TY  - JOUR
AB  - OBJECTIVE: A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss-of-function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders. METHODS: Cases with NUS1-related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform. Clinical data were acquired through retrospective case-note review. RESULTS: We identified 41 subjects carrying 38 different pathogenic or likely pathogenic heterozygous NUS1 variants. The majority of cases displayed developmental delays and intellectual disability of variable severity. Epilepsy was present in 68.3% of cases (28/41) with onset typically in early childhood. Strikingly, 87.8% of cases (36/41) presented with movement disorders and for 13 of these cases the movement disorder was not accompanied by epilepsy. The phenomenology of the movement disorders was complex with myoclonus observed in 68.3% of cases (28/41), either in isolation or in combination with dystonia, ataxia, and/or parkinsonism. Seven cases that otherwise did not have prominent movement disorders had mild incoordination and intention tremor, suggestive of cerebellar dysfunction. There was no observed genotype-phenotype correlation, suggesting that other genetic or acquired factors impact the clinical presentation. INTERPRETATION: Heterozygous NUS1 pathogenic variants cause a complex neurological disorder, variably featuring developmental and epileptic encephalopathies and a broad spectrum of movement disorders, which represent the major source of neurological disability for most cases. ANN NEUROL 2025.
AU  - Brooker, S.M.*
AU  - Novelli, M.*
AU  - Coukos, R.*
AU  - Prakash, N.*
AU  - Kamel, W.A.*
AU  - Amengual-Gual, M.*
AU  - Anheim, M.*
AU  - Barcia, G.*
AU  - Bardakjian, T.M.*
AU  - Baur, F.*
AU  - Berweck, S.*
AU  - Bölsterli, B.K.*
AU  - Brugger, M.*
AU  - Cassini, T.*
AU  - Chatron, N.*
AU  - Corner, B.*
AU  - Dafsari, H.S.*
AU  - de Sainte Agathe, J.M.*
AU  - Ellis, C.A.*
AU  - Ezell, K.M.*
AU  - Foucard, C.*
AU  - Frucht, S.J.*
AU  - Garcia, M.C.*
AU  - Gill, D.*
AU  - Guimier, A.*
AU  - Hamid, R.*
AU  - Heine-Suner, D.*
AU  - Herkenrath, P.*
AU  - Hully, M.*
AU  - Isaias, I.U.*
AU  - Januel, L.*
AU  - Laurencin, C.*
AU  - Laut, T.*
AU  - Lavillaureix, A.*
AU  - Lesca, G.*
AU  - Lesieur-Sebellin, M.*
AU  - Magistrelli, L.*
AU  - Marelli, C.*
AU  - Mefford, H.C.*
AU  - Mendelsohn, B.A.*
AU  - Mercimek-Andrews, S.*
AU  - Miller, C.A.*
AU  - Mohammad, S.S.*
AU  - Morgante, F.*
AU  - Nandipati, S.*
AU  - Opladen, T.*
AU  - Padmanaban, M.*
AU  - Pauni, M.*
AU  - Pezzoli, G.*
AU  - Piton, A.*
AU  - Ramond, F.*
AU  - Riboldi, G.M.*
AU  - Rougeot-Jung, C.*
AU  - Santos-Simarro, F.*
AU  - Scheffer, I.E.*
AU  - Serari, N.*
AU  - Stahl, C.M.*
AU  - Kung, A.S.*
AU  - Tarongí Sanchez, S.*
AU  - Thauvin-Robinet, C.*
AU  - Till, M.*
AU  - Tranchant, C.*
AU  - Troedson, C.*
AU  - Tropea, T.F.*
AU  - Vanakker, O.*
AU  - Vega, P.*
AU  - Wiese, M.L.*
AU  - Wieshmann, U.C.*
AU  - Williams, L.J.*
AU  - Wirth, T.*
AU  - Zech, M.
AU  - Zempel, H.*
AU  - Roze, E.*
AU  - Leuzzi, V.*
AU  - Galosi, S.*
AU  - Fung, V.S.C.*
AU  - Carvill, G.L.*
AU  - Krainc, D.*
AU  - Gérard, E.*
AU  - Mencacci, N.E.*
C1  - 75044
C2  - 57782
TI  - The spectrum of neurologic phenotypes associated with NUS1 pathogenic variants: A comprehensive case series.
JO  - Ann. Neurol.
PY  - 2025
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Genetic dystonia is a complex movement disorder with diverse clinical manifestations resulting from pathogenic mutations in associated genes. A recent paradigm shift emphasizes the functional convergence among dystonia genes, hinting at a shared pathomechanism. However, the neural dynamics supporting this convergence remain largely unexplored. METHODS: Herein, we analyzed microelectrode recordings acquired during pallidal deep brain stimulation surgery from 31 dystonia patients with pathogenic mutations in the AOPEP, GNAL, KMT2B, PANK2, PLA2G6, SGCE, THAP1, TOR1A, and VPS16 genes. We identified 1,694 single units whose activity was characterized by a broad set of neural features. RESULTS: AOPEP, PANK2, and THAP1 displayed higher firing regularity, whereas GNAL, PLA2G6, KMT2B, and SGCE shared a large fraction of bursting neurons (> 26.6%), significantly exceeding the rate in other genes. TOR1A and VPS16 genes constituted an intermediate group, bridging these 2 groups, due to having the highest degree of spiking irregularity. Hierarchical clustering algorithms based on these dynamics confirmed the results obtained with first-order comparisons. INTERPRETATION: Despite lacking common molecular pathways, dystonia genes share largely overlapping structures of neural patterns, in particular the degree of pallidal spiking regularity and bursting activity. We propose that the degree of desynchronization facilitated by pallidal neural bursts may explain the variability in deep brain stimulation (DBS) of the globus pallidus internus (GPi) surgery outcomes across genetic dystonia syndromes. Lastly, investigating the effects of genetic mutations on low-frequency pallidal activity could optimize personalized adaptive DBS treatments in patients with genetic dystonia. ANN NEUROL 2025.
AU  - Kaymak, A.*
AU  - Colucci, F.*
AU  - Ahmadipour, M.*
AU  - Andreasi, N.G.*
AU  - Rinaldo, S.*
AU  - Israel, Z.*
AU  - Arkadir, D.*
AU  - Telese, R.*
AU  - Levi, V.*
AU  - Zorzi, G.*
AU  - Carpaneto, J.*
AU  - Carecchio, M.*
AU  - Prokisch, H.
AU  - Zech, M.
AU  - Garavaglia, B.*
AU  - Bergman, H.*
AU  - Eleopra, R.*
AU  - Mazzoni, A.*
AU  - Romito, L.M.*
C1  - 73238
C2  - 56968
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Spiking patterns in the globus pallidus highlight convergent neural dynamics across diverse genetic dystonia syndromes.
JO  - Ann. Neurol.
PB  - Wiley
PY  - 2025
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Dystonia research focuses on the identification of converging biological pathways, allowing to define molecular drivers that serve as treatment targets. We summarize evidence supporting the concept that aberrations in purine metabolism intersect with dystonia pathogenesis. The recent discovery of IMPDH2-related dystonia introduced a gain-of-function paradigm in purinergic system defects, offering new perspectives to understand purine-pool imbalances in brain diseases. We discuss commonalities between known dystonia-linked mechanisms and mechanisms emerging from studies of purine metabolism disorders including Lesch-Nyhan disease. Together, we hypothesize that a greater appreciation of the relevance of purine perturbances in dystonia can offer fresh avenues for therapeutic intervention. ANN NEUROL 2025.
