*2.2.4 Mitochondrial-linked NSHL*

Despite the crucial role of mitochondria producing the energy for the cell, there are mtDNA mutations which lead to non-syndromic hearing impairment. The carriers exhibited sensorineural hearing loss with variable severity and onset [45]. These mutations have been reported in the mitochondrial genes encoding for 12S rRNA and tRNA genes [46, 47].

### **2.3 Age-related hearing loss**

The auditory system exhibits senescent changes with the past time which could trigger to acquire sensorineural hearing loss. The most of acquired-hearing loss are characterized by a bilateral inner ear degeneration determined by genetic factors superimposed with environmental stress [48], excluding injuries and severe infections. Noise, drugs, aging and/or other systemic conditions (i.e., diabetes or hypertension [49, 50]) are numerous variables that can contribute to the final outcome of the disease [51, 52]. It is habitual among the causes of life related hearing loss that the severity progress beginning as mild loss and worsening over time.

The noise-induced hearing loss (NIHL) is one of the most common work-related diseases caused by the extreme exposure to noise. Recurrent exposure to noise causes physical damage to hair cells in the cochlea. Moreover, genetic predisposition and systemic conditions also contribute to the prevalence and severity of the phenotype making it difficult to distinguish the cause [53]. In the same line, there is a correlation between hazardous daily noise exposure and the prevalence of hearing loss among youth population [54, 55].

Ototoxic agents like certain drugs or heavy metals could contribute to the development of hearing impairment. Drugs such as cisplatin and aminoglycoside trigger hair cells apoptosis by enhancing the production of oxygen reactivity spices and has up to 50% reported incidence of irreversible hearing loss [56, 57].

The age-related hearing loss (ARHL) or presbycusis is caused by progressive atrophy of the inner ear during aging [58, 59]. The onset and prevalence of the disease vary widely as is multifactorial and many components (genetic and environmental) could play a role. Moreover, the heritability of AHRL had been stablished around 50% [60–64] and through genome-wide association studies and animal models, several age-related hearing loss genes had been identified [65–67]. The estimated prevalence of ARHL is one-third of adults above 65 years old and it doubles by each decade of life span [68, 69].

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**Table 3.**

*ARHL-related genes.*

*Genetics and Acquired Hearing Loss*

*DOI: http://dx.doi.org/10.5772/intechopen.86664*

ARHL had been well-documented during the years because of its high prevalence in the population. Characterized cochlea manly by atrophy in the basal turns of the cochlea and is manifested by abrupt high-tone hearing loss [70, 71]. ARHL is commonly classified as sensory, neural and metabolic. Sensory ARHL stems from the progressive degeneration of organ of Corti [72], neural ARHL is considered when there is 50% or more of cochlear neurons loss [73] and metabolic ARHL is

**Gene Gene name Phenotype Study Ref.** *APOE* Apolipoprotein E undefined GWAS [79] *ARHI* Age-related Hearing Loss SN, M GWAS [80–82]

*COX 3* cytochrome c oxidase subunit 3 M Model [87, 88]

*GRHL2* Grainyhead-like 2 SN GWAS [91] *GRM7* Metabotropic glutamate receptor type 7 SN GWAS [92]

*IQGAP2* IQ motif containing GTPase activating protein 2 undefined GWAS [96, 97] *ITGA8* Integrin, alpha 8 SN Model [98, 99]

*NAT2* N-acetyltransferase 2 M GWAS [105–107] *P2X* Ligand-gated ion channel purinergic receptor 2 undefined GWAS [108]

*PTPRD* tyrosine phosphatase, receptor type D undefined GWAS [111] *SLC26A4* Solute carrier family 26 member 4 SN Model [112]

*SPATC1L* Spermatogenesis and centriole associated 1 undefined GWAS [114] *SPNS2* Spinster homolog 2 M Model [115, 116]

*TNF* Tumor necrosis factor M GWAS [119] *UCP2* Uncoupling protein 2 SN GWAS [120, 121] *Inner ear phenotype classification: sensorineural (SN), metabolic (M) and both of them (SN and M). Study type:* 

*PCDH15* Protocadherin-related 15 SN Model,

*SLC7A8* Solute carrier family 7 member 8 SN, M Model,

*SLC9A3R1* Regulator 1 of SLC9 transporter SN Model,

*TBL1Y* Transducin beta-like 1 Y-linked SN Model,

*THRB* Thyroid hormone receptor 1 SN, M Model,

*genome-wide association study and study-case (GWAS) and in vitro or in vivo model (Model).*

GWAS

GWAS

GWAS

SN Model [100]

SN, M Model,

SN GWAS [101, 102]

GWAS

GWAS

GWAS

GWAS

GWAS

GWAS

[83–86]

[89, 90]

[93–95]

[103, 104]

[109, 110]

[67]

[113]

[117]

[118]

