Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.

Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin.

Dystonia is a neurologic disorder associated with an increasingly large number of genetic variants in many genes, resulting in characteristic disturbances in volitional movement. Dissecting the relationships between these mutations and their functional outcomes is critical in understanding the pathways that drive dystonia pathogenesis. Here we established a pipeline for characterizing an allelic series of dystonia-specific mutations. We used this strategy to investigate the molecular consequences of genetic variation in THAP1, which encodes a transcription factor linked to neural differentiation. Multiple pathogenic mutations associated with dystonia cluster within distinct THAP1 functional domains and are predicted to alter DNA-binding properties and/or protein interactions differently, yet the relative impact of these varied changes on molecular signatures and neural deficits is unclear. To determine the effects of these mutations on THAP1 transcriptional activity, we engineered an allelic series of eight alterations in a common induced pluripotent stem cell background and differentiated these lines into a panel of near-isogenic neural stem cells (n = 94 lines). Transcriptome profiling followed by joint analysis of the most robust signatures across mutations identified a convergent pattern of dysregulated genes functionally related to neurodevelopment, lysosomal lipid metabolism, and myelin. On the basis of these observations, we examined mice bearing Thap1-disruptive alleles and detected significant changes in myelin gene expression and reduction of myelin structural integrity relative to control mice. These results suggest that deficits in neurodevelopment and myelination are common consequences of dystonia-associated THAP1 mutations and highlight the potential role of neuron-glial interactions in the pathogenesis of dystonia.

Basal Ganglia Atrophy as a Marker for Prodromal X-Linked Dystonia-Parkinsonism.

In neurodegenerative diseases, the characterization of the prodromal phase is essential for the future application of disease-modifying therapies. X-linked dystonia-parkinsonism is a hereditary neurodegenerative movement disorder characterized by severe adult-onset dystonia accompanied by parkinsonism. Distinct striatal and pallidal atrophy is present already in early disease stages indicating a long-lasting presymptomatic degenerative process. To gain insight into the prodromal phase of X-linked dystonia-parkinsonism, structural and iron-sensitive magnetic resonance imaging (MRI) was performed in 10 non-manifesting carriers and 24 healthy controls in a double-blind fashion. Seventeen patients with X-linked dystonia-parkinsonism were recruited to replicate previous findings of basal ganglia pathology and iron accumulation. Age at onset was estimated in non-manifesting carriers and patients using the repeat length of the hexanucleotide expansion and 3 single-nucleotide polymorphisms associated with age at onset. Voxel-based morphometry and subcortical volumetry showed striatal and pallidal atrophy in non-manifesting carriers (~10%) and patients (~40%). Substantia nigra volume was similarly reduced in patients (~40%). Caudate volume correlated with time to estimated onset in non-manifesting carriers. Susceptibility-weighted imaging confirmed iron deposition in the anteromedial putamen in patients. Non-manifesting carriers also showed small clusters of iron accumulation in the same area after lowering the statistical threshold. In conclusion, basal ganglia atrophy and iron accumulation precede the clinical onset of X-linked dystonia-parkinsonism and can be detected years before the estimated disease manifestation. It thereby highlights the potential of multimodal imaging to identify clinically unaffected mutation carriers with incipient neurodegeneration and to monitor disease progression independent of clinical measures. Longitudinal studies are needed to further elucidate the onset and progression rate of neurodegeneration in prodromal X-linked dystonia-parkinsonism. ANN NEUROL 2023;93:999-1011.

Prodromal X-Linked Dystonia-Parkinsonism is Characterized by a Subclinical Motor Phenotype.

