Abstract
Pelizaeus–Merzbacher disease (PMD; MIM#312080) is a rare X-linked recessive neurodegenerative
disorder. The main cause of PMD is alterations in the proteolipid protein 1 gene (PLP1) on chromosome Xq22.2. Duplications and point mutations of PLP1 have been found in 70% and 10–25% of all patients with PMD, respectively, with a
wide clinical spectrum. Since the underlining genomic abnormalities are heterogeneous
in patients with PMD, clarification of the genotype-phenotype correlation is the object
of this study. Comprehensive genetic analyses using microarray-based comparative genomic
hybridization (aCGH) analysis and genomic sequencing were applied to fifteen unrelated
male patients with a clinical diagnosis of PMD. Duplicated regions were further analyzed
by fiber-fluorescence in situ hybridization (FISH) analysis. Four novel and one known nucleotide alterations were
identified in five patients. Five microduplications including PLP1 were identified by aCGH analysis with the sizes ranging from 374 to 951-kb. The directions
of five PLP1 duplications were further investigated by fiber-FISH analysis, and all showed tandem
duplications. The common manifestations of the disease in patients with PLP1 mutations or duplications in this study were nystagmus in early infancy, dysmyelination
revealed by magnetic resonance imaging (MRI), and auditory brain response abnormalities.
Although the grades of dysmyelination estimated by MRI findings were well correlated
to the clinical phenotypes of the patients, there is no correlation between the size
of the duplications and the phenotypic severity.
Keywords
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Article info
Publication history
Published online: March 31, 2009
Accepted:
February 22,
2009
Received in revised form:
February 2,
2009
Received:
November 22,
2008
Identification
Copyright
© 2009 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
