Brain Advance Access originally published online on February 2, 2005
Brain 2005 128(4):743-751; doi:10.1093/brain/awh409
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Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus–Merzbacher disease
1 Clinical and Molecular Genetics and 2 Neuroscience Unit, Institute of Child Health, 3 North East London Regional Cytogenetics Laboratory and 4 Radiology, GOSH, London, 5 Medical Genetics, University Hospital of Wales, Cardiff, UK, 6 Paediatric Neurology, University Children's Hospital, Heidelberg, Germany, 7 Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands, 8 Alfred I. duPont Hospital for Children, Wilmington, DE, 9 Jefferson Medical College, Philadelphia, PA, 10 University of California San Francisco Children's Hospital, San Francisco, CA, 11 Department of Neurology and Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA and 12 Kaunas University of Medicine, Kaunas, Lithuania
Correspondence to: Dr Karen Woodward, Clinical and Molecular Genetics, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail: k.woodward{at}ich.ucl.ac.uk
We describe five boys from different families with an atypically severe form of Pelizaeus–Merzbacher disease (PMD) who have three, and in one case, five copies of the proteolipid protein (PLP1) gene. This is the first report of more than two copies of PLP1 in PMD patients and clearly demonstrates that severe clinical symptoms are associated with increased PLP1 gene dosage. Previously, duplications, deletions and mutations of the PLP1 gene were reported to give rise to this X-linked disorder. Patients with PLP1 duplication are usually classified as having either classical or transitional PMD rather than the more rare severe connatal form. The clinical symptoms of the five patients in this study included lack of stable head control and severe mental retardation, with three having severe paroxysmal disorder and two dying before the first year of life. Gene dosage was determined using interphase FISH (fluorescence in situ hybridization) and the novel approach of multiple ligation probe amplification (MLPA). We found FISH unreliable for dosage detection above the level of a duplication and MLPA to be more accurate in determination of specific copy number. Our finding that three or more copies of the gene give rise to a more severe phenotype is in agreement with observations in transgenic mice where severity of disease increased with Plp1 gene dosage and level of overexpression. The patient with five copies of PLP1 was not more affected than those with a triplication, suggesting that there is possibly a limit to the level of severity or that other genetic factors influence the phenotype. It highlights the significance of PLP1 dosage in CNS myelinogenesis as well as the importance of accurate determination of PLP1 gene copy number in the diagnosis of PMD and carrier detection.
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