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A Distinct Entity Caused by Mutation in the Glial Fibrillary Acid Protein Gene

Erika Stumpf, MD, MA; Hélène Masson, MD, FRCPC; Antoine Duquette, MD; France Berthelet, MD; Julia McNabb; Anne Lortie, MD, FRCPC; Jacques Lesage, MD, FRCPC; Jacques Montplaisir, MD, PhD, CRCPC; Bernard Brais, MD, MPhil, PhD; Patrick Cossette, MD, MSc, FRCPC

Arch Neurol. 2003;60:1307-1312.

Background  Infantile and juvenile forms of Alexander disease are well characterized and are caused by de novo mutations in the glial fibrillary acid protein (GFAP) gene. In contrast, the adult form of the disease has been rarely described, and the etiology of this variant remains unknown.

Objective  To characterize the clinical phenotype and identify the gene causing an autosomal dominant form of adult Alexander disease.

Methods  We identified a large kindred segregating clinical features compatible with adult Alexander disease in an autosomal dominant fashion. A neurological examination was performed on all affected members of this family. Most of these patients also underwent magnetic resonance imaging of the brain and a polysomnographic study. The diagnosis was confirmed pathologically in 2 individuals. We screened all coding regions of the GFAP gene in affected individuals by means of direct sequencing and single-stranded conformational polymorphisms analysis.

Results  We found a novel D78E mutation in GFAP in all affected individuals. This mutation was not detected in more than 100 control subjects. Clinical and radiological features of affected individuals were clearly different from those of patients with the infantile and juvenile forms of the disease. The most consistent finding was the presence of bulbar signs. In addition, sleep disturbance (mainly sleep apnea), symptoms of dysautonomia, and dysmorphism were found in all affected individuals. In younger patients, magnetic resonance imaging showed T2 signal abnormalities in the medulla compatible with an area of demyelination. In contrast, in older patients, we found marked atrophy of the medulla without signal abnormalities. None of the affected individuals exhibit signs of demyelination of the cerebral white matter.

Conclusions  The present study is the first demonstration of a mutation in GFAP that causes an autosomal dominant form of Alexander disease and establishes the existence of the adult variant. Clinical evaluation in individuals carrying mutation in the GFAP gene allowed a better definition of this heterogeneous clinical syndrome and will help increase its recognition in neurological practice.

From the Service de neurologie et Unité de Neurogénétique (Drs Stumpf, Masson, Duquette, Brais, and Cossette and Ms McNabb), Service de neuropathologie (Dr Berthelet), and the Département de Radiologie (Dr Lesage), Centre Hospitalier de l'Université de Montréal-Hôpital Notre-Dame, the Service de neurologie, Hôpital Sainte-Justine (Dr Lortie), and the Laboratoire des troubles du sommeil, Hôpital du Sacré-Cur a(Dr Montplaisir), Montréal, Québec.

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