Open access peer-reviewed chapter
Abstract
Mitochondrial hearing loss (MHL) arises from mutations in mitochondrial DNA (mtDNA) or in nuclear genes coding for mitochondrial proteins, which impair inner ear function resulting in hearing loss. Diagnosis of MHL requires a comprehensive evaluation, including genetic tests, clinical assessments, and audiological examination. Treatment options for MHL are limited, with supportive measures to enhance communication and restore hearing function being the primary options. Ongoing research is investigating new therapies that target mitochondrial dysfunction and regenerative techniques to restore hearing function. It is crucial to understand the underlying mechanisms of MHL and develop effective interventions to mitigate its negative impact.
Keywords
- mitochondria
- hearing loss
- diagnosis
- treatment
- neurogenetics
1. Introduction
Mitochondria, subcellular organelles found within eukaryotic cells, form a flexible network and serve various functions in addition to their well-known role in cellular energy production. These organelles have evolved to acquire multiple cellular functions over time including provision of cellular energy through ATP generation, crucial involvement in metabolic pathways, and apotosis. Consequently, when mitochondria fail to function properly, it can negatively impact various aspects of cellular physiology and contribute to the development of different human diseases, including hearing loss.
The process of hearing relies on the conversion of sound pressure waves into neural signals by the inner hair cells of the cochlea. These signals are then transmitted to the auditory cortex through auditory neurons. Any disruption along this pathway can result in hearing loss, a complex condition influenced by multiple factors that can affect both individuals with mitochondrial disease and the general population.
Mitochondrial diseases are both genetically and phenotypically heterogeneous and can be caused by mutations in mitochondrial DNA (mtDNA) or the nuclear genes that encode mitochondrial proteins. Mitochondrial disease can involve potentially any organ at any age and involve either a single or multiple organs [1].
MHL is an important feature of many mitochondrial diseases, both in isolation (non-syndromic) and as a feature of systemic disease (syndromic). Some of the syndromes associated with mitochondrial hearing loss include Kearns-Sayre syndrome (KSS), Mitochondrial encephalopathy, lactic acidosis and stroke-like syndrome (MELAS), and maternally inherited diabetes and deafness (MIDD) syndrome. Each of these syndromes is associated with the loss of hearing along with multiple other systemic manifestations [2, 3, 4].
Mitochondrial disease is rare, affecting approximately 1 in 5000 individuals, but it contributes significantly to the overall burden of hearing loss [2, 5]. Mitochondrial dysfunction is estimated to contribute to around 5% of non-syndromic post-lingual hearing loss and approximately 1% of pre-lingual cases [3, 5]. Additionally, studies suggest that mitochondrial mutations may also contribute to age-related hearing loss [3].
Mitochondria play a vital role in producing cellular energy through oxidative phosphorylation. In the auditory system, the inner ear contains specialized sensory hair cells that convert sound vibrations into electrical signals for the brain to interpret. Any disruption in mitochondrial function can severely impact the energy supply and cellular homeostasis of these hair cells, leading to hearing loss. Additionally, mitochondrial dysfunction can affect functionality of the stria vascularis, which is responsible for endolymph production and ion composition maintenance [1, 5]. Moreover, the spiral ganglion neurons can also be impacted by mtDNA mutations that result in loss of signal transduction from the auditory nerve to the brain.
Mitochondrial hearing loss is primarily caused by mutations in the mitochondrial DNA, which can occur in various genes responsible for mitochondrial function [1, 5, 3, 6]. These mutations are usually inherited from the mother due to the maternal inheritance pattern of mitochondrial DNA [1, 4]. However, spontaneous mutations can also occur during mitochondrial DNA replication, leading to mitochondrial hearing loss [2, 3, 6].
