A novel familial mutation in Alexander disease with marked variation in clinical severity

Abstract

Objective: Alexander disease is a rare, often lethal disorder characterized by white-matter degeneration and cytoplasmic inclusions in astrocytes known as Rosenthal fibers, which are immunohistochemically positive to glial fibrillary acidic protein (GFAP). The disease typically results from dominant mutations in GFAP that arise de novo. However, series of familial cases with variable clinical manifestations have been described suggesting a potential recessive inheritance or germline mosaicism. We report a male infant with typical Alexander disease, inherited by his asymptomatic father with positive neuroimaging markers of the disease. Methods: Clinical histories were obtained and whole exome sequencing (WES) analyses in blood samples were performed through next generation sequencing. Results: We report a 6-month male, born of an uneventful term pregnancy, who presented with generalized hypotonia, chorioathetosis and drug-resistant seizures, without macrocephaly. Brain MRI showed symmetrical abnormalities of the basal ganglia, subcortical white matter abnormalities, mainly of the frontal area with contrast enhancement along with high intensity periventricular rim on T1. WES analysis of the patient revealed a heterozygous missense mutation, c.1120G>A (p.Glu374Lys) in GFAP gene, resulting in the substitution of the aminoacid glutamic acid with lysine at the protein level. Although this genetic change is novel, it was considered as pathogenic from in silico analysis. We therefore proceeded to genetic analyses of the remaining members of the family that revealed the same mutation in the asymptomatic father. A subsequent brain MRI showed white matter abnormalities suggestive of adult-onset Alexander disease. Conclusion: We present a familial case of Alexander disease caused by a novel mutation on GFAP gene. There is a marked discrepancy on clinical presentation between the father and the affected child imposing that there is a striking variation on penetrance of the mutated gene of unknown etiology. We suggest genetic analysis on parents of patients with Alexander disease even if asymptomatic.