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Inge A. Meijer, PhD; Ana A. Simoes-Lopes, MD; Sandra Laurent; Tanya Katz, BSc; Judith St-Onge, DEC; Dominique J. Verlaan, PhD; Nicolas Dupré, MD, MSc; Manon Thibault, MD; Johanne Mathurin, MD; Jean-Pierre Bouchard, MD; Guy A. Rouleau, MD, PhD

Arch Neurol. 2008;65(11):1496-1501.

Objective:  To identify the underlying locus and disease-causing mutation for adult-onset autosomal dominant leukodystrophy (ADLD).

Design  Previously, an adult-onset ADLD locus on chromosome 5q23 was mapped between markers D5S1495 and CTT/CCT15. This region contains 13 known and putative candidate genes. A 2-point linkage analysis confirmed linkage of a large multigenerational French Canadian family to chromosome 5q23. In addition, screening of the 13 genes within the candidate interval as well as 5 neighboring genes was completed, followed by comparative genomic hybridization.

Subjects  A multigenerational French Canadian family with ADLD mimicking progressive multiple sclerosis was identified and studied. Eight affected family members were available for the study and presented with autonomic dysfunction as well as upper motorneuron signs affecting gait.

Results  The thorough candidate gene approach did not identify any mutation. Consequently, a whole-chromosome comparative genomic hybridization for chromosome 5 identified a 280-kilobase duplication within the chromosomal band 5q23.2 in 2 affected individuals. This duplication contains 3 genes: LMNB1, FLJ36242, and MARCH3.

Conclusion  We have identified a novel duplication on chromosomal band 5q23.2 in a French Canadian family with ADLD that supports the implication of duplicated LMNB1 as the disease-causing mutation. However, additional functional studies of lamin B1 overexpression are necessary to elucidate the involvement of lamin B1 in myelination and in degenerative disorders such as ADLD and multiple sclerosis.

Author Affiliations: Centre of Excellence in Neuromics, Centre Hospitalier de l’Université de Montreal and Ste-Justine Hospital, Montreal (Drs Meijer, Lopes, Verlaan, and Rouleau and Mss Laurent and Katz); Centre Hospitalier Affilié Universitaire de Quebéc–Hôpital de l'Enfant-Jésus, Department of Neurological Sciences, Université Laval, Québec City (Drs Dupré, Thibault, and Bouchard); Centre Hospital Affilié Hôtel-Dieu de Lévis, Department of Radiology, Lévis, Quebec, Canada (Dr Mathurin).

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