BACKGROUND: Early diagnosis in patients with neurodegenerative disorders is crucial to initiate disease-modifying therapies at a time point where progressive neurodegeneration can still be modified. OBJECTIVES: The objective of this study was to determine whether motor or non-motor signs of the disease occur as indicators of a prodromal phase of X-linked dystonia-parkinsonism (XDP), a highly-penetrant monogenic movement disorder with striking basal ganglia pathology. METHODS: In addition to a comprehensive clinical assessment, sensor-based balance and gait analyses were performed in non-manifesting mutation carriers (NMCs), healthy controls (HCs), and patients with XDP. Gradient-boosted trees (GBT) methodology was utilized to classify groups of interest. RESULTS: There were no clinically overt disease manifestations in the NMCs. Balance analysis, however, revealed a classification accuracy of 90% for the comparison of NMC versus HC. For the gait analysis, the best-performing GBT-based model showed a balanced accuracy of 95% (NMC vs. HC; walking at maximum speed). Using a separate analysis of genetic modifiers, several gait parameters correlated strongly with the estimated age at disease onset in the NMC group. CONCLUSIONS: Our study unraveled balance and gait abnormalities in NMCs that preceded the onset of XDP. These findings demonstrate prodromal motor changes among NMCs who will develop XDP with a very high likelihood in the future. Gait abnormalities had a predictive value for the estimated age at onset highlighting the impact of genetic modifiers in personalized treatment in monogenic neurodegenerative disorders. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genotype-Phenotype Relations for Isolated Dystonia Genes: MDSGene Systematic Review.

This comprehensive MDSGene review is devoted to 7 genes - TOR1A, THAP1, GNAL, ANO3, PRKRA, KMT2B, and HPCA - mutations in which may cause isolated dystonia. It followed MDSGene's standardized data extraction protocol and screened a total of ~1200 citations. Phenotypic and genotypic data on ~1200 patients with 254 different mutations were curated and analyzed. There were differences regarding age at onset, site of onset, and distribution of symptoms across mutation carriers in all 7 genes. Although carriers of TOR1A, THAP1, PRKRA, KMT2B, or HPCA mutations mostly showed childhood and adolescent onset, patients with GNAL and ANO3 mutations often developed first symptoms in adulthood. GNAL and KMT2B mutation carriers frequently have 1 predominant site of onset, that is, the neck (GNAL) or the lower limbs (KMT2B), whereas site of onset in DYT-TOR1A, DYT-THAP1, DYT-ANO3, DYT-PRKRA, and DYT-HPCA was broader. However, in most DYT-THAP1 and DYT-ANO3 patients, dystonia first manifested in the upper half of the body (upper limb, neck, and craniofacial/laryngeal), whereas onset in DYT-TOR1A, DYT-PRKRA and DYT-HPCA was frequently observed in an extremity, including both upper and lower ones. For ANO3, a segmental/multifocal distribution was typical, whereas TOR1A, PRKRA, KMT2B, and HPCA mutation carriers commonly developed generalized dystonia. THAP1 mutation carriers presented with focal, segmental/multifocal, or generalized dystonia in almost equal proportions. GNAL mutation carriers rarely showed generalization. This review provides a comprehensive overview of the current knowledge of hereditary isolated dystonia. The data are also available in an online database (http://www.mdsgene.org), which additionally offers descriptive summary statistics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genotype-Phenotype Relations in Primary Familial Brain Calcification: Systematic MDSGene Review.

