@article{MuellerGirardHopfneretal.2016,
  author    = {M{\"u}ller, Stefanie H. and Girard, Simon L. and Hopfner, Franziska and Merner, Nancy D. and Bourassa, Cynthia V. and Lorenz, Delia and Clark, Lorraine N. and Tittmann, Lukas and Soto-Ortolaza, Alexandra I. and Klebe, Stephan and Hallett, Mark and Schneider, Susanne A. and Hodgkinson, Colin A. and Lieb, Wolfgang and Wszolek, Zbigniew K. and Pendziwiat, Manuela and Lorenzo-Betancor, Oswaldo and Poewe, Werner and Ortega-Cubero, Sara and Seppi, Klaus and Rajput, Alex and Hussl, Anna and Rajput, Ali H. and Berg, Daniela and Dion, Patrick A. and Wurster, Isabel and Shulman, Joshua M. and Srulijes, Karin and Haubenberger, Dietrich and Pastor, Pau and Vilari{\~n}o-G{\"u}ell, Carles and Postuma, Ronald B. and Bernard, Genevi{\`e}ve and Ladwig, Karl-Heinz and Dupr{\´e}, Nicolas and Jankovic, Joseph and Strauch, Konstantin and Panisset, Michel and Winkelmann, Juliane and Testa, Claudia M. and Reischl, Eva and Zeuner, Kirsten E. and Ross, Owen A. and Arzberger, Thomas and Chouinard, Sylvain and Deuschl, G{\"u}nther and Louis, Elan D. and Kuhlenb{\"a}umer, Gregor and Rouleau, Guy A.},
  title     = {Genome-wide association study in essential tremor identifies three new loci},
  series = {Brain},
  volume    = {139},
  journal   = {Brain},
  doi       = {10.1093/brain/aww242},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186541},
  pages     = {3163-3169},
  year      = {2016},
  abstract  = {We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.},
  language  = {en}
}
@article{PirothBoelmansAmtageetal.2017,
  author    = {Piroth, Tobias and Boelmans, Kai and Amtage, Florian and Rijntjes, Michel and Wierciochin, Anna and Musacchio, Thomas and Weiller, Cornelius and Volkmann, Jens and Klebe, Stephan},
  title     = {Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult},
  series = {Frontiers in Neurology},
  volume    = {8},
  journal   = {Frontiers in Neurology},
  number    = {108},
  doi       = {10.3389/fneur.2017.00108},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171001},
  year      = {2017},
  abstract  = {Niemann-Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty.},
  language  = {en}
}
@article{KarleSchueleKlebeetal.2013,
  author    = {Karle, Kathrin N. and Sch{\"u}le, Rebecca and Klebe, Stephan and Otto, Susanne and Frischholz, Christian and Liepelt-Scarfone, Inga and Sch{\"o}ls, Ludger},
  title     = {Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)},
  series = {Orphanet Journal of Rare Diseases},
  volume    = {8},
  journal   = {Orphanet Journal of Rare Diseases},
  number    = {158},
  issn      = {1750-1172},
  doi       = {10.1186/1750-1172-8-158},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124763},
  year      = {2013},
  abstract  = {Background: Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP. Methods: We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed. Results: Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27\% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40\%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms. Conclusions: Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials.},
  language  = {en}
}
@article{MencacciIsaiasReichetal.2014,
  author    = {Mencacci, Niccol{\´o} E. and Isaias, Ioannis U. and Reich, Martin M. and Ganos, Christos and Plagnol, Vincent and Polke, James M. and Bras, Jose and Hersheson, Joshua and Stamelou, Maria and Pittman, Alan M. and Noyce, Alastair J. and Mok, Kin Y. and Opladen, Thomas and Kunstmann, Erdmute and Hodecker, Sybille and M{\"u}nchau, Alexander and Volkmann, Jens and Samnick, Samuel and Sidle, Katie and Nanji, Tina and Sweeney, Mary G. and Houlden, Henry and Batla, Amit and Zecchinelli, Anna L. and Pezzoli, Gianni and Marotta, Giorgio and Lees, Andrew and Alegria, Paulo and Krack, Paul and Cormier-Dequaire, Florence and Lesage, Suzanne and Brice, Alexis and Heutink, Peter and Gasser, Thomas and Lubbe, Steven J. and Morris, Huw R. and Taba, Pille and Koks, Sulev and Majounie, Elisa and Gibbs, J. Raphael and Singleton, Andrew and Hardy, John and Klebe, Stephan and Bhatia, Kailash P. and Wood, Nicholas W.},
  title     = {Parkinson's disease in GTP cyclohydrolase 1 mutation carriers},
  series = {Brain},
  volume    = {137},
  journal   = {Brain},
  number    = {9},
  doi       = {10.1093/brain/awu179},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121268},
  pages     = {2480-92},
  year      = {2014},
  abstract  = {GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75\%) than in controls (6/5935 = 0.1\%; odds ratio 7.5; 95\% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.},
  language  = {en}
}