TGM6 variants in Parkinson’s disease: clinical findings and functional evidence

Chen, Kui; Lu, Yuanzheng; Peng, Fang; Yu, Huapeng; Wu, Jiayan; Tan, Yan; Zhao, Yanxin

doi:10.31083/j.jin.2020.01.1203

Cited by 5 publications

(11 citation statements)

References 39 publications

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“…The clinical picture of a markedly asymmetric, progressive ataxia–dystonia syndrome with oculomotor apraxia and vertical supranuclear gaze palsy resembled NPC but was instead associated with a new pathogenic variant (T206P) in TGM6 , previously reported as the genetic etiology of SCA35, and with an unanticipated pathology consistent with PSP. While the clinical features were broadly compatible with the syndrome of spinocerebellar ataxia, SCA35 has never been reported to be associated with supranuclear gaze palsy (as per a systematic review of 66 cases reported; Supplementary Table S1 [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ] and Figure S1 ), nor with an underlying 4R tau proteinopathy compatible with PSP pathology. That said, in the background of severe DaT deficit on imaging and vertical supranuclear gaze palsy on examination, PSP was clinically excluded by the hyperkinetic rather than the parkinsonian phenotype, as well as the presence of appendicular and axial ataxia, which are exclusionary [ 16 ].…”

Section: Discussionmentioning

confidence: 93%

Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

Marsili

Sharma

Espay

et al. 2021

IJMS

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The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.

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Section: Discussionmentioning

confidence: 93%

Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

Marsili

Sharma

Espay

et al. 2021

IJMS

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“…A total of 54 individuals (from 40 different families) with TGM6 variants were selected from 10 articles after excluding irrelevant articles and duplicate searches and including the clinical details of the case described above. 3 4 5 6 7 8 9 10 11 12 Out of these, one was a whole-exome sequencing-based clinical study to identify novel variants responsible for SCA, with a paucity of adequate clinical details, and the six cases identified in this study with TGM6 missense mutations were variants of uncertain significance. Hence, the six cases described in this study were excluded from the final analysis.…”

Section: Resultsmentioning

confidence: 99%

“… 15 TGM6 is expressed in basal ganglia and cerebellum, especially in Purkinje cells, thereby explaining ataxia and parkinsonism in patients with pathogenic TGM6 variants. 3 4 12 …”

Section: Discussionmentioning

confidence: 99%

“…Pathogenicity of reported mutations by functional assay, including their role in autophagy and α-synuclein production, has been demonstrated. 4 5 6 7 8 9 10 11 12 However, outside the East Asia region, only a few cases of SCA-35 have been reported. We are describing the first case of Indian origin with TGM6 mutation of Indian origin with the SCA-35 phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Clinical Spectrum of TGM6-Related Movement Disorders: A New Report with a Pooled Analysis of 48 Patients

Sharawat

Panda

Bhunia

2021

JNRP

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Background Spinocerebellar ataxias (SCAs) are a diverse group of progressive neurodegenerative disorders. Until now, more than 20 genes have been implicated to be associated with this phenotype and TGM6 is one of these genes, associated with spinocerebellar ataxia-35 (SCA-35). The majority of disease-causing variants in the TGM6 gene predominantly have been reported from China and Taiwan and the association with Parkinson's disease (PD) have also been reported recently. Methods We report the first Indian case with SCA-35 in a 16-year-old-boy with atypical age of onset at 9 years, prominent extrapyramidal features, intellectual disability, and a novel missense mutation in the TGM6 gene. We also reviewed and collated all previously published cases with pathogenic TGM6 variants. Results Including the index case, 54 cases were identified from 10 relevant articles in literature and 48 cases had adequate clinical details to be included in the pooled analysis. Around two-thirds of reported cases had SCA-35 phenotype, with cerebellar atrophy. Onset in the majority of cases was the fourth decade of life onwards. A proportion of SCA-35 cases also had spasmodic torticollis, impaired proprioception, extrapyramidal features, and myoclonic jerks. The patients with PD had often early-onset milder symptoms, slower progression, and favorable response to levodopa/carbidopa. One patient each presented with episodic ataxia and dystonic tremor of the upper limb. Most of the cases had missense mutations, without any definite hotspot or genotype–phenotype correlation. Conclusions TGM6 mutation should be suspected in patients with SCA like presentation, especially when it is accompanied by extrapyramidal features, spasmodic torticollis, impaired proprioception, or myoclonus.

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“…. Other candidate genes have recently been reported in different cohorts (i.e., RAD51B, 114 DYRK1A, 127 CHCHD2, 128 VPS35 (PARK17), 129,130 RAB39B, 131 TMEM230, 132 TGM6,133 …”

mentioning

confidence: 98%

Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics

Cacabelos

Carrera

Martínez

et al. 2021

Medicinal Research Reviews

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Atremorine is a novel bioproduct obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba.Atremorine is a potent dopamine (DA) enhancer with powerful effects on the neuronal dopaminergic system, acting as a neuroprotective agent in Parkinson's disease (PD). Over 97% of PD patients respond to a single dose of Atremorine (5 g, p.o.) 1 h after administration. This response is gender-, time-, dose-, and genotype-dependent, with optimal doses ranging from 5 to 20 g/day, depending upon disease severity and concomitant medication. Drug-free patients show an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ ml; and patients chronically treated with anti-PD drugs show an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effects of conventional anti-PD drugs. Atremorine also influences the levels of other neurotransmitters (adrenaline, noradrenaline) and hormones which are regulated by DA (e.g., prolactin, PRL), with no effect on serotonin or histamine. The variability in Atremorine-induced DA response is highly attributable to pharmacogenetic factors.

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TGM6 variants in Parkinson’s disease: clinical findings and functional evidence

Cited by 5 publications

References 39 publications

Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

Clinical Spectrum of TGM6-Related Movement Disorders: A New Report with a Pooled Analysis of 48 Patients

Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics

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