Identification of Fetal and Neonatal Magnetic Resonance (MRI) Findings Alone Does Not Predict Clinical Phenotype and Outcome in Alexander Disease

Abstract

Background: Alexander disease (AD) is a progressive, autosomal dominant leukodystrophy caused by pathogenic variants in the GFAP gene. The clinical spectrum is broad, with neonatal, infantile, juvenile and adult-onset forms. Characteristic MRI brain abnormalities in AD include frontal-dominant leukodystrophy, T2 hypointense/ T1 hyperintense periventricular rim, T2 hyperintensity and swelling or atrophy of basal ganglia and thalami, brainstem abnormalities and contrast enhancement of one or more structures. Aim/ Methods: We describe the outcomes of two patients with AD with fetal/neonatal MRI abnormalities. Results: Case 1 had a fetal MRI at 33 weeks gestation demonstrating aqueduct stenosis with severe ventriculomegaly. MRI on day 2 of life showed frontal-dominant white matter changes and basal ganglia atrophy. Repeat MRI at 4 months (for severe global developmental delay, failure to thrive and refractory seizures) demonstrated a frontal-dominant leukodystrophy, caudate nucleus and brainstem T2 hyperintensity and swelling, and contrast enhancement of basal ganglia, frontal white matter, dentate nucleus, ventricular lining and brainstem. Genetic testing confirmed a pathogenic GFAP variant c.716G>A. The patient died at 6 months from neurological deterioration. Patient 2 had a head ultrasound at age 3 weeks showing enlarged thalami. MRI performed at 6 weeks and 4 months identified T2 hyperintensity and swelling of basal ganglia, and symmetrical frontal white matter changes. Neurological examination and neurodevelopment are normal at 5 years. AD was confirmed genetically (pathogenic c.236G>A GFAP variant identified.) Conclusion: This series shows that neonatal MRI changes alone do not predict the clinical outcome of AD. It also shows that AD can present with fetal aqueduct stenosis.