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Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication.

Fuchs, J; Nilsson, Christer LU ; Kachergus, J; Munz, M; Larsson, Elna-Marie LU ; Schule, B; Langston, J W; Middleton, F A; Ross, O A and Hulihan, M, et al. (2007) In Neurology 68(12). p.916-922
Abstract
Background: The " Lister family complex," an extensive Swedish family with autosomal dominant Parkinson disease, was first described by Henry Mjones in 1949. On the basis of clinical, molecular, and genealogic findings on a Swedish and an American family branch, we provide genetic evidence that explains the parkinsonism in this extended pedigree. Methods: Clinical methods included a detailed neurologic exam of the proband of the Swedish family branch, MRI, and ([ 123] I) - beta - CIT SPECT imaging. Genomic analysis included alpha-synuclein sequencing, SNCA real-time PCR dosage, chromosome 4q21 microsatellite analysis, and high-resolution microarray genotyping. The geographic origin and ancestral genealogy of each pedigree were researched... (More)
Background: The " Lister family complex," an extensive Swedish family with autosomal dominant Parkinson disease, was first described by Henry Mjones in 1949. On the basis of clinical, molecular, and genealogic findings on a Swedish and an American family branch, we provide genetic evidence that explains the parkinsonism in this extended pedigree. Methods: Clinical methods included a detailed neurologic exam of the proband of the Swedish family branch, MRI, and ([ 123] I) - beta - CIT SPECT imaging. Genomic analysis included alpha-synuclein sequencing, SNCA real-time PCR dosage, chromosome 4q21 microsatellite analysis, and high-resolution microarray genotyping. The geographic origin and ancestral genealogy of each pedigree were researched in the medical literature and Swedish Parish records. Results: The proband of the Swedish family branch presented with early dysautonomia followed by progressive parkinsonism suggestive of multiple system atrophy. Molecular analysis identified a genomic duplication of < 0.9 Mb encompassing alpha-synuclein and multimerin 1 ( SNCA- MMRN1), flanked by long interspersed repeat sequences ( LINE L1). Microsatellite variability within the genomic interval was identical to that previously described for a Swedish American family with an alpha- synuclein triplication. Subsequent genealogic investigation suggested that both kindreds are ancestrally related to the Lister family complex. Conclusion: Our findings extend clinical, genetic, and genealogical research on the Lister family complex. The genetic basis for familial parkinsonism is an SNCA- MMRN11 multiplication, but whereas SNCA- MMRN1 duplication in the Swedish proband ( Branch J) leads to late- onset autonomic dysfunction and parkinsonism, SNCA- MMRN1 triplication in the Swedish American family ( Branch I) leads to early- onset Parkinson disease and dementia. (Less)
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type
Contribution to journal
publication status
published
subject
in
Neurology
volume
68
issue
12
pages
916 - 922
publisher
American Academy of Neurology
external identifiers
  • wos:000245034400009
  • scopus:34147109175
ISSN
1526-632X
DOI
10.1212/01.wnl.0000254458.17630.c5
language
English
LU publication?
yes
id
fef0bfeb-5c01-4470-ad57-003c8a07f7bb (old id 164655)
date added to LUP
2007-07-23 09:49:40
date last changed
2017-11-12 03:50:41
@article{fef0bfeb-5c01-4470-ad57-003c8a07f7bb,
  abstract     = {Background: The " Lister family complex," an extensive Swedish family with autosomal dominant Parkinson disease, was first described by Henry Mjones in 1949. On the basis of clinical, molecular, and genealogic findings on a Swedish and an American family branch, we provide genetic evidence that explains the parkinsonism in this extended pedigree. Methods: Clinical methods included a detailed neurologic exam of the proband of the Swedish family branch, MRI, and ([ 123] I) - beta - CIT SPECT imaging. Genomic analysis included alpha-synuclein sequencing, SNCA real-time PCR dosage, chromosome 4q21 microsatellite analysis, and high-resolution microarray genotyping. The geographic origin and ancestral genealogy of each pedigree were researched in the medical literature and Swedish Parish records. Results: The proband of the Swedish family branch presented with early dysautonomia followed by progressive parkinsonism suggestive of multiple system atrophy. Molecular analysis identified a genomic duplication of &lt; 0.9 Mb encompassing alpha-synuclein and multimerin 1 ( SNCA- MMRN1), flanked by long interspersed repeat sequences ( LINE L1). Microsatellite variability within the genomic interval was identical to that previously described for a Swedish American family with an alpha- synuclein triplication. Subsequent genealogic investigation suggested that both kindreds are ancestrally related to the Lister family complex. Conclusion: Our findings extend clinical, genetic, and genealogical research on the Lister family complex. The genetic basis for familial parkinsonism is an SNCA- MMRN11 multiplication, but whereas SNCA- MMRN1 duplication in the Swedish proband ( Branch J) leads to late- onset autonomic dysfunction and parkinsonism, SNCA- MMRN1 triplication in the Swedish American family ( Branch I) leads to early- onset Parkinson disease and dementia.},
  author       = {Fuchs, J and Nilsson, Christer and Kachergus, J and Munz, M and Larsson, Elna-Marie and Schule, B and Langston, J W and Middleton, F A and Ross, O A and Hulihan, M and Gasser, T and Farrer, M J},
  issn         = {1526-632X},
  language     = {eng},
  number       = {12},
  pages        = {916--922},
  publisher    = {American Academy of Neurology},
  series       = {Neurology},
  title        = {Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication.},
  url          = {http://dx.doi.org/10.1212/01.wnl.0000254458.17630.c5},
  volume       = {68},
  year         = {2007},
}