This systematic MDSGene review covers individuals with confirmed genetic forms of primary familial brain calcification (PFBC) available in the literature. Data on 516 (47% men) individuals, carrying heterozygous variants in SLC20A2 (solute carrier family 20 member 2, 61%), PDGFB (platelet-derived growth factor subunit B, 12%), XPR1 (xenotropic and polytropic retrovirus receptor, 16%), or PDGFRB (platelet-derived growth factor receptor beta, 5%) or biallelic variants in MYORG (myogenesis-regulating glycosidase, 13%) or JAM2 (junctional adhesion molecule 2, 2%), were extracted from 93 articles. Nearly one-third of the mutation carriers were clinically unaffected. Carriers of PDGFRB variants were more likely to be clinically unaffected (~54%), and the penetrance of SLC20A2 and XPR1 variants (<70%) was lower in comparison to the remaining three genes (>85%). Among the 349 clinically affected patients, 27% showed only motor and 31% only nonmotor symptoms/signs, whereas the remaining 42% had a combination thereof. While parkinsonism and speech disturbance were the most frequently reported motor manifestations, cognitive deficits, headache, and depression were the major nonmotor symptoms/signs. The basal ganglia were always calcified, and the cerebellum, thalamus, and white matter contained calcifications in 58%, 53%, and 43%, respectively, of individuals. In autosomal-dominant PFBC, mutation severity influenced the number of calcified brain areas, which in turn correlated with the clinical status, whereby the risk of developing symptoms/signs more than doubled for each additional region with calcifications. Our systematic analysis provides the most comprehensive insight into genetic, clinical, and neuroimaging features of known PFBC forms, to date. In addition, it puts forth the penetrance estimates and newly discovered genotype-phenotype relations that will improve counseling of individuals with mutations in PFBC genes. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Isolated dystonia: clinical and genetic updates.

Four genes associated with isolated dystonia are currently well replicated and validated. DYT-THAP1 manifests as young-onset generalized dystonia with predominant craniocervical symptoms; and is associated with mostly deleterious missense variation in the THAP1 gene. De novo and inherited missense and protein truncating variation in GNAL as well as primarily missense variation in ANO3 cause isolated focal and/or segmental dystonia with preference for the upper half of the body and older ages at onset. The GAG deletion in TOR1A is associated with generalized dystonia with onset in childhood in the lower limbs. Rare variation in these genes causes monogenic sporadic and inherited forms of isolated dystonia; common variation may confer risk and imply that dystonia is a polygenic trait in a subset of cases. Although candidate gene screens have been successful in the past in detecting gene-disease associations, recent application of whole-genome and whole-exome sequencing methods enable unbiased capture of all genetic variation that may explain the phenotype. However, careful variant-level evaluation is necessary in every case, even in genes that have previously been associated with disease. We review the genetic architecture and phenotype of DYT-THAP1, DYT-GNAL, DYT-ANO3, and DYT-TOR1A by collecting case reports from the literature and performing variant classification using pathogenicity criteria.

Combined dystonias: clinical and genetic updates.

The genetic combined dystonias are a clinically and genetically heterogeneous group of neurologic disorders defined by the overlap of dystonia and other movement disorders such as parkinsonism or myoclonus. The number of genes associated with combined dystonia syndromes has been increasing due to the wider recognition of clinical features and broader use of genetic testing. Nevertheless, these diseases are still rare and represent only a small subgroup among all dystonias. Dopa-responsive dystonia (DYT/PARK-GCH1), rapid-onset dystonia-parkinsonism (DYT/PARK-ATP1A3), X-linked dystonia-parkinsonism (XDP, DYT/PARK-TAF1), and young-onset dystonia-parkinsonism (DYT/PARK-PRKRA) are monogenic combined dystonias accompanied by parkinsonian features. Meanwhile, MYC/DYT-SGCE and MYC/DYT-KCTD17 are characterized by dystonia in combination with myoclonus. In the past, common molecular pathways between these syndromes were the center of interest. Although the encoded proteins rather affect diverse cellular functions, recent neurophysiological evidence suggests similarities in the underlying mechanism in a subset. This review summarizes recent developments in the combined dystonias, focusing on clinico-genetic features and neurophysiologic findings. Disease-modifying therapies remain unavailable to date; an overview of symptomatic therapies for these disorders is also presented.

Imaging gradual neurodegeneration in a basal ganglia model disease.