Mitochondrial DNA mutations can result in decreased ATP production, leading to cellular dysfunction in the inner ear [1, 7]. ATP deficiency can impair the normal functioning of hair cells, which are responsible for transmitting sound signals to the brain. Additionally, the stria vascularis can be impacted due to lack of proper ion composition of the endolymph. Mitochondria play a crucial role in generating reactive oxygen species (ROS) within cells during oxidative phosphorylation. The presence of noise has been shown to elevate the production of mitochondrial ROS, surpassing the cellular antioxidants’ capacity and leading to oxidative stress. Consequently, cochlear hair cells may undergo apoptosis triggered by mitochondria, potentially resulting in their demise [1, 2, 5, 6, 8, 9].
2. Clinical presentation
Mitochondrial hearing loss presents with a diverse range of clinical manifestations, exhibiting considerable heterogeneity in terms of severity, age of onset, and progression of hearing impairment [1, 2, 4, 5, 6, 8]. The clinical features can vary among affected individuals and can include unilateral or bilateral hearing loss. The age at which hearing loss manifests can range from infancy to adulthood, and the progression of the condition can be gradual or sudden.
The degree of hearing impairment observed in individuals with mitochondrial hearing loss can vary widely, ranging from mild to profound [5, 8]. The specific frequencies of sound that are affected may also vary, resulting in different patterns of hearing loss. Some individuals may experience greater difficulty perceiving high-frequency sounds, while others may have impairments in the low-frequency range.
It is important to note that mitochondrial dysfunction can extend beyond the auditory system and affect other organ systems, leading to a wide array of associated symptoms. Neurological abnormalities, such as seizures, developmental delays, and cognitive impairments, may be observed in individuals with mitochondrial hearing loss [2, 5, 6, 8, 9, 10]. Additionally, myopathy, characterized by muscle weakness and fatigue, and visual impairment, including optic atrophy and retinitis pigmentosa, can be present in syndromic disease [2, 3, 5, 8].
There are various syndromic causes of mitochondrial hearing loss. One major cause is maternally inherited diabetes and deafness (MIDD), which is characterized by the development of both diabetes and hearing loss, typically in adulthood [4]. The severity of hearing loss can vary from mild to profound. Kearns-Sayre Syndrome is a rare mitochondrial disorder characterized by a triad of symptoms: progressive external ophthalmoplegia, heart block, and pigmentary retinopathy [3, 8, 9]. Hearing loss is a common feature of KSS, and it can be sensorineural, conductive, or mixed.
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) syndrome is a multisystem disorder caused by mitochondrial DNA mutations [8, 9]. While it primarily affects the brain, it can also lead to hearing loss, among other symptoms such as muscle weakness, impaired exercise tolerance, stroke-like episodes, encephalopathy, and high levels of lactic acid in the blood [3, 8, 9, 11].
There are several diseases inherited from mothers have been linked to mutations in mitochondrial DNA. Specifically, the mt.1555A>G mutation (see Figure 1) occurring in mtDNA impacts the gene responsible for rRNA, leading to a structural alteration in the human ribosome [12]. Consequently, this renders the ribosome vulnerable to binding with the widely used antibiotic, aminoglycosides. This particular mutation has been associated with non-syndromic hearing loss and is prevalent among Asian populations as one of the most frequently observed mitochondrial DNA mutations [11, 12].
Figure 1.
Primary mtDNA mutations linked to human disease. A selection of clinically relevant primary mtDNA mutations linked to mitochondrial disease with their associated phenotypes. LHON, Leber’s hereditary optic neuropathy; NARP, neurogenic weakness, ataxia and retinitis pigmentosa; KSS, Kearns-Sayre syndrome; CPEO, chronic progressive external ophthalmoplegia; MERRF, myoclonic epilepsy and ragged red fibres; MELAS, mitochondrial myopathy lactic acidosis and stroke like episodes; MDD, maternally inherited diabetes and deafness.
Moreover, the mt.3243A>G mutation (see Figure 1) is linked to patients with MELAS syndrome [13]. This variant is associated with early-onset hearing loss that typically occurs in early infancy with a gradual course. Due to the stroke-like episodes that occur in this syndrome, there are also cases of sudden onset hearing loss with this mitochondrial DNA variant [14].
