European Journal of Neurology 2004, 11: 83–89S P E C I A L A R T I C L E / C M E A R T I C L EEFNS task force – therapy of nystagmus and oscillopsiaA. Straubea, R. J. Leighb, A. Bronsteinc, W. Heided, P. Riordan-Evae, C. C. Tijssenf, I. Dehaenegand D. StraumannhaDepartment of Neurology, University of Munich, Munich, Germany; bDepartment of Neurology, Case Western Reserve University,Clevela
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Microsoft word - 130430 markmd pes 1-48.docIAPP on novel genetic and phenotypic markers of Parkinson's disease and Essential Tremor
Grant agreement no.: 230596
SUMMARY OF MARKMD
Find genetic markers (CNVs) associated with Parkinson’s disease or Essential Tremor (WP1 and WP4) Test genetic markers in patients‘ cohorts and detailed clinical phenotyping of patients (WP2 and WP4) Test genetic markers in at-risk persons and detailed clinical phenotyping (WP3 and WP4) WP1
CNVs showing suggestive association in the Icelandic PD sample were tested for association in the
larger PD sample from Germany. Association with CNVs associated with PD prior to MarkMD
were confirmed (unpublished data). deCODE and Tubingen also combined their data in a search for
SNPs associating with PD and both groups joined a large PD meta-analysis. Through the meta-
analysis several genome-wide significant associations were uncovered and results have been
published in Lancet . Additional markers could be associated with PD[1-5] and MarkMD partners
contributed also to discoveries of markers conferring high-risk of AD[6, 7].
Papers describing pathway analysis  of PD markers and heritability estimates derived for PD 
have been published. The CNV analyses of PD are resulting in a publication.
In particular, the MarkMD partners focussed on homozygous deletions in the Parking gene. In a
manuscript (being prepared for publication) we show that the heterozygotes carrying a CNV in the
Parkin gene are also at risk of PD.
Also, MarkMD establish tools for the detection of uniparental disomy in the deCODE trio cohort in
order to detect these potentially phenotype-associated genetic alterations in patients and controls in
order to test the coincidence of segmental uniparental disomy hotspot regions within the
human genome with know PD risk loci.
Furthermore, analysis of genetic markers in iron genes and BBB genes was done and the
association with iron binding capacity in the Icelandic cohort was tested. Moreover, the elucidate
additional genetic markers and complementing the human studies we utilized gene expression
datasets of two double-transgenic mouse models of PD overexpressing A30P α-synuclein in
combination with Synphilin-1 and with a knockout of Calpastatin, an inhibitor of Calpain).
WP2 and WP3
Detailed clinical phenotyping in Tubingen concentrated on thorough clinical and imaging
characterization [11, 12] of patients with Parkinson syndromes. All patients newly recruited were
besides the neurological examination including motor scales and transcranial sonography submitted to
a non-motor assessment battery including testing for olfaction, mood and cognitive function. In
particular, a longitudinal follow up of 93 PD subjects for detection and determination of cognitive
impairment was performed. This knowledge on phenotyping was transferred from Tubingen to
deCODE for evaluating high-risk carriers using a battery of tests overlapping in part with that used
in Tubingen. 50 heterozygous Parkin CNV carriers have been carefully phenotyped. The
phenotyping, thus, included a battery of neuropsychological tests, questionnaires for learning
difficulties, the MINI interview and MRI for obtaining data on brain structure phenotypes. Brain
structure phenotypes and cognitive phenotypes were not associated with a group of control subjects
heterozygous for CNVs in the Parkin gene.
Genotyping as well as CNV and SNP analysis is completed. deCODE and Tubingen associated
variants in the LINGO1 gene with ET . LINGO1 and clinical characteristics of essential tremor
ET have been thoroughly investigated and the role of LINGO1 in the aetiology of ET was further
clarified. More particular the effect of the SNP rs9652490 on a range of ET characteristics: sex, age
at onset, presence or absence of family history and head tremor, response to propranolol medication
and alcohol, and the outcome of finger-nose and spirography tests (Archimedes spirals) was studied.
Tuebingen put a particular focus on the assessment of ET/PD through a particular assessment
battery. The clinical characterisation of 70-100 patients with ET/PD in Tübingen was carried out
including (i) Medical History (PD-specific, ET-specific (OH-response), medication, family history,
premotor symptoms, epidemiological data), (ii) Assessments (complete neurological: PD: UK-
PDBrainBankCriteria, new UPDRS; ET: Tremor assessment (Fahn Tremor Rating Scale (FTRS);
standardized video; Premotor: Sniffin-Sticks, MoCA-Test/Mini-Mental-Status-Test, BDI, Parkinson’s
Disease Sleep Scale (PDSS), RBD – Questionnair, QoL, ADL, TCS) and (iii) Bloods (DNA, Serum). A
first clinical manuscript on ET/PD is in preparation.
Through a transfer of knowledge a more detailed phenotyping of Islandic ET patients could be
carried out to see, whether a specific genetic marker on chromosome 3 is associated with a specific
subgroup. Similar to previously published data slight association of this SNP and the phenotypic
subgroup of ET plus writers cramp was found. Few subjects with ET have been MRI scanned at
deCODE mainly since subjects carrying high-risk variants are very few and power in the analysis is
In early summer 2010 MarkMD organized a European ET meeting where several groups from all
over Europe and the US were invited. Through this effort, collaboration with a group from Kiel was
Main results achieved
Foltynie, T., et al., A genome wide linkage disequilibrium screen in Parkinson's disease. J Neurol, 2005. 252(5): p. 597-602. Holmans, P., et al., A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease. Hum Mol Genet, 2012. Keller, M.F., et al., Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. Hum Mol Genet, 2012. 21(22): p. 4996-5009. Lill, C.M., et al., Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database. PLoS Genet, 2012. 8(3): p. e1002548. Nalls, M.A., et al., Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet, 2011. 377(9766): p. 641-9. Jonsson, T., et al., A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature, 2012. 488(7409): p. 96-9. Jonsson, T., et al., Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med, 2013. 368(2): p. 107-16. Petursson, H., LINGO1 and clinical characteristics of essential tremor. Masters theses, University of Iceland, 2012. Holmans, P., et al., A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease. Hum Mol Genet, 2013. 22(5): p. 1039-49. Stefansson, H., et al., Variant in the sequence of the LINGO1 gene confers risk of essential tremor. Nat Genet, 2009. 41(3): p. 277-9. Srulijes K et al. Fluorodeoxyglucose positron emission tomography in Richardson’s syndrome and progressive supranuclear palsy-parkinsonism.Mov Disord. 2012 Jan;27(1):151-5. Liscic RM et al. Differentiation of Progressive Supranuclear Palsy: clinical, imaging and laboratory tools. Acta Neurol Scand. 2013 May;127(5):362-70.
Final results and their potential impact
MarkMD succeeded to build a lasting collaboration between leading research organisations with complementory expertise and resources. New projects have been jointly applied for and been awarded such as NeurOmics (www.rd-neuromics.eu).
Dr. Holm Graessner, [email protected], +49 7071 2985944
Project web site
REGIONE DEL VENETO AZIENDA OSPEDALIERA DI PADOVA DELIBERAZIONE DEL DIRETTORE GENERALE n. 683 del 12/06/2012 OGGETTO: Unità Operativa di Pneumologia. Incarico professionale allaDott.ssa Emanuela Rossi. Determinazioni. Il Direttore della SC Incarichi Professionali ed Att. Extraistituzionale riferisce: Con deliberazione n. 1051 del 05.12.2011, a seguito di pubblica selezione, è sta