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

Abstract

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.

Spinocerebellar Ataxia Type 35 Caused by a New TGM6 Variant: Video Documentation of a German Family

“…An episodic ataxia-like phenotype has also been reported. 4 There is some debate whether TGM6 variants are causative for ATX-TGM6 (SCA35), as benign or low penetrant variants might be misclassified as pathogenic and therefore, might also occur in patients with various neurologic diseases or normal controls. 5,6 TGM6 is neuronally expressed and catalyzes various posttranslational modifications in proteins and peptides, 7 but its exact role in ATX-TGM6 (SCA35) pathogenesis is still elusive.…”

“…Department of Neurology, University Medical Center Göttingen, Göttingen, Germany; 2 Department of Neuroradiology, University Medical Center Göttingen, Göttingen, Germany;3 CeGaT, Center for Genomics and Transcriptomics, Tübingen, Germany;4 Germany Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany…”