucleic acid (RNA), the GTP bound to eIF2 is hydrolyzed to GDP, which renders eIF2 inactive. To begin another round of protein synthesis, eIF2B must reactivate eIF2 by exchanging GDP for GTP [12].

●Cellular response to stress – Although eIF2B is necessary for cap-dependent protein translation, its relationship to VWM appears to be primarily in its role of regulating the cellular response to stress, known as the integrated stress response (ISR) [20,21].

The ISR can be triggered through a variety of mechanisms, such as trauma, heat, or infection. Upon stress, eIF2B is phosphorylated, which leads to two effects: downregulation of cap-dependent mRNA translation and activation of the stress-response cascade, a pathway leading to expression of genes that protect the cell from effects of stress.

An impaired ability to cease chronic ISR activation appears to be a key feature caused by pathogenic variants in the eIF2B genes [20,22,23]. Further, this abnormal ISR would explain the association of VWM-related disease onset and/or rapid deterioration with stress, injury, or infection [8,24]. (See 'Provoking factors and events' below.)

Cellular stress causes the misfolding of proteins, which can lead to apoptosis of the cell by activating the unfolded protein response in the endoplasmic reticulum (ER) [19].During periods of stress, the cytoplasmic kinase domain of eIF2B phosphorylates eIF2 and limits further translation of ER-destined proteins. Downregulation of eIF2B activity by eIF2 kinases enables two responses: a general reduction in the translation of most mRNAs, and a simultaneous enhancement of translation of stress-responsive mRNAs encoding rescue proteins. Counterintuitively, the translation of certain mRNAs is enhanced under conditions of reduced levels of eIF2-GTP/Met-tRNAi(Met) ternary complexes. This mechanism is mediated by regulatory short upstream open reading frames (uORFs) within their 5'-untranslated region, upstream of the major coding region [18,25]. This process leads to synthesis of rescue proteins that promote cell survival during stress.

●Cellular mechanisms – A variety of cellular mechanisms and of cell types are reported to mediate the deleterious effects of ISR activation in VWM. The available data suggest that astrocytes are the primary responsible cell type of VWM pathophysiology [26-28]. Other effects in VWM include defective mitochondrial oxidative respiration, which has been demonstrated in mouse embryonic fibroblasts, astrocytes, and oligodendrocyte precursor cells [29,30].

Increased abundance of mitochondria in oligodendrocytes is seen in mouse models and human patients; this may reflect a compensatory change in response to mitochondrial dysfunction [29,31]. Hypomorphic variants in eIF2B may impair regulation of the complex and coordinated protein synthesis from two genomes (cellular and mitochondrial) that is required for normal mitochondrial function [32]. Glial cells appear to have a selective vulnerability to decreased eIF2B activity, which explains the predominant involvement of white matter in the brain seen in VWM [8,33].

Genotype-phenotype correlations — Phenotypic heterogeneity of VWM has been observed among members of the same family and among individuals with the same pathogenic variant, suggesting that the phenotype is influenced by the environment and perhaps by other genetic factors [8,24].

New pathogenic variants causing VWM continue to be reported [34], and the prevalence of pathogenic variants reported in the literature will likely be refined as more patients are identified, including those from minority groups and from other regions of the world. However, certain genotype-phenotype correlations have been described, as illustrated by the following examples:

●The most frequent pathogenic variant reported from the literature is a point variant in EIF2B5, which encodes eIF2B-epsilon. In this variant, a single nucleotide substitution (338G>A) produces an amino acid change (p.Arg113His). This variant is associated with very mild disease. Individuals who are homozygous for p.Arg113His typically have adult-onset type VWM and slow disease progression [35,36]. This variant has never been associated with the infantile subtype [33]. Patients who are homozygous for the p.Arg113His substitution have a milder phenotype than those who are compound heterozygous for p.Arg113His plus another disease variant [37].

●A milder clinical course, with late onset and slow progression, has also been associated with the 638A>G variant (p.Glu213Gly) in EIF2B2 [36].

●Homozygosity for a 584G>A missense variant in exon 4 of EIF2B5, resulting in a p.Arg195His substitution, was identified in patients with Cree leukoencephalopathy [12]; this variant is always associated with early onset and short survival.

