# Association Between Rapid Progression, Early Mortality, and Imaging in Neonatal-Onset Alexander Disease

## TL;DR

This case study explores how rapid disease progression in neonatal-onset Alexander disease is linked to specific genetic mutations and imaging findings.

## Contribution

The study identifies a specific GFAP mutation (c.1106T > C; p.Leu369Pro) associated with rapid clinical deterioration and early death in neonatal Alexander disease.

## Key findings

- The c.1106T > C; p.(Leu369Pro) mutation in GFAP is linked to rapid clinical deterioration and early death.
- High-resolution ultrasound is a useful tool for monitoring brain changes in neonatal Alexander disease.
- Rapid accumulation of GFAP, as seen on brain imaging, correlates with poor prognosis.

## Abstract

Alexander disease represents a rare genetic leukodystrophy caused by abnormal astrocytic accumulations of intracytoplasmic proteinaceous inclusions with astrocyte dysfunction. With neonatal onset, survival ranges from 1.5 months to more than 7.5 years, with a possible association between the underlying point mutation, the level of protein accumulation in the cerebral white matter, disease progression, and survival time. We describe the clinical and cerebral imaging features of a female newborn with neonatal-onset Alexander disease caused by a heterozygous de novo point mutation c.1106T > C; p.(Leu369Pro) located in the coil 2B area of the glial fibrillary acidic protein (GFAP). Early-onset seizures, lethargy, and rapid loss of spontaneous movements were accompanied by rapidly evolving brain morphologic abnormalities and early death. The progression of cerebral abnormalities was monitored by magnetic resonance imaging and serial cranial ultrasound exams. As shown in this case study and the accompanying literature review, rapid accumulation of GFAP, as indicated by volume expansion of affected structures on brain imaging, combined with early onset of seizures and rapid clinical deterioration, seems to be associated with poor prognosis. In this case, high-resolution ultrasound offered an easily accessible, serial bedside imaging tool for the detection and follow-up of pathognomonic features of Alexander disease. We observed a close genotype-phenotype interaction in neonatal-onset Alexander disease, with the c.1106T > C; p.(Leu369Pro) mutation in coil2B associated with early death.