AU  - Sorrentino, U.*
AU  - O'Neill, A.G.*
AU  - Kollman, J.M.*
AU  - Jinnah, H.A.*
AU  - Zech, M.
C1  - 73573
C2  - 57109
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 809-825
TI  - Purine metabolism and dystonia: Perspectives of a long-promised relationship.
JO  - Ann. Neurol.
VL  - 97
IS  - 5
PB  - Wiley
PY  - 2025
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The objective was to evaluate the effects of deep brain stimulation (DBS) in an international cohort of patients with VPS16-related dystonia. METHODS: This observational study collected preoperative and postoperative demographic, clinical, stimulation, genetic, neuroimaging, and neurophysiological data of medically refractory DYT-VPS16 patients with implanted DBS in 10 international centers. Motor symptoms and disability outcomes were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale Motor (BFMDRS-M) and Disability (BFMDRS-D) scales. A cut-off threshold for considering response to DBS was set at 25% of BFMDRS-M improvement at the last follow-up (FU) compared to baseline. RESULTS: The cohort consisted of 26 participants (17 men, 65.4%). Age at dystonia onset and surgery was 17.8 ± 10.9 and 35.3 ± 14.8 years, respectively. At the last FU, 102.5 ± 57.3 months (range, 2-216), the mean BFMDRS-M improvement was 41.6 ± 37.3% (26/26 patients) and 34.8 ± 42.6% for the BFMDRS-D (23/26 patients). Most patients (19/26, 73%) were considered responders. Higher motor improvement was associated with stimulation of the ventroposterior portion of the internal globus pallidus. A significant inverse relationship was observed between improvement in BFMDRS-M at last FU, and the presence of spasticity (p = 0.027) and fixed skeletal deformities (p = 0.001) before surgery. Non-responders had a younger age at disease onset and at implantation, shorter disease duration at DBS surgery, and higher baseline BFMDRS scores. INTERPRETATION: DBS was an effective treatment for three-quarters of patients with pathogenic VPS16 variants in our cohort. Mean motor improvement was most pronounced at the 1-year FU, but persisted at the last FU despite disease progression. ANN NEUROL 2025.
AU  - Svorenova, T.*
AU  - Romito, L.M.*
AU  - Kaymak, A.*
AU  - Mulroy, E.*
AU  - Cif, L.*
AU  - Moro, E.*
AU  - Zeuner, K.E.*
AU  - Zittel, S.*
AU  - Petry-Schmelzer, J.N.*
AU  - Gruber, D.*
AU  - Centen, L.*
AU  - Albanese, A.*
AU  - Ostrozovičová, M.*
AU  - Han, V.*
AU  - Magocova, V.*
AU  - Knorovsky, K.*
AU  - Kollova, A.*
AU  - Garavaglia, B.*
AU  - Golfrè-Andreasi, N.*
AU  - Reale, C.*
AU  - Mazzoni, A.*
AU  - Zorzi, G.*
AU  - Eleopra, R.*
AU  - Levi, V.*
AU  - Foltynie, T.*
AU  - Limousin, P.*
AU  - Akram, H.*
AU  - Zrinzo, L.*
AU  - Magrinelli, F.*
AU  - Murphy, D.*
AU  - Houlden, H.*
AU  - Kurian, M.A.*
AU  - Baiata, C.*
AU  - Paschen, S.A.*
AU  - Lohmann, K.*
AU  - Volkmann, J.*
AU  - Hamel, W.*
AU  - Barbe, M.T.*
AU  - van Egmond, M.E.*
AU  - Tijssen, M.A.*
AU  - Ambro, L.*
AU  - Jurkova, V.*
AU  - Jech, R.*
AU  - Havránková, P.*
AU  - Winkelmann, J.
AU  - Zech, M.
AU  - Škorvánek, M.*
C1  - 74987
C2  - 57777
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Deep brain stimulation for VPS16-related dystonia: A multicenter study.
JO  - Ann. Neurol.
PB  - Wiley
PY  - 2025
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - OBJECTIVE: De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism. METHODS: Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells. RESULTS: We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells. INTERPRETATION: Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024.
AU  - Blackburn, P.R.*
AU  - Ebstein, F.*
AU  - Hsieh, T.C.*
AU  - Motta, M.*
AU  - Radio, F.C.*
AU  - Herkert, J.C.*
AU  - Rinne, T.*
AU  - Thiffault, I.*
AU  - Rapp, M.*
AU  - Alders, M.*
AU  - Maas, S.*
AU  - Gérard, B.*
AU  - Smol, T.*
AU  - Vincent-Delorme, C.*
AU  - Cogné, B.*
AU  - Isidor, B.*
AU  - Vincent, M.*
AU  - Bachmann-Gagescu, R.*
AU  - Rauch, A.*
AU  - Joset, P.*
AU  - Ferrero, G.B.*
AU  - Ciolfi, A.*
AU  - Husson, T.*
AU  - Guerrot, A.M.*
AU  - Bacino, C.A.*
AU  - Macmurdo, C.*
AU  - Thompson, S.S.*
AU  - Rosenfeld, J.A.*
AU  - Faivre, L.*
AU  - Mau-them, F.T.*
AU  - Deb, W.*
AU  - Vignard, V.*
AU  - Agrawal, P.B.*
AU  - Madden, J.A.*
AU  - Goldenberg, A.*
AU  - Lecoquierre, F.*
AU  - Zech, M.
AU  - Prokisch, H.
AU  - Necpál, J.*
AU  - Jech, R.*
AU  - Winkelmann, J.
AU  - Koprusakova, M.T.*
AU  - Konstantopoulou, V.*
AU  - Younce, J.R.*
AU  - Shinawi, M.*
AU  - Mighton, C.*
AU  - Fung, C.*
AU  - Morel, C.F.*
AU  - Lerner-Ellis, J.*
AU  - DiTroia, S.*
AU  - Barth, M.*
AU  - Bonneau, D.*
AU  - Krapels, I.P.*
AU  - Stegmann, A.P.A.*
AU  - van der Schoot, V.*
AU  - Brunet, T.*
AU  - Bußmann, C.*
AU  - Mignot, C.*
AU  - Zampino, G.*
AU  - Wortmann, S.B.*
AU  - Mayr, J.A.*
AU  - Feichtinger, R.G.*
AU  - Courtin, T.*
AU  - Ravelli, C.*
AU  - Keren, B.*
AU  - Ziegler, A.*
AU  - Hasadsri, L.*
AU  - Pichurin, P.N.*
AU  - Klee, E.W.*
AU  - Grand, K.*
AU  - Sanchez-Lara, P.A.*
AU  - Krüger, E.*
AU  - Bézieau, S.*
AU  - Klinkhammer, H.*
AU  - Krawitz, P.M.*
AU  - Eichler, E.E.*
AU  - Tartaglia, M.*
AU  - Küry, S.*
AU  - Wang, T.*
C1  - 71777
C2  - 56293
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder.
JO  - Ann. Neurol.
