Neuropsychological Functioning in Alexander Disease: A Case Series

Abstract

Limited information is known about neuropsychological outcomes in Alexander disease, a rare leukodystrophy. Two pediatric cases are summarized. Case 1 (evaluations at 6, 7, 9, and 12 years of age) represents Type I Alexander disease with associated seizures. Case 2 (evaluations at 12, 13, and 16 years of age) represents Type II Alexander disease without additional complications. Case 1 experienced declines in intellectual functioning, visual motor skills, receptive vocabulary, verbal memory, and academic achievement. Case 2 experienced variable neurocognitive change and academic functioning, with average word reading and spelling. Verbal memory also remained intact. Taken together, individuals with Alexander disease may experience cognitive decline to variable degrees. Type I Alexander disease, associated with earlier onset and additional neurological complications, may presage greater cognitive decline than Type II. Due to variability in functioning over time, it is critical to follow individuals across development to make recommendations for educational and treatment planning.

Quantitative diffusion imaging and genotype‐by‐sex interactions in a rat model of Alexander disease

“…A clinical hallmark of type 1 AxD are the cognitive deficits associated with the disease, presumably on the basis of its association with white matter structures in the frontal lobe 4 . Previous work also reports cognitive deficits being present in type 1 AxD patients and mice, respectively 6–8,24,25 . We extend these findings with additional evidence of deleterious microstructural changes in regions of the brain such as the hippocampus, neocortex, and amygdala, further supporting and identifying potential neurobiological substrates for these findings.…”

“…4 Previous work also reports cognitive deficits being present in type 1 AxD patients and mice, respectively. [6][7][8]24,25 We extend these findings with additional evidence of deleterious microstructural changes in regions of the brain such as the hippocampus, neocortex, and amygdala, further supporting and identifying potential neurobiological substrates for these findings. Specifically, the findings of decreased neurite density and decreased dispersion of neurites suggest the presence of marked neuronal injury (and their microstructural alterations) as a consequence of GFAP mutation affecting the astrocytes in these animals.…”

“…Characteristic MRI biomarkers of AxD include extensive cerebral white matter changes with frontal predominance, a periventricular rim with high signal on T 1 ‐weighted images, low signal on T 2 ‐weighted images, abnormalities of basal ganglia and thalami, atypical brain stem findings, and contrast enhancement of gray and white matter structures 5 . Currently, many clinicians and scientists use these criteria for clinical diagnosis as well as when reporting on case studies in specific populations 6–8 …”

“…5 Currently, many clinicians and scientists use these criteria for clinical diagnosis as well as when reporting on case studies in specific populations. [6][7][8] Although the diagnostic and neuroimaging approach to the clinical diagnosis of AxD has overall proved to be successful, there are many overlapping clinical symptoms and imaging biomarkers for different subtypes of AxD (e.g., juvenile and adult onset) that remain difficult to distinguish from one another. 3 Further, the neurobiological substrates, and how they might differ between the subtypes of AxD, also remain unclear.…”

Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases

“…Type one is characterized by early-onset convulsions, macrocephaly, progressive psychomotor and cognitive delays, and failure to thrive due to lesions in the forebrain [ 39 ]. Type two manifests as posterior brain lesions and associated symptoms such as palatal myoclonus, ataxia, dysphagia, and morphological dysfunction, and it can occur at any age [ 40 , 41 ]. The characteristic pathological features in both groups is the presence of Rosenthal fibers, which are aggregates of astrocyte cytoplasmic proteins, especially in perivascular, subcutaneous areas and subepithelial areas [ 42 ].…”