●Ovarioleukodystrophy (VWM with ovarian failure) can be caused by pathogenic variants in EIF2B2, EIF2B4, and EIF2B5 genes [38].

●Another point variant in EIF2B5 (925G>C; p.Val309Leu) is associated with increased disease severity [16,33].

Pathology — At autopsy, gross sections of the brain demonstrate extensive cystic, gelatinous, or cavitary degeneration involving the periventricular and immediate subcortical white matter, with partial sparing of the U-fibers (picture 1) [8,11,31,39-41]. Symmetric brainstem lesions within the central tegmental tracts may be present (image 1) [39].

Microscopically, the white matter demonstrates marked rarefaction, severe loss of myelin with spongy degeneration, vacuolation, and atypical astrocytic gliosis [11]. Myelin loss is seen in the retrobulbar optic nerve in some patients [31].

Oligodendrocyte abnormalities in VWM include both increased and decreased cell numbers [42], altered morphology, and apoptotic cell death.

●An increased density of oligodendrocytes may be seen in areas of preserved white matter in the cerebrum, cerebellum, and pons [31,39,40,42]. While one report interpreted this finding as an artifact caused by compaction of brain parenchyma during cell loss [31], a later case-control study observed statistically significant increases in oligodendrocyte densities in cases of VWM compared with age-matched controls [42].

●Abnormal foamy oligodendroglial cells, characterized by abundant cytoplasm; mitochondria filled with circular, membranous structures; and the absence of lysosomes, are pathognomonic for VWM [31].

●Reduced numbers of oligodendrocytes are seen in areas of cavitary white matter degeneration [11,41].

●Reduced numbers of dystrophic astrocytes are reported, especially in the childhood-onset forms [43].

●Apoptotic labeling of oligodendrocytes has been observed in some patients, particularly those with early-onset severe VWM [42].

It is thought that oligodendrocytes are exposed to conflicting proliferative, proapoptotic, and prosurvival signals during the course of VWM [19,42]. Oligodendrocyte apoptosis may occur particularly during periods of neurologic crises [42]. However, some oligodendrocytes can persist and proliferate, particularly in patients with later-onset and less severe VWM.

EPIDEMIOLOGY — VWM disease is rare, but it may be one of the more common leukodystrophies [33]. The exact incidence and prevalence of VWM is unknown. In the Netherlands, the estimated live-birth incidence was ≥1:80,000 live-births [44], while an incidence as low as 1:700,000 live-births was calculated using genomic sequencing data [45]. A precise determination is not possible because systemic population screening has not been performed, and there are concerns that some cases may be mistaken for other diseases such as multiple sclerosis or other adult white matter disorders.

In a study of 50 unaffected Cree adults, 1 in 10 were heterozygous for a G584A pathogenic variant in the EIF2B5 gene [12], suggesting a high carrier rate in certain populations.

CLINICAL FEATURES — The most distinctive clinical feature of VWM disease is progressive neurologic deterioration, often with prominent ataxia and spasticity [9-11]. However, there is an extremely broad range of VWM phenotypes that vary primarily by age of disease onset.

Early onset

Antenatal — The antenatal form presents in the third trimester of gestation with decreased fetal movements and oligohydramnios. At birth, affected neonates have feeding difficulties, hypotonia, and microcephaly. Renal hypoplasia and contractures are present, likely related to the decreased amniotic fluid.

In this VWM variant, systemic involvement is most pronounced. Growth failure, cataracts, pancreatitis, hepatosplenomegaly, and ovarian dysgenesis may be found [46]. Patients develop intractable epilepsy, apneic spells, and coma. Affected infants die before the age of one year [33,44].

In antenatal VWM, the brain magnetic resonance imaging (MRI) may initially show features of immaturity with hyperintense T2 signal and hypointense T1 signal of white matter consistent with unmyelinated white matter [8,46,47]. With disease progression, the cerebral white matter undergoes rarefaction and cystic atrophy.

Infantile — The infantile form of VWM is a severe type that presents in the first year of life, with death occurring within months of onset [44]. Reported cases are few, but onset in the first year of life was seen in two infants who developed irritability and stupor with a rapid decline in motor abilities [48].