PB  - Wiley
PY  - 2024
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Infantile striatonigral degeneration is caused by a homozygous variant of the nuclear-pore complex (NPC) gene NUP62, involved in nucleo-cytoplasmic trafficking. By querying sequencing-datasets of patients with dystonia and/or Leigh(-like) syndromes, we identified three unrelated individuals with biallelic variants in NUP54. All variants clustered in the C-terminal protein region that interacts with NUP62. Associated phenotypes were similar to those of NUP62-related disease, including early-onset dystonia with dysphagia, choreoathetosis, and T2-hyperintense lesions in striatum. In-silico and protein-biochemical studies gave further evidence for the argument that the variants were pathogenic. We expand the spectrum of NPC component-associated dystonic conditions with localized basal-ganglia abnormalities.
AU  - Harrer, P.
AU  - Schalk, A.*
AU  - Shimura, M.
AU  - Baer, S.*
AU  - Calmels, N.*
AU  - Spitz, M.A.*
AU  - Abi Warde, M.T.*
AU  - Schaefer, E.*
AU  - Kittke, V.
AU  - Dincer, Y.*
AU  - Wagner, M.
AU  - Dzinovic, I.
AU  - Berutti, R.
AU  - Sato, T.*
AU  - Shirakawa, T.*
AU  - Okazaki, Y.*
AU  - Murayama, K.*
AU  - Oexle, K.
AU  - Prokisch, H.
AU  - Mall, V.*
AU  - Melčák, I.*
AU  - Winkelmann, J.
AU  - Zech, M.
C1  - 66606
C2  - 53240
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 330-335
TI  - Recessive NUP54 variants underlie early-onset dystonia with striatal lesions.
JO  - Ann. Neurol.
VL  - 93
IS  - 2
PB  - Wiley
PY  - 2023
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Leigh syndrome (LS) is a heterogeneous neurodegenerative disease and the most frequent pediatric manifestation of mitochondrial disease. In the largest patient collection to date, this study aimed to provide new insights into the clinical and genetic spectrum of LS, defect-specific associations, and predictors of disease course and survival. METHODS: Clinical, metabolic, neuroimaging, onset, and survival data were collected from the medical records of 209 patients referred to the Beijing Children's Hospital with symmetrical basal ganglia and/or brainstem neuroimaging changes indicative of LS by 30 centers from the Chinese network of mitochondrial disease (mitoC-NET) between January 2013 and July 2021 for exploratory analysis. RESULTS: Pathogenic variants were identified in 52 genes, most frequently MT-ATP6, SURF1, and PDHA1. Maternally inherited variants accounted for 42% (heteroplasmy level ≥ 90% in 64%). Phenotypes spanned 92 Human Phenotype Ontology terms. Elevated serum lactate (144/195), global developmental delay (142/209), and developmental regression (103/209) were most frequent. Discriminating neuroimaging and/or clinical features were identified for MT-ATP6 (m.9176 T > C), MT-ND5, PDHA1, SUCLG1, and SURF1. Poorest survival was associated with MT-ND5, MT-ATP6 (m.8993 T > C and m.9176 T > C), SURF1, and ALDH5A1 (≤50% 3 year survival), in contrast to milder defects with specific treatment (ECHS1 and SLC19A3, 100% 3 year survival). INTERPRETATION: Our data define phenotype, onset, and survival of LS in a defect-specific manner, identifying features discriminating between genetic defects and predictive of disease outcome. These findings are essential to early diagnosis, in optimizing family counselling, and to the design and monitoring of future clinical trials, the next frontier of LS research. This article is protected by copyright. All rights reserved.
AU  - Stenton, S.
AU  - Zou, Y.*
AU  - Cheng, H.*
AU  - Liu, Z.*
AU  - Wang, J.*
AU  - Shen, D.*
AU  - Jin, H.*
AU  - Ding, C.*
AU  - Tang, X.*
AU  - Sun, S.*
AU  - Han, H.*
AU  - Ma, Y.*
AU  - Zhang, W.*
AU  - Jin, R.*
AU  - Wang, H.*
AU  - Sun, D.*
AU  - Lv, J.L.*
AU  - Prokisch, H.
AU  - Fang, F.*
C1  - 64259
C2  - 51901
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 466-482
TI  - Leigh syndrome: A study of 209 patients at the Beijing Children's Hospital.
JO  - Ann. Neurol.
VL  - 91
IS  - 4
PB  - Wiley
PY  - 2022
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - OBJECTIVE: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. METHODS: Whole-exome sequencing in cohorts with 2,962 mitochondrial-disease- and/or dystonia-diagnosed individuals and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from five patients. RESULTS: We present ten total individuals with biallelic or de-novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de-novo heterozygous missense variants in ATP5F1A, whereas another three were heterozygous for ATP5MC3 de-novo missense changes. Bioinformatics methods and populational data supported the variants` pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in cells bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). INTERPRETATION: Our results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. This article is protected by copyright. All rights reserved.
AU  - Zech, M.
AU  - Kopajtich, R.
AU  - Steinbrücker, K.*
AU  - Bris, C.*
AU  - Gueguen, N.*
AU  - Feichtinger, R.G.*
AU  - Achleitner, M.T.*
AU  - Duzkale, N.*
AU  - Périvier, M.*
AU  - Koch, J.*
AU  - Engelhardt, H.*
AU  - Freisinger, P.*
AU  - Wagner, M.
AU  - Brunet, T.
AU  - Berutti, R.
AU  - Smirnov, D.
AU  - Navaratnarajah, T.*
AU  - Rodenburg, R.J.T.*
AU  - Pais, L.S.*
AU  - Austin-Tse, C.*
AU  - O'Leary, M.*
AU  - Boesch, S.*
AU  - Jech, R.*
AU  - Bakhtiari, S.*
AU  - Jin, S.C.*
AU  - Wilbert, F.*
AU  - Kruer, M.C.*
AU  - Wortmann, S.B.*
AU  - Eckenweiler, M.*
AU  - Mayr, J.A.*
AU  - Distelmaier, F.*
AU  - Steinfeld, R.*
AU  - Winkelmann, J.
AU  - Prokisch, H.
C1  - 63869
C2  - 51714
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 225-237
TI  - Variants in mitochondrial ATP synthase cause variable neurologic phenotypes.
JO  - Ann. Neurol.
VL  - 91
IS  - 2
PB  - Wiley
PY  - 2022
SN  - 0364-5134
ER  - 

TY  - JOUR
AU  - Musacchio, T.*
AU  - Zech, M.
AU  - Reich, M.M.*
AU  - Winkelmann, J.
AU  - Volkmann, J.*
C1  - 61837
C2  - 50482
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1257-1258
TI  - A recurrent EIF2AK2 missense variant causes autosomal-dominant isolated dystonia.
JO  - Ann. Neurol.
VL  - 89
IS  - 6
PB  - Wiley
PY  - 2021
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy. METHODS: Whole exome sequencing (WES) was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p.R433W were investigated by Seahorse XF Assay in fibroblasts of two patients. RESULTS: Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Post mortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate (ECAR) upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls. INTERPRETATION: Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function.
AU  - Schänzer, A.*
AU  - Achleitner, M.*
AU  - Trümbach, D.
AU  - Hubert, L.*
AU  - Munnich, A.*
AU  - Ahlemeyer, B.*
AU  - AlAbdulrahim, M.M.*
AU  - Greif, P.A.*
AU  - Vosberg, S.*
AU  - Hummer, B.*
AU  - Feichtinger, R.G.*
AU  - Mayr, J.A.*
AU  - Wortmann, S.B.