Furthermore, the impact of mitochondrial hearing loss extends beyond the physical manifestations, affecting various aspects of an individual’s life, including communication, social interactions, and educational attainment. Difficulties in speech understanding, particularly in noisy environments, can lead to challenges in daily communication and academic performance [1, 3]. Consequently, individuals with mitochondrial hearing loss may benefit from speech therapy, educational accommodations, and support services to optimize their communication abilities and overall quality of life.
3. Diagnosis
Accurate diagnosis of mitochondrial hearing loss relies on a comprehensive evaluation that includes clinical assessment, genetic testing, and audiological examinations [1, 2]. A thorough patient history and physical examination can provide valuable insights into the clinical features and potential risk factors associated with mitochondrial dysfunction. Healthcare providers should inquire about a family history of hearing loss, other associated symptoms, and the presence of neurologic or visual abnormalities [1, 2, 15].
Genetic testing plays a crucial role in confirming the diagnosis of mitochondrial hearing loss. It involves analyzing the mitochondrial DNA (mtDNA) for specific mutations known to be associated with hearing loss. Molecular genetic techniques are utilized to identify the presence of pathogenic mutations in mtDNA [8, 15]. It is important to note that mutations in mtDNA can be heteroplasmic, meaning they are present in varying proportions within an individual’s cells. Therefore, genetic testing may require the analysis of multiple tissues, such as blood, saliva, or skin fibroblasts, to accurately assess the mutation load [5, 15].
Whole exome sequencing (WES) can be a valuable tool for investigating the genetic basis of sensorineural hearing loss (SNHL). WES allows for a comprehensive analysis of the protein-coding regions of the genome, including those genes coding for mitochondrial proteins. It enables the simultaneous screening of thousands of genes associated with various genetic disorders, including those known to be related to SNHL. This broad approach increases the likelihood of identifying the underlying genetic cause of SNHL in patients [13, 16]. WES can uncover novel genetic variants that may not have been previously associated with SNHL. This can lead to the identification of new genes or pathways involved in hearing loss, expanding our understanding of the condition and potentially leading to new therapeutic targets [13, 16]. Additionally, knowledge of the genetic cause of SNHL can have implications for personalized treatment and management strategies. It can help determine the prognosis, guide the selection of appropriate interventions, and inform decisions regarding hearing aids, cochlear implants, or other assistive devices [13, 16, 17].
Another approach that can be used to aid diagnosis is mitochondrial DNA sequencing. The mitochondrial genome is separate and contained within the mitochondria, therefore whole genome sequencing cannot provide any information about mt DNA. Mitochondrial DNA sequencing can provide valuable information regarding genetic coding of essential proteins that contribute the functionality of auditory structures [16].
Audiological testing is an integral component of the diagnostic workup for mitochondrial hearing loss. Pure-tone audiometry is performed to assess hearing thresholds across different frequencies, providing information about the type, severity, and configuration of hearing loss [10]. Speech audiometry evaluates an individual’s ability to understand speech and discriminate between different speech sounds. Otoacoustic emissions (OAEs) and auditory brainstem response (ABR) testing can help assess the function of the inner ear and the auditory nerve pathways (see Figure 2). These audiological examinations aid in confirming the presence of hearing loss, characterizing its nature and extent, and ruling out other potential causes of hearing impairment [10, 17].
Figure 2.