Cree leukoencephalopathy — A rapidly progressive infantile-onset form of VWM was first described in Native American infants in northern Quebec and Manitoba and designated "Cree leukoencephalopathy" [49]. These infants presented with hypotonia, followed by seizures between three and six months of age, and progressive disease characterized by lethargy, spasticity, developmental regression, and cessation of head growth; death occurred by two years of age.

Later onset

Early childhood — The early childhood form of VWM is the most common subtype (figure 1). This form typically presents between one and four years of age [33]. This form is characterized by the classic phenotype of cerebellar ataxia with spasticity [9-11]. Motor symptoms tend to predominate with increasing tremor, spasticity, dysarthria, and gait difficulty progressing to loss of ambulation [33,44]. Cognition is relatively spared but may decline over time [44,50]. Seizures and optic atrophy with visual loss may also occur. Most affected children die within a few years after onset, although some have lived only a few months, while others have survived for several decades [9-11,39].

Late childhood/juvenile — The late-childhood/juvenile form presents between 4 and 18 years [33]. The course is usually more slowly progressive than earlier-onset forms of VWM, with spastic diplegia, relative sparing of mentation, and typically (but not always) longer survival [39].

Adult — The adult form presents at ≥18 years of age. Adults may present with neuropsychiatric symptoms or cognitive decline as their first disease manifestation [44,51]; the adult form is otherwise characterized by the same neurologic findings as childhood and juvenile forms but with greater spasticity than ataxia [35,52-54]. In general, the course may be milder and slower than younger-onset forms of VWM, but it is still often progressive. Coma is less frequent than in children.

In one adult series, 16 patients from 14 families with pathogenic variants in EIF2B were followed for a mean of 11 years (range 2 to 22 years) [51]. The mean age of onset was 31 years (range 16 to 62 years). The initial manifestations were neurologic (predominantly gait disturbance with spastic paraparesis and/or cerebellar ataxia) in 11 patients, psychiatric (depression and schizophrenia) in two, and endocrine (ovarian failure) in two. One family member was asymptomatic when diagnosed at age 16. Stress-induced deterioration at onset or during the course of the disease was reported for six patients, including precipitation of death in two. One death occurred after a minor head trauma led to irreversible brain edema, and the other after a generalized seizure led to intractable status epilepticus. Among the 14 survivors, disease was progressive in all but three, with loss of independent ambulation in 11 (including three who became bedridden) at a mean age of 47 years (range 16 to 62 years) and cognitive decline in eight. One patient remained asymptomatic.

Another series included 18 patients with onset from age 16 to 60 years caused by pathogenic variants in EIF2B5 or EIF2B3; cognitive and motor decline were the most prominent symptoms, while stroke-like events were the first presentation in a minority [55]. Smaller studies in adults have also reported mental decline, dementia, epilepsy, psychotic symptoms, and deterioration with illness and trauma [35,52,54,56-58]. In one series of five patients with onset of VWM between 14 and 45 years, the time to death ranged from a few months to 14 years [39].

Provoking factors and events — Onset of symptoms or deterioration in VWM can be triggered by apparently minor stressors, such as a mild viral infection or minor head trauma, causing sudden neurologic deterioration that may lead to lethargy or coma with incomplete recovery [11,39,44,59]. The likely mechanism is disruption of the cellular response to stress due to loss-of-function pathogenic variants in the EIF2B genes. (See 'eIF2B function' above.)

Other clinical aspects

●Clinical progression varies by age of onset – Patients with an earlier age of onset have a more severe course and more rapid decline (figure 2) [44,60]. A longitudinal cohort study of 296 patients with VWM distinguished two different but not strictly separated disease courses [44]. Patients who presented before the age of four years generally had a rapidly progressive course; within this group, earlier onset was associated with greater severity and higher mortality. By contrast, patients who presented at or beyond four years of age generally had a milder course with low mortality; within this group, there was a wide variation in severity that was independent of age at onset.

●Ovarian failure – VWM with primary or secondary ovarian failure is also known as ovarioleukodystrophy when it occurs with the juvenile- and adult-onset subtypes [38,61]. However, ovarian failure may occur with any of the VWM subtypes regardless of onset age. Outside of the brain, the ovaries are the most frequently affected organs in females with VWM, and primary or secondary ovarian failure is a common finding [8,38,44,46,47,61].

