Adult-onset Alexander disease with typical "tadpole" brainstem atrophy and unusual bilateral basal ganglia involvement: a case report and review of the literature

Abstract

BackgroundAlexander disease (ALX) is a rare neurological disorder characterized by white matter degeneration and cytoplasmic inclusions in astrocytes called Rosenthal fibers, labeled by antibodies against glial fibrillary acidic protein (GFAP). Three subtypes are distinguished according to age at onset: infantile (under age 2), juvenile (age 2 to 12) and adult (over age 12). Following the identification of heterozygous mutations in GFAP that cause this disease, cases of adult-onset ALX have been increasingly reported.Case PresentationWe present a 60-year-old Japanese man with an unremarkable past and no family history of ALX. After head trauma in a traffic accident at the age of 46, his character changed, and dementia and dysarthria developed, but he remained independent. Spastic paresis and dysphagia were observed at age 57 and 59, respectively, and worsened progressively. Neurological examination at the age of 60 revealed dementia, pseudobulbar palsy, left-side predominant spastic tetraparesis, axial rigidity, bradykinesia and gaze-evoked nystagmus. Brain MRI showed tadpole-like atrophy of the brainstem, caused by marked atrophy of the medulla oblongata, cervical spinal cord and midbrain tegmentum, with an intact pontine base. Analysis of the GFAP gene revealed a heterozygous missense mutation, c.827G>T, p.R276L, which was already shown to be pathogenic in a case of pathologically proven hereditary adult-onset ALX.ConclusionThe typical tadpole-like appearance of the brainstem is strongly suggestive of adult-onset ALX, and should lead to a genetic investigation of the GFAP gene. The unusual feature of this patient is the symmetrical involvement of the basal ganglia, which is rarely observed in the adult form of the disease. More patients must be examined to confirm, clinically and neuroradiologically, extrapyramidal involvement of the basal ganglia in adult-onset ALX.

Neuroimaging and clinical features in type II (late-onset) Alexander disease

“…5,7,15 We also confirmed frequent involvement of the dentate with less frequent coexisting cerebellar white matter change. 5 Compared with infantile or type I AxD, involvement of the periventricular white matter was sparse.…”

“…7 Bilateral involvement of the middle cerebellar peduncle is useful in narrowing the differential diagnosis. In a series of 27 cases of bilateral middle cerebellar peduncle involvement on MRI, multiple system atrophy, spinocerebellar ataxia, Wilson disease, liver cirrhosis, adrenoleukodystrophy, posterior reversible encephalopathy syndrome, and neoplasms were the most frequent causes, but AxD was not listed as a potential cause.…”

“…Available studies suggest that the clinical and radiologic presentation differs significantly from infantile-onset cases. [5][6][7][8][9][10][11] Adult-onset cases appear to have less cerebral white matter involvement. Medullary and spinal cord atrophy occurs in most, but often with a mixture of additional findings that may present diagnostic challenges.…”

Imaging of adult leukodystrophies

“…MRI shows mild-to-severe atrophy of the medulla oblongata extending caudally to the cervical spinal cord, sometimes associated with signal abnormalities ( Figure 5). Midbrain tegmentum atrophy has also been described, with preservation of the pontine base and this finding is quite specific of adult-onset Alexander disease 17 . Basal ganglia abnormalities (diffuse or patchy) have also been described, especially in patients under 40 years of age.…”

Juvenile Alexander Disease: a Case Report

“…These studies have transformed our view of this disorder and opened new directions for investigation and clinical practice, particularly with respect to diagnosis [22,23].…”