Unusual variants of Alexander's disease

Abstract

The purpose of this study was to describe unusual variants of Alexander's disease. We studied 10 patients who did not meet previously established magnetic resonance imaging (MRI) criteria for Alexander's disease, but for whom this diagnosis was considered because of Rosenthal fibers at histological examination or presence of some MRI features suggestive of Alexander's disease. Sequence analysis of the GFAP gene was performed. In eight patients, MRI results showed predominantly posterior fossa lesions, especially multiple tumor-like brainstem lesions. One patient had asymmetrical frontal white matter abnormalities and basal ganglia abnormalities. One patient (Patient 10) developed degeneration of the frontal white matter. In nine patients, a mutation was found that was concluded to be pathogenic, because the mutation was de novo (five patients), a known mutation was found (two patients), or assembly of the glial fibrillary acidic protein was abnormal in cultured cells (two patients). In Patient 10, a DNA variation was found that was also present in the patient's clinically unaffected father and was concluded to be a polymorphism. In conclusion, DNA diagnostics is warranted in patients who display MRI features suggestive of Alexander's disease, even if they do not meet the full set of previously established MRI criteria.

Isolated macrocerebellum: description of six cases and literature review

“…Alexander disease is characterized by a dramatic and diffuse loss of myelin in both the cerebral hemispheres, in the CB and brainstem with associated increase of the density of the astrocytes from which derives an increase in the brain size (megalencephaly) (19). In 2005, Van Der Knaap and colleagues described a variant in which the posterior fossa was mainly involved, with tumour-like lesions and increase of the volume of the CB and of the brainstem (8). Overtime the neuronal structures involved became atrophic.…”

“…An abnormal enlargement of the CB can be also seen in some well-known metabolic and genetic diseases or clinical syndromes such as Lhermitte-Duclos (3,4), Sotos syndrome (5), Costello syndrome (6), Williams syndrome (7), Alexander disease (8), mucopolysaccharidoses (9) Original Article Isolated macrocerebellum: description of six cases and literature review and fucosidosis (10).…”

Late onset Alexander’s disease presenting as cerebellar ataxia associated with a novel mutation in the GFAP gene

“…The present case report highlights the importance of MR imaging in the differential diagnosis of adult onset leukodystrophies. Although our patient met only three out five MRI criteria for AD [7], the severe atrophy of the medulla oblongata along with signal abnormalities in the hilus of the dentate nucleus were suggestive of AOAD [5,6,8]. However, the symmetrical signal abnormalities of the globus pallidus on T2-weighted images are only rarely seen in AOAD [5,6,8].…”

“…Nearly all AD mutations involve amino acid substitutions, and a dominant toxic or gain-of-function effect for mutant GFAP protein was hypothesized [2,3]. While AD in infants and children typically presents with psychomotor retardation, seizures, ataxia and progressive spasticity leading to death within a few years [1,2], clinical phenotypes with AOAD vary considerably and the clinical course is more protracted [4][5][6]. MRI criteria have been proposed for the diagnosis of AD [7].…”

“…MRI criteria have been proposed for the diagnosis of AD [7]. However, more recent case series of patients with AOAD involving individuals with atypical clinical and MRI features not fully meeting the above diagnostic criteria, suggest that the spectrum of clinical phenotypes of AOAD may be broader than previously expected [4][5][6]8].…”