Histopathological Proof of the Pathogenetic Role of a Rare GFAP Mutation in Alexander´s Disease with Isolated Flaccid Paraparesis

Background: Alexander’s disease is a rare progressive leukodystrophy that typically presents with progressive psychomotor retardation, progressive macrocephaly, and refractory epilepsy. Diagnosis is made on clinical and cMRI features characterized by extensive changes of cMRI signal intensity of the white matter with frontal preponderance as well as changes of basal ganglia and medulla oblongata with variable contrast enhancement. Genetic confirmation finds autosomal dominant mutations in the glial fibrillary acidic protein (GFAP) gene.

Case Report: We report a boy presented at 21 months of age with flaccid paraparesis and areflexia. Cognitive and fine motor skills and muscular strength of the upper extremities were appropriate for age. Auxological data were within normal range including head circumference (P 75). Clinical or electroencephalographic signs of seizures were absent. Spinal MRI showed hyperintense swelling of the lumbar spinal cord and cervical spine, while cMRI revealed bifrontal cystic and high signal intensity changes with contrast rims, as well as space-occupying changes of the nucleus caudatus and putamen. CSF and blood chemistry showed normal results. Histopathology of a subcortical lesion revealed large amounts of Rosenthal fibers and protein droplets characteristic of Alexander’s disease. Sequencing detected a heterozygous mutation of the GFAP gene (c.205G>A; p.(Glu69Lys)) that has been reported before as probably pathogenetic in another case of lower spinal involvement. Parents declined genetic testing.

Conclusion: This well-documented case turns attention to slowly progressive spinal manifestations of Alexander’s disease and gives histopathological proof of the pathogenetic role of a rare GFAP mutation with marked spinal involvement.