AU  - Aichner, H.*
AU  - Rudnik-Schöneborn, S.*
AU  - Ruiz, A.*
AU  - Gabau, E.*
AU  - Sánchez, J.P.*
AU  - Ellard, S.*
AU  - Homfray, T.*
AU  - Stals, K.L.*
AU  - Wurst, W.
AU  - Neubauer, B.A.*
AU  - Acker, T.*
AU  - Bohlander, S.K.*
AU  - Asensio, C.*
AU  - Besmond, C.*
AU  - Alkuraya, F.S.*
AU  - AlSayed, M.D.*
AU  - Hahn, A.*
AU  - Weber, A.*
C1  - 62104
C2  - 50451
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 143-158
TI  - Mutations in HID1 cause syndromic infantile encephalopathy and hypopituitarism.
JO  - Ann. Neurol.
VL  - 90
IS  - 1
PB  - Wiley
PY  - 2021
SN  - 0364-5134
ER  - 

TY  - JOUR
AU  - Stenton, S.
AU  - Zou, Y.*
AU  - Cheng, H.*
AU  - Prokisch, H.
AU  - Fang, F.*
C1  - 60964
C2  - 49723
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 218-232
TI  - Pediatric leigh syndrome: Neuroimaging features and genetic correlations.
JO  - Ann. Neurol.
VL  - 88
IS  - 2
PB  - Wiley
PY  - 2021
SN  - 0364-5134
ER  - 

TY  - JOUR
AU  - Zech, M.
AU  - Steel, D.*
AU  - Kurian, M.A.*
AU  - Winkelmann, J.
C1  - 60759
C2  - 49972
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Reply to "Truncating VPS16 mutations are rare in early-onset dystonia".
JO  - Ann. Neurol.
VL  - 89
IS  - 3
PB  - Wiley
PY  - 2021
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Objectives The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. Methods We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. Results Analysis revealed a significant burden forVPS16(Fisher's exact testpvalue, 6.9 x 10(9)).VPS16encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-functionVPS16variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants inVPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients withVPS16andVPS41showed vacuolar abnormalities suggestive of impaired lysosomal function. Interpretation Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020
AU  - Steel, D.*
AU  - Zech, M.
AU  - Zhao, C.
AU  - Barwick, K.E.*
AU  - Burke, D.*
AU  - Demailly, D.*
AU  - Kumar, K.R.*
AU  - Zorzi, G.*
AU  - Nardocci, N.*
AU  - Kaiyrzhanov, R.*
AU  - Wagner, M.
AU  - Iuso, A.
AU  - Berutti, R.
AU  - Škorvánek, M.*
AU  - Necpál, J.*
AU  - Davis, R.*
AU  - Wiethoff, S.*
AU  - Mankad, K.*
AU  - Sudhakar, S.*
AU  - Ferrini, A.*
AU  - Sharma, S.*
AU  - Kamsteeg, E.J.*
AU  - Tijssen, M.A.*
AU  - Verschuuren, C.*
AU  - van Egmond, M.E.*
AU  - Flowers, J.M.*
AU  - McEntagart, M.*
AU  - Tucci, A.*
AU  - Coubes, P.*
AU  - Bustos, B.I.*
AU  - Gonzalez-Latapi, P.*
AU  - Tisch, S.*
AU  - Darveniza, P.*
AU  - Gorman, K.M.*
AU  - Peall, K.J.*
AU  - Bötzel, K.*
AU  - Koch, J.C.*
AU  - Kmieć, T.*
AU  - Plecko, B.*
AU  - Boesch, S.*
AU  - Haslinger, B.*
AU  - Jech, R.*
AU  - Garavaglia, B.*
AU  - Wood, N.*
AU  - Houlden, H.*
AU  - Gissen, P.*
AU  - Lubbe, S.J.*
AU  - Sue, C.M.*
AU  - Cif, L.*
AU  - Mencacci, N.E.*
AU  - Anderson, G.*
AU  - Kurian, M.A.*
AU  - Winkelmann, J.
C1  - 59922
C2  - 49121
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 867-877
TI  - Loss-of-function variants in HOPS complex genes VPS16 and VPS41 cause early onset dystonia associated with lysosomal abnormalities.
JO  - Ann. Neurol.
VL  - 88
IS  - 5
PB  - Wiley
PY  - 2020
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Objective Early discrimination of patients with ischemic stroke (IS) from stroke mimics (SMs) poses a diagnostic challenge. The circulating metabolome might reflect pathophysiological events related to acute IS. Here, we investigated the utility of early metabolic changes for differentiating IS from SM. Methods We performed untargeted metabolomics on serum samples obtained from patients with IS (N = 508) and SM (N = 349; defined by absence of a diffusion weighted imaging [DWI] positive lesion on magnetic resonance imaging [MRI]) who presented to the hospital within 24 hours after symptom onset (median time from symptom onset to blood sampling = 3.3 hours; interquartile range [IQR] = 1.6-6.7 hours) and from neurologically normal controls (NCs; N = 112). We compared diagnostic groups in a discovery-validation approach by applying multivariable linear regression models, machine learning techniques, and propensity score matching. We further performed a targeted look-up of published metabolite sets. Results Levels of 41 metabolites were significantly associated with IS compared to NCs. The top metabolites showing the highest value in separating IS from SMs were asymmetrical and symmetrical dimethylarginine, pregnenolone sulfate, and adenosine. Together, these 4 metabolites differentiated patients with IS from SMs with an area under the curve (AUC) of 0.90 in the replication sample, which was superior to multimodal cranial computed tomography (CT; AUC = 0.80) obtained for routine diagnostics. They were further superior to previously published metabolite sets detected in our samples. All 4 metabolites returned to control levels by day 90. Interpretation A set of 4 metabolites with known biological effects relevant to stroke pathophysiology shows unprecedented utility to identify patients with IS upon hospital arrival, thus encouraging further investigation, including multicenter studies.
AU  - Tiedt, S.*
AU  - Brandmaier, S.
AU  - Kollmeier, H.*
AU  - Duering, M.*
AU  - Artati, A.
AU  - Adamski, J.
AU  - Klein, M.*
AU  - Liebig, T.*
AU  - Holdt, L.M.*
AU  - Teupser, D.*
AU  - Wang-Sattler, R.
AU  - Schwedhelm, E.*
AU  - Gieger, C.
AU  - Dichgans, M.*
C1  - 59839
C2  - 48973
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 736-746
TI  - Circulating metabolites differentiate acute ischemic stroke from stroke mimics.
JO  - Ann. Neurol.
VL  - 88
IS  - 4
PB  - Wiley
PY  - 2020
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Objective Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. Methods We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. Results Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. Interpretation Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2019
AU  - Tilch, E.
AU  - Schormair, B.
AU  - Zhao, C.
AU  - Salminen, A.V.
AU  - Antic Nikolic, A.
AU  - Holzknecht, E.*
AU  - Högl, B.*
AU  - Poewe, W.*
AU  - Bachmann, C.G.*
AU  - Paulus, W.*
AU  - Trenkwalder, C.*
AU  - Oertel, W.H.
AU  - Hornyak, M.*
AU  - Fietze, I.*
AU  - Berger, K.*
AU  - Lichtner, P.
AU  - Gieger, C.
AU  - Peters, A.
AU  - Müller-Myhsok, B.*
AU  - Hoischen, A.*
AU  - Winkelmann, J.
