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Sydenham’s chorea is less clear. Several autoantibodies have been described in Sydenham’s chorea. Initial reports were of anti-basal ganglia antibodies, but no sign was seen that these might bind to cortex.18 More recent work has highlighted the existence of D2-receptor auto-antibodies.19 These do occur in cortex and potentially could influence axonal thresholds, although no proof of this has been found. Alternatively, dopaminergic activity may change the release probability of synaptic vesicles at cortical excitatory synapses.20 If this were the case, axonal threshold could be normal, but with less excitatory transmitter released per presynaptic action potential the AMT would be higher than normal. Unlike Huntington’s disease,6,7,10,12 we did not find any changes in the cortical silent period or trascallosal inhibition, which has not been examined to our knowledge in Huntington’s disease, suggesting that GABABergic function may be relatively normal. Short interval intracortical inhibition is thought to test primarily GABAA receptor-mediated inhibition and has been reported to be reduced 8 or normal.9 Unfortunately, we were unable to assess short interval intracortical inhibition in our patients, so it is not possible to exclude abnormalities of GABAA-ergic function. Finally, we note that there was no difference between the hemispheres in any of our measures despite obvious clinical asymmetry, suggesting that they may not be directly causal to the patients’ symptoms. In conclusion, the higher axonal thresholds suggest the presence of cortical pathological conditions in Sydenham’s chorea.

10.

Modugno N, Curra‘ A, Giovanelli M, et al. The prolonged cortical silent period in patients with Huntington’s disease. Clin Neurophysiol. 2001;112:1470-1474.

11.

Meyer B, Noth J, Lange H, et al. Motor responses evoked by magnetic stimulation in Huntington’s disease. Electroencephalogr Clin Neurophysiol 1992;85:197-208.

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Eisen A, Bohlega S, Bloch M, Hayden M. Silent periods, longlatency reflexes and cortical MEPs in Huntington’s disease and atrisk relatives. Electroencephalogr Clin Neurophysiol 1989;74:444449.

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Schippling S, Schneider SA, Bhatia KP, M€ unchau A, Rothwell JC, Tabrizi SJ, Orth M. Abnormal motor cortex excitability in preclinical and very early Huntington’s disease. Biol Psychiatry 2009;65: 959-965.

14.

Edgar TS. Oral pharmacotherapy of childhood movement disorders. J Child Neurol 2003;18:40-49.

15.

Khedr EM, Ahmed MA, Mohamed KA. Motor and visual cortical excitability in migraineurs patients with or without aura: transcranial magnetic stimulation. Clin Neurophysiol 2006;36:1318.

16.

Lorenzano C, Dinapoli L, Gilio F, et al. Motor cortex excitability studied with repetitive transcranial magnetic stimulation in patients with Huntington’s disease. Clin Neurophysiol 2006;117:1677-1681.

17.

Rosas HD, Liu AK, Hersch S, et al. Regional and progressive thinning of the cortical ribbon in Huntington’s disease. Neurology 2002;58:695-701.

18.

Church AJ, Cardoso F, Dale RC, Lees AJ, Thompson EJ,Giovannoni G . Anti-basal ganglia antibodies in acuteand persistent Sydenham’s chorea. Neurology 2002;59:227-231.

19.

Brimberg L, Benhar I, Mascaro-Blanco A, et al. Behavioral, pharmacological, and immunological abnormalities afterstreptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders. Neuropsychopharmacology 2012;37:20762087.

20.

Glovaci I, Caruana DA, Chapman CA. Dopaminergic enhancement of excitatory synaptic transmission in layer II entorhinal neurons is dependent on D1-like receptor-mediated signaling. Neuroscience 2013;258:74-83.

A 7.5-Mb Duplication at Chromosome 11q21-11q22.3 Is Associated With a Novel Spastic Ataxia Syndrome

References 1.

