Published online before print January 24, 2007, doi:10.1212/01.wnl.0000254458.17630.c5)
NEUROLOGY 2007;68:916-922
© 2007 American Academy of Neurology
Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication
J. Fuchs, MD,
C. Nilsson, MD, PhD,
J. Kachergus, BSc,
M. Munz, MD,
E.-M Larsson, MD,
B. Schüle, MD,
J. W. Langston, MD,
F. A. Middleton, PhD,
O. A. Ross, PhD,
M. Hulihan, MPH,
T. Gasser, MD and
M. J. Farrer, PhD
From the Hertie Institute for Clinical Brain Research (J.F., M.M., T.G.), Department of Neurodegenerative Diseases, Center for Neurology, University of Tübingen, Germany; Department of Clinical Medicine (C.N., E.-M.L.), Divisions of Geriatric Psychiatry (C.N.) and Diagnostic Radiology (E.-M.L.), Lund University, Sweden; Department of Neuroscience (J.K., O.A.R., M.H., M.J.F.), Mayo Clinic College of Medicine, Jacksonville, FL, Parkinson's Institute (B.F., J.W.L.), Sunnyvale, CA, and Center for Neuropsychiatric Genetics (F.A.M.), Microarray Core Facility, SUNY Upstate Medical University, Syracuse, NY.
Address correspondence and reprint requests to Dr. T. Gasser, Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, Hoppe-Seyler Str. 3, 72076 Tübingen,Germany; e-mail: thomas.gasser{at}med.uni-tuebingen.de
Background: The "Lister family complex," an extensive Swedish family with autosomal dominant Parkinson disease, was first described by Henry Mjönes 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  -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 -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 -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.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the March 20 issue to find the title link for this article.
This article was previously published in electronic format as an Expedited E-Pub on January 24, 2007, at www.neurology.org.
Supported by Lund University Hospital Faculty grants, the German Competence Network for Parkinson's Disease and the German National Genome Network (NGFN; German Ministry for Education and Research), and the Morris K. Udall Parkinson's Disease Research Center of Excellence (National Institute of Neurological Disorders and Stroke P01 NS40256).
C.N. and T.G. are members of the European MSA–Study group.
Disclosure: The authors report no conflicts of interest.
Received July 28, 2006. Accepted in final form November 21, 2006.
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