●Headache and hemibody symptoms – Several reports have described children and adults with transient episodes of severe headache accompanied by hemiparesis or hemiparesthesia as the presenting features of VWM [62-64]. The episodes can be triggered by stress.

●Asymptomatic patients identified incidentally – On occasion, an otherwise healthy child or an adult undergoes a brain MRI for a headache, minor head trauma, or other transient symptoms and is found to have abnormalities compatible with VWM that are then confirmed genetically. Such a person may eventually become symptomatic or remain asymptomatic for years [51,65]. The prevalence of prolonged subclinical VWM is unknown.

Brain MRI findings

●Classic MRI appearance – In the early-childhood classic type of VWM, as myelinated white matter "vanishes" over time, the signal intensity of white matter changes from high to low on fluid-attenuated inversion recovery (FLAIR) images due to the progressive rarefaction of white matter, leaving only a meshwork of linear strands in the abnormal white matter (image 2) [11,39].

FLAIR MRI sequences are best able to differentiate between white matter that is rarefied, with intermediate to high signal intensity, or cystic, with low signal intensity that is the same signal intensity as cerebrospinal fluid (CSF) (image 3) [66]. Diffusion-weighted imaging shows increased diffusion in areas of rarefied or cystic white matter [67]. Reduced water diffusivity has been observed in several relatively spared brain regions (ie, cortical U-fibers, cerebellar white matter, middle cerebellar peduncles, pyramidal tracts, corpus callosum, and posterior limb of the internal capsule), predominantly in younger patients with a shorter disease duration [68]. Contrast enhancement usually does not occur in VWM [8].

In late stages of VWM, the cerebral white matter is diffusely abnormal [69], approaching the intensity of CSF on all MRI sequences, that is, low signal on T1-weighted and FLAIR images (image 4 and image 5) and high signal on T2-weighted images [11,39]. Despite the severe involvement of the white matter, the lateral ventricles usually remain of normal size [9].

The cerebral cortex is typically spared in this disease, showing little atrophy even in advanced stages. In children, the cortical gyri may appear swollen and slightly broader than normal [11]. Despite early involvement of the cerebrum in VWM, head circumference in affected children is usually normal.

The cerebellum and brainstem are generally (but not always) spared by the process of white matter rarefaction and cystic degeneration [8,11,39]. However, MRI signal abnormalities can occur in the brainstem, which may undergo some degree of atrophy over time (image 6). Mild to severe cerebellar atrophy, especially involving the vermis, may also be seen.

●MRI findings vary by age of onset – Like clinical progression, earlier onset is associated with faster progression of white matter loss on brain MRI. In a retrospective study of 461 MRI examinations in 270 patients with VWM, younger age at onset correlated with increased cystic cerebral white matter decay, while older age at onset correlated with increased cerebral white matter atrophy and gliosis [60].

General trends in the variation of MRI findings by age of onset are listed below but do not represent strict categories, given variation and overlap among the groups [60]:

•With infantile onset, brain MRI typically shows extensive loss of white matter over several months, progressing to complete cystic white matter degeneration and ventricular dilatation (image 2) [60].

•In early-childhood VWM, the white matter disappears over time, sometimes rapidly, but often appears swollen on MRI and may be accompanied in a minority by macrocephaly (image 2) [44,60]. There is no evidence of gliosis on MRI.

•In late-childhood/juvenile VWM, brain MRI shows more gradual and incomplete white matter loss and cystic degeneration (image 2), and gliosis may develop [60].

•In most adult-onset VWM cases, white matter does not "vanish" as in infantile and early-childhood VWM. Rather, brain MRI shows mainly white matter atrophy and gliosis; there is little or no evidence of white matter loss or cystic degeneration (image 2) [60].

EVALUATION AND DIAGNOSIS

When to suspect VWM — Clinical findings that raise suspicion for VWM disease vary by age.

●Early onset – With antenatal or early-infantile onset, clinical findings that suggest VWM include oligohydramnios, intrauterine growth retardation, and reduced fetal movements before birth. Severe encephalopathy, microcephaly, contractures, renal hypoplasia, cataracts, pancreatitis, and hepatosplenomegaly are apparent after birth [33,46]. (See 'Early onset' above.)