Garvey MA, Swedo SE. Sydenham’s chorea. Clinical and therapeutic update. Adv Exp Med Biol. 1997;418:115-20.

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Oosterveer DM, Overweg-Plandsoen WC, Roos RA. Sydenham’s chorea: a practical overview of the current literature. Pediatr Neurol 2010;43:1-6.

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Nausieda PA, Bieliauskas LA, Bacon LD, Hagerty M, Koller WC, Glantz RN. Chronic dopaminergic sensitivity after Sydenham’s chorea. Neurology 1983;33:750-754.

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Freeman JM, Aron AM, Collard JE, Mackay MC. The emotional correlates of Sydenham’s chorea. Pediatrics 1965;35:4249.

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Roick H, Giesen Hv, Lange H, Benecke R. Postexcitatory inhibition in Huntington’s disease. Mov Disord 1992;7:27.

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Priori A, Berardelli A, Inghilleri M, Polidori L, Manfredi M. Electromyographic silent period after transcranial brain stimulation in Huntington’s disease. Mov Disord 1994;9:178-182.

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Tegenthoff M, Vorgerd M, Juskowiak F, Roos V, Malin J. Postexcitatory inhibition after transcranial magnetic single and double brain stimulation in Huntington’s disease. Electroencephalogr Clin Neurophysiol 1996;101:298-303.

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Abbruzzese G, Buccolieri A, Marchese R, Trompetto C, Mandich P, Schieppati M. Intracortical inhibition and facilitation are abnormal in Huntington’s disease: a paired magnetic stimulation study. Neurosci Lett 1997;228:87-90.

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Janel O. Johnson, PhD,1,2 Giovanni Stevanin, PhD,3,4,5,6 Joyce van de Leemput, PhD,1,2 Dena G. Hernandez, MS,1,2 Sampath Arepalli, MS,1 Sylvie Forlani, PhD,3,4,5 Reza Zonozi, MD,1 J. Raphael Gibbs, PhD,1,2 Alexis Brice, MD,3,4,5 Alexandra Durr, MD, PhD,3,4,5 and Andrew B. Singleton, PhD1* 1

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, 2Department of Molecular Neuroscience and Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, Queen Square, London, UK, 3INSERM, U1127, Paris, France, 4Sorbonne Unis, UPMC Univ Paris 6, UMR_S1127, Institut du Cerveau et de versite pinie`re, Paris, France 5CNRS, UMR7225, Paris, France, la Moelle e 6 Ecole Pratique des Hautes Etudes, Paris, France

ABSTRACT Background: The autosomal dominant spinocerebellar ataxias are most commonly caused by nucleotide repeat expansions followed by base-pair changes in functionally

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important genes. Structural variation has recently been shown to underlie spinocerebellar ataxia types 15 and 20. Methods: We applied single-nucleotide polymorphism (SNP) genotyping to determine whether structural variation causes spinocerebellar ataxia in a family from France. Results: We identified an approximately 7.5-megabasepair duplication on chromosome 11q21-11q22.3 that segregates with disease. This duplication contains an estimated 44 genes. Duplications at this locus were not found in control individuals. Conclusions: We have identified a new spastic ataxia syndrome caused by a genomic duplication, which we have denoted as spinocerebellar ataxia type 39. Finding additional families with this phenotype will be important C 2014 to identify the genetic lesion underlying disease. V International Parkinson and Movement Disorder Society Key Words: whole-genome genotyping; genomic duplications; spinocerebellar ataxia; structural variation; SCA39