AU  - Oexle, K.
C1  - 57501
C2  - 47817
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 184-193
TI  - Identification of restless legs syndrome genes by mutational load analysis.
JO  - Ann. Neurol.
VL  - 87
IS  - 2
PB  - Wiley
PY  - 2020
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095
AU  - Gauthier, J.*
AU  - Meijer, I.A.*
AU  - Lessel, D.*
AU  - Mencacci, N.E.*
AU  - Krainc, D.*
AU  - Hempel, M.*
AU  - Tsiakas, K.*
AU  - Prokisch, H.
AU  - Rossignol, E.*
AU  - Helm, M.H.*
AU  - Rodan, L.H.*
AU  - Karamchandani, J.*
AU  - Carecchio, M.*
AU  - Lubbe, S.J.*
AU  - Telegrafi, A.*
AU  - Henderson, L.B.*
AU  - Lorenzo, K.*
AU  - Wallace, S.E.*
AU  - Glass, I.A.*
AU  - Hamdan, F.F.*
AU  - Michaud, J.L.*
AU  - Rouleau, G.A.*
AU  - Campeau, P.M.*
C1  - 53217
C2  - 44493
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1089-1095
TI  - Recessive mutations in > VPS13D cause childhood onset movement disorders.
JO  - Ann. Neurol.
VL  - 83
IS  - 6
PB  - Wiley
PY  - 2018
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - ObjectiveTo visualize and quantify differences of microstructural nerve damage in distal symmetric diabetic neuropathy (DPN) between type 1 diabetes (T1D) and type 2 diabetes (T2D), and to detect correlations between neuropathic symptoms and serological risk factors. MethodsThree-tesla magnetic resonance neurography of the sciatic nerve was performed in 120 patients (T1D, n=35; T2D, n=85) with either DPN (n=84) or no DPN (n=36). Results were subsequently correlated with clinical, serological, and electrophysiological patient data. ResultsT2-weighted (T2w)-hyperintense lesions correlated negatively with tibial compound motor action potential (r=-0.58, p<0.0001) and peroneal nerve conduction (r=0.51, p=0.0002), and positively with neuropathy disability score (NDS; r=-0.54, p<0.0001), neuropathy symptom score (NSS; r=0.52, p<0.0001), and HbA1c level (r=0.23, p=0.014). T2w-hypointense lesions correlated positively with NDS (r=0.28, p=0.002), NSS (r=0.36, p<0.0001), and serum triglycerides (r=0.34, p=0.0003), and negatively with serum high-density lipoprotein (HDL; r=-0.48, p<0.0001). For DPN in T1D, elevated values of T2w-hyperintense lesions (19.674.13% vs 12.49 +/- 1.23%, p=0.027) and HbA1c (8.74 +/- 0.29% vs 7.11 +/- 0.16%, p<0.0001) were found when compared to T2D. For DPN in T2D, elevated T2w-hypointense lesions (23.41 +/- 2.69mm(3) vs 11.43 +/- 1.74mm(3), p=0.046) and triglycerides (220.70 +/- 23.70mg/dl vs 106.60 +/- 14.51mg/dl, p<0.0001), and lower serum HDL (51.29 +/- 3.02mg/dl vs 70.79 +/- 4.65mg/dl, p<0.0001) were found when compared to T1D. InterpretationThe predominant type of nerve lesion in DPN differs between T1D and T2D. Correlations found between lesion type and serological parameters indicate that predominant nerve lesions in T1D are associated with poor glycemic control and loss of nerve conduction, whereas predominant lesions in T2D are associated with changes in lipid metabolism. These findings may be helpful for future studies on the underlying pathophysiological pathways and possible treatments for DPN in T1D and T2D. Ann Neurol 2018;83:588-598
AU  - Jende, J.M.E.*
AU  - Groener, J.B.*
AU  - Oikonomou, D.*
AU  - Heiland, S.*
AU  - Kopf, S.*
AU  - Pham, M.*
AU  - Nawroth, P.P.
AU  - Bendszus, M.*
AU  - Kurz, F.T.*
C1  - 53265
C2  - 44640
CY  - Hoboken
SP  - 588-598
TI  - Diabetic neuropathy differs between type 1 and type 2 diabetes: Insights from magnetic resonance neurography.
JO  - Ann. Neurol.
VL  - 83
IS  - 3
PB  - Wiley
PY  - 2018
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - ObjectiveAutoantibodies against myelin oligodendrocyte glycoprotein (MOG) occur in a proportion of patients with inflammatory demyelinating diseases of the central nervous system (CNS). We analyzed their pathogenic activity by affinity-purifying these antibodies (Abs) from patients and transferring them to experimental animals.MethodsPatients with Abs to MOG were identified by cell-based assay. We determined the cross-reactivity to rodent MOG and the recognized MOG epitopes. We produced the correctly folded extracellular domain of MOG and affinity-purified MOG-specific Abs from the blood of patients. These purified Abs were used to stain CNS tissue and transferred in 2 models of experimental autoimmune encephalomyelitis. Animals were analyzed histopathologically.ResultsWe identified 17 patients with MOG Abs from our outpatient clinic and selected 2 with a cross-reactivity to rodent MOG; both had recurrent optic neuritis. Affinity-purified Abs recognized MOG on transfected cells and stained myelin in tissue sections. The Abs from the 2 patients recognized different epitopes on MOG, the CC and the FG loop. In both patients, these Abs persisted during our observation period of 2 to 3 years. The anti-MOG Abs from both patients were pathogenic upon intrathecal injection in 2 different rat models. Together with cognate MOG-specific T cells, these Abs enhanced T-cell infiltration; together with myelin basic protein-specific T cells, they induced demyelination associated with deposition of C9neo, resembling a multiple sclerosis type II pathology.InterpretationMOG-specific Abs affinity purified from patients with inflammatory demyelinating disease induce pathological changes in vivo upon cotransfer with myelin-reactive T cells, suggesting that these Abs are similarly pathogenic in patients. Ann Neurol 2018;84:315-328
AU  - Spadaro, M.*
AU  - Winklmeier, S.*
AU  - Beltrán, E.*
AU  - Macrini, C.*
AU  - Höftberger, R.*
AU  - Schuh, E.*
AU  - Thaler, F.S.*
AU  - Gerdes, L.A.*
AU  - Laurent, S.A.*
AU  - Gerhards, R.*
AU  - Brändle, S.*
AU  - Dornmair, K.*
AU  - Breithaupt, C.*
AU  - Krumbholz, M.*
AU  - Moser, M.*
AU  - Kirshnamoorthy, G.*
AU  - Kamp, F.*
AU  - Jenne, D.
AU  - Hohlfeld, R.*
AU  - Kümpfel, T.*
AU  - Lassmann, H.*
AU  - Kawakami, N.*
AU  - Meinl, E.*
C1  - 53956
C2  - 45144
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 315-328
TI  - Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein.
JO  - Ann. Neurol.
VL  - 84
IS  - 2
PB  - Wiley
PY  - 2018
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Objective: 3-Methylglutaconic aciduria, dystonia–deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Results: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days–33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in > 40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic “putaminal eye” was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. Interpretation: MEGDHEL syndrome is a progressive deafness–dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004–1015.