●Later onset – Clinical findings that suggest VWM include cerebellar ataxia, spasticity, and hyperreflexia [33]. The course may be chronic progressive or subacute and episodic; disease onset or progression may be provoked by stressors, including infection and minor head trauma. Motor symptoms tend to predominate in children, while cognitive decline or behavioral change may be the presenting or predominant symptoms in adults. (See 'Later onset' above.)

Making the diagnosis — The diagnosis of VWM is typically made by the presence of suggestive clinical findings and genetic testing [33], together with consistent brain MRI findings and/or a family history of disease [8,33,70]. In all cases, genetic confirmation of VWM is essential to establish the diagnosis. (See 'Clinical features' above and 'MRI protocol and criteria' below.)

Strict diagnostic criteria for VWM have not been formally established.

MRI protocol and criteria — The brain MRI protocol in most cases should include T1-weighted, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted, and postcontrast T1-weighted sequences; the latter is most useful when excluding other diagnoses.

MRI criteria for VWM are relevant to the classic early-childhood type but are variably found in infants with the antenatal form or the adult-onset form of VWM. Presymptomatic patients may have these features, but without secondary cavitation of the abnormal white matter [8]. These criteria, based on expert opinion, include [8]:

●There are extensive signal abnormalities involving the periventricular and deep cerebral white matter; subcortical white matter may be spared (image 4 and image 6).

●As white matter "vanishes," abnormal white matter has a signal intensity close to or the same as cerebrospinal fluid (CSF) on FLAIR images. This finding is more common in cases with childhood or juvenile onset of disease.

●The disappearance of the cerebral white matter occurs in a diffuse "melting away" pattern (image 2).

●The temporal lobes are relatively spared in the extent of the abnormal signal and/or degree of cystic destruction.

●The cerebellar white matter may be abnormal but does not contain cysts.

●There is no contrast enhancement.

Additional MRI findings that are suggestive of VWM are as follows [8]:

●A pattern of radiating stripes within abnormal white matter is seen on sagittal and coronal T1-weighted or FLAIR images; dots and stripes are seen within the abnormal white matter on axial images, representing cross-sections of the stripes seen on sagittal and coronal images (image 6).

●Lesions within the central tegmental tracts in the pontine tegmentum (image 6).

●Involvement of the inner rim of the corpus callosum, with sparing of the outer rim.

Genetic testing — Genetic testing is essential for diagnosis and is confirmatory if positive. However, negative testing does not eliminate the possibility of VWM disease because of the potential for false-negative results (such as an intronic mutation) or previously unreported variants that may be missed by the testing laboratory. Approximately 95 percent of individuals diagnosed by clinical and MRI criteria have biallelic pathogenic variants in one of the five causative genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) [33].

Genetic testing may be particularly important to establish the diagnosis of VWM in patients with neonatal or early infantile-onset variants, as brain MRI features in early-onset disease may be atypical and are unlikely to meet MRI criteria for VWM.

Laboratory testing — Routine laboratory tests are generally normal in patients with VWM [33]. Lumbar puncture is not routinely needed for the diagnosis; CSF analysis is typically normal.

DIFFERENTIAL DIAGNOSIS

Acquired disorders — The differential diagnosis of VWM disease includes conditions associated with rapid neurologic deterioration and abnormal changes to the white matter, including multiple sclerosis (MS) and related neuro-autoimmune conditions such as acute disseminated encephalomyelitis (ADEM) and encephalitis.

●Multiple sclerosis (MS) – Children with MS generally have a clinical presentation that is similar to that of adults, with one or more clinically distinct episodes of optic neuritis, diplopia, brainstem or cerebellar syndrome, or partial transverse myelitis, followed by at least partial resolution. A minority of children present with encephalopathy (ie, headache, vomiting, seizure, or altered consciousness). Unlike VWM, MRI in MS typically shows multiple well-demarcated lesions in the periventricular, cortical or juxtacortical, infratentorial, and spinal cord white matter. These areas of demyelination are best recognized on T2 fluid-attenuated inversion recovery (FLAIR) images. (See "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".)