OBJECTIVE: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease with adult onset dystonia and subsequent parkinsonism. Postmortem and imaging studies revealed remarkable striatal pathology, with a predominant involvement of the striosomal compartment in the early phase. Here, we aimed to disentangle sequential neurodegeneration in the striatum of XDP patients, provide evidence for preferential loss of distinct striatal areas in the early phase, and investigate whether iron accumulation is present. METHODS: We used multimodal structural magnetic resonance imaging (voxel-based morphometry and relaxometry) in 18 male XDP patients carrying a TAF1 mutation and 19 age-matched male controls. RESULTS: Voxel-based relaxometry and morphometry revealed (1) a cluster in the anteromedial putamen showing high iron content and severe atrophy (-55%) and (2) a cluster with reduced relaxation rates as a marker for increased water levels and a lower degree of atrophy (-20%) in the dorsolateral putamen. Iron deposition correlated with the degree of atrophy (ρ = -0.585, p = 0.011) and disease duration (ρ = 0.632, p = 0.005) in the anteromedial putamen. In the dorsolateral putamen, sensorimotor putamen atrophy correlated with disease severity (ρ = -0.649, p = 0.004). INTERPRETATION: This multimodal approach identified a patchy pattern of atrophy within the putamen. Atrophy is advanced and associated with iron accumulation in rostral regions of the striatum, whereas neurodegeneration is moderate and still ongoing in dorsolateral areas. Given the short disease duration and predominant dystonic phenotype, these results are well in line with early and preferential degeneration of striosome-rich striatal areas in XDP. ANN NEUROL 2019;86:517-526.

A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism.

OBJECTIVE: X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP. METHODS: We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients. RESULTS: RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain. INTERPRETATION: The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN-dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812-822.

Expanding Data Collection for the MDSGene Database: X-linked Dystonia-Parkinsonism as Use Case Example.

MDSGene is an online database on movement disorders that collates genetic and clinical knowledge using a standardized published literature abstraction strategy. This review is dedicated to X-linked dystonia-parkinsonism (XDP). We screened 233 citations and curated phenotypic and genotypic data for 414 cases. To reduce data missingness, we (1) contacted authors and engaged the research community to provide additional clinical and genetic information, and (2) revisited previously unpublished data from a cohort of XDP patients seen at our institution. Using these approaches, we expanded the cohort to 577 cases and increased information available for important clinical and genetic features such as age at onset, initial manifestation, predominant motor symptoms, functional impairments, and repeat size information. We established the use of mining unpublished data to expand the MDSGene workflow and present an up-to-date description of the phenomenology of XDP using an extensive collection of previously reported and unreported data. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Basal ganglia and cerebellar pathology in X-linked dystonia-parkinsonism.

X-linked dystonia-parkinsonism is a neurodegenerative movement disorder characterized by adult-onset dystonia combined with parkinsonism over the disease course. Previous imaging and pathological findings indicate exclusive striatal atrophy with predominant pathology of the striosomal compartment in the dystonic phase of X-linked dystonia-parkinsonism. The striosome occupies 10-15% of the entire striatal volume and the density of striosomes follows a rostrocaudal gradient with the rostral striatum being considered striosome-rich. Recent quantitative MRI analyses provided evidence for an additional involvement of the white matter and the pallidum. In this study, we aimed to (i) disentangle the degree of atrophy in the different subdivisions of the striatum; (ii) investigate changes of cortical morphology; and (iii) elucidate the role of the cerebellum in X-linked dystonia-parkinsonism. T1-weighted MRI scans were acquired in 17 male X-linked dystonia-parkinsonism patients with predominant dystonia (40.1 ± 7.5 years) and 17 ethnicity-matched male healthy controls (35.2 ± 7.4 years). Voxel-based morphometry used a region of interest-based approach for the basal ganglia and primary motor cortex, whole brain analysis, and a separate analysis of the cerebellum. Cortical thickness and subcortical volume were measured. Volume loss in X-linked dystonia-parkinsonism affected all parts of the striatum (-29% voxel intensity) but was most pronounced in the associative subdivision (-41%; P < 0.001). The volume loss also involved the external and internal pallidum, albeit to a lesser extent than the striatum (-19% and -12%, P<0.001). Cortical thickness was reduced in the frontal (-4.3%) and temporal cortex (-6.1%). In addition, we found grey matter pathology in the associative part of the cerebellum and increased voxel intensities in the anterior sensorimotor part of the cerebellum and the dorsal ponto-mesencephalic brainstem. Taken together, our analysis of subcortical and cortical grey matter in the dystonic phase of X-linked dystonia-parkinsonism showed that (i) the striosome-enriched rostral striatum was most severely affected; and (ii) cortical thickness was only reduced in those regions that predominantly have anatomical connections to striosomes. Moreover, the cerebellum may be implicated in both disease-related and compensatory changes, highlighting the significance of the cerebellum in the pathophysiology of dystonia.