AU  - Maas, R.R.*
AU  - Iwanicka-Pronicka, K.*
AU  - Kalkan Ucar, S.*
AU  - Alhaddad, B.*
AU  - AlSayed, M.*
AU  - Al-Owain, M.A.*
AU  - Al-Zaidan, H.I.*
AU  - Balasubramaniam, S.*
AU  - Barić, I.*
AU  - Bubshait, D.K.*
AU  - Burlina, A.*
AU  - Christodoulou, J.*
AU  - Chung, W.K.*
AU  - Colombo, R.*
AU  - Darin, N.*
AU  - Freisinger, P.*
AU  - Garcia Silva, M.T.*
AU  - Grunewald, S.*
AU  - Haack, T.B.*
AU  - van Hasselt, P.M.*
AU  - Hikmat, O.*
AU  - Hörster, F.*
AU  - Isohanni, P.*
AU  - Ramzan, K.*
AU  - Kovács-Nagy, R.*
AU  - Krumina, Z.*
AU  - Martin-Hernandez, E.*
AU  - Mayr, J.A.*
AU  - McClean, P.*
AU  - De Meirleir, L.*
AU  - Naess, K.*
AU  - Ngu, L.H.*
AU  - Pajdowska, M.*
AU  - Rahman, S.*
AU  - Riordan, G.*
AU  - Riley, L.*
AU  - Röeben, B.*
AU  - Rutsch, F.*
AU  - Santer, R.*
AU  - Schiff, M.*
AU  - Seders, M.*
AU  - Sequeira, S.*
AU  - Sperl, W.*
AU  - Staufner, C.*
AU  - Synofzik, M.*
AU  - Taylor, R.W.*
AU  - Trubicka, J.*
AU  - Tsiakas, K.*
AU  - Unal, O.*
AU  - Wassmer, E.*
AU  - Wedatilake, Y.*
AU  - Wolff, T.*
AU  - Prokisch, H.
AU  - Morava, E.*
AU  - Pronicka, E.*
AU  - Wevers, R.A.*
AU  - de Brouwer, A.P.*
AU  - Wortmann, S.B.
C1  - 52594
C2  - 44171
CY  - Hoboken
SP  - 1004-1015
TI  - Progressive deafness–dystonia due to SERAC1 mutations: A study of 67 cases.
JO  - Ann. Neurol.
VL  - 82
IS  - 6
PB  - Wiley
PY  - 2017
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - ObjectiveWe have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset. MethodsThis study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta-analysis of PD genome-wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset. ResultsOur polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome-wide association cohorts (minimum p=3.76 x 10(-6)). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p=0.00014). InterpretationThis provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes.
AU  - Escott-Price, V.*
AU  - Nalls, M.A.*
AU  - Morris, H.R.*
AU  - Lubbe, S.*
AU  - Brice, A.*
AU  - Gasser, T.*
AU  - Heutink, P.*
AU  - Wood, N.W.*
AU  - Hardy, J.*
AU  - Singleton, A.B.*
AU  - Williams, N.M.*
AU  - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T.
AU  - Lichtner, P.)
C1  - 44464
C2  - 36966
CY  - Hoboken
SP  - 582-591
TI  - Polygenic risk of Parkinson disease is correlated with disease age at onset.
JO  - Ann. Neurol.
VL  - 77
IS  - 4
PB  - Wiley-blackwell
PY  - 2015
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Objective: Serum antibodies against the glial potassium channel KIR4.1 are found in a subpopulation of multiple sclerosis (MS) patients. Little is known about the expression of KIR4.1 in human normal brain tissue and in MS lesions. Methods: We analyzed the expression pattern of KIR4.1 in normal brain tissue and MS lesions of the subcortical white matter by immunohistochemistry. Markers of related glial proteins, myelin, and inflammatory cells were analyzed in parallel. Results: KIR4.1 is expressed in oligodendrocytes and astrocytes in the adult human brain. In oligodendrocytes, KIR4.1 appears as a homotetramer channel, in astrocytes as homo- and heterotetramer channels together with KIR5.1. In acute MS lesions, KIR4.1 immunoreactivity (IR) was differentially lost on periplaque oligodendrocytes and perivascular astrocytes. In part of acute lesions, complement activation, apoptotic KIR4.1(+) glial cells, and phagocytes containing KIR4.1(+) fragments accompanied loss of glial KIR4.1 IR. Periplaque reactive astrocytes showed enhanced IR for both KIR4.1 and KIR5.1. In chronic active MS lesions, apart from a general loss of oligodendrocytes in the demyelinated area, we observed a decrease of astroglial KIR4.1 but not glial fibrillary acidic protein IR. In chronic inactive and remyelinating MS lesions, KIR4.1 IR was restored on astrocytes and found in a subset of presumably new myelinating oligodendrocytes. Interpretation: The expression profile of KIR4.1 in glial cells and stage-dependent alterations of KIR4.1 IR in MS lesions are compatible with an immune response against KIR4.1 at least in a subset of MS patients.
AU  - Schirmer, L.*
AU  - Srivastava, R.*
AU  - Kalluri, S.R.*
AU  - Boettinger, S.*
AU  - Herwerth, M.*
AU  - Carassiti, D.*
AU  - Srivastava, B.
AU  - Gempt, J.*
AU  - Schlegel, J.*
AU  - Kuhlmann, T.*
AU  - Korn, T.*
AU  - Reynolds, R.*
AU  - Hemmer, B.*
C1  - 31892
C2  - 34851
CY  - Hoboken
SP  - 810-828
TI  - Differential loss of KIR4.1 immunoreactivity in multiple sclerosis lesions.
JO  - Ann. Neurol.
VL  - 75
IS  - 6
PB  - Wiley-blackwell
PY  - 2014
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Intrathecal synthesis of immunoglobulin gamma (IgG) synthesis is frequently observed in patients with multiple sclerosis (MS). Whereas the extent of intrathecal IgG synthesis varies largely between patients, it remains rather constant in the individual patient over time. The aim of this study was to identify common genetic variants associated with the IgG index as a marker of intrathecal IgG synthesis in MS. METHODS: We performed a genome-wide association study of the IgG index in a discovery series of 229 patients. For confirmation we performed a replication in 2 independent series comprising 256 and 153 patients, respectively. The impact of associated single nucleotide polymorphisms (SNPs) on MS susceptibility was analyzed in an additional 1,854 cases and 5,175 controls. RESULTS: Significant association between the IgG index and 5 SNPs was detected in the discovery and confirmed in both replication series reaching combined p values of p = 6.5 × 10(-11) to p = 7.5 × 10(-16) . All identified SNPs are clustered around the immunoglobulin heavy chain (IGHC) locus on chromosome 14q32.33 and are in linkage disequilibrium (r(2) range, 0.71-0.95). The best associated SNP is located in an intronic region of the immunoglobulin gamma3 heavy chain gene. Additional sequencing identified the GM21* haplotype to be associated with a high IgG index. Further evaluation of the IGHC SNPs revealed no association with susceptibility to MS in our data set. INTERPRETATION: The extent of intrathecal IgG in MS is influenced by the IGHC locus. No association with susceptibility to MS was found. Therefore GM haplotypes might affect intrathecal IgG synthesis independently of the underlying disease.
AU  - Buck, D.*
AU  - Albrecht, E.
AU  - Aslam, M.*
AU  - Goris, A.*
AU  - Hauenstein, N.*
AU  - Jochim, A.*
AU  - International Multiple Sclerosis Genetics Consortium (*)
AU  - Wellcome Trust Case Control Consortium 2 (WTCCC2) (*)
AU  - Cepok, S.*
AU  - Grummel, V.*
AU  - Dubois, B.*
AU  - Berthele, A.*
AU  - Lichtner, P.