*CDH23* Cadherin-related 23 SN, M Model,

*EDN1* Endothelin-1 M Model,

*GST* Glutathione S-transferase M Model,

*KCNMA1* Potassium large conductance calcium-activated channel, subfamily M, alpha member 1

*KCNQ1* Potassium voltage-gated channel, KQT-like subfamily, member 1

*KCNQ4* Potassium voltage-gated channel, KQT-like subfamily, member 4

#### *Genetics and Acquired Hearing Loss DOI: http://dx.doi.org/10.5772/intechopen.86664*

*Geriatric Medicine and Gerontology*

*2.2.3 X-linked NSHL*

[43]. Other genes are listed in **Table 2**.

females hearing loss is post-lingual and less severe.

*2.2.4 Mitochondrial-linked NSHL*

rRNA and tRNA genes [46, 47].

loss among youth population [54, 55].

doubles by each decade of life span [68, 69].

**2.3 Age-related hearing loss**

inner hair cell of the cochlea. Mutation in *MYO6* causes DFNB37, a form of nonsyndromic deafness characterized by prelingual severe to profound hearing loss

This form of hearing loss is very rare and only few genes are associated with non-syndromic hearing loss (**Table 2**). This form of hearing loss is characterized by progressive, conductive and sensorineural hearing loss. Mutations in *POU3F4* gene which cause DFNX2, account for 50% of the cases [44]. *POU3F4* gene encode for POU domain class 3 transcription factor 4 protein, which regulates the proliferation of neural cells in middle and inner ear early during development. Because this form of hearing loss is X-linked, the severity of hearing loss differs from male to female. In males, hearing loss is prelingual and range from severe to profound while in

Despite the crucial role of mitochondria producing the energy for the cell, there

The auditory system exhibits senescent changes with the past time which could trigger to acquire sensorineural hearing loss. The most of acquired-hearing loss are characterized by a bilateral inner ear degeneration determined by genetic factors superimposed with environmental stress [48], excluding injuries and severe infections. Noise, drugs, aging and/or other systemic conditions (i.e., diabetes or hypertension [49, 50]) are numerous variables that can contribute to the final outcome of the disease [51, 52]. It is habitual among the causes of life related hearing loss that

The noise-induced hearing loss (NIHL) is one of the most common work-related

Ototoxic agents like certain drugs or heavy metals could contribute to the development of hearing impairment. Drugs such as cisplatin and aminoglycoside trigger hair cells apoptosis by enhancing the production of oxygen reactivity spices and has

The age-related hearing loss (ARHL) or presbycusis is caused by progressive atrophy of the inner ear during aging [58, 59]. The onset and prevalence of the disease vary widely as is multifactorial and many components (genetic and environmental) could play a role. Moreover, the heritability of AHRL had been stablished around 50% [60–64] and through genome-wide association studies and animal models, several age-related hearing loss genes had been identified [65–67]. The estimated prevalence of ARHL is one-third of adults above 65 years old and it

diseases caused by the extreme exposure to noise. Recurrent exposure to noise causes physical damage to hair cells in the cochlea. Moreover, genetic predisposition and systemic conditions also contribute to the prevalence and severity of the phenotype making it difficult to distinguish the cause [53]. In the same line, there is a correlation between hazardous daily noise exposure and the prevalence of hearing

the severity progress beginning as mild loss and worsening over time.

up to 50% reported incidence of irreversible hearing loss [56, 57].

are mtDNA mutations which lead to non-syndromic hearing impairment. The carriers exhibited sensorineural hearing loss with variable severity and onset [45]. These mutations have been reported in the mitochondrial genes encoding for 12S

**122**

ARHL had been well-documented during the years because of its high prevalence in the population. Characterized cochlea manly by atrophy in the basal turns of the cochlea and is manifested by abrupt high-tone hearing loss [70, 71]. ARHL is commonly classified as sensory, neural and metabolic. Sensory ARHL stems from the progressive degeneration of organ of Corti [72], neural ARHL is considered when there is 50% or more of cochlear neurons loss [73] and metabolic ARHL is


*Inner ear phenotype classification: sensorineural (SN), metabolic (M) and both of them (SN and M). Study type: genome-wide association study and study-case (GWAS) and in vitro or in vivo model (Model).*

**Table 3.** *ARHL-related genes.* caused by the atrophy of the stria vascularis resulting in a decrease in endolymphatic potential [74]. Also, there is a mixed type where the progressive degeneration of sensory cells is observed along loss of cochlear neurons [75–77]. Moreover, still controversial if the loss of neurons is a secondary consequence or a primary cause.

