Vanishing white matter disease

INTRODUCTION AND HISTORY — Leukoencephalopathy with vanishing white matter (VWM; MIM #603896), also known as childhood ataxia with central nervous system hypomyelination (CACH), myelinopathia centralis diffusa, and Cree leukoencephalopathy, is a chronic and progressive white matter disorder (leukodystrophy), 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]. In 1988, a study from Canada described a severe infantile leukodystrophy in three Cree Indian villages termed "Cree leukoencephalopathy" [9], a condition that is now recognized as a phenotypic variant of VWM [10]. However, VWM was not recognized as a clinical syndrome until the 1990s.

●The disease was first recognized in 1992 [11]. A detailed 1994 report from the United States described four unrelated patients with progressive ataxic diplegia and characteristic magnetic resonance imaging (MRI) features that was named "childhood ataxia with diffuse central nervous system hypomyelination" [12].

●A 1993 study from Germany identified similar features in three children with normal early development who rapidly declined with progressive ataxia and spasticity, followed later by bulbar symptoms, optic atrophy, and seizures; brain MRI showed a diffuse hypodensity of the white matter similar to the signal of the ventricles [13].

●In 1997, a study from the Netherlands described a cohort of nine children, including three affected sibling pairs, who had similar clinical, radiographic, and pathologic characteristics and were diagnosed with a "new leukoencephalopathy with vanishing white matter" [14].

This review will use the term "vanishing white matter disease" (VWM) for this condition. Later studies have revealed the genetic underpinnings and the phenotypic variability of VWM, as described below.

GENETICS — Inheritance of VWM is autosomal recessive. Mutations in any of the five genes that encode subunits of the eukaryotic translation initiation factor eIF2B are the cause of VWM and its phenotypic variants [10,15].

The eIF2B protein complex is composed of five different subunits (eIF2Balpha, eIF2Bbeta, eIF2Bgamma, eIF2Bdelta, and eIF2Bepsilon). 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.

PATHOGENESIS — eIF2B is a eukaryotic initiation factor involved in the translation of mRNA to polypeptides. A general discussion of translation is found separately (see "Basic genetics concepts: DNA regulation and gene expression"). Although eIF2B is necessary for cap-dependent protein translation, its relationship to VWM appears to be primarily in its related role of regulating the cellular response to stress, known as the integrated stress response (ISR) [16,17].

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: down-regulation 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 mutations in the eIF2B genes [16,18,19]. Further, this abnormal ISR response would explain the association of VWM-related disease onset and/or rapid deterioration with stress, injury, or infection [8,20].

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 [21].During periods of stress, the cytoplasmic kinase domain of eIF2B phosphorylates eIF2 and limits further translation of ER-destined proteins. Down-regulation 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-guanosine triphosphate (GTP)/Met-tRNAi(Met) ternary complexes. This regulatory mechanism is mediated by regulatory short upstream open reading frames (uORFs) within their 5'-untranslated region, upstream of the major coding region [22,23]. This process leads to synthesis of rescue proteins that promote cell survival during stress.

The biochemical function of the eIF2B protein complex is via initiation of protein synthesis and activation of the initiation factor eIF2 [10,21]. In this role, eIF2B catalyzes the exchange of guanosine diphosphate (GDP), which is bound to inactive eIF2, for 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 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 [10].

Most of the mutations 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 [23-25]. Some mutations, including some associated with severe disease, have little or no decreased in eIF2B activity and some actually cause an increase in GEF activity.

A variety of cellular mechanisms and of cell types are reported as mediating 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]. In an effort to compensate for the mitochondrial dysfunction, increased mitochondrial abundance is seen in oligodendrocytes in the mouse models and human patients [29,30]. Hypomorphic mutations in eIF2B may impair regulation of the complex and coordinated protein synthesis from two genomes that is required for normal mitochondrial function [31]. Glial cells appear to have a selective vulnerability to decreased eIF2B activity, which explains the predominant involvement of white matter in the brain as seen in VWM [8,32].