The Basal Ganglia Striosomes Affect the Modulation of Conflicts by Subliminal Information-Evidence from X-Linked Dystonia Parkinsonism.

Cognitive control is relevant when distracting information induces behavioral conflicts. Such conflicts can be produced consciously and by subliminally processed information. Interestingly, both sources of conflict interact suggesting that they share neural mechanisms. Here, we ask whether conjoint effects between different sources of conflict are modulated by microstructural basal ganglia dysfunction. To this end, we carried out an electroencephalography study and examined event-related potentials (ERPs) including source localization using a combined flanker-subliminal priming task in patients with X-linked dystonia Parkinsonism (XDP) and a group of healthy controls. XDP in its early stages is known to predominantly affect the basal ganglia striosomes. The results suggest that conjoint effects between subliminal and conscious sources of conflicts are modulated by the striosomes and were stronger in XDP patients. The neurophysiological data indicate that this effect is related to modulations in conflict monitoring and response selection (N2 ERP) mechanisms engaging the anterior cingulate cortex. Bottom-up perceptual gating, attentional selection, and motor response activation processes in response to the stimuli (P1, N1, and lateralized readiness potential ERPs) were unaffected. Taken together, these data indicate that striosomes modulate the processing of conscious and subliminal sources of conflict suggesting that microstructural basal ganglia properties are relevant for cognitive control.

Genome editing in induced pluripotent stem cells rescues TAF1 levels in X-linked dystonia-parkinsonism.

BACKGROUND: The most likely genetic cause of X-linked dystonia-parkinsonism, a neurodegenerative movement disorder endemic to the Philippines, is a 2672-bp-long retrotransposon insertion in intron 32 of the TAF1 gene. The objectives of this study were to investigate whether (1) TAF1 expression is altered in induced pluripotent stem cells and differentiated neuronal models and (2) excision of the retrotransposon insertion restores normal TAF1 expression. METHODS: Expression of TAF1 and its neuronal isoform were determined in induced pluripotent stem cells and in induced pluripotent stem cell-derived cortical neurons and spiny projection neurons using quantitative PCR. Genome editing-based excision of the retrotransposon insertion was performed on induced pluripotent stem cells from 3 X-linked dystonia-parkinsonism patients. Edited and unedited induced pluripotent stem cells from X-linked dystonia-parkinsonism patients and controls were differentiated into cortical neurons and spiny projection neurons, and TAF1 expression was compared across groups. RESULTS: TAF1 was reduced in patient-derived induced pluripotent stem cells (P < 0.05) and spiny projection neurons (P < 0.01). After genome editing, we observed higher TAF1 expression in edited compared with unedited induced pluripotent stem cells (P < 0.0001). In edited spiny projection neurons, TAF1 expression was also increased, but did not reach statistical significance. No expression differences were observed in cortical neurons. CONCLUSIONS: (1) TAF1 reduction in X-linked dystonia-parkinsonism is likely due to the retrotransposon insertion and is recapitulated in induced pluripotent stem cells and differentiated spiny projection neurons. (2) TAF1 reduction is a tractable molecular phenotype of X-linked dystonia-parkinsonism that can be driven by excision of the retrotransposon insertion. (3) Successful rescue of the molecular phenotype in an endogenous, genome-edited model serves as a proof of principle that may successfully be transferred to other inherited neurodegenerative diseases. © 2018 International Parkinson and Movement Disorder Society.

