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binding protein 43 (TDP-43) were distributed asymmetrically with a higher concentration in the left
hemisphere language cortices [111] . A retrospective report suggested that the mutations in the three genes most
commonly associated with FTD [GRN, open-reading chromosome 9-frame 72 (C9ORF72); the microtubule-
associated tau protein (MAPT)] were not correlated with PPA [112] . However, these results must be taken with
caution as the resulting sample had an over-representation of PPA with speech disease, which often predicts
the pathology of AD.

Prion protein gene (PRNP) modulates PPA disease, leading to specific regional hypoperfusion according to
different molecular pathways [106,111] . Methionine/valine polymorphism of codon 129 may be over-represented
in this disease compared to controls, bvFTD, and motor neuron disease, with the possibility that codon 129
polymorphisms could influence the selective susceptibility to the language network to neurodegeneration,
even when the condition is unrelated to prion disorders. However, subsequent studies have failed to replicate
the results [111] .

Developmental language disorder
Developmental language disorder (DLD) is a disorder diagnosed in childhood with a delay or disturbance
in language development. An early sign is a delay in language acquisition, and then they take time to put
words together to form sentences. Spoken language can be immature. In many children with DLD, receptive
language is also affected [113] .

CNTNAP2
This gene has been highlighted previously in several speech disorders. However, its link to language deficits
[5]
is also relevant. CNTNAP2 expression is regulated by the transcription factor FOXP2 . It encodes a protein,
neurexin, which plays its role in shaping potassium channels in developing neurons (nodes of Ranvier)
and plays an important function in facilitating axonal-glial interactions and cell growth [114] . It locates
on chromosome 7q, and it shows a wide range of alterations in other neurological disorders, including
neuropsychiatric conditions, such as schizophrenia, ADHD or bipolar disorder. Homozygous mutations lead
to CASPR2 deficiency disorder (CDD), a rare and severe syndrome with epilepsy, language impairment and
intellectual disability [115] . CNTNAP2 was the first gene to be associated with genetically complex forms of
DLD and involved in early language acquisition [116] . However, its association with DLD needs replication, as
the specific causal variants and underlying mechanisms by which it may contribute to language alteration
have not been elucidated. CNTNAP2 deletions in children with apraxia of speech unrelated to DLD implies
the great phenotypic heterogeneity of this gene [117] . However, a study conducted by Toma et al. [115] that
exhaustively examined the role of CNTNAP2 in susceptibility to psychiatric disorders demonstrated that
the distribution of CNVs from previous reports was no different from the controls in the genomic variant
database. These gene-based association tests found no common variants in psychiatric phenotypes such
as autism and schizophrenia. Cntnap2 alters neurons by increasing the number of active synaptic sites
and facilitating network activity. In mice, Cntnap2 knockdown had the most pronounced effects in the
[11]
hippocampus . Initially, outbred KO Cntnap2 mice had no macroscopic anatomical or neurological
abnormalities, but when these mice were crossed with the C57BL/6J strain, subsequent generations exhibited
neurologic abnormalities. Their abnormalities are similar to patients with cortical dysplasia and focal
epilepsy syndrome [118] . Cntnap2 expression in robust nucleus of the arcopallium (RA) is important for the
proper production of learned vocalizations in songbirds. In adult zebra finches, the Cntnap2 transcription is
enriched in cortical nuclei in the song production system. Adult females have moderate transcription levels
in RA and the lateral magnocellular nucleus of the anterior neostriatum (LMAN), with a uniform Cntnap2
distribution throughout striatopallidum. Interestingly, in young females, Cntnap2 is enriched in RA to the
same degree as for males and decreases to the level of the surrounding RA with age. The reduction in gene
expression coincides with the sensorimotor period of song learning in male, a time when the songbird begins to
[119]
practice singing. The percentage of cells that express the protein in female RA decreases at this time .