Audiological assessment of diagnosos of hearing loss. (A) Schematic representation of the auditory conduction pathway from the cochlea via neuronal auditory brain structures to the auditory cortex. (i) OAFs: A speaker generated tone is delivered to the ear by an indwelling ear probe which also measures the modulated product (in the case of DPOAEs) generated by the stimulated cochlear outer hair cells. Cochlea function is specifically measured (represented by blue diagrammatic brackets in Panel A). (ii) (a) Auditory brainstem response (ABR): position of skull electrodes and representation of elecrophysilogical response of auditory pathway (waves I–V marked). (ii) (b) PTA: Audioframs of the right and left ears showing pan-frequency hearing loss with raised thresholds (lower limit of normal hearing marked with horizontal blue line). Subject responds to different frequency tones presented by headphones. (ii) Both ABR and PTA measure response of the entire auditory pathway (represented by red diagrammatic bracketsin Panel A).
In cases where the clinical suspicion for mitochondrial hearing loss is high but genetic testing results are inconclusive or unavailable, other diagnostic modalities may be considered. Biochemical analyses, such as measuring the activity of respiratory chain complexes in muscle biopsies or assessing lactate and pyruvate levels in blood or cerebrospinal fluid, can provide indirect evidence of mitochondrial dysfunction [5, 7]. Neuroimaging techniques, including magnetic resonance imaging (MRI), can help identify structural abnormalities or functional changes in the brain or inner ear that may be associated with mitochondrial dysfunction [7].
Moreover, the diagnosis of mitochondrial hearing loss requires specialized expertise and a multidisciplinary approach. Audiologists, geneticists, otolaryngologists, and other healthcare professionals with experience in mitochondrial disorders play a crucial role in the accurate diagnosis and appropriate management of individuals with mitochondrial hearing loss.
4. Management
The management of mitochondrial hearing loss involves a multidisciplinary approach aimed at optimizing communication abilities and addressing the specific needs of affected individuals. While currently there is no cure for mitochondrial hearing loss, various strategies can be employed to improve functional outcomes and enhance quality of life.
As previously discussed, there are various syndromes that are associated with mitochondrial hearing loss. As a result, it is important to acknowledge the management required for the complex systemic manifestations associated with these syndromes. It’s important for individuals with such syndromes to receive regular medical follow-ups to monitor their condition, manage symptoms, and address any new developments. The management approach may vary depending on the specific needs and symptoms of each individual, so it’s essential to work closely with a healthcare team experienced in mitochondrial disorders [1, 8]. For example, symptomatic treatment is provided for other manifestations of MELAS syndrome, such as cardiac abnormalities, hearing loss, muscle weakness, and gastrointestinal issues [1, 3, 15]. Medications, therapies, and lifestyle modifications may be employed based on the specific symptoms and their severity. Additionally, in the case of KSS, it is essential to consider the ophthalmic symptoms including regular eye exams, corrective lenses, cardiologic interventions and close monitoring [1, 3, 8].
Audiological rehabilitation plays a central role in managing mitochondrial hearing loss. Hearing aids are commonly prescribed to individuals with residual hearing to amplify sound and enhance audibility. These devices can improve speech understanding and facilitate communication in daily activities. Regular audiological assessments and adjustments are important to ensure that hearing aids are appropriately fitted and calibrated to individual needs [8, 17].
In cases of very severe hearing loss, another therapy option is the use of cochlear implants. As another form of sensorineural hearing loss, mitochondrial hearing loss in theory should have the same efficacy in improving auditory symptoms. Some studies have cited improvement of hearing in patients with Kearns-Sayre and MNGIE syndromes [15]. A recent systematic review identified 9 of 11 studies showing favorable audiometric outcomes with CI in patients with MHL [17]. Karkos et al. conducted a 12-month review of MELAS patients with CI indicating positive results are preserved for at least 12 months [18]. However, larger studies with longer follow up are needed to determine whether hearing results are preserved long term.
In addition to hearing aids, assistive listening devices (ALDs) can further enhance communication abilities for individuals with mitochondrial hearing loss. ALDs include devices such as personal FM systems, induction loop systems, and Bluetooth-enabled devices. These technologies improve sound transmission and reduce background noise, particularly in challenging listening environments, such as classrooms, public venues, or workplaces [6, 8, 9, 17]. Audiologists can provide guidance on selecting and using ALDs effectively.