Since the discovery of the first genetic linkage for spinocerebellar ataxia (SCA) in 1990, numerous genetic defects underlying the hereditary SCAs have been identified. Thirty loci are now known, for which over half of the causative genes have been identified, and the list continues to expand. The mechanisms that lead to neurodegeneration include polyglutamine repeat expansions (SCA1, 2, 3, 6, 7, 17, DRPLA, and in part SCA8), intronic expansions (SCA10, 31), point mutations (SCA5, 11, 14, 15, 27, 28), and structural genomic rearrangements (SCA15, 20) in genes of ostensibly divergent functions. Whether the respective pathways function independently or whether they converge is unclear.1,2 The current genome-wide single-nucleotide polymorphism (SNP) genotyping technologies allow direct detection of structural variation across the genome and have shown that rearrangements such as large deletions and duplications are more common than expected. These platforms have facilitated the investigation of the role of genomic copy number variation

-----------------------------------------------------------*Correspondence to: Dr. Andrew B. Singleton, 9000 Rockville Pike Building 35/Rm1A1000, Bethesda MD, 20892, E-mail: [email protected]. gov Funding agencies: This study was supported by the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, in part by the European Union (to the The NEUROMICS Consortium Network), the Verum foundation, the association Connaitre les Syndromes re belleux (France) and the Programme Hospitalier de Recherche Clinique ce (to A.D.) Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 12 November 2013; Revised: 28 July 2014; Accepted: 25 August 2014 Published online 27 December 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26059

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in disease.3 SCA15 and SCA20 are caused by such rearrangements.4,5 Given that the SCAs have recently been attributed to structural rearrangements, we employed genome-wide SNP genotyping of five affected members of an autosomal dominant spinocerebellar ataxia family to assess whether structural variability is associated with this disease. Here we provide a detailed clinical description of this family and provide evidence to suggest a novel genetic cause of disease in affected family members.

Methods The family was collected at the University Hospital Salp^etrie`re in Paris (index case) and at their home (other family members). This study was approved by the local Bioethics committee (approval No. 03-12-07 of the Comite Consultatif pour la Protection des Personnes et la Recherche Biomedicale Paris-Necker to Dr. D€ urr and Dr. Brice). Written informed consent was obtained from all participating members of the families before blood samples were collected for DNA extraction. DNA was stored in the DNA and Cell Bank of the CR-icm at the Pitie-Salp^etrie`re hospital in Paris. SNP genotyping was carried out on family members 277-10, 277-015, 277-014, and 277-011, and 277-05 using Illumina Infinium HD 610quad Bead Chips as per the manufacturer’s instructions (Illumina Inc, CA). As previously described, the B Allele frequency and Log R Ratio were used to identify genomic deletions and duplications.3,6 These two metrics were viewed within the Genome Viewer tool of Bead Studio (Illumina Inc, CA); these data on each chromosome were viewed in all genotyped family members by an experienced user (J.O.J.). We examined the region on chromosome 11 containing the segregating duplication in Illumina Infinium genotyping data (HumanHap550 arrays) from 605 neurologically normal white individuals from North America genotyped as a part of a separate genome-wide association study.7

Results Family SAL- 277, from Northern France (Supplemental Data Fig. S1), has been examined by A.D. at the University Hospital Pitie-Salp^etrie`re in Paris (Fig. 1A). Polyglutamine expansions in SCA genes, SCA10 and SCA12 expansions, as well as conventional mutations in SCA5, 13, 14, and 28, have been previously excluded in the index patient.

Patient 277-10 (Index Case) Onset of symptoms in this 46-year-old man was difficult to assess, but at infancy he already had difficulties running and learning. He had to use a cane at age 30 and became wheelchair-bound at age 41. He

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FIG. 1. Duplication of ~7Mb on chromosome 11 associated with SCA39. The upper panel shows genotyping data from affected family member 277-14, generated using Illumina HumanHap610quad Bead Chips. Shown is B Allele frequency for each single-nucleotide polymorphism (SNP) assayed, in which a value of 0 indicates a homozygous A/A genotype, a value of 1 indicates a homozygous B/B genotype, and a value of 0.5 represents a heterozygous A/B genotype. The boxed region delimits the duplicated segment; within this region are a lack of heterozygous calls and clusters of points at a B allele frequency of ~0.33 and ~0.66, which, coupled with increased signal (not shown), are indicative of A/A/B and A/B/B genotype calls, respectively. Figure plotted using R.