AU  - Gieger, C.
AU  - Winkelmann, J.
AU  - Hemmer, B.*
C1  - 23006
C2  - 30981
SP  - 86-94
TI  - Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis.
JO  - Ann. Neurol.
VL  - 73
IS  - 1
PB  - Wiley-Blackwell
PY  - 2013
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Objective Loss of function mutations in PINK1 typically lead to early onset Parkinson disease (PD). Zebrafish (Danio rerio) are emerging as a powerful new vertebrate model to study neurodegenerative diseases. We used a pink1 mutant (pink-/-) zebrafish line with a premature stop mutation (Y431*) in the PINK1 kinase domain to identify molecular mechanisms leading to mitochondrial dysfunction and loss of dopaminergic neurons in PINK1 deficiency. Methods The effect of PINK1 deficiency on the number of dopaminergic neurons, mitochondrial function, and morphology was assessed in both zebrafish embryos and adults. Genome-wide gene expression studies were undertaken to identify novel pathogenic mechanisms. Functional experiments were carried out to further investigate the effect of PINK1 deficiency on early neurodevelopmental mechanisms and microglial activation. Results PINK1 deficiency results in loss of dopaminergic neurons as well as early impairment of mitochondrial function and morphology in Danio rerio. Expression of TigarB, the zebrafish orthologue of the human, TP53-induced glycolysis and apoptosis regulator TIGAR, was markedly increased in pink-/- larvae. Antisense-mediated inactivation of TigarB gave rise to complete normalization of mitochondrial function, with resulting rescue of dopaminergic neurons in pink-/- larvae. There was also marked microglial activation in pink-/- larvae, but depletion of microglia failed to rescue the dopaminergic neuron loss, arguing against microglial activation being a key factor in the pathogenesis. Interpretation Pink1-/- zebrafish are the first vertebrate model of PINK1 deficiency with loss of dopaminergic neurons. Our study also identifies TIGAR as a promising novel target for disease-modifying therapy in PINK1-related PD.
AU  - Flinn, L.J.*
AU  - Keatinge, M.*
AU  - Bretaud, S.*
AU  - Mortiboys, H.*
AU  - Matsui, H.*
AU  - de Felice, E.*
AU  - Woodroof, H.I.*
AU  - Brown, L.*
AU  - McTighe, A.*
AU  - Soellner, R.
AU  - Allen, C.E.*
AU  - Heath, P.R.*
AU  - Milo, M.
AU  - Muqit, M.M.K.*
AU  - Reichert, A.S.*
AU  - Köster, R.W.
AU  - Ingham, P.W.*
AU  - Bandmann, O.*
C1  - 30788
C2  - 33869
SP  - 837-847
TI  - TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency.
JO  - Ann. Neurol.
VL  - 74
IS  - 6
PY  - 2013
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. METHODS: We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. RESULTS: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 x 10(-7)), PDXK (vitamin B6/dopamine metabolism, p = 3.27 x 10(-6)), SRGAP3 (axon guidance, p = 5.65 x 10(-6)), and TRAPPC4 (vesicle transport, p = 5.81 x 10(-6)). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 x 10(-7) (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44). INTERPRETATION: We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD.
AU  - Elstner, M.
AU  - Morris, C.M.*
AU  - Heim, K.
AU  - Lichtner, P.
AU  - Bender, A.*
AU  - Mehta, D.
AU  - Schulte, C.*
AU  - Sharma, M.*
AU  - Hudson, G.*
AU  - Goldwurm, S.*
AU  - Giovanetti, A.*
AU  - Zeviani, M.*
AU  - Burn, D.J.*
AU  - McKeith, I.G.*
AU  - Perry, R.H.*
AU  - Jaros, E.*
AU  - Kruger, R.*
AU  - Wichmann, H.-E.
AU  - Schreiber, S.*
AU  - Campbell, H.*
AU  - Wilson, J.F.*
AU  - Wright, A.F.*
AU  - Dunlop, M.*
AU  - Pistis, G.*
AU  - Toniolo, D.*
AU  - Chinnery, P.F.*
AU  - Gasser, T.*
AU  - Klopstock, T.*
AU  - Meitinger, T.
AU  - Prokisch, H.
AU  - Turnbull, D.M.*
C1  - 936
C2  - 26542
SP  - 792-798
TI  - Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.
JO  - Ann. Neurol.
VL  - 66
IS  - 6
PB  - Wiley-Blackwell
PY  - 2009
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Recent studies have identified a major locus for risk for coronary artery disease and myocardial infiarction on chromosome 9p21.3. Stroke, in particular, ischemic stroke caused by atherosclerotic disease, shares common mechanisms with myocardial infarction. We investigated whether the 9p21 region contributes to ischemic stroke risk. Methods: In an initial screen, 15 single nucleotide polymorphisms (SNPs) covering the critical genetic interval on 9p21 were genotyped in samples from Southern Germany (1,090 cases, 1,244 control subjects) and the United Kingdom (758 cases, 872 control subjects, 3 SNPs). SNPs significantly associated with ischemic stroke or individual stroke subtypes in either of the screening samples were Subsequently genotyped in 2,528 additional cases and 2,189 additional control Subjects from Europe and North America. Results: Genotyping of the screening samples demonstrated associations between seven SNPs and atherosclerotic stroke (all p < 0.05). Analysis of the full sample confirmed associations between six SNPs and atherosclerotic stroke in multivariate analyses controlling for demographic variables, coronary, artery disease, myocardial infarction, and vascular risk factors (all p < 0.05). The odds ratios for the lead SNP (rs1537378-C) were similar in the various subsamples with a pooled odds ratio of 1.21 (95% confidence interval, 1.07-1.37) under both fixed- and random-effects models (p = 0.002). The point estimate for the population attributable risk is 20.1% For atherosclerotic stroke. Interpretation: The chromosome 9p21.3 region represents a major risk locus for atherosclerotic stroke. The effect of this locus on stroke appears to be independent of its relation to coronary artery disease and other stroke risk factors. Our findings support a broad role of the 9p21 region in arterial disease.
AU  - Gschwendtner, A.*
AU  - Bevan, S.*
AU  - Cole, J.W.*
AU  - Plourde, A.*
AU  - Matarin, M.*
AU  - Ross-Adams, H.*
AU  - Meitinger, T.
AU  - Wichmann, H.-E.
AU  - Mitchell, B.D.*
AU  - Furie, K.*
AU  - Slowik, A.*
AU  - Rich, S.S.*
AU  - Syme, P.D.*
AU  - MacLeod, M.J.*
AU  - Meschia, J.F.*
AU  - Rosand, J.*
AU  - Kittner, S.J.*
AU  - Markus, H.S.*
AU  - Müller-Myhsok, B.*
AU  - Dichgans, M.*
C1  - 1093
C2  - 26246
SP  - 531-539
TI  - Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke.
JO  - Ann. Neurol.
VL  - 65
IS  - 5
PB  - Wiley-Blackwell
PY  - 2009
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - To test whether the synucleinopathies Parkinson's disease and multiple system atrophy (MSA) share a common genetic etiology, we performed a candidate single nucleotide polymorphism (SNP) association study of the 384 most associated SNPs in a genome-wide association study of Parkinson's disease in 413 MSA cases and 3,974 control subjects. The 10 most significant SNPs were then replicated in additional 108 MSA cases and 537 controls. SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 × 1012; odds ratio 6.2). © 2009 American Neurological Association.