EPIDEMIOLOGY — The exact incidence and prevalence of VWM is unknown, but it may be one of the more common leukodystrophies [32]. In the Netherlands, the estimated incidence was ≥1:80,000 live births [33]. However, an incidence as low as 1 in 700,000 live births was calculated using genomic sequencing data [34]. A precise determination is not possible because there has not been a systemic screening of a population, and there are concerns that some cases may be mistaken for other diseases (eg, multiple sclerosis).

In a study of 50 unaffected Cree adults, 1 in 10 adults were heterozygous for a G584A mutation on the EIF2B5 gene [10], suggesting a high carrier rate in select populations.

CLINICAL FEATURES — The most distinctive clinical feature of VWM is progressive neurologic deterioration, often with prominent ataxia and spasticity [12-14], that is provoked by a stressor such as a minor illness or a minor fall. Optic atrophy is rare and seizures can occur relatively late in the disease course. Intellectual functioning is usually relatively spared early in disease course; adult patients may present with neuropsychiatric symptoms as their first disease manifestations. Febrile illness, minor head trauma, or severe fright have all been reported to cause the sudden neurologic deterioration, including leading to coma, and typically with incomplete recovery [14,35,36].

There are five clinical subtypes of VWM based on age of onset which correlate well with disease course [32]:

●Antenatal

●Infantile

●Early childhood

●Late childhood/juvenile

●Adult (over 15 years)

Patients with earlier age of onset have a more severe course and with more rapid decline. A longitudinal cohort study of 296 patients with VWM distinguished two different but not strictly separated disease courses [33]. Patients presenting before four years of age, and particularly before age two years, generally had a rapidly progressive course; within this group, earlier onset was associated with greater severity and higher mortality. In contrast, patients presenting at four years of age and older generally had a less progressive course with low mortality; within this group, there was a wide variation in severity that was independent of age at onset.

Antenatal — The antenatal form presents in the third trimester 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 variant, systemic involvement is most pronounced. Growth failure, cataracts, pancreatitis, hepatosplenomegaly, and ovarian dysgenesis may be found [37]. Patients develop intractable epilepsy, apneic spells, and coma. Affected infants die before the age of one [32].

Infantile — The infantile form of VWM is a severe type that presents in the first year of life. 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 [38].

A rapidly progressive infantile-onset form of VWM was first described in Native American infants in northern Quebec and Manitoba and designated "Cree leukoencephalopathy" [9]. 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.

Early childhood — The early childhood form of VWM is the most common variant and presents between one and five years of age. This form is characterized by the classic phenotype of cerebellar ataxia with less prominent spasticity and little if any cognitive decline [12-14]. As noted above, 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 [12-14,35].

Late childhood/juvenile — The late childhood/juvenile form presents between 5 and 15 years. 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) with longer survival [35].

Adult — The adult form is characterized by the same neurologic findings as childhood and juvenile forms but with greater spasticity than ataxia [39-42]. 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 EIF2B mutations were followed for a mean of 11 years (range 2 to 22 years) [43]. The following observations were made:

●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.

●Brain magnetic resonance imaging (MRI) findings included cerebral atrophy in all 16 patients, cystic leukoencephalopathy in 13, and cerebellar atrophy in 12.

●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 evolution 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.

Smaller studies in adults have also reported mental decline, dementia, epilepsy, psychotic symptoms, and deterioration with illness and trauma [39,40,42,44,45]. 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 [35].

Ovarioleukodystrophy — VWM with ovarian failure is also known as ovarioleukodystrophy [46,47]. 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 [8,14,37,46-48].

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 [49-51]. 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 [43,52]. The prevalence of prolonged subclinical VWM is unknown.