presented with moderate spasticity of the lower limbs, and cerebellar dysmetria in the upper limbs and moderate dysarthria. Reflexes were increased with ankle clonus and positive Hoffmann and Babinski signs. Vibration sense was abolished up to the hips, and there was distal lower limb muscle wasting. In addition to a strabismus, oculomotor signs included saccadic pursuit and horizontal gaze palsy. There was a clinical impression of mild mental retardation with normal Mini Mental Status (28/30). Cerebral magnetic resonance imaging (MRI) showed cerebellar atrophy with periventricular white matter hyperintensities (Fig. 2). Electroneuromyography showed a neurogenic pattern and normal conduction velocities. Auditory evoked brainstem potentials were prolonged. The index case displayed the general phenotype observed by patients in the family. Additional features observed in patients include hearing impairment, thoracic deformation, and foot deformation.

We observed a single structural genomic variant that was present in each of the five affected family members tested. B allele frequency and log R ratio indicated that this variant is an intrachromosomal duplication that lies between rs11021461 and rs10488755 on chromosome 11. This spans 7.5 Mb, containing an estimated 44 individual transcripts (Fig. 1). We failed to identify this duplication, or any duplication greater than 451Kb in size at this locus, in 605 control individuals. No other genomic structural variant was observed in all affected family members in other regions of the genome.

Discussion Development of recent technologies has facilitated a greater understanding of the contribution of genetic variation to disease. The human genome is highly polymorphic at the individual base pair level, and

FIG. 2. Brain magnetic resonance imaging images of proband SAL-277-010. (A) T1-weighted sagittal image showing mild atrophy of the upper part of the cerebellar vermis and thin corpus callosum. (B) T2-weighted axial image showing mild periventricular white matter hyperintensities.

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techniques such as next-generation sequencing have made it possible to study the genome at this level with considerable depth. Next-generation sequencing is novel, and algorithms are being developed to best assess the genome at the level of structural variation.8 However, at present, detection of structural variation is more effective on established platforms such as genome-wide SNP genotyping arrays. The extent of structural variation has only more recently been realized. Large deletions, insertions, and duplications may occur in up to 12% of the genome, and the presence of functional sequences within and around these copy number variants suggests that they make a substantial contribution to phenotypic variability.9 We did not identify single base pair mutations in family 277 in known spinocerebellar ataxia genes. Therefore, in the assessment of family 277, we considered that a structural change might account for the presence of the spinocerebellar ataxia syndrome. We identified an approximately 7.5-Mb chromosome 11 duplication now denoted SCA39 (Submitted to the HUGO Gene Nomenclature Committee, Hinxton, UK). The duplication is shared by all affected members of the family and absent in more than 1,200 control chromosomes. Nonaffected individual DNA was not available for structural assessment. Although this may be simply a rare benign copy number variant, the presence of the duplicated segment with those affected with early-onset disease in this family, the absence of a similar, overlapping duplication in control individuals, and the fact that the multiplication contains a dense array of functional sequences strongly supports the notion that this will have phenotypic consequences. Conceivably increased genetic load of individual transcripts underlie this disease, as in other neurodegenerative disorders,10,11 but possibly disruption of the genes at the breakpoints of the duplication may produce the phenotype. Although examination of the B allele frequency in affected family members suggests intergenic breakpoints on both the centromeric and telomeric sides of the duplication, this method only provides an approximate interval for the breakpoint, and thus further delineation of the breakpoints may be necessary. Chromosomal rearrangements have been associated with several disorders in which the causitive gene is unknown.12,13 Given the variety of pathways to spinocerebellar ataxia syndromes, any of the genes in this interval are potential candidates. In this family, spastic ataxia was the main clinical feature, but the phenotype is complex. Intellectual disability is also present in at least three of the five patients examined, whereas such impairment is suggested anecdotally for the remaining two. Moreover, several patients have hearing impairment and reduced visual acuity. The brain MRI of the proband, who essentially displays the overall clinical picture of the family, shows both atrophy and developmental abnormality of the brain (eg,

