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

Laryngeal Dystonia [44,48] Hyperk TOR1A Torsin 1A 9q34
HPCA Hippocalcin 1p35
TUBB4 Tubulin beta 4A 19p13
THAP1 Thao domain-containing protein 1 8p11
DYT7 Dystonia 7 18p
DYT13 Dystonia 13 1p36
CIZ1 CDKN1A-interacting zinc finger protein 1 9q34
ANO3 Anoctamin 3 11p14
GNAL Guanine nucleotide-binding protein, alpha activity polypeptide, 18p11
olfactory type
Tourette Syndrome [59-61] Hyperk IMMP2L Inner mitocondrial membranepeptidase subunit 2 7q31.1
PNKD Myofibrillogenesis regulator 1 2q35
CNTNAP2 Contactin Associated Protein 2 7q35-q36
Huntington Disease [62-64] Hyperk HTT Huntingtin 9p16.3
FOXP1 Forkhead box 1 3p13
Essential Tremor [67] Hyperk DRD3 Dopamine receptor D3 3q13.31
FUS Fused in sarcoma 16p11-2
TENM4 Teneurin transmembrane protein 4 11q14.4
ETM2 Essential tremor 2 hereditary 22p5-p22
ETM3 Essential tremor 3 hereditary 6p23

Hyperk: hyperkinetic; Hypok: hypokinetic

early speech therapy intervention improves the patient’s ability to communicate . Concerning Prader Willi
[18]
syndrome, anatomical alterations in the mouth and larynx, and the underlying brain dysfunction, contribute
to alterations in speech and language. Oral motor function, tone level and resonance are altered, with a
[19]
characteristic flaccid pattern . A summary of the main genes involved in both conditions are included in
Table 2.

Ataxic dysarthria
Ataxic dysarthria relates to disorders that alter the cerebellar pathway. It is characterized by interruptions
[12]
in the articulation of speech, irregularity in the intensity of the tone and marked vocal tension . This
group includes hereditary ataxia. So far, reports have identified over 30 genotypes. Hereditary ataxia may
be progressive, such as spinocerebellar ataxia (SCA) and Friedreich’s ataxia (FRDA), or sporadic, such as
episodic ataxia (EA). SPAX also refers to those ataxias that often have a prominent component of spasticity,
thus changing the patient’s dysarthric characteristics .
[20]

Trinucleotide expansion diseases relate to some hereditary ataxias, with mutations where repetitions of
trinucleotides in certain genes or introns exceed the normal stable threshold that differs by gene, by unstable
microsatellites that occur throughout all genomic sequences. This is the case of SCA1-7 and SCA17, where
the repeated codon is CAG, which is the coding region for glutamine (Q), resulting in a polyglutamine
(polyQ) tract. FRDA, SCA8, and SCA12 are other examples, but they do not code for glutamine and
[21]
categorize as non-PolyQ diseases .

For those patients in whom the genetic screening tests for SCA1, 2, 3, 6, 7, and FRDA are negative (The most
frequent ataxias), the study of small pathogenic intragenic variants for PRKCG, TTBK2, SETX, SPTBN2,
SACS, MRE11, KCNC3 and DARS2 might be useful, as these are more prevalent secondary groups. It is
especially helpful in patients with progressive onset disorders in childhood or adolescence and/or with a
[20]
family history . Several studies assessed the phenotypic particularities of disorders that generate ataxic
dysarthria [22-24] . Clinical characterization of the voice helps to discriminate between different types of ataxia
[24]
and guides vocal therapy .
Friedreich ataxia (FRDA): Friedreich ataxia (FRDA gene, locus 9q21.11) is the most common progressive
hereditary ataxia, with an autosomal recessive inheritance pattern. It produces degeneration, among other
structures, of white matter cerebellar areas and afferent pathways of different brainstem nuclei. Speech