Genotype-phenotype correlations — Phenotypic heterogeneity of VWM has been observed among members of the same family and among individuals with the same mutation, suggesting that the phenotype is influenced by the environment and perhaps by other genetic factors [8,20]. New mutations causing VWM continue to be reported [53] and the prevalence of mutations reported in the literature will likely be refined as more patients are identified including in minority groups and from other more regions of the world. However, certain genotype-phenotype correlations have been described, as illustrated by the following examples:

●The most frequent mutation reported from the literature, a 338G>A nucleotide substitution (p.Arg113His) in EIF2B5, is the mildest. EIF2B5 mutations homozygous for p.Arg113His typically are associated with adult-onset type VWM and slow disease progression [40,54], and have never been associated with the infantile subtype [32]. In addition, patients homozygous for the p.Arg113His substitution have a milder phenotype than those who are compound heterozygous for p.Arg113His [55].

●A milder clinical course (ie, late onset and slow progression) has also been associated with the 638A>G mutation (p.Glu213Gly) in EIF2B2 [54].

●A homozygous 584G>A missense mutation in exon 4 of EIF2B5, resulting in a p.Arg195His substitution of eIF2Bepsilon, was identified in patients with Cree leukoencephalopathy [10] and is always associated with early onset and short survival.

●Ovarioleukodystrophy (ie, VWM with ovarian failure) is caused by mutations in EIF2B2, EIF2B4, and EIF2B5 genes [47].

●The 925G>C mutation (p.Val309Leu) in EIF2B5 is associated with increased disease severity [24,32].

Neuroimaging — Diffuse white matter abnormality is present even before the appearance of clinical signs or symptoms. In the infantile classic type of VWM, as the cerebral white matter "vanishes" over time, the MRI signal changes from high to low intensity on proton density and fluid-attenuated inversion recovery (FLAIR) sequences due to the progressive replacement of the white matter by cerebrospinal fluid, leaving only a meshwork of strands in the abnormal white matter (image 1 and image 2) [14,35]. Proton density and FLAIR MRI sequences are best able to differentiate between white matter that is rarefied, with high to intermediate signal intensity, or cystic, with low signal intensity (image 3 and image 4) [56]. Diffusion-weighted imaging shows increased diffusion in areas of rarefied or cystic white matter [57]. Restricted diffusion 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 [58]. Contrast enhancement usually does not occur in VWM [8].

In late stages of infantile VWM, the cerebral white matter is diffusely abnormal [59], approaching the intensity of cerebrospinal fluid on all MRI sequences, with low signal on T1-weighted images (image 2 and image 3) and high signal on T2-weighted, FLAIR, and proton density images [14,35]. As noted above, a meshwork of strands may be seen radiating through the rarefied and cystic abnormal white matter on T1-weighted, FLAIR, and proton density MRI [14,35]. Importantly, despite the severe involvement of the white matter, lateral ventricles remain of normal size [12].

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 [14]. Despite early involvement of the cerebrum in VWM, head circumference in affected children is usually normal.

The cerebellum and brainstem are generally spared by the process of white matter rarefaction and cystic degeneration [8,14,35]. However, MRI signal abnormalities may occur in the brainstem, which may undergo some degree of atrophy over time (image 1). Mild to severe cerebellar atrophy, especially involving the vermis, may also be seen.

In the antenatal and early infantile VWM, the brain MRI may initially show only features of immaturity [8,37,48]. As the disease progresses, the cerebral white matter may undergo the process of rarefaction and cystic atrophy. Unlike the later onset VWM variants, the white matter becomes severely atrophic in some cases of the antenatal variant.

In parallel with the progressive loss of cerebral white matter, magnetic resonance spectroscopy (MRS) shows an increased loss over time of the normal N-acetylaspartate, choline, and creatine signals in the cerebral white matter [13,14,35,60,61].

In the late stages of VWM, when cystic white matter and cerebrospinal fluid predominates, all normal metabolic peaks may be absent in the white matter on MRS. Furthermore, there are small additional peaks corresponding to lactate and to glucose [14]. As lactate and glucose are present in cerebrospinal fluid, these findings confirm the replacement of cellular elements with cerebrospinal fluid.

White matter does not "vanish" in most slowly progressing adult forms. In juvenile and adult onset cases, the white matter is much better preserved with the exception of some cavitation best seen on FLAIR MRI images [43,46,59]. Instead of the rarefaction seen in infantile-onset VWM, there is progressive dilation of the lateral ventricles due to white matter loss, a picture much closer to a classic demyelinating leukodystrophy such as metachromatic leukodystrophy.

