A novel large exon deletion in GFAP gene, Adult Alexander disease in Iran; The first report in the world

Background and Aim : Alexander disease is a type of leukodystrophy characterized by the destruction of the myelin sheath (the fatty covering that acts as an insulator around nerve fiber) and abnormal protein deposits known as Rosenthal fibers. Most cases of Alexander disease begin before age 2 years (the infantile form). Symptoms of the infantile form include an enlarged brain and head, seizures, stiffness in the arms and/or legs, mental retardation, and delayed physical development. Less frequently, onset occurs later in childhood (the juvenile form) or adulthood. Common problems in juvenile and adult forms of Alexander disease include speech abnormalities, swallowing difficulties, and poor coordination. Alexander disease is caused by mutations in the GFAP gene. While this condition is inherited in an autosomal dominant fashion, most cases result from new mutations in the gene. Methods : Our case is a 52-year-old woman with nonspecific of generalized weakness that depression has been added in recent years. She referred with cognition symptoms to Neurologic Clinic in Roozbeh Hospital. White matter lesions were seen on MRI which was suspected of having leukoencephalopathy evaluated. Next generation sequencing for the all genes that causing leukodystrophy was done.Results : This individual has a large heterozygous deletion (exons1-9) in the GFAP gene, so the case is suffering from Alexander disease.Conclusion : Our patient with a large deletion (exons1-9) in the glial fibrillary acid protein (GFAP) gene developed adult Alexander disease. To the best of our knowledge, this is the first reported case of AxD with exons deletion (1-9) in GFAP. Alexander disease is inherited in an autosomal dominant manner. The risk to the sibs of the proband depends on the genetic status of the proband s parents. If a parent is affected or has a pathogenic variant in GFAP, the risk to the sibs of inheriting the GFAP pathogenic variant is 50%. Sibs of a proband are at low risk for Alexander disease if the pathogenic variant is de novo (as is usually the case), but the risk to the children of the case is 50%. Genetic counseling is important for this case and her family especially for her 30-year-old son. however, the possibility of germline mosaicism exists. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.

کلیدواژه ها:

leukodystrophy ، Next generation sequencing ، Alexander disease ، GFAP gene ، genetic counseling