Vanishing white matter disease
Vanishing white matter (VWM) disease is a rare, progressive neurological disorder primarily affecting children but also seen in young adults. It is characterized by the deterioration of the brain's white matter, impacting the myelin sheath that insulates nerve fibers. The disease arises from mutations in one of five genes associated with the eukaryotic initiation factor 2B (eIF2B), leading to impaired protein synthesis in response to stress, which exacerbates symptoms. Clinical signs can include spasticity, cerebellar ataxia, seizures, and in some cases, optic atrophy. The onset of symptoms varies greatly, with some individuals presenting symptoms in infancy while others may do so in adulthood.
Diagnosis typically involves magnetic resonance imaging (MRI) to reveal white matter abnormalities and genetic testing to identify specific mutations. Currently, there is no cure for VWM disease; treatment focuses on managing symptoms and minimizing stressors that might trigger exacerbations. Prognosis can vary widely, with more severe outcomes often linked to earlier onset of symptoms. Genetic counseling and testing are recommended for families with a history of the disease, given its autosomal recessive inheritance pattern.
Vanishing white matter disease
ALSO KNOWN AS: Myelinosis centralis difusa; childhood ataxia with central nervous system hypomyelination (CACH); Cree leukoencephalopathy; leukoencephalopathy with vanishing white matter; VWM
DEFINITION Vanishing white matter (VWM) disease is a rare, progressive, panethnic autosomal recessive disorder that affects the central nervous system predominantly in children, but also in young adults. The disease leads to a deterioration of the white matter (leukodystrophy). The fatty myelin sheath that insulates nerve fibers, giving white matter its color, is affected.
Risk Factors
Family history is an important risk factor.
Etiology and Genetics
The disease is caused by mutations in one of the five genes coding for the eukaryotic initiation factor 2B (eIF2B): EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, located on chromosomes 12q24.31, 14q24.3, 1p34.1, 2p23.3, and 3q27.1, respectively. The genes encode the five subunits of EIF2B complex, which regulates translation initiation and ultimately protein synthesis in the cell. A defective EIF2B leads to an impaired cellular ability to regulate protein synthesis under normal conditions, as well as in response to physical, chemical, and oxidative stress. This might explain the exacerbation of clinical symptoms under stress conditions.
To date, more than eighty mutations have been identified, including punctiform mutations (the majority), deletions, and insertions. The process of identification of the first two genes involved in VWM, EIF2B5 and EIF2B2, was facilitated by two founder effects in the Dutch population. At present, it appears that gene EIF2B5 contains most mutations (65 percent), frequently R113H. Interestingly, brain glial cells (astrocytes and oligodendrocytes) are particularly susceptible to EIF2B5 mutations. Neuropathologic examination reveals a unique and selective disruption of the glial cells, with spared neurons. White matter rarefaction, cavitating lesions, and increased numbers of “foamy” oligodendrocytes are observed. Studies show that, in astrocytes, EIF2B5 alterations lead to cellular maturation defects, but the basis of their selective vulnerability is still poorly understood.
The pattern of inheritance is autosomal recessive, signifying that both copies of the gene in each cell display the mutation. Patients are homozygotes or compound heterozygotes for mutations that are on the same gene. The parents of a patient each carry a copy of the affected gene without showing any signs of disease.
Symptoms
Frequently reported clinical characteristics include spasticity, cerebellar ataxia, optic atrophy (inconstant), ovarian insufficiency, and seizures. The first signs may occur antenatally, in infancy, early childhood, late childhood, or adulthood. The severity of clinical presentation is highly variable. Mental abilities are relatively preserved. The progression is slow, with exacerbations (triggered by injuries, febrile illness, even fright) leading to partial recovery or coma and death. Lengthy periods of relative stability and even mild improvements are possible.
Screening and Diagnosis
The initial diagnosis relies on clinical symptoms and magnetic resonance imaging (MRI) findings. Imaging reveals diffuse abnormal signal of the cerebral white matter and cystic degeneration (cavitation). The diagnosis also involves detection of EIF2B mutations via sequence analysis or mutation scanning. Carrier testing is available for family members once mutation has been identified in a proband. Routine studies of cerebrospinal fluid (CSF), blood, and urine are unremarkable. The lymphoblasts of these patients show a decreased intrinsic activity of the eIF2B factor. A marked reduction in the amount of asialo-transferrin in CSF is a recently described biochemical abnormality that can become a clinical diagnostic biomarker.
The five types of VWM syndrome are classified by the age of onset. These are prenatal, infantile, childhood, juvenile, and adult onset.
Treatment and Therapy
At present, there is no cure for this disease. Treatment is symptomatic. Antibiotics and vaccines should be used rigorously. In children with frequent upper respiratory infections, daily low-dose antibiotics can be considered. Corticosteroids are sometimes useful in the acute phase. Minimizing “cellular stress” is important. Affected individuals should avoid psychological stressors, trauma (contact sports), and high body temperature.
Prevention and Outcomes
Genetic counseling, prenatal testing, and testing of family members can be pursued by individuals with relevant family history. Prognosis appears to correlate with the time of onset, with early forms being more severe (for example, Cree leukoencephalopathy, a fatal infantile form). The phenotype varies widely, from early demise in antenatal onset to slowly progressive disease in the adult form. Most patients survive for a few years after diagnosis.
Bibliography
Filareto, Ilaria, et al. "E1F2B2 Gene Mutation Causing Early Onset Vanishing White Matter Disease: A Case Report." Italian Journal of Pediatrics, vol. 48, 2022, doi.org/10.1186/s13052-022-01325-3. Accessed 9 Sept. 2024.
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Kami, Atefe, et al. "Leudoencephalopathy with Vanishing White Matter Disease: A Case Report Study." Annals of Medicine & Surgery, vol. 85, no. 8, 2023, pp. 4087-4091, doi: 10.1097/MS9.0000000000001017. Accessed 9 Sept. 2024.
Klug, William S., Sarah M. Ward, et al. Essentials of Genetics. Boston, Pearson, 2013.
Meoded, A., et al. "Leukoencephalopathy with Vanishing White Matter: Serial MRI of the Brain and Spinal Cord Including Diffusion Tensor Imaging." Neuropediatrics, vol. 42, no. 2, 2011, pp. 82–85.
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Rosenberg, Roger N., et al., eds. The Molecular and Genetic Basis of Neurologic and Psychiatric Disease. 4th ed. Lippincott, 2007.
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