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Page 12 of 31 Guerra et al. J Transl Genet Genom 2019;3:9. I https://doi.org/10.20517/jtgg.2018.03

an intermediate endophenotype and primary marker of LD. Meanwhile, the genes involved in synaptic
transmission and the development of neurons may be related to the molecular pathogenesis of this disorder.
Patients with LD have abnormal functional connectivity that affects speech production and auditory-motor
integration as phenotypic characteristics. Structures initially described were the internal capsule and the
[47]
cerebellum, as well as the thalamus, the corticobulbar tract and the basal ganglia . Other imaging studies
have reported alterations at left dorsal primary sensorimotor cortex, especially in the abductor forms. It
also affects the frontoparietal cortex, at the angular gyrus, and shows a significant relationship with the age
at onset [48,49] . Abnormalities in these regions correlate with underlying alterations in grey matter volume,
cortical thickness and white matter downstream pathways as well as the genetic relationship with the
[49]
functional connectivity of the premotor/primary sensory-motor and frontoparietal cortex .
LD genotypes are associated with structural changes in the extra Sylvian superior order regions and their
pathways, suggesting a role for the temporal lobe in the pathogenesis of LD. Genotypic alterations are
present in sporadic cases vs. familiar LD in the supplementary motor area (SMA) and superior temporal
gyrus (STG), as well as in the superior longitudinal fasciculus. Computerized tomography (CT) differences
in SMA may reflect different processing from the motor functions closest to those performed by the primary
motor cortex. Other specific genotypic alterations in LD were located at the anterior portion of STG, where
functional identification has shown greater activation in association with vocal auditory stimuli compared
to non-voice sounds. Also, these abnormalities in STG may particularly affect individuals without a familiar
[46]
background of dystonia .

Up to 12% of patients with LD report a familiar background. Genetic mutations suggest a weak
predisposition that contributes to mechanisms that cause a non-progressive abnormality in the control of the
[50]
laryngeal motor neuron for speech but not for vocal emotional expression . More than 20 different types
of dystonia, called DYT, can be distinguished genetically. Some of these associate with other neurological
[45]
[48]
signs . Some causative genes are highly expressed during early brain development . The most common
cause of primary generalized dystonia in childhood is DYT1 dystonia, caused by a 3 bp deletion (ΔGAG)
in the TOR1A gene that encodes the Torsin A protein. Symptoms usually occur before the age of 21 with
sustained involuntary muscle contractions caused by the position of a foot, leg or arm, with laryngeal
[51]
involvement in some cases . Genetic variation captured by the polygenic risk score and encompassing
[52]
genes related to these biological processes may be directly relevant to the pathogenesis causing LD .

DYT6 dystonia typically affects the cranial muscles and arms, with voice involvement as the predominant
characteristic. The causative gene is a protein associated with apoptosomes that contain the protein domain
correlated with Thanatos 1 (THAP1), which encodes a DNA-binding protein. THAP1 can generate both
generalized and isolated cases of dystonia. Identification of this mutation only appears in a few patients,
[53]
usually middle-aged women .

Polymorphisms may also be implicated in the higher or lower risk for developing LD. In the DYT1 gene,
polymorphisms have been identified as associated with adult-onset primarily focal dystonias, including LD,
[51]
and may increase or decrease the risk for developing dystonia . In cases of non-familiar dystonia in the
Icelandic population, a significant association was observed between dystonia and some markers comprising
[55]
[54]
the DYT1 gene . However, further results did not replicate the association . Also, a study conducted
[56]
by Sharma et al. on a large cohort of focal and segmental dystonia, including LD and cervical dystonia
patients, revealed a significant association between SNP rs3842225 and protection from the development of
focal or segmental dystonia.

A functional magnetic resonance image (fMRI) study compared a single carrier of GNAL mutations with
a larger group of isolated LD cases without known mutations. GNAL encodes the G-protein stimulating