Genotype-Phenotype Relations for the Parkinson's Disease Genes Parkin, PINK1, DJ1: MDSGene Systematic Review.

This first comprehensive MDSGene review is devoted to the 3 autosomal recessive Parkinson's disease forms: PARK-Parkin, PARK-PINK1, and PARK-DJ1. It followed MDSGene's standardized data extraction protocol and screened a total of 3652 citations and is based on fully curated phenotypic and genotypic data on >1100 patients with recessively inherited PD because of 221 different disease-causing mutations in Parkin, PINK1, or DJ1. All these data are also available in an easily searchable online database (www.mdsgene.org), which also provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including early onset (median age at onset of ∼30 years for carriers of at least 2 mutations in any of the 3 genes) of an overall clinically typical form of PD with excellent treatment response, dystonia and dyskinesia being relatively common and cognitive decline relatively uncommon. However, when comparing actual data with common expert knowledge in previously published reviews, we detected several discrepancies. We conclude that systematic reporting of phenotypes is a pressing need in light of increasingly available molecular genetic testing and the emergence of first gene-specific therapies entering clinical trials. © 2018 International Parkinson and Movement Disorder Society.

Alternating Hemiplegia of Childhood as a New Presentation of Adenylate Cyclase 5-Mutation-Associated Disease: A Report of Two Cases.

Mutations in the adenylate cyclase 5 (ADCY5) gene recently have been identified as the cause of a childhood-onset disorder characterized by persistent or paroxysmal choreic, myoclonic, and/or dystonic movements. The 2 novel mutations we identified expand the clinical spectrum of ADCY5 mutations to include alternating hemiplegia of childhood.

Striosomal dysfunction affects behavioral adaptation but not impulsivity-Evidence from X-linked dystonia-parkinsonism.

BACKGROUND: Executive functions including behavioral adaptation and impulse control are commonly impaired in movement disorders caused by striatal pathology. However, as yet it is unclear what aspects of behavioral abnormalities are related to pathology in which striatal subcomponent, that is, the matrix and the striosomes. We therefore studied cognitive control in X-linked dystonia-parkinsonism, a model disease of striosomal degeneration, using behavioral paradigms and EEG. METHODS: We studied genetically confirmed X-linked dystonia-parkinsonism patients (N = 21) in their early disease stages and healthy matched controls. Error-related behavioral adaptation was tested in a flanker task and response inhibition in a Go/Nogo paradigm during EEG. We focused on error-related negativity during error processing and the Nogo-N2 and Nogo-P3 in the response inhibition task. Source localization analyses were calculated. In addition, total wavelet power and phase-locking factor reflecting neural synchronization processes in time and frequency across trials were calculated. RESULTS: Error processing and behavioral adaptation predominantly engaging the anterior cingulate cortex was markedly impaired in X-linked dystonia-parkinsonism. This was reflected in abnormal reaction times correlating with error-related negativity amplitudes, error related theta band activity, and the phase-locking factor. Also, abnormal error processing correlated with dystonia severity but not with parkinsonism. Response inhibition and corresponding EEG activity were normal. CONCLUSIONS: This dissociable pattern of cognitive deficits most likely reflects predominant dysfunction of the striosomal compartment and its connections to the anterior cingulate cortex in X-linked dystonia-parkinsonism. The results underscore the importance of striosomes for cognitive function in humans and suggest that striosomes are relays of error-related behavioral adaptation but not inhibitory control. © 2017 International Parkinson and Movement Disorder Society.

Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism.

