Objective: To identify functional and structural brain organization relevant to disease penetrance and clinical manifestation in patients with familial laryngeal dystonia (LD) and their unaffected relatives.

Background: LD is a task-specific focal dystonia causing involuntary voice breaks and strained, strangled or breathy voice quality during speech production. There is converging evidence for genetic susceptibility factors with reduced penetrance in LD. However, our knowledge of neural bases of LD development and phenotypic manifestation is scarce.

Method: We examined alterations of functional brain activity and connectivity during symptomatic speech production and gray matter volume in 21 familial LD patients (age 56.2±15.8 years; 19 females/2 males), 21 unaffected first-degree relatives (age 48.6±16.2; 17 females/4 males), and 32 healthy controls (age 50.2±11.0; 20 females/12 males). The significance level was set at family-wise error-corrected p ≤ 0.05.

Results: Compared to healthy controls, both patients with familial LD and their unaffected relatives showed significantly reduced gray matter volume in the left thalamus and increased activity in the bilateral inferior frontal gyrus (IFG), left caudate nucleus and anterior cingulate cortex. Compared to their unaffected relatives, patients showed increased activity in the right superior parietal lobule and bilateral supplementary motor area, as well as decreased gray matter volume in the right cerebellar lobule VIII. Conversely, unaffected relatives of LD patients showed increased activity in the right middle temporal gyrus. Functional relatedness between family members was found in the left IFG, whereas structural relatedness was found in the right cerebellum. Functional connectivity analysis showed that patients and their unaffected relatives had similarly increased coupling between left IFG and right primary sensorimotor cortex, supplementary motor area, and left operculum.

Conclusion: Common structural and functional abnormalities in patients with familial LD and their unaffected relatives exhibit represent an endophenotypic trait of dystonia penetrance. On the other hand, structural and functional features that distinguished familial LD patients from their unaffected relatives likely contribute to the manifestation of LD phenotype. These neural markers of the genetic status may be utilized for the identification of family members with higher susceptibility and risk to developing LD symptoms.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neural-bases-of-dystonia-penetrance-and-manifestation/