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Possible Post-Traumatic Focal Dystonia Associated with Tau Pathology Localized to Putamen-Globus Pallidus.

ABSTRACT: Background:Dystonia is often associated with damage to basal ganglia (BG), but neuropathological assessments of these cases are infrequent. Methods:A brain was assessed with possible post-traumatic focal dystonia that appeared after an accident occurred during childhood. Results:Tau pathology was found within putamen and globus pallidus of the right hemisphere, and chronic traumatic encephalopathy (CTE) was observed in the cortex of the left hemisphere. No diffuse axonal injury (DAI), ?-amyloid, ubiquitin, p62, or pTDP43 pathology was found. Conclusions:Post-traumatic dystonia could be associated with post-traumatic tau pathology formation. However, more cases are necessary to establish causality. The tau lesions found in the BG of this patient did not fit within CTE criteria. We hypothesize that due to the anatomo-histological characteristics of the BG, tau pathology associated with brain traumas produce histopathological patterns different from sulcal-tau pathology, which is the only tau pathology distribution currently accepted as pathognomonic of CTE.

SUBMITTER: Iacono D

PROVIDER: S-EPMC6207110 | biostudies-literature | 2018 Sep-Oct

REPOSITORIES: biostudies-literature

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Possible Post-Traumatic Focal Dystonia Associated with Tau Pathology Localized to Putamen-Globus Pallidus.

Iacono Diego D Lee Patricia P Hallett Mark M Perl Daniel D

Movement disorders clinical practice 20180808 5

<h4>Background</h4>Dystonia is often associated with damage to basal ganglia (BG), but neuropathological assessments of these cases are infrequent.<h4>Methods</h4>A brain was assessed with possible post-traumatic focal dystonia that appeared after an accident occurred during childhood.<h4>Results</h4>Tau pathology was found within putamen and globus pallidus of the right hemisphere, and chronic traumatic encephalopathy (CTE) was observed in the cortex of the left hemisphere. No diffuse axonal in ...[more]

PMID: 30637269

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Project description:Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.

Project description:IntroductionDystonic opisthotonus is defined as a backward arching of the neck and trunk, which ranges in severity from mild backward jerks to life-threatening prolonged severe muscular spasms. It can be associated with generalized dystonic syndromes or, rarely, present as a form of axial truncal dystonia. The etiologies vary from idiopathic, genetic, tardive, hereditary-degenerative, or associated with parkinsonism. We report clinical cases of dystonic opisthotonus associated with adult-onset dystonic syndromes, that benefitted from globus pallidus internus (GPi) deep brain stimulation (DBS).MethodsClinical data from patients with dystonic syndromes who underwent comprehensive medical review, multidisciplinary assessment, and tailored medical and neurosurgical managements were prospectively analyzed. Quantification of dystonia severity pre- and postoperatively was performed using the Burke-Fahn-Marsden Dystonia Rating Scale and quantification of overall pain severity was performed using the Visual Analog Scale.ResultsThree male patients, with age of onset of the dystonic symptoms ranging from 32 to 51 years old, were included. Tardive dystonia, adult-onset dystonia-parkinsonism and adult-onset idiopathic axial dystonia were the etiologies identified. Clinical investigation and management were tailored according to the complexity of the individual presentations. Although they shared common clinical features of adult-onset dystonia, disabling dystonic opisthotonus, refractory to medical management, was the main indication for GPi-DBS in all patients presented. The severity of axial dystonia ranged from disturbance of daily function to life-threatening truncal distortion. All three patients underwent bilateral GPi DBS at a mean age of 52 years (range 48-55 years), after mean duration of symptoms prior to DBS of 10.7 years (range 4-16 years). All patients showed a rapid and sustained clinical improvement of their symptoms, notably of the dystonic opisthotonos, at postoperative follow-up ranging from 20 to 175 months. In some, the ability to resume activities of daily living and reintegration into the society was remarkable.ConclusionAdult-onset dystonic syndromes predominantly presenting with dystonic opisthotonus are relatively rare. The specific nature of dystonic opisthotonus remains a treatment challenge, and thorough investigation of this highly disabling condition with varying etiologies is often necessary. Although patients may be refractory to medical management and botulinum toxin injection, Globus pallidus stimulation timed and tailored provided symptomatic control in this cohort and may be considered in other carefully selected cases.

Project description:BACKGROUND:The pathophysiology underlying different types of dystonia is not yet understood. We report microelectrode data from the globus pallidus interna (GPi) and globus pallidus externa (GPe) in children undergoing deep brain stimulation (DBS) for dystonia and investigate whether GPi and GPe firing rates differ between dystonia types. METHODS:Single pass microelectrode data were obtained to guide electrode position in 44 children (3.3-18.1?years, median 10.7) with the following dystonia types: 14 primary, 22 secondary Static and 8 progressive secondary to neuronal brain iron accumulation (NBIA). Preoperative stereotactic MRI determined coordinates for the GPi target. Digitised spike trains were analysed offline, blind to clinical data. Electrode placement was confirmed by a postoperative stereotactic CT scan. FINDINGS:We identified 263 GPi and 87 GPe cells. Both GPi and GPe firing frequencies differed significantly with dystonia aetiology. The median GPi firing frequency was higher in the primary group than in the secondary static group (13.5?Hz vs 9.6?Hz; p=0.002) and higher in the NBIA group than in either the primary (25?Hz vs 13.5?Hz; p=0.006) or the secondary static group (25?Hz vs 9.6?Hz; p=0.00004). The median GPe firing frequency was higher in the NBIA group than in the secondary static group (15.9?Hz vs 7?Hz; p=0.013). The NBIA group also showed a higher proportion of regularly firing GPi cells compared with the other groups (p<0.001). A higher proportion of regular GPi cells was also seen in patients with fixed/tonic dystonia compared with a phasic/dynamic dystonia phenotype (p<0.001). The GPi firing frequency showed a positive correlation with 1-year outcome from DBS measured by improvement in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-m) score (p=0.030). This association was stronger for the non-progressive patients (p=0.006). INTERPRETATION:Pallidal firing rates and patterns differ significantly with dystonia aetiology and phenotype. Identification of specific firing patterns may help determine targets and patient-specific protocols for neuromodulation therapy. FUNDING:National Institute of Health Research, Guy's and St. Thomas' Charity, Dystonia Society UK, Action Medical Research, German National Academic Foundation.

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Possible Post-Traumatic Focal Dystonia Associated with Tau Pathology Localized to Putamen-Globus Pallidus.

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Possible Post-Traumatic Focal Dystonia Associated with Tau Pathology Localized to Putamen-Globus Pallidus.

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