Adult-onset Alexander disease with a heterozygous D128N GFAP mutation: a pathological study
Juan José Cabrera-Galván1,2,4, María Soledad Martínez-Martin1,2, Daniel Déniz-García2, Eduardo Araujo-Ruano2 and María del Mar Travieso-Aja3
1Pathological Anatomy Service, Maternal and Insular Hospital Complex of the Canary Health Service (SCS), 2Pathology Unit, Morphology Department, Las Palmas de Gran Canaria University (ULPGC), 3Department of Radiology, Hospital Group San Roque and 4Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBIS), Las Palmas de Gran Canaria, Spain
*Ondine Lucaciu and Dragos Apostu have equal contribution
Offprint requests to: Juan J. Cabrera-Galván, Pathology Unit, Morphology Department, Faculty of Health Sciences, ULPGC, Blas Cabrera Felipe s/n, 35016 Las Palmas de Gran Canaria, Spain. e-mail: juanjose.cabrera@ulpgc.es
Summary. The various forms of Alexander disease (AD) have been linked to heterozygous point mutations in the coding region of the Human glial fibrillary acidic protein (GFAP) gene. The aim of this study was to confirm and characterise an adult variant of AD based on the presence of Rosenthal fibres, which were identified at brain autopsy.
We performed histological and immunohisto-chemical studies and mutation screening by cycle sequencing of exons 1, 4, 6, and 8. A heterozygous D128N GFAP mutation, previously described in three other cases of adult-onset AD (AOAD), was genetically confirmed. The mutation was seemingly sporadic. Symptoms of the female, 65-year-old patient started with occasionally asymmetric motor impairment and concluded, 23 months later, with a lack of spontaneous movement in all four limbs, reduced consciousness, an acute respiratory problem, and eventually lethal exitus. The most striking characteristics were a cerebellar syndrome with subsequent clinical signs due to brainstem and spinal cord involvement. The final diagnosis was based on a complete autopsy, detection of Rosenthal fibres, GFAP, vimentin, alpha B-crystallin, ubiquitin, hsp27, neurofilament, and synaptophysin, and the identification of the corresponding GFAP gene mutation. Blood analyses were positive for ANA and rheumatoid factor.
In conclusion, this work describes sporadic, rapidly advancing AOAD in a female patient and links it with other published cases with the same mutation. Reflections are provided on the influence of vasculitis and ANA in AD as well as the presence of Rosenthal fibres in the neurohypophysis. Histol Histopathol 34, 1073-1088 (2019)
Key words: Alexander disease, D128N GFAP mutation, Immunohistochemistry, MRI, Pathology
DOI: 10.14670/HH-18-110