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) [8,14,30,35,62,63]. Symmetric brainstem lesions within the central tegmental tracts may be present (image 5) [35].

Microscopically, the white matter demonstrates marked rarefaction, severe loss of myelin with spongy degeneration, vacuolation, and atypical astrocytic gliosis [14]. Myelin loss is seen in the retrobulbar optic nerve in some patients [30].

Oligodendrocyte abnormalities in VWM include both increased and decreased cell numbers [64], 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 [30,35,62,64]. While one report interpreted this finding as an artifact caused by compaction of brain parenchyma during cell loss [30], a later case-control study observed statistically significant increases in oligodendrocyte densities in cases of VWM compared with age-matched controls [64].

●Abnormal foamy oligodendroglial cells, characterized by abundant cytoplasm, mitochondria filled with circular, membranous structures, and the absence of lysosomes, are pathognomonic for VWM [30].

●Reduced numbers of oligodendrocytes are seen in areas of cavitary white matter degeneration [14,63].

●Reduced numbers of dystrophic astrocytes are reported, especially in the childhood onset forms [65].

●Apoptotic labeling of oligodendrocytes has been observed in some patients, particularly those with early-onset severe VWM [64].

It is thought that oligodendrocytes are exposed to conflicting proliferative, proapoptotic, and prosurvival signals during the course of VWM [21,64]. Oligodendrocyte apoptosis may occur particularly during periods of neurologic crises [64]. However, some oligodendrocytes are able to persist and proliferate, particularly in patients with later-onset and less severe VWM.

DIAGNOSIS — Strict criteria have not been formally established. The diagnosis of VWM is typically made by the presence of clinical symptoms, genetic testing using sequence analysis [32], together with consistent brain magnetic resonance imaging (MRI) findings and/or a family history of disease [8,32,66]. (See 'Clinical features' above and 'MRI criteria' below.)

MRI criteria — Commonly accepted MRI criteria for the diagnosis of VWM include:

●There are diffuse or extensive signal abnormalities involving the cerebral white matter; the adjacent subcortical white matter may be spared (image 1 and image 2 and image 3 and image 4)

●Part or all of the abnormal white matter has a signal intensity close to or the same as cerebrospinal fluid on proton density or fluid-attenuated inversion recovery (FLAIR) images

●There is a fluid-filled space (not a total collapse of the white matter) between the ependymal lining and the cortex if proton density and FLAIR images suggest that all cerebral white matter has disappeared

●The disappearance of the cerebral white matter occurs in a diffuse "melting away" pattern (image 1)

●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

Proposed suggestive MRI criteria for the diagnosis 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 1)

●There are lesions within the central tegmental tracts in the pontine tegmentum (image 1)

●There is involvement of the inner rim of the corpus callosum, with sparing of the outer rim

These MRI criteria are relevant to the classic infantile type but are variably found in infants with the antenatal form of VWM or the adult forms of VWM. Presymptomatic patients may have these features, but without secondary cavitation of the abnormal white matter [8]. In all cases, genetic confirmation of VWM is essential to establish the diagnosis.

Genetic testing — Approximately 90 percent of individuals diagnosed by clinical and MRI criteria have mutations in one of the five causative genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) [32]. More than 120 mutations of EIF2B genes have been reported [67]. Mutations in the EIF2B5 gene account for more than one-half of cases [67,68]. About 5 percent of patients with typical clinical and neuroimaging features of VWM will have no EIF2B mutations. These have other yet undiscovered etiologies or may be related to the presence of intronic mutations.

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 [32]. Standard cerebrospinal fluid (CSF) analysis is likewise normal.

Research work has shown that a reduced CSF asialotransferrin/total transferrin ratio, as determined by two-dimensional gel electrophoresis, may be a useful biomarker for the identification of patients with EIF2B mutations. In a sample of six patients with VWM and confirmed EIF2B mutations who were compared with 54 controls (including six patients with a clinical presentation consistent with VWM but no EIF2B mutations), an asialotransferrin/transferrin ratio of <8 percent had a sensitivity and specificity of 100 and 94 percent, respectively, for the identification of patients with EIF2B mutations [69].