●Acute disseminated encephalomyelitis (ADEM) – ADEM should be suspected in a child who develops multifocal neurologic abnormalities with encephalopathy (altered mental status or behavioral change that cannot be explained by fever). ADEM may present one to two weeks after a viral infection. Unlike children with VWM, those with ADEM may have evidence of inflammation in the cerebrospinal fluid (CSF). MRI of the brain and spinal cord typically shows asymmetric multifocal white matter abnormalities, best defined by T2-weighted and FLAIR sequences. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis".)

●Encephalitis – Encephalitis is a febrile illness with signs and symptoms of neurologic dysfunction (eg, cranial nerve palsies, seizures, paralysis, dysarthria) and/or altered state of consciousness related to parenchymal brain involvement. MRI of the brain may show lesions of white and gray matter.

Contrast enhancement may be seen in encephalitis or ADEM but is typically not present in VWM, although at least one such case has been described [71].

Inherited disorders — The differential diagnosis of VWM also includes inherited disorders presenting in infancy and childhood with progressive neurologic deterioration and diffuse white matter abnormalities.

●Mitochondrial disorders – Mitochondrial disorders (eg, pyruvate dehydrogenase deficiency and pyruvate carboxylase deficiency) can cause leukoencephalopathy with diffuse rarefaction and cystic degeneration of white matter [72,73].

●Alexander disease – Alexander disease causes variable symptoms depending on age, such as megalencephaly, psychomotor retardation, pseudobulbar signs, spasticity, and ataxia, with progressive deterioration. Serial MRI scans demonstrate increasing frontoparietal white matter atrophy with cystic degeneration. Unlike VWM, contrast enhancement of selected gray and white matter structures is characteristic of Alexander disease. (See "Alexander disease".)

●Megalencephalic leukoencephalopathy with subcortical cysts (MLC) – MLC presents with macrocephaly in the first year of life [74,75]. Other symptoms include mild developmental delay, ataxia, spasticity, and seizures. Cognition is relatively spared. The disorder is caused by pathogenic variants in the MLC1 and HEPACAM genes. Unlike VWM, the cerebral white matter does not undergo diffuse rarefaction and cystic degeneration in MLC [33]. However, the MRI does show diffuse supratentorial white matter abnormalities in patients with MLC, and cystic brain lesions are seen, mostly in the frontoparietal border zone region and anterior-temporal subcortical white matter [74].

●AARS2-associated disorders – Pathogenic variants in the AARS2 gene have been identified in rare disorders with variable clinical manifestations, including movement disorders, cognitive impairment, spasticity, hyperreflexia, behavioral or psychiatric symptoms, or infantile cardiomyopathy; many patients have imaging evidence of leukoencephalopathy, and premature ovarian failure is common in affected females [76,77].

●Other leukodystrophies – Other leukodystrophies, such as adrenoleukodystrophy, metachromatic leukodystrophy, and Krabbe disease, tend to have different clinical features or MRI features and are not associated with diffuse cystic cerebral white matter degeneration. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy" and "Krabbe disease" and "Metachromatic leukodystrophy".)

Although other leukodystrophies can typically be ruled out based upon the pattern of abnormalities on brain MRI [69] or on distinctive clinical features, confirmation by genetic testing should be performed.

MANAGEMENT

Supportive care — Supportive care for VWM disease is similar to that for other chronic neurologic diseases. Physical and occupational therapy are useful for motor problems, particularly ataxia and spasticity [33]. Orthopedic interventions such as ankle-foot orthotics are appropriate for patients with weakness of ankle dorsiflexion.

The need for surgical procedures such as for scoliosis or spasticity management should be counterbalanced with the low but potential risk of VWM exacerbation caused by surgery. There are no indications for prophylactic use of glucocorticoids or other anti-inflammatory medications.

Antiseizure medications are used in VWM patients with epilepsy. Epilepsy in some patients with VWM can be quite problematic and can be associated with neurologic worsening. The management of seizures and epilepsy is discussed elsewhere. (See "Treatment of neonatal seizures" and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Overview of the management of epilepsy in adults".)