The task to distinct between genetic and environmental factors in acquired hearing loss is very challenging. In this regard, to progress the understanding of the mechanisms that lead to the damage, physiopathology of age-related hearing loss had been assessed by *in vitro* (cell lines) and *in vivo* (rodents and zebrafish) models [70]. The studies provided evidences of specific inner damage such as inflammation, oxidative stress, reduced cochlear blood flow, disrupted ion hemostasis and death of sensory and neuronal cells [78]. **Table 3** summarizes all current knowledge on ARHL-related genetic factors.

#### *2.3.1 Consequences of suffering ARHL*

Age-related hearing loss affects communication and information reception reducing the quality of live and psychosocial well-being (e.g., anxiety or depression) of elder population. Limitation in communication has an impact on social and personal relationships triggering to loss of autonomy and dependency [122, 123]. Even though the World Health Organization estimates that by 2025 approximately 500 million will suffer from age-related hearing loss; there is a lack of awareness by health care professionals as well as no educational programs on how patients could overcome obstacles caused by hearing loss.

Few studies have investigated the psychological factor and how individuals develop their lives in the presence of hearing loss. The studies reveal that maladaptive behavior (e.g., escape, avoiding social interaction and/or pretending to understand) has a negative effect on well-being of elder patients comparing to adaptive strategies (e.g., training verbal skills or self-awareness) [124, 125]. Additionally, there is a significant increase of hearing aids use by cases who attend audiology clinic with a relative than others attending alone [126]. Therefore, elder population with acquired hearing loss requires social support from family and health care professionals. Educational programs on how to use hearing aids and communication strategies as well as counseling for follow-up and feedback are needed in order to increase adherence to treatment and improve life quality [127].

#### **3. Hearing loss treatments**

Hearing loss is not a curable disease however science made some considerable progress. Current therapies based on cochlear implants (a device that provides direct electrical stimulation to the auditory nerve in the inner ear) and hearing aids (are non-surgically placed in the ear canal) which help patients to recover partly hearing.

Hearing aids could be a stigma in the society as are negatively perceived as well as expensive making that only one out of five people who could benefit from a hearing aid actually wears it (WHO, [128]). Therefore, the major barriers to improve hearing in elder population include perception that hearing loss is a normal part of aging or is not amenable to treatment.

Based on the animal research studies, several clinical trials are working to investigate the effects of a variety of drugs to prevent hearing loss including antioxidants, ROS scavengers, alpha lipoic acid, N-acetylcysteine or anti-inflammatory agents [129–134].

New generation treatments based on microRNA, short interfering RNA as well as tissue regeneration using stem cells are promising tools [135, 136]. Due to

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**Author details**

**Acknowledgements**

JSREP07-03-3-006.

**Conflict of interest**

There is no conflict of interest.

Moza Al-Kowari\* and Meritxell Espino-Guarch

provided the original work is properly cited.

\*Address all correspondence to: malkowari@sidra.org

Translational Medicine, Sidra Medicine Hospital, Doha, Qatar

*Genetics and Acquired Hearing Loss*

**4. Conclusion**

*DOI: http://dx.doi.org/10.5772/intechopen.86664*

problems which limit stem cells application in humans.

the in-depth study of stem cell and its therapeutic potential, stem cell technology opened new approaches for hair cell and auditory nerve regeneration [137, 138]. By using two strategies of endogenous stem cell activation and exogenous stem cell transplantation, exciting results on restoring hearing function are showed. Even though the use of stem cells to repair cochlear injury is relatively new, they appear to be a very promising possibility for the treatment of hearing loss induced by noise, aging or ototoxic drugs. These three causes comprise a major part of the burden of hearing loss, so if this approach were successful could have a large public health effect of hearing impairment. Further research should be supported to solve the

Of the senses that humans use to interact with their environment, hearing is considered as one of the dominant after vision. The loss of hearing can occur through genetic mutations, through environmental factors or through a combination of both. ARHL is an increasingly important public health problem which reduces life's quality, isolation, dependence and frustration. Besides basic research and more effective therapies for the optimal treatment, management of the condition is still a pending task. Social support by the family and health care professionals is critical to the life quality of the older adults with hearing loss. The quality of care and well-being could be improved by active education and counseling to

Meritxell Espino-Guarch received funding from Qatar Foundation Grant ID:

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

provide appropriate support to facilitate everyday communication.

#### *Genetics and Acquired Hearing Loss DOI: http://dx.doi.org/10.5772/intechopen.86664*

the in-depth study of stem cell and its therapeutic potential, stem cell technology opened new approaches for hair cell and auditory nerve regeneration [137, 138]. By using two strategies of endogenous stem cell activation and exogenous stem cell transplantation, exciting results on restoring hearing function are showed. Even though the use of stem cells to repair cochlear injury is relatively new, they appear to be a very promising possibility for the treatment of hearing loss induced by noise, aging or ototoxic drugs. These three causes comprise a major part of the burden of hearing loss, so if this approach were successful could have a large public health effect of hearing impairment. Further research should be supported to solve the problems which limit stem cells application in humans.