AU  - Scholz, S.W.*
AU  - Houlden, H.*
AU  - Schulte, C.*
AU  - Sharma, M.*
AU  - Li, A.*
AU  - Berg, D.*
AU  - Melchers, A.*
AU  - Paudel, R.*
AU  - Gibbs, J.R.*
AU  - Simon-Sanchez, J.*
AU  - Paisan-Ruiz, C.*
AU  - Bras, J.*
AU  - Ding, J.*
AU  - Chen, H.*
AU  - Traynor, B.J.*
AU  - Arepalli, S.*
AU  - Zonozi, R.R.*
AU  - Revesz, T.*
AU  - Holton, J.*
AU  - Wood, N.*
AU  - Lees, A.*
AU  - Oertel, W.*
AU  - Wüllner, U.*
AU  - Goldwurm, S.*
AU  - Pellecchia, M.T.*
AU  - Illig, T.
AU  - Riess, O.*
AU  - Fernandez, H.H.*
AU  - Rodriguez, R.L.*
AU  - Okun, M.S.*
AU  - Poewe, W.*
AU  - Wenning, G.K.*
AU  - Hardy, J.A.*
AU  - Singleton, A.B.*
AU  - Gasser, T.*
C1  - 1091
C2  - 26244
SP  - 610-614
TI  - SNCA variants are associated with increased risk for multiple system atrophy.
JO  - Ann. Neurol.
VL  - 65
IS  - 5
PB  - Wiley-Blackwell
PY  - 2009
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Elucidation of the entire human genomic sequence is one of the greatest achievements of science. Understanding the functional role of 30,000 human genes and more than 2 million polymorphisms was possible through a multidisciplinary approach using microarrays and bioinformatics. Polymorphisms, variations in DNA sequences, occur in 1% of the population, and a vast majority of them are single nucleotide polymorphisms. Genotype analysis has identified genes important in thrombosis, cardiac defects, and risk of cardiac disease. Many of the genes show a significant correlation with polymorphisms and the incidence of coronary artery disease and heart failure. In this chapter, the application of current state-of-the-art genomic analysis to a variety of these disorders is reviewed.
AU  - Gretarsdottir, S.*
AU  - Gieger, C.
C1  - 4685
C2  - 25998
SP  - 402-409
TI  - Risk Variants for Atrial Fibrillation on Chromosome 4q24 Associate with Ischemic Stroke.
JO  - Ann. Neurol.
VL  - 64
IS  - 4
PB  - Wiley-Blackwell
PY  - 2008
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Objective: Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by magnetic resonance imaging (MRI) changes in basal ganglia. Both missense and nonsense mutations have been found in such patients in a gene encoding the mitochondrial pantothenate kinase (PANK2). Methods: We completed a mutation screen in 72 patients with the diagnosis NBIA based on clinical findings and radiological imaging. The entire coding region of the PANK2 gene (20p12.3) was investigated for point mutations and deletions. Results: We uncovered both mutant alleles in 48 patients. Deletions accounted for 4% of mutated alleles. Patients with two loss-of-function alleles (n = 11) displayed symptoms always at an early stage of life. In the presence of missense mutations (n = 37), the age of onset correlated with residual activity of the pantothenate kinase. Progression of disease measured by loss of ambulation was variable in both groups. We did not observe a strict correlation between the eye-of-the-tiger sign and PANK2 mutations. In 24 patients, no PANK2 mutation was identified. Interpretation: Deletion screening of PANK2 should be part of the diagnostic spectrum. Factors other than enzymatic residual activity are determining the course of disease. There are strong arguments in favor of locus heterogeneity. © 2006 American Neurological Association.
AU  - Hartig, M.B.
AU  - Hörtnagel, K.
AU  - Garavaglia, B.*
AU  - Zorzi, G.*
AU  - Kmiec, T.*
AU  - Klopstock, T.*
AU  - Rostasy, K.*
AU  - Svetel, M.*
AU  - Kostic, V.S.*
AU  - Schuelke, M.*
AU  - Botz, E.
AU  - Weindl, A.*
AU  - Novakovic, I.*
AU  - Nardocci, N.*
AU  - Prokisch, H.
AU  - Meitinger, T.
C1  - 1554
C2  - 23453
SP  - 248-256
TI  - Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation.
JO  - Ann. Neurol.
VL  - 59
IS  - 2
PB  - Wiley
PY  - 2006
SN  - 0364-5134
ER  - 

TY  - JOUR
AU  - Biskup, S.
AU  - Mueller, J.C.
AU  - Sharma, M.*
AU  - Lichtner, P.
AU  - *
AU  - Berg, D.*
AU  - Wüllner, U.*
AU  - Illig, T.
AU  - Meitinger, T.
AU  - Gasser, T.*
C1  - 4799
C2  - 23065
SP  - 905-908
TI  - Common variants of LRRK2 are not associated with sporadic parkinson's disease.
JO  - Ann. Neurol.
VL  - 58
PB  - Wiley
PY  - 2005
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - α-Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of α-synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the α-synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case–control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the α-synuclein gene. Several markers within the 3′-block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5′-block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age.
AU  - Mueller, J.C.
AU  - Fuchs, J.*
AU  - Hofer, A.*
AU  - *
AU  - Lichtner, P.
AU  - Illig, T.
AU  - Berg, D.*
AU  - Wüllner, U.*
AU  - Meitinger, T.
AU  - Gasser, T.*
C1  - 4195
C2  - 22769
SP  - 535-541
TI  - Multiple regions of alpha-synuclein are associated with parkinson's disease.
JO  - Ann. Neurol.
VL  - 57
IS  - 4
PB  - Wiley
PY  - 2005
SN  - 0364-5134
ER  - 

TY  - JOUR
AB  - Mutations in the gene for ε-sarcoglycan (SGCE) have been found to cause myoclonus-dystonia syndrome. We now report clinical and genetic findings in nine additional European families with myoclonus-dystonia syndrome. The clinical presentation in 24 affecteds was homogeneous with myoclonus predominantly of neck and upper limbs in 23 of them and dystonia, presenting as cervical dystonia and/or writer's cramp, in 13 cases. Six novel and one previously known heterozygous SGCE mutations were identified. SGCE deficiency seems to be the common pathogenetic mechanism in myoclonus-dystonia syndrome.
AU  - Asmus, F.*
AU  - *
AU  - Tezenas du Montcel, S.*
AU  - Kabus, C.*
AU  - Deuschl, G.*
AU  - Kupsch, A.*
AU  - Ziemann, U.*
AU  - Castro, M.*
AU  - Kühn, A.A.*
AU  - Strom, T.M.
AU  - Vidailhet, M.*
AU  - Bhatia, K.P.*
AU  - Dürr, A.*
AU  - Wood, N.W.*
AU  - Brice, A.*
AU  - Gasser, Th.*
C1  - 22005
C2  - 20549
SP  - 489-492
TI  - Myoclonus-Dystonia Syndrome : e-Sarcoglycan Mutations and Phenotype.
JO  - Ann. Neurol.
VL  - 52
IS  - 4
PB  - Wiley
PY  - 2002
SN  - 0364-5134
ER  -