Avoidance of triggers — Common practices that lack definitive data include avoiding factors associated with exacerbation of VWM [8,33]. (See 'Provoking factors and events' above.)

●Contact sports should be avoided since even minor head trauma can lead to worsening.

●Since infection and fever can have deleterious effects, antibiotics and antipyretics should be used as indicated. Vaccinations, such as the influenza vaccine, should be administered as recommended. (See "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule' and "Standard immunizations for nonpregnant adults" and "Immunizations during pregnancy".)

●Major surgery should be avoided if possible.

●Avoidance of overly psychologically stressful emotional or physical situations is sometimes recommended, although evidence is minimal.

However, such measures are insufficient to prevent VWM onset and progression [8].

Support groups — Several groups provide information and support for patients, families, and caregivers with leukodystrophies, including VWM:

●Vanishing White Matter Consortium

●United Leukodystrophy Foundation

●Hunter's Hope

Investigational therapies — There is no cure or specific treatment for VWM. Animal models for leukodystrophy, including VWM, are in development [78]. Preliminary clinical trials for VWM are underway in Europe [79] and the United States [80].

SUMMARY AND RECOMMENDATIONS

●Definition – Leukodystrophy with vanishing white matter disease (VWM; MIM #603896) is a chronic and progressive white matter disorder with autosomal recessive inheritance, often exacerbated by infection or head trauma.

●Genetics – Pathogenic variants in any of the five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) that encode subunits of the eukaryotic translation initiation factor 2B (eIF2B) are the cause of VWM and its phenotypic variants. These variants usually result in decreased activity of eIF2B, which is thought to disrupt the cellular response to stress. (See 'Genetics' above and 'Pathogenesis' above.)

●Epidemiology – VWM is a rare disease, but it may be one of the more common leukodystrophies. Estimates of incidence range from 1:80,000 to 1:700,000 live-births. (See 'Epidemiology' above.)

●Clinical features – There are five overlapping clinical subtypes of VWM that exist along a spectrum (antenatal, infantile, early childhood, late childhood/juvenile, and adult). Patients with an earlier age of onset have a more rapid decline (figure 2). Stressors including illness and minor head trauma often lead to sudden neurologic deterioration with incomplete recovery.

In the early-childhood variant, which is the most common (figure 1), the major clinical features are progressive neurologic deterioration with prominent ataxia and spasticity. Intellectual functioning and swallowing ability are usually relatively spared. Adults may present with neuropsychiatric symptoms or cognitive decline as their first disease manifestation. (See 'Clinical features' above.)

●Neuroimaging features – In early-onset forms, the brain MRI signal of the cerebral white matter changes from high to low intensity on T1 and fluid-attenuated inversion recovery (FLAIR) sequences as the white matter "vanishes" over time and is progressively replaced by cerebrospinal fluid (CSF) (image 2 and image 4).

These changes are less prominent in late-childhood/juvenile and adult forms. Younger age at onset correlates with increased cystic cerebral white matter decay, while older age at onset correlates with increased cerebral white matter atrophy and gliosis (image 2). (See 'Brain MRI findings' above.)

●Evaluation and diagnosis – The diagnosis of VWM is suspected in patients with suggestive clinical findings and consistent brain MRI findings and/or a family history of disease.

The diagnosis should be confirmed by genetic testing demonstrating biallelic pathogenic variants in one of the five causative genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5). (See 'Evaluation and diagnosis' above.)

●Differential diagnosis – Acquired and inherited disorders presenting in infancy and childhood with progressive neurologic deterioration and white matter abnormalities are considerations in the differential diagnosis of VWM, including multiple sclerosis, acute disseminated encephalomyelitis, encephalitis, mitochondrial disorders, Alexander disease, megalencephalic leukoencephalopathy with subcortical cysts, AARS2-associated disorders, and other leukodystrophies. (See 'Differential diagnosis' above.)

●Management – There is no cure or specific treatment for VWM. Supportive care is the mainstay of treatment. Measures to avoid or reduce the risk of events that may trigger deterioration in VWM (eg, head trauma, infection, and fever) are advised. (See 'Management' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Alan Percy, MD, and Raphael Schiffmann, MD, MHSc, FAAN, who contributed to an earlier version of this topic review.