Communication strategies and education are vital for individuals with mitochondrial hearing loss and their families. Techniques such as lip-reading, sign language, and speech therapy can supplement auditory input and facilitate effective communication. Speech therapy can help improve speech production, language skills, and overall communication abilities. Additionally, educating family members, friends, and educators about mitochondrial hearing loss and its impact can foster understanding and support in various social settings [1, 17].
Living with hearing loss can have a significant psychological and emotional impact on individuals. Psychosocial support and counseling services can provide a supportive environment for individuals with mitochondrial hearing loss and their families. These services can help individuals cope with the challenges associated with hearing loss, manage stress, and promote overall mental well-being. Support groups and online communities can also offer a platform for sharing experiences, seeking advice, and finding a sense of belonging [8, 6].
Genetic counseling is an important aspect of the management of mitochondrial hearing loss. Genetic counselors can provide information about the inheritance patterns, recurrence risks, and available genetic testing options. They can guide individuals and families in making informed decisions regarding family planning and reproductive options. Genetic counseling also facilitates the identification of at-risk family members who may benefit from early detection and intervention [6, 7, 8, 17, 19].
Finally, regular monitoring and consistent follow-up are crucial for individuals with mitochondrial hearing loss. Audiological evaluations should be conducted at regular intervals to assess changes in hearing thresholds, adjust hearing aids or assistive devices, and provide ongoing support. Additionally, individuals with mitochondrial hearing loss may benefit from periodic assessments by otolaryngologists, geneticists, and other specialists to monitor overall health and address any associated systemic manifestations of mitochondrial dysfunction [2, 5, 6, 8].
5. Future directions of mitochondrial disease treatment
While significant progress has been made in understanding mitochondrial hearing loss, further research is needed to advance our knowledge and develop more effective strategies for diagnosis, treatment, and prevention of the condition. Several areas of investigation show promise for future directions in the field.
Genetic discoveries and personalized medicine: continued exploration of the genetic basis of mitochondrial hearing loss will contribute to the identification of novel causative genes and mutations. Whole-exome sequencing and genome-wide association studies hold potential for unraveling the complex genetic architecture underlying the condition. Such discoveries will facilitate the development of personalized medicine approaches, enabling tailored interventions based on an individual’s specific genetic profile [6].
Targeting mitochondrial dysfunction: further understanding of the molecular mechanisms involved in mitochondrial dysfunction in hearing loss is essential for the development of targeted therapies. Emerging evidence suggests that various therapeutic agents, such as antioxidants, mitochondrial biogenesis enhancers, and modulators of mitochondrial dynamics, may hold promise for preserving or improving mitochondrial function in the auditory system [2]. Preclinical studies and clinical trials investigating the efficacy and safety of these interventions are warranted.
Regenerative medicine: regenerative approaches aimed at restoring damaged or lost auditory structures offer a potential avenue for treating mitochondrial hearing loss. Stem cell-based therapies, including the use of pluripotent stem cells and induced pluripotent stem cells, hold promise for generating functional hair cells and auditory neurons in vitro and in vivo [19]. The integration of tissue engineering and gene editing technologies further enhances the prospects of regenerating damaged auditory tissues, paving the way for potential curative interventions.
Novel drug therapies: the identification of small molecules and pharmacological agents that can specifically target the underlying molecular pathways involved in mitochondrial dysfunction may offer new avenues for therapeutic intervention. High-throughput screening techniques can aid in the discovery of potential drug candidates that enhance mitochondrial function, reduce oxidative stress, and mitigate cellular damage in the auditory system [2]. An example of mitochondrial disease enzyme replacement therapy is the use of fusion propionyl co-A carboxylase (PCC) for the fatal metabolic disorder propionic acidemia [20].