Currently, determination of the asialotransferrin/transferrin ratio by two-dimensional gel electrophoresis is available only on a research basis [32].

Differential diagnosis — The differential diagnosis of VWM includes conditions associated with rapid neurologic deterioration and abnormal changes to the white matter, for example following a febrile infection [8], including multiple sclerosis and related neuro-autoimmune conditions, such as acute disseminated encephalomyelitis (ADEM) and encephalitis.

●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 VWM, children with ADEM may have evidence of inflammation in the cerebrospinal fluid. 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 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 [70].

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 (eg, pyruvate dehydrogenase deficiency and pyruvate carboxylase deficiency) can cause leukoencephalopathy with diffuse rarefaction and cystic degeneration of white matter [71,72]. [73]

●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) 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 mutations in the MLC1 and HEPACAM genes. Unlike VWM, the cerebral white matter does not undergo diffuse rarefaction and cystic degeneration in MLC [32]. 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].

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 [59] or on distinctive clinical features, confirmation by genetic testing should be performed.

Ovarian dysfunction occurs also in patients with AARS2 mutations [76].

MANAGEMENT — There is no cure or specific treatment for VWM. However, clinical trials for VWM are currently underway in Europe and are expected shortly in the United States as well.

Common practices that lack definitive data include avoiding head trauma and illnesses. Since even minor head trauma can lead to worsening, contact sports should be avoided. Since infection and fever can have deleterious effects, antibiotics and antipyretics should be used as indicated, and vaccinations, such as the influenza vaccine, should be kept up-to-date [8]. (See "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)

Avoidance of stressful situations that may trigger deterioration in VWM are sometimes recommended, although such measures are insufficient to prevent VWM onset and progression [8]. There are not indications for prophylactic use of steroids or other anti-inflammatory medications. The need for surgical procedures such as for scoliosis or spasticity management should be counterbalanced with the low but potential risk of VWM exacerbation.

Antiseizure medications are used in VWM patients with epilepsy. 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".)

SUMMARY AND RECOMMENDATIONS — Leukodystrophy with vanishing white matter disease (VWM; MIM #603896) is a chronic and progressive white matter disorder, often exacerbated by infection or head trauma.

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

●The precise incidence and prevalence of VWM is unknown, but it may be one of the more common leukodystrophies. VWM may be mistaken for other more common conditions such as multiple sclerosis. (See 'Epidemiology' above.)

●There are five clinical subtypes in a continuum (antenatal, infantile, early childhood, late childhood/juvenile, and adult) of VWM by age of onset. Patients with an earlier age of onset have a more rapid decline. In the early childhood variant, which is the most common, the major clinical features of VWM are progressive neurologic deterioration with prominent ataxia and spasticity. Optic atrophy is rare, but seizures can occur, especially in the advanced stage. Intellectual functioning and swallowing ability are usually relatively spared. Febrile illness, minor head trauma, or severe fright often lead to sudden neurologic deterioration, including coma, with incomplete recovery. (See 'Clinical features' above.)

●The brain MRI signal of the cerebral white matter changes from high to low intensity on proton density and fluid-attenuated inversion recovery (FLAIR) sequences as the white matter "vanishes" over time and is progressively replaced by cerebrospinal fluid (image 1 and image 2 and image 3 and image 4). These changes are less prominent in adult forms. (See 'Neuroimaging' above.)

●At autopsy, gross sections of the brain demonstrate extensive cystic, gelatinous, or cavitary degeneration involving the periventricular and immediate subcortical white matter (picture 1). (See 'Pathology' above.)

●The diagnosis of VWM should be confirmed by genetic testing in concert with MRI evaluation and consideration of clinical features. (See 'Diagnosis' above.)

●There is no cure or specific treatment for VWM. Avoidance of specific situations (head trauma from contact sports) that may trigger deterioration in VWM is important. (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.