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INHERITED MONOGENIC DISEASES

           

Leukoencephalopathy with vanishing white matter

Leukoencephalopathy with vanishing white matter is a disease with an autosomal recessive inheritance. It has been shown to be one of the most common leukoencephalopathies in children. The classic and most frequent variant has its onset in infancy, most often between the ages of 2 and 6 years. The disease is characterized by chronic progressive neurological deterioration with cerebellar ataxia, usually less prominent spasticity, and relatively mild mental decline. Optic atrophy with loss of vision may occur, but not in all patients. Epilepsy is present in most patients, but is rarely a prominent feature. Characteristically, there are additional episodes of major and rapid deterioration following minor head trauma and especially febrile infections. Occasionally, these episodes are provoked by stress. During these episodes, patients rapidly lose motor faculties and become very hypotonic. Irritability, vomiting, and seizures usually progress to somnolence and loss of consciousness. These episodes may end in coma. Death usually follows an episode of coma.

Some patients have a more severe variant of the disease with onset within the first year of life and early demise. An example is found in so-called “Cree leukoencephalopathy,” a disease that was described among the Cree Indians. The onset of Cree leukoencephalopathy is between the ages of 3 and 9 months, and death occurs before the age of 2 years.

Some (non-Cree) patients have an even more severe phenotype with antenatal onset. In the third trimester of pregnancy, decreased fetal movements, oligohydramnios, growth failure, and development of microcephaly occur. At birth, contractures may be seen. From birth onwards or from soon after birth, there are increasing problems, with a rapid downhill course characterized by feeding problems, vomiting, failure to thrive, irritability, apathy, axial hypotonia, limb hypertonia or hypotonia, seizures, apneic episodes, coma, respiratory failure, and death within a few months. In these infants evidence may be found of involvement of other organs, including cataract, hepatosplenomegaly, kidney hypoplasia, pancreas involvement, and ovarian dysgenesis.

At the other end of the clinical spectrum are patients who are completely normal until onset of the disease in adulthood. In some patients occasional seizures are the first sign of the disease. In other patients, the disease starts with psychiatric symptoms. Some patients slowly develop dementia. In other patients motor deterioration dominates the clinical picture. The episodes of major deterioration are usually less marked in patients with a later onset. Later onset most often implies a slower and more protracted disease course, although unexpected rapid progression and death within a few months may also occur.

This disease is related to mutations in the five EIF2B genes encoding the five subunits of the 2B initiation factor (EIF2B), involved in the synthesis of proteins and their regulation under cellular stress. The pathophysiology of the disease will involve a deficiency in the maturation of astrocytes leading to an increase in the susceptibility of the white matter to cellular stress.

To date, 148 cases have been reported. The prevalence of this disease remains unknown.

DNA tests are available for diagnostic confirmation, carrier testing and prenatal diagnosis. The diagnosis is based on the detection of mutations in the EIF2B5 gene.

No specific treatment exists besides the “prevention” of cellular stress. Corticosteroids sometimes proved to be useful in acute phases.

Prognosis seems to be correlated with the age of onset, the earliest forms being more severe.

GENE OR REGION STUDIED


  • EIF2B5 (DTDST)

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