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white matter hyperintensities and dysgenesis of the corpus callosum). Interestingly, the phenotype and imaging of family 277 patients are reminiscent of SPG11, an autosomal recessive subtype of hereditary spastic paraplegia. The genetic causes of SPG11 are single-base-pair and frameshift mutations in KIAA1840 on chromosome 15q21.1, which encodes spatacsin.14 Possibly that disease is caused by a single gene defect with a wild-type function similar to that of KIAA1840. Alternatively, this disorder may be caused by the aggregate effects of multiple genes at the SCA39 locus. The contiguous gene syndrome is not a concept uncommon to disorders in which very large chromosomal rearrangements are involved15 and is more likely with broad, earlyonset phenotypes. In summary, we present here a new form of spastic ataxia segregating genomic duplication, which we have denoted as SCA39. There are several plausibly relevant genes across the critical interval. Clearly, finding additional families or individuals with a spastic ataxia phenotype and interval overlapping SCA39 will be key to isolating the critical gene/genes in this region. Acknowledgments: We thank the patients and their families for taking part in this research. Many thanks to Drs. Nadine Leforestier and Miche`le Mathieu, who referred family members to us, and to the DNA and cell bank of the CR-icm for sample preparation. We also thank the Programme d’investissement et d’avenir (ANR-10-IAIHU-06) and the French National Agency for Research.

References 1.

Orr HT. Unstable nucleotide repeat minireview series: a molecular biography of unstable repeat disorders. J Biol Chem 2009;284:7405.

2.

Paulson H. Yet another spinocerebellar ataxia: will it ever end? Lancet Neurol. 2002;1:471.

3.

Gibbs JR, Singleton A. Application of genome-wide single nucleotide polymorphism typing: simple association and beyond. PLoS Genet 2006;2:e150.

4.

Knight MA, Hernandez D, Diede SJ, et al. A duplication at chromosome 11q12.2-11q12.3 is associated with spinocerebellar ataxia type 20. Hum Mol Genet 2008;17:3847-3853.

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van de Leemput J, Chandran J, Knight MA, et al. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet. 2007;3:e108.

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Simon-Sanchez J, Scholz S, Fung HC, et al. Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals. Hum Mol Genet 2007;16:1-14.

7.

Simon-Sanchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009;41:1308-1312.

8.

Tan R, Wang Y, Kleinstein SE, et al. An evaluation of copy number variation detection tools from whole-exome sequencing data. Hum Mutat 2014;35:899-907.

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Wain LV, Armour JA, Tobin MD. Genomic copy number variation, human health, and disease. Lancet 2009;374:340-350.

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Rovelet-Lecrux A, Hannequin D, Raux G, et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 2006;38: 24-26.

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Singleton AB, Farrer M, Johnson J, et al. Alpha-synuclein locus triplication causes Parkinson’s disease. Science 2003;302:841.

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Guerrini R, Parrini E. Neuronal migration disorders. Neurobiol Dis 2010;38:154-166.

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van Kogelenberg M, Ghedia S, McGillivray G, et al. Periventricular heterotopia in common microdeletion syndromes. Mol Syndromol 2010;1:35-41.

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Schule R, Schols L. Genetics of hereditary spastic paraplegias. Semin Neurol 2011;31:484-493.

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van de Kamp J, Errami A, Howidi M, et al. Genotype-phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1. Clin Genet 2014. doi: 10.1111/cge.12355.

Supporting Data Additional Supporting Information may be found in the online version of this article at the publisher’s web-site.

