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Guerra et al. J Transl Genet Genom 2019;3:9. I https://doi.org/10.20517/jtgg.2018.03 Page 13 of 31

subunit α, Golf, required in the dopaminergic, adenosine and corticotropin signaling pathways. The effects
of striatal dopaminergic abnormalities may be reflected in aberrant frontoparietal cortical activity, leading
to further alterations in the integrative preparatory and sensory-motor stages of GNAL mutation carriers
[50]
compared to other LD patients .
TUBB4 is mostly expressed in brain development during the fetal period. The main regions of expression
are the amygdala, hypothalamus, thalamus and prefrontal cortex. TUBB4 mutations implicate abnormal
[57]
microtubule function, generating whispered voice DYT4 dystonia and other phenotypes of LD .

[58]
Some reports of isolated cases exist, such as the one proposed by Peng et al. that described a patient with
myoclonus, affecting the hands and arms, harboring the most common mutation in mitochondrial DNA
causing myoclonic epilepsy with ragged red fibers syndrome (MERRF) [A->G substitution in the 8344
nucleotide tRNA (Lys) gene] that correlated with LD. Other genes involved in dystonia affecting laryngeal
[48]
function are summarized in Table 2 .

Tourette syndrome: The internal mitochondrial membrane protein 2L (IMMP2L) gene (7q22-q31) is an
interesting candidate for Tourette syndrome (TS). IMMP2L encodes subunit 2 of the internal membrane
peptidase, a mitochondrial protease involved in cleaving the space-sorting signals of mitochondrial
membrane proteins. Defective IMMP2L can lead to altered mitochondrial function. The breakpoint in chr7
[59]
was assigned to 7q22-q31, between D7S515 and D7S552. This gene is also involved in autism and SLD .
Interestingly, a familial balanced reciprocal translocation t(7;15)(q35;q26.1) has been identified in one patient,
[60]
interrupting the CNTNAP2 gene in phenotypically normal individuals .
The PNKD gene, widely expressed in the brain, regulates myofibrillogenesis and has been associated with
TS and speech disorders. One report identified a G89R nonsense mutation in a child affected by intermittent
[61]
ataxia, diarrhea, exercise intolerance, and speech articulation problems .
Huntington’s disease (HD): Huntington’s disease is an inherited neurodegenerative disorder that causes
motor, cognitive and neuropsychiatric disorders. It follows a pattern of autosomal dominant inheritance,
initiating symptoms in the middle-aged, although it may also appear earlier or later. An unstable expansion
of a CAG sequence within the Huntingtin gene (HTT) causes this disorder, located on chromosome 4. The
protein encoded by the HTT gene plays a role in the normal development of the brain and neurons. The
expanded CAG sequence leads to the production of an abnormal protein that causes brain cell dysfunction
and ultimately neuronal cell death primarily in the basal ganglia, but also the thalamus and cerebral
[62]
cortex .
FOXP1, one of the most studied genes involved in a range of speech and language disorders and will be
described in more detail later, implicates transcriptional HD dysregulation, interacting with mHtt. The
combined analysis of microarrays and ChIP-seq in a striatal cell line that over-expresses this transcription
factor identified a set of target genes, including those associated with inflammatory and immunological
disorders. According to in vitro results, viral transduction of Foxp1 mainly led to the suppression of genes
related to the immune system in the adult striatum [63,64] .

Essential tremor: Essential laryngeal tremor has phenotypic characteristics of hyperkinetic dysarthria. It
occurs in greater proportion in women from the seventh decade of life onwards, and there may be a family
[63]
component . It may associate with other parts of the body and, as with essential tremor, improves with
alcohol intake [65,66] . Genes correlating systemic clinical symptoms with dysarthria include DRD3 (3q13.31),
[67]
FUS (16p11), TENM4 (11q14), and two loci: 2p25-p22 and 6p23 .