Non-invasive monitoring techniques: the development of non-invasive methods for monitoring mitochondrial function and assessing disease progression in individuals with mitochondrial hearing loss is an area of ongoing research. Imaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), hold potential for evaluating mitochondrial metabolism and bioenergetics in vivo [7]. These non-invasive monitoring tools can provide valuable insights into the efficacy of therapeutic interventions and aid in the assessment of treatment outcomes.
Preventive strategies: identifying individuals at risk for mitochondrial hearing loss and implementing preventive measures are crucial for minimizing the impact of the condition. Genetic counseling and carrier screening programs can help identify individuals who are at risk of passing on mitochondrial mutations to their offspring. Early detection and intervention, such as newborn hearing screening programs and regular audiological assessments, may enable timely intervention and support for affected individuals, leading to improved outcomes.
6. Conclusion
Mitochondrial hearing loss is an umbrella terms that describes a range of conditions affecting mitochondrial function in pertinent structures of the auditory pathway. These conditions can be caused by mutations to mitochondrial DNA, as well as nuclear genes that cause dysfunction of inner ear hair cells, the stria vascularis, and even the auditory neurons as well. Although its pathogenesis remains poorly understood, current research points toward factors like ATP deficiency and oxidative damage being crucial factors. Diagnosing mitochondrial hearing loss requires comprehensive evaluation including clinical assessment, genetic testing and audiological tests - unfortunately there is currently no cure available and treatment focuses mainly on improving communication abilities and supporting quality-of-life improvements.
Additional research initiatives are required to increase our understanding of the pathogenesis of mitochondrial hearing loss and develop effective treatments. The development of mitochondrial-targeted therapies, such as antioxidants and gene therapy, holds promise for the treatment of mitochondrial hearing loss [2]. Additionally, research into stem cell-based regenerative therapies for the repair and regeneration of hair cells in the inner ear is being explored as a potential treatment strategy [5]. These treatment modalities will be tailored to the unique biophysical profile of each patient and provides the potential for a greater and more specific clinical response.
In conclusion, mitochondrial hearing loss is a complex condition that requires further research and understanding. While there are currently limited treatment options, ongoing research holds promise for the development of effective therapies to mitigate the impact of mitochondrial hearing loss and improve the lives of affected individuals. Continued efforts in research, diagnosis, and treatment of mitochondrial hearing loss are essential to improve upon our knowledge base and provide better management strategies for individuals with this condition.
References
- 1.
Fancello V, Fancello G, Palma S, Monzani D, Genovese E, Bianchini C, et al. The Role of Primary Mitochondrial Disorders in Hearing Impairment: An Overview. Medicina (Kaunas). 19 Mar 2023; 59 (3):608. doi: 10.3390/medicina59030608. PMID: 36984609; PMCID: PMC10058207 - 2.
Kang J, Wang C, Lu Y. Mitochondrial-targeted therapies for hearing loss: A mini-review. Frontiers in Cellular Neuroscience. 2021; 15 :674768 - 3.
Liu Y, Xue J, Zhao D, Chen L, Yuan Y, Wang Z. Audiological evaluation in Chinese patients with mitochondrial encephalomyopathies. Chinese Medical Journal. 2014; 127 (12):2304-2309 - 4.
Smith RJ, Bale JF Jr, White KR. Sensorineural hearing loss in children. Lancet. 2005; 365 (9462):879-890. DOI: 10.1016/S0140-6736(05)71047-3 - 5.
Fernandez-Vizarra E, Enriquez JA, Perez-Martos A, Montoya J, Fernandez-Silva P. Tissue-specific differences in mitochondrial activity and biogenesis. Mitochondrion. 2011; 11 (1):207-213. DOI: 10.1016/j.mito.2010.09.011 - 6.
Lieberman AP, Shakkottai VG, Albin RL, Anderson KE, Ard MC, Ashizawa T, et al. Patient-centered outcome measures as decision-making tools for the management of neurodegenerative diseases: A multi-stakeholder perspective. Journal of Personalized Medicine. 2020; 10 (3):103 - 7.
