IDENTIFICATION OF THE GENE FOR A NOVEL WHITE MATTER DISORDER

The main objective of this project is to identify the gene responsible for a novel autosomal recessive leukoencephalopathy that we have recently described in 7 Italian cases originating from a small village. This disorder is characterized by a slowly progressive neurological impairment, peripheral neuropathy, mental retardation, and diffuse white matter abnormalities on MRI. Preliminary molecular studies allowed the identification of a 3.2 Mb homozygous segment in all affected patients demonstrating the genetic origin of the disorder. Inherited leukoencephalopathies of childhood represent a heterogeneous group of conditions, selectively affecting the white matter of the brain, that are usually characterized by a severe and progressive handicap, with a high risk of family recurrence. The percentage of undefined leukoencephalopathies, i.e. cases without a specific diagnosis despite extensive investigations, is still high (up to 50%). Recently, however, the combined use of clinical, laboratory and neuroradiological protocols in the systematic analysis of unclassified cases, allowed the identification of novel genetic syndromes, following a common path. The first step requires the careful description of the clinical and neuroradiological characteristics in order to define homogenous patient groups who are subjected to molecular investigations.When successful, they result in determining a chromosomal locus for the disorder and the affected gene. Finally, further researches are provided to better understand the pathogenetic mechanisms underlying the disorder. Furthermore, the newly discovered genetic marker may lead to diagnose the disease in previously unrecognized patients. In conclusion, the identification of the gene for a novel leukoencephalopathy may have significant impact by improving our diagnostic ability, providing new insights into pathogenesis of myelin disorders and by adding valuable information on brain development and functioning.