The molecular dysfunction in X-linked dystonia-parkinsonism is not completely understood. Thus far, only noncoding alterations have been found in genetic analyses, located in or nearby the TATA-box binding protein-associated factor 1 (TAF1) gene. Given that this gene is ubiquitously expressed and is a critical component of the cellular transcription machinery, we sought to study differential gene expression in peripheral models by performing microarray-based expression profiling in blood and fibroblasts, and comparing gene expression in affected individuals vs. ethnically matched controls. Validation was performed via quantitative polymerase chain reaction in discovery and independent replication sets. We observed consistent downregulation of common TAF1 transcripts in samples from affected individuals in gene-level and high-throughput experiments. This signal was accompanied by a downstream effect in the microarray, reflected by the dysregulation of 307 genes in the disease group. Gene Ontology and network analyses revealed enrichment of genes involved in RNA polymerase II-dependent transcription, a pathway relevant to TAF1 function. Thus, the results converge on TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism, and provide evidence of altered expression of a canonical gene in this disease. Furthermore, our study illustrates a link between the previously described genetic alterations and TAF1 dysfunction at the transcriptome level.

Novel Dystonia Genes: Clues on Disease Mechanisms and the Complexities of High-Throughput Sequencing.

Dystonia is a genetically heterogenous disease and a prototype disorder where next-generation sequencing has facilitated the identification of new pathogenic genes. This includes the first two genes linked to recessively inherited isolated dystonia, that is, HPCA (hippocalcin) and COL6A3 (collagen VI alpha 3). These genes are proposed to underlie cases of the so-called DYT2-like dystonia, while also reiterating two distinct pathways in dystonia pathogenesis. First, deficiency in HPCA function is thought to alter calcium homeostasis, a mechanism that has previously been forwarded for CACNA1A and ANO3. The novel myoclonus-dystonia genes KCTD17 and CACNA1B also implicate abnormal calcium signaling in dystonia. Second, the phenotype in COL6A3-loss-of-function zebrafish models argues for a neurodevelopmental defect, which has previously been suggested as a possible biological mechanism for THAP1, TOR1A, and TAF1 based on expression data. The newly reported myoclonus-dystonia gene, RELN, plays also a role in the formation of brain structures. Defects in neurodevelopment likewise seem to be a recurrent scheme underpinning mainly complex dystonias, for example those attributable to biallelic mutations in GCH1, TH, SPR, or to heterozygous TUBB4A mutations. To date, it remains unclear whether dystonia is a common phenotypic outcome of diverse underlying disease mechanisms, or whether the different genetic causes converge in a single pathway. Importantly, the relevance of pathways highlighted by novel dystonia genes identified by high-throughput sequencing depends on the confirmation of mutation pathogenicity in subsequent genetic and functional studies. However, independent, careful validation of genetic findings lags behind publications of newly identified genes. We conclude with a discussion on the characteristics of true-positive reports.

Primary familial brain calcification in the 'IBGC2' kindred: All linkage roads lead to SLC20A2.

BACKGROUND: Linkage analyses of families with primary familial brain calcification (formerly idiopathic basal ganglia calcification [IBGC]) identified 3 candidate loci (IBGC1-3). Recently, SLC20A2 mutations were found in the IBGC1 and IBGC3 families, merging these 2 loci. We here elucidate the genetic cause of primary familial brain calcification in the 'IBGC2' kindred. METHODS: We sequenced known primary familial brain calcification genes and quantified SLC20A2 and PDGFB. Moreover, CT scans of affected and unaffected family members were evaluated by 2 blinded neuroradiologists for distribution of brain calcification. RESULTS: A heterozygous multiexonic SLC20A2 deletion was detected in several affected family members. A reevaluation of neuroimaging data revealed a subset of mutation-negative individuals with only mild and/or unilateral calcification. CONCLUSIONS: The identified SLC20A2 mutation resolves the genetic cause of primary familial brain calcification in the 'IBGC2' kindred, collapsing 'IBGC2' into IBGC1. We suggest an algorithm for predicting the chances of finding genetic mutations that has to be validated in further studies. Our study enhances criteria for the evaluation of neuroimaging data, contributing further to the much needed harmonization of diagnostic and research data collection in primary familial brain calcification. © 2016 International Parkinson and Movement Disorder Society.