Muller BA, Kamerer AM, Epperson CN. Positron emission tomography (PET) neuroimaging biomarkers for preclinical detection of Alzheimer’s disease. Neurobiology of Disease. 2020; 134 :104699 - 8.
Kullar PJ, Quail J, Lindsey P, et al. Both mitochondrial DNA and mitonuclear gene mutations cause hearing loss through cochlear dysfunction. Brain. 2016; 139 (Pt 6):e33. DOI: 10.1093/brain/aww051 - 9.
Li JN, Han DY, Ji F, et al. Successful cochlear implantation in a patient with MNGIE syndrome. Acta Oto-Laryngologica. 2011; 131 (9):1012-1016. DOI: 10.3109/00016489.2011.579623 - 10.
Doosti A, Lotfi Y, Moosavi A, Bakhshi E, Talasaz AH. Distortion product otoacoustic emission (DPOAE) as an appropriate tool in assessment of otoprotective effects of antioxidants in noise-induced hearing loss (NIHL). Indian Journal of Otolaryngology Head and Neck Surgery. 2014; 66 (3):325-329. DOI: 10.1007/s12070-014-0721-7 - 11.
Li P, Li S, Wang L, et al. Mitochondrial dysfunction in hearing loss: Oxidative stress, autophagy and NLRP3 inflammasome. Frontiers in Cell and Development Biology. 2023; 11 :1119773. DOI: 10.3389/fcell.2023.1119773 - 12.
Ou YH, Chen AW, Fan JY, et al. Aminoglycoside-associated nonsyndromic deafness and speech disorder in mitochondrial A1555G mutation in a family: A case report. Medicine (Baltimore). 2018; 97 (42):e12878. DOI: 10.1097/MD.0000000000012878 - 13.
Sun C, Wu S, Chen R, et al. Whole exome sequencing is an alternative method in the diagnosis of mitochondrial DNA diseases. Molecular Genetics & Genomic Medicine. 2022; 10 (6):e1943. DOI: 10.1002/mgg3.1943 - 14.
Uimonen S, Moilanen JS, Sorri M, Hassinen IE, Majamaa K. Hearing impairment in patients with 3243A-->G mtDNA mutation: Phenotype and rate of progression. Human Genetics. 2001; 108 (4):284-289. DOI: 10.1007/s004390100475 - 15.
Scarpelli M, Zappini F, Filosto M, Russignan A, Tonin P, Tomelleri G. Mitochondrial sensorineural hearing loss: A retrospective study and a description of cochlear implantation in a MELAS patient. Genetic Research International. 2012; 2012 :287432. DOI: 10.1155/2012/287432 - 16.
Ye F, Samuels DC, Clark T, Guo Y. High-throughput sequencing in mitochondrial DNA research. Mitochondrion. 2014; 17 :157-163. DOI: 10.1016/j.mito.2014.05.004 - 17.
Zia N, Nikookam Y, Muzaffar J, Kullar P, Monksfield P, Bance M. Cochlear implantation outcomes in patients with mitochondrial hearing loss: A systematic review and narrative synthesis. Journal of International Advanced Otology. 2021; 17 (1):72-80. DOI: 10.5152/iao.2020.9226 - 18.
Karkos P, Anari S, Johnson I. Cochlear implantation in patients with MELAS syndrome. European Archives of Oto-Rhino-Laryngology. 2004; 262 :322-324 - 19.
Roccio M, Edge AS, Perny M. Regenerative medicine for the treatment of hearing loss. Clinical Pharmacology & Therapeutics. 2020; 107 (3):572-579 - 20.
Darvish-Damavandi M, Ho HK, Kang TS. Towards the development of an enzyme replacement therapy for the metabolic disorder propionic acidemia. Molecular Genetics in Metabolism Report. 2016; 8 :51-60. DOI: 10.1016/j.ymgmr.2016.06.009