GFAP variants leading to infantile Alexander disease: Phenotype and genotype analysis of 135 cases and report of a de novo variant

Objectives: Alexander disease (AxD) is a rare autosomal dominant disorder due to GFAP mutations; infantile AxD is the most common severe form which usually results in death. In this study, phenotype and genotype analysis of all reported cases with IAxD are reported as well as a de novo variant. Methods: We conduct a comprehensive review on all reported Infantile AxD due to GFAP mutation. Clinical data and genetics of the reported patients were analyzed. Clinical evaluations, pedigree drawing, MRI and sequencing of GFAP were performed. Results: 135 patients clinically diagnosed with IAxD had GFAP mutations. A total of fifty three variants of GFAP were determined; 19 of them were located at 1A domain. The four common prevalent variants (c 0.715C>T, c 0.236G�A, c 0.716G�A, and c 0.235C�T) were responsible for 64/135 (47.4) of the patients. Seizure was the dominant clinical symptom (62.3) followed by macrocephaly (41), developmental delay (23.9) and spasticity (23.9). A de novo variant c 0.715C�T was found in the presented Iranian case. Discussion: The majority of GFAP variant are located in a specific domain of the protein. Seizure as the most common symptom of IAxD could be considered. This study highlighted the role of genetic testing for diagnosing AxD. © 2021 Elsevier B.V