Mortality in Parkinson’s Disease: A 38-Year Follow-up Study Bernadette Pinter, MD,1 Anja Diem-Zangerl, MD,1 Gregor Karl Wenning, MD, PhD,1 Christoph Scherfler, MD,1 Willi Oberaigner, MD,2 Klaus Seppi, MD,1* and Werner Poewe, MD1* 1

Department for Neurology, Medical University Innsbruck, Austria Tyrolean State Hospitals Ltd, Institute for Clinical Epidemiology, Innsbruck, Austria

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years.4-7 In this study, we report on the outcome, including overall and cause-specific mortality of PD patients followed for up to 38 years at a single academic referral center. This is an extension study of our previous report on mortality in a cohort of 237 PD patients followed for up to 38 years.1

Patients and Methods Two hundred thirty-seven patients were seen between 1974 and 1984 and were followed for a mean of 32.5 years. Details on patient recruitment, including inclusion and exclusion criteria, were reported previously.1 Deceased patients were identified through multiple converging sources, including the national death registries1,8-10; cause and date of death were tabulated using International Classification of Diseases (ICD) 10 codes.11 Similar to the previous report,1 causes of death were subsequently grouped into eight general disease categories: (1) pneumonia; (2) cerebrovascular diseases; (3) cardiovascular diseases; (4) cancer; (5) PD; (6) gastrointestinal and genitourinary diseases; (7) accident/injury; and (8) others (diabetes, infection, and other neurological diseases). Different codes describing the same disease category were put together to enable further statistical evaluation.

ABSTRACT

Statistical Analysis

Background: In this study we report on the outcome including overall and cause-specific mortality of Parkinson’s disease (PD) patients subsequent to 38 years of surveillance. This is an extension study of our previous report on mortality. Methods: Two hundred thirty-seven patients with a symptom onset between 1974 and 1984 were followed until the date of December 31, 2012 or death, representing a follow-up period of up to 38 years. Overall and cause-specific standardized mortality ratios (SMRs) were calculated, and predictors for survival at disease onset were estimated. Results and Conclusion: Two hundred thirty patients had died by December 31, 2012; a total of 3,489 personyears were available for observation. The SMR at 38 years of follow-up was 2.02 (1.76-2.29). Employing Cox’s proportional hazard modeling, male sex, gait disorder, absence of classical rest tremor, and absence of asymmetry predicted poor survival in this cohort. Increased cause-specific SMRs were found for pneumonia and C 2014 cerebrovascular and cardiovascular diseases. V International Parkinson and Movement Disorder Society Key Words: Parkinson’s disease; mortality; SMR; cause-specific mortality; late stage

Standardized mortality ratios (SMRs) were calculated at the last follow-up at approximately 38 years after symptom onset, employing the same method explained previously.1 Furthermore, SMRs were calculated separately for men and women as well as for those patients with younger (younger than 60 years, n 5 85; 35.86%) versus older age of onset (60 years or older, n 5 152, 64.14%). To estimate the causespecific mortality, SMRs were tabulated for four of the eight disease categories. The SMR analysis could not be performed for the remaining four disease categories because of the low number of deceased within the disease categories. The SMRs were considered significantly different if the lower limit of the 95%

A number of studies have addressed the issue of mortality in Parkinson’s disease (PD),1-3 but in only a few studies were outcomes followed for 20 or more

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-----------------------------------------------------------*Correspondence to: Werner Poewe, Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria, E-mail: [email protected]; Klaus Seppi Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria, E-mail: [email protected] Funding agencies: This study was supported by the Austrian science fund (FWF). Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 4 June 2014; Revised: 18 September 2014; Accepted: 26 September 2014 Published online 1 December 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26060

A 7.5-Mb duplication at chromosome 11q21-11q22.3 is associated with a novel spastic ataxia syndrome.

The autosomal dominant spinocerebellar ataxias are most commonly caused by nucleotide repeat expansions followed by base-pair changes in functionally ...
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