PMID- 15689360
OWN - NLM
STAT- MEDLINE
DCOM- 20050420
LR  - 20220330
IS  - 1460-2156 (Electronic)
IS  - 0006-8950 (Linking)
VI  - 128
IP  - Pt 4
DP  - 2005 Apr
TI  - Three or more copies of the proteolipid protein gene PLP1 cause severe 
      Pelizaeus-Merzbacher disease.
PG  - 743-51
AB  - 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.
FAU - Wolf, Nicole I
AU  - Wolf NI
AD  - Clinical and Molecular Genetics, Institute of Child Health, London, UK.
FAU - Sistermans, Erik A
AU  - Sistermans EA
FAU - Cundall, Maria
AU  - Cundall M
FAU - Hobson, Grace M
AU  - Hobson GM
FAU - Davis-Williams, Angelique P
AU  - Davis-Williams AP
FAU - Palmer, Rodger
AU  - Palmer R
FAU - Stubbs, Paula
AU  - Stubbs P
FAU - Davies, Sally
AU  - Davies S
FAU - Endziniene, Milda
AU  - Endziniene M
FAU - Wu, Yvonne
AU  - Wu Y
FAU - Chong, Wui K
AU  - Chong WK
FAU - Malcolm, Sue
AU  - Malcolm S
FAU - Surtees, Robert
AU  - Surtees R
FAU - Garbern, James Y
AU  - Garbern JY
FAU - Woodward, Karen J
AU  - Woodward KJ
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20050202
PL  - England
TA  - Brain
JT  - Brain : a journal of neurology
JID - 0372537
RN  - 0 (Membrane Proteins)
RN  - 0 (Myelin Proteolipid Protein)
RN  - 0 (PLP1 protein, human)
SB  - IM
MH  - Brain/pathology
MH  - Female
MH  - Gene Dosage
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Infant, Newborn
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Membrane Proteins/*genetics
MH  - Myelin Proteolipid Protein/*genetics
MH  - Nucleic Acid Amplification Techniques/methods
MH  - Pelizaeus-Merzbacher Disease/*genetics/pathology
EDAT- 2005/02/04 09:00
MHDA- 2005/04/21 09:00
CRDT- 2005/02/04 09:00
PHST- 2005/02/04 09:00 [pubmed]
PHST- 2005/04/21 09:00 [medline]
PHST- 2005/02/04 09:00 [entrez]
AID - awh409 [pii]
AID - 10.1093/brain/awh409 [doi]
PST - ppublish
SO  - Brain. 2005 Apr;128(Pt 4):743-51. doi: 10.1093/brain/awh409. Epub 2005 Feb 2.