TOR1A – Early-Onset Generalized Limb-Onset Dystonia

Early-onset generalized limb-onset dystonia (DYT1) is an autosomal dominant movement disorder caused predominantly by a three–nucleotide in-frame deletion in TOR1A (c.907_909del (p.Glu303del)), leading to childhood-onset limb dystonia that often generalizes. The canonical ΔGAG deletion accounts for the majority of DYT1 cases and exhibits reduced penetrance (~30%), variable expressivity, and a founder effect in Ashkenazi Jewish and other populations (PMID:18322712).

Genetic studies have ascertained over 50 unrelated index cases and more than 100 affected relatives harboring the c.907_909del mutation, with multiple large families demonstrating autosomal dominant segregation (PMID:18322712; PMID:9667600). In single families, additional non-ΔGAG variants including c.385G>A (p.Val129Ile) and c.863G>A (p.Arg288Gln) have been reported in focal or segmental adult-onset dystonia, confirming a broader mutational spectrum (PMID:26297380; PMID:18477710).

Functional assays reveal that torsinA ΔGAG and rare missense variants impair ATPase activity, disrupt oligomerization, and induce perinuclear membrane abnormalities in cell models (PMID:18477710; PMID:19955557). Conditional knock-in mouse models demonstrate that the ΔGAG allele is hypomorphic without overt gain-of-function toxicity, and that selective expression in hindbrain circuits is insufficient to recapitulate dystonic movements, supporting complex circuit involvement (PMID:26370418).

Alternative TOR1A variants have variable impact: p.Glu121Lys was found in Parkinson disease and healthy controls, arguing against a clear pathogenic role (PMID:31892495). Nonetheless, the ΔGAG deletion remains the most penetrant and diagnostic variant in DYT1 dystonia.

Integration of genetic and experimental data solidifies the causal role of TOR1A haploinsufficiency/dominant-negative effects in early-onset generalized dystonia. The recurrent ΔGAG deletion serves as a key diagnostic marker, and emerging non-ΔGAG variants warrant functional validation in vitro and in vivo.

Key Take-Home: TOR1A testing for the ΔGAG deletion is essential in early-onset dystonia diagnosis, and identification of rarer variants should prompt functional assays to guide clinical interpretation.

References

• Neurogenetics • 2008 • Is the early-onset torsion dystonia (EOTD) linked to TOR1A gene as frequent as expected in France? PMID:18322712
• Annals of neurology • 1998 • Phenotypic expression of the DYT1 mutation: a family with writer's cramp of juvenile onset. PMID:9667600
• Parkinsonism & related disorders • 2003 • Unusual phenotypic expression of the DYT1 mutation. PMID:12781594
• Journal of the Formosan Medical Association = Taiwan yi zhi • 2022 • Investigating DYT1 in a Taiwanese dystonia cohort. PMID:34092466
• Journal of neurology, neurosurgery, and psychiatry • 2008 • Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1). PMID:18477710
• Journal of medical genetics • 2010 • Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia. PMID:19955557
• Human molecular genetics • 2015 • A novel conditional knock-in approach defines molecular and circuit effects of the DYT1 dystonia mutation. PMID:26370418
• Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia • 2020 • The matter of significance - Has the p.(Glu121Lys) variant of TOR1A gene a pathogenic role in dystonia or Parkinson disease? PMID:31892495

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