Adult-onset Alexander disease

Abstract

Pathogenic, dominant, de novo missense mutations in the glial fibrillary acidic protein (GFAP) have been found in the three subtypes of infantile, juvenile and adult Alexander disease. Here we describe four members of an Italian family (32 to 66-yearsold, 2 women and 2 men) affected by adult Alexander disease, the least common and the most clinically variable form. Direct sequencing of all coding regions of the GFAP gene, neurological examination and brain MRI were performed. Two novel missense mutations were found involving two very close codons, c.[988C > G, 994G > A], leading to p.[Arg330Gly, Glu332Lys]. Clinically, two members exhibited pseudo-bulbar signs, gait ataxia and spasticity, one showed a severe cranial sensory symptomatology, and one subject was asymptomatic.Medulla and cervical cord atrophy was present in all of them on MRI. Although adult Alexander disease shows a wide clinical variability, a more frequent pattern can be identified characterized by bulbar or pseudo-bulbar signs, gait ataxia, and spasticity, and including on MRI medulla and cervical cord atrophy. Our findings also confirm that the clinical spectrum of adult Alexander disease includes cases without overt neurological involvement and with minimal brain MRI alterations.

Can MR Imaging Diagnose Adult-Onset Alexander Disease?

“…cord junction, a diagnosis requires that the neuroradiologist be aware of the characteristic features of AOAD. Although in recent years several single case reports and small series of mixed juvenile and adult patients with AD have shown the predominant lower brain stem involvement, 1,[7][8][9][10][11][12][13][14][15][16][17][18][19][20] no detailed analysis of a large number of AOAD has been reported. It is peculiar that in the period of collection of our AOAD series, no juvenile cases came to our observation.…”

“…2,3 Milder forms with spastic paraparesis, ataxia, or lower brain stem signs and juvenile (2-12 years of age) or adult onset (Ն13 years) had been diagnosed as AD at postmortem examination because of the presence of Rosenthal fibers. 4 After 2001, the discovery that mutations in the glial fibrillary acidic protein gene (GFAP) were responsible for the disease 5,6 allowed recognition during life of juvenile or adult forms 1,[7][8][9][10][11][12][13][14][15][16][17][18][19][20] that have an MR imaging pattern remarkably different from that observed in children, with predominant focal involvement of the lower brain stem.…”

MR Imaging Characteristics and Neuropathology of the Spinal Cord in Adult-Onset Autosomal Dominant Leukodystrophy with Autonomic Symptoms

“…34 Adult-onset (Ն13 years) forms with clinical and radiologic findings different from those of the infantile type have been reported. [35][36][37][38][39][40][41][42][43][44][45] Ataxia, 35,36,[38][39][40][42][43][44] pyramidal signs, 35,[38][39][40][41]43,44 and autonomic dysfunction 39,41,45 overlap the clinical features of ADLD with autonomic symptoms. However, palatal tremor and palatal myoclonus, common in adult-onset Alexander disease, 35,[38][39][40]43,45 have not been reported in adult-onset ADLD with autonomic symptoms.…”

“…Due to genetic characterization and diagnosis of the disease, new radiologic patterns have been described, even in asymptomatic family members. 43,44 In families with adult-onset Alexander disease, atrophy of the medulla oblongata and the upper spinal cord can be the most important MR imaging findings. 35,[37][38][39][40][41][42][43][44] In adult-onset ADLD with autonomic symptoms, the entire spinal cord is atrophic.…”

Identification of a novel nonsense mutation in the rod domain of GFAP that is associated with Alexander disease

“…First, there have been reports on individuals who came to the clinic because of symptoms unrelated to AxD and were later found to harbor mutations in GFAP. [32][33][34][35] Second, even in these individuals, their MRI findings varied. For example, MRI of the patients 5 and 9 in the study of Farina et al 22,34 revealed severe atrophy and signal changes in the brain stem and cervical spinal cord, whereas MRI of the patients no.…”