TY  - JOUR
AU  - Baumeister, S.
AU  - Meisinger, C.
AU  - Leitzmann, M.*
AU  - Teumer, A.*
AU  - Bahls, M.*
AU  - Karch, A.*
AU  - Baurecht, H.*
C1  - 60474
C2  - 49697
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 334-335
TI  - Physical activity and Parkinson's disease: A two-sample Mendelian randomisation study.
JO  - J. Neurol. Neurosurg. Psychiatr.
VL  - 92
IS  - 3
PB  - Bmj Publishing Group
PY  - 2021
SN  - 0022-3050
ER  - 

TY  - JOUR
AB  - Objectives Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.Methods Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.Conclusions We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.
AU  - Müller, K.*
AU  - Brenner, D.*
AU  - Weydt, P.*
AU  - Meyer, T.*
AU  - Grehl, T.*
AU  - Petri, S.*
AU  - Grosskreutz, J.*
AU  - Schuster, J.*
AU  - Volk, A.E.*
AU  - Borck, G.*
AU  - Kubisch, C.*
AU  - Klopstock, T.*
AU  - Zeller, D.*
AU  - Jablonka, S.*
AU  - Sendtner, M.*
AU  - Klebe, S.*
AU  - Knehr, A.*
AU  - Günther, K.*
AU  - Weis, J.*
AU  - Claeys, K.G.*
AU  - Schrank, B.*
AU  - Sperfeld, A.D.*
AU  - Hübers, A.*
AU  - Otto, M.*
AU  - Dorst, J.*
AU  - Meitinger, T.
AU  - Strom, T.M.
AU  - Andersen, P.M.*
AU  - Ludolph, A.C.*
AU  - Weishaupt, J.H.*
C1  - 53741
C2  - 44978
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 817-827
TI  - Comprehensive analysis of the mutation spectrum in 301 German ALS families.
JO  - J. Neurol. Neurosurg. Psychiatr.
VL  - 89
IS  - 8
PB  - Bmj Publishing Group
PY  - 2018
SN  - 0022-3050
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Spinocerebellar ataxia 36 (SCA36) is an autosomal-dominant neurodegenerative disorder caused by a large (>650) hexanucleotide GGCCTG repeat expansion in the first intron of the NOP56 gene. The aim of this study is to clarify the prevalence, clinical and genetic features of SCA36. METHODS: The expansion was tested in 676 unrelated SCA index cases and 727 controls from France, Germany and Japan. Clinical and neuropathological features were investigated in available family members. RESULTS: Normal alleles ranged between 5 and 14 hexanucleotide repeats. Expansions were detected in 12 families in France (prevalence: 1.9% of all French SCAs) including one family each with Spanish, Portuguese or Chinese ancestry, in five families in Japan (1.5% of all Japanese SCAs), but were absent in German patients. All the 17 SCA36 families shared one common haplotype for a 7.5 kb pairs region flanking the expansion. While 27 individuals had typically long expansions, three affected individuals harboured small hexanucleotide expansions of 25, 30 and 31 hexanucleotide repeat-units, demonstrating that such a small expansion could cause the disease. All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense, with the age at onset ranging between 39 and 65 years, and clinical features were indistinguishable between individuals with short and typically long expansions. Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected. CONCLUSIONS: SCA36 is rare with a worldwide distribution. It can be caused by a short GGCCTG expansion and associates various extracerebellar symptoms.
AU  - Obayashi, M.*
AU  - Stevanin, G.*
AU  - Synofzik, M.*
AU  - Monin, M.L.*
AU  - Duyckaerts, C.*
AU  - Sato, N.*
AU  - Streichenberger, N.*
AU  - Vighetto, A.*
AU  - Desestret, V.*
AU  - Tesson, C.*
AU  - Wichmann, H.-E.
AU  - Illig, T.
AU  - Huttenlocher, J.*
AU  - Kita, Y.*
AU  - Izumi, Y.*
AU  - Mizusawa, H.*
AU  - Schöls, L.*
AU  - Klopstock, T.*
AU  - Brice, A.*
AU  - Ishikawa, K.*
AU  - Dürr, A.*
C1  - 42907
C2  - 35806
CY  - London
SP  - 986-995
TI  - Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion.
JO  - J. Neurol. Neurosurg. Psychiatr.
VL  - 86
IS  - 9
PB  - Bmj Publishing Group
PY  - 2015
SN  - 0022-3050
ER  - 

TY  - JOUR
AU  - Synofzik, M.*
AU  - Kernstock, C.*
AU  - Haack, T.B.
AU  - Schöls, L.*
C1  - 31240
C2  - 34272
CY  - London
SP  - 580-581
TI  - Ataxia meets chorioretinal dystrophy and hypogonadism: Boucher-Neuhäuser syndrome due to PNPLA6 mutations.
JO  - J. Neurol. Neurosurg. Psychiatr.
VL  - 86
IS  - 5
PB  - Bmj Publishing Group
PY  - 2015
SN  - 0022-3050
ER  - 

TY  - JOUR
AB  - The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
AU  - Klebe, S.*
AU  - Golmard, J.L.*
AU  - Nalls, M.A.*
AU  - Saad, M.*
AU  - Singleton, A.B.*
AU  - Bras, J.M.*
AU  - Hardy, J.*
AU  - Simon-Sanchez, J.*
AU  - Heutink, P.*
AU  - Kuhlenbäumer, G.*
AU  - Charfi, R.*
AU  - Klein, C.*
AU  - Hagenah, J.*
AU  - Gasser, T.*
AU  - Wurster, I.*
AU  - Lesage, S.*
AU  - Lorenz, D.*
AU  - Deuschl, G.*
AU  - Durif, F.*
AU  - Pollak, P.*
AU  - Damier, P.*
AU  - Tison, F.*
AU  - Dürr, A.*
AU  - Amouyel, P.*
AU  - Lambert, J.C.*
AU  - Tzourio, C.*
AU  - Maubaret, C.*
AU  - Charbonnier-Beaupel, F.*
AU  - Tahiri, K.*
AU  - Vidailhet, M.*
AU  - Martinez, M.*
AU  - Brice, A.*
AU  - Corvol, J.C.*
AU  - French Parkinson's Disease Genetics Study Group (*)
AU  - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T.
AU  - Lichtner, P.)
C1  - 25494
C2  - 31863
SP  - 666-673
TI  - The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism.
JO  - J. Neurol. Neurosurg. Psychiatr.
VL  - 84
IS  - 6
PB  - BMJ Publishing
PY  - 2013
SN  - 0022-3050
ER  - 

TY  - JOUR
AU  - Horvath, R.*
AU  - Abicht, A.*
AU  - Holinski-Feder, E.*
AU  - Laner, A.*
AU  - Gemper, K.*
AU  - Prokisch, H.
AU  - Lochmüller, H.*
AU  - Klopstock, T.*
AU  - Jaksch, M.*
C1  - 5126
C2  - 24219
SP  - 74-76
TI  - Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA).
JO  - J. Neurol. Neurosurg. Psychiatr.
VL  - 77
PY  - 2006
SN  - 0022-3050
ER  -