A report of two cases of bulbospinal form Alexander disease and preliminary exploration of the disease

Abstract

Alexander disease (AxD) is a cerebral white matter disease affecting a wide range of ages, from infants to adults. In the present study, two cases of bulbospinal form AxD were reported, and a preliminary exploration of AxD was conducted thorough clinical, functional magnetic resonance imaging (fMRI) and functional analyses. In total, two de novo mutations in the glial fibrillary acidic protein (GFAP) gene (c.214G>A and c.1235C>T) were identified in unrelated patients (one in each patient). Both patients showed increased regional neural activity and functional connectivity in the cerebellum and posterior parietal cortex according to fMRI analysis. Notably, grey matter atrophy was discovered in the patient with c.214G>A variant. Functional experiments revealed aberrant accumulation of mutant GFAP and decreased solubility of c.1235C>T variant. Under pathological conditions, autophagic flux was activated for GFAP aggregate degradation. Moreover, transcriptional data of AxD and healthy human brain samples were obtained from the Gene Expression Omnibus database. Gene set enrichment analysis revealed an upregulation of immune-related responses and downregulation of ion transport, synaptic transmission and neurotransmitter homeostasis. Enrichment analysis of cell-specific differentially expressed genes also indicated a marked inflammatory environment in AxD. Overall, the clinical features of the two patients with bulbospinal form AxD were thoroughly described. To the best of our knowledge, the brain atrophy pattern and spontaneous brain functional network activity of patients with AxD were explored for the first time. Cytological experiments provided evidence of the pathogenicity of the identified variants. Furthermore, bioinformatics analysis found that inflammatory immune-related reactions may play a critical role in AxD, which may be conducive to the understanding of this disease.

Identification of a novel de novo pathogenic variant in GFAP in an Iranian family with Alexander disease by whole-exome sequencing

“…Most of the reported mutations in GFAP gene are de novo and with 100% penetrance [ 3 , 32 ]. A study conducted by Xiaoxuan Song et al in 2021, two de novo mutations naming c.214G > A and c.1235C > T were reported in two unrelated individuals [ 33 ]. Both patients indicate regional neural activity increase.…”

“… Mutation Protein change Total recruited patients Number of carriers Age DTR Ataxia Hypertonia Myoclonus Encephalopathy Scoliosis Bulbar signs Nystagmus Palatal myoclonus Spasticity Status epilepticus Seizures Atrophy Mental retardation Developmental Delay Gait Macrocephaly Slurred speech Clumsiness Unsteadiness Elective mutism Standing on one foot Other Ref. 1 c.214G > A c.1235C > T E72K T412I 2 2 26 33 2 2 2 1 [ 33 ] 2 c.731C > T A244V 65 1 10 …”

Adult-Onset Alexander Disease with late-presenting vestibulopathy: A case report

“…10 Functional MRI of patients withbulbospinal type AxDrevealed higher neuronal activities in the cerebellar vermis, cerebellopontine angle, and posterior parietal cortex and voxel-based morphometry indicated overlapping white matter atrophy overlapped in these regions, along with the medulla. 11 Notably, brain MRI did not show significant white matter lesions, suggesting a potential overload and collapse of the brain network with compensatory mechanism for cerebellum, medulla and surrounding structures. 11 In addition, it's crucial to consider the possibility of late-onset vestibular symptoms in the context of AxD cases, as previous reports have linked symptom exacerbation to minor head trauma.…”

“…11 Notably, brain MRI did not show significant white matter lesions, suggesting a potential overload and collapse of the brain network with compensatory mechanism for cerebellum, medulla and surrounding structures. 11 In addition, it's crucial to consider the possibility of late-onset vestibular symptoms in the context of AxD cases, as previous reports have linked symptom exacerbation to minor head trauma. [12][13][14] Commonly reported symptoms following such trauma included deteriorating gait disturbance, dysarthria, and dysphagia, with no observable changes on brain or cervical MRI in most cases.…”