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include MS2 on chromosome 10p15, MS3 on chromosome 5p13, MS4 on chromosome 1p36 and MS5,
[30]
influenced by the variation in the TNFRSF1A gene on chromosome 12p13 . Several genes can modify
the evolution of the disease. FN1 and CD24v/v are associated with an early-onset MS [31-33] . Besides this,
ITGA4, SPP1, SPP1, PSMG4, and NLRP5 relate to the disease severity, with SNPs having an allelic dosing
effect [31,34] . PSMG4 encodes a chaperone protein implicated in the assembly of the 26S proteasome (a primary
protein deletion pathway). The reduced activity of proteasome 26S has proved to cause neuronal death from
abnormal protein degradation. Proteasome 26S hydrolyzes the basic myelin protein to produce antigenic
[30]
peptides for presentation to T-cells . CACNA1H takes part in relapsing-remitting MS at clinical onset.
Polymorphisms in PD-1, NLRP5 and EIF2AK1 associate with disease progression [34,35] . MC1R relates to late-
[34]
onset clinical symptoms . Its protein encodes the melanocyte stimulating hormone receptor, and the
[31]
identified variant associates with the phenotype of rutilism .
Hypokinetic dysarthria
Alterations in the circuit that controls the basal ganglia (substantia nigra) cause hypokinetic dysarthria. The
patients who suffer this disease speak in a monotone voice, with a reduction in tonal volume, a tendency to
a speed up speech, inappropriate silences and palilalia. Patients show unexpressive facies, rigidity and body
[11]
tremor. Parkinson’s disease (PD) and other degenerative parkinsonims represent this disorder .
[36]
Parkinson’s disease: A relevant gene in Parkinson’s disease is SCNA, which encodes α-synuclein (aSyn) .
This protein plays a role in the brain, maintaining a supply of synaptic vesicles in the presynaptic terminals
[37]
by grouping synaptic vesicles . Transgenic mice that over-express human wild-type aSyn under a
broad neuronal promoter (Thy1-aSyn) present initial motor and non-progressive motor deficits, followed
by parkinsonism with dopamine loss. These motor deficits include early and progressive vocalization
disorders [38,39] . PINK1 is a gene involved on early-onset PD. Pink1-KO rats have mitochondrial abnormalities,
and proteinase K-resistant aSyn aggregates in different brain regions [40,41] . Additionally, rats exhibit
[39]
significant vocalization deficits dependent on age, intensity, bandwidth, and peak frequency .
Speech disturbances may be early markers for PD detection. A preliminary study of cognitive disorders in
the Chinese Han population revealed an absence of significant differences in neuropsychological tests in
[42]
language fluency between carriers of a known PD mutation (LRRK2 S1647T) and noncarriers . However,
a later report with more specific language criteria in Argentinian patients with asymptomatic mutations
(PARK2 and LRRK2) who performed executive, semantic, verb construction, and syntactic tasks, showed
alterations in a syntactic test with a minimal amount of working memory. These results suggest that these
[43]
mutations may play a role in language processing .

Hyperkinetic dysarthria
Hyperkinetic dysarthria relates to alterations in the basal ganglia pathway (caudate/putamen nucleus). It
[11]
generates tense speech, swaying voice volume, suddenly forced breathing and multiple voice interruptions .
Laryngeal dystonia (LD): Laryngeal dystonia is a form of focal dystonia characterized by intermittent spasms
in the vocal folds that selectively affect speech production. Its etiology is multifactorial and polygenic.
Metabolic, neurodegenerative, and environmental factors such as exposure to viruses or voice abuse can
[44]
induce LD in genetically predisposed patients . Dopaminergic, GABAergic, glutamatergic and cholinergic
[45]
neurotransmission is required in the pathogenesis of dystonia .
LD shows different clinical forms. In the most common adductor form, over-adduction of the vocal folds
leads to voice interruptions in the vowels and the quality of the tense voice. The abductive form is rarer, with
[46]
voice breakdowns in the consonants and whispered voice .
Although the genotype and phenotype characteristics of LD are different, functional connectivity
alterations in the sensory-motor and frontoparietal cortex correlates with polygenic risk and may represent