Neonatal Alexander Disease: Novel GFAP Mutation and Comparison to Previously Published Cases

Abstract

Alexander disease (AxD) is a genetic leukodystrophy caused by mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD. Genetic analysis of the proband identified a novel missense mutation and a splice site mutation segregating with the BFNE phenotype in the family. The mutation was located in the coil 2B region of GFAP protein, similar to most neonatal-onset AxD cases with an early death. The clinical and neuroradiological features of the previously published neonatal AxD patients are presented. This study further supports the classification of neonatal-onset AxD as a distinct phenotype based on the age of onset.

GFAP variant p. Tyr366Cys demonstrated widespread brain cavitation in neonatal Alexander disease.

“…In our case and others, hydrocephalus due to aqueductal stenosis, periventricular rim in the brain MRI, and elevated CSF protein levels were observed in the early phase of neonatal AxD [14 , 15] . Aqueductal stenosis is the result of GFAP accumulation in the subependymal area and brainstem and the consequent proliferation of astrocytes in the brainstem [16] .…”

Leukodystrophy with Macrocephaly, Refractory Epilepsy, and Severe Hyponatremia—The Neonatal Type of Alexander Disease

“…Both these classifications lacked a neonatal type distinguished from variable infantile AxD, which was proposed by Springer et al [ 11 ]. This separation is necessary due to a uniform pattern of severe clinical presentation in neonatal AxD [ 10 , 11 , 14 , 16 , 18 , 19 ]. To date, the neonatal form was described only in approximately 20 patients [ 14 , 16 , 19 ].…”

The Spectrum of KCNQ2- and KCNQ3-Related Epilepsy

“…[36][37][38][39][42][43][44][45] The MRI study frequently demonstrates encephalic anomalies including bilateral or asymmetric hyperintensities, especially in the basal ganglia and thalamus, reduction of white matter, thin corpus callosum, enlargement of extra-axial spaces, and atrophy of frontal lobes. 1,27,36,37,[46][47][48][49] Other Clinical Presentation of KCNQ2 Mutation Continuous spike-waves during sleep (CSWS): it is a form of encephalopathy in which the EEG anomalies occur during the sleep, with a better outcome compared with EIEE7 with mild or moderate developmental delay. It has been described by Lee et al and in two patients, showing a c.1534G > C mutation: one of them also had a positive familial history for BFNE.…”

“…[36][37][38][39][42][43][44][45] The MRI study frequently demonstrates encephalic anomalies including bilateral or asymmetric hyperintensities, especially in the basal ganglia and thalamus, reduction of white matter, thin corpus callosum, enlargement of extra-axial spaces, and atrophy of frontal lobes. 1,27,36,37,[46][47][48][49]…”