Journal of

Clinical Medicine

Review
Auditory Neuropathy Spectrum Disorders: From
Diagnosis to Treatment: Literature Review and
Case Reports
Romolo Daniele De Siati *, Flora Rosenzweig, Guillaume Gersdorff, Anaïs Gregoire ,
Philippe Rombaux and Naïma Deggouj
Department of Oto-Rhino-Laryngology and Head and Neck Surgery, Cliniques Universitaires Saint-Luc,
Université Catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium;
[email protected] (F.R.); [email protected] (G.G.);
[email protected] (A.G.); [email protected] (P.R.); [email protected] (N.D.)
* Correspondence: [email protected]; Tel.: +32–2–764–3253




Received: 28 February 2020; Accepted: 1 April 2020; Published: 10 April 2020


Abstract: Auditory neuropathy spectrum disorder (ANSD) refers to a range of hearing impairments
characterized by deteriorated speech perception, despite relatively preserved pure-tone detection
thresholds. Affected individuals usually present with abnormal auditory brainstem responses (ABRs),
but normal otoacoustic emissions (OAEs). These electrophysiological characteristics have led to the
hypothesis that ANSD may be caused by various dysfunctions at the cochlear inner hair cell (IHC)
and spiral ganglion neuron (SGN) levels, while the activity of outer hair cells (OHCs) is preserved,
resulting in discrepancies between pure-tone and speech comprehension thresholds. The exact
prevalence of ANSD remains unknown; clinical findings show a large variability among subjects
with hearing impairment ranging from mild to profound hearing loss. A wide range of prenatal
and postnatal etiologies have been proposed. The study of genetics and of the implicated sites of
lesion correlated with clinical findings have also led to a better understanding of the molecular
mechanisms underlying the various forms of ANSD, and may guide clinicians in better screening,
assessment and treatment of ANSD patients. Besides OAEs and ABRs, audiological assessment
includes stapedial reflex measurements, supraliminal psychoacoustic tests, electrocochleography
(ECochG), auditory steady-state responses (ASSRs) and cortical auditory evoked potentials (CAEPs).
Hearing aids are indicated in the treatment of ANSD with mild to moderate hearing loss, whereas
cochlear implantation is the first choice of treatment in case of profound hearing loss, especially in case
of IHC presynaptic disorders, or in case of poor auditory outcomes with conventional hearing aids.

Keywords: ANSD; auditory neuropathy spectrum disorder; auditory synaptopathy; hidden hearing
loss; genetics; cochlear implant

1. Introduction
Auditory neuropathy spectrum disorder (ANSD) refers to a range of hearing dysfunctions
characterized by compromised signal processing along the auditory nerve or by deficient transmission
of this signal to the auditory nerve by the presynaptic inner hair cells (IHCs). Its diagnosis is in part
based on evidence of altered neural processing such abnormal auditory brainstem responses (ABRs),
with a reduced or absent wave V, despite evidence of preserved outer hair cells (OHCs) responses,
such as otoacoustic emissions (OAEs) and/or cochlear microphonic (CM). [1–4]. The affected subjects
present important speech discrimination difficulties, particularly in background noise, that are out
of proportion compared to their pure-tone detection thresholds [5]. Impairments in the coding of

J. Clin. Med. 2020, 9, 1074; doi:10.3390/jcm9041074 www.mdpi.com/journal/jcm

J. Clin. Med. 2020, 9, 1074 2 of 29

temporal features of acoustic stimuli seem to be the main underlying mechanism responsible for these
difficulties. These temporal encoding deficiencies may also account for the frequently limited benefits
of acoustic hearing aids [6].
ANSD was first described by A. Starr and colleagues in 1996 in ten patients presenting with
evidence of normal OHCs function but impaired neural transmission in the peripheral auditory
system [7]. The term of “auditory neuropathy” was then proposed to initially describe hereditary
sensorimotor neuropathies [8]. Later, several authors suggested the more comprehensive term of
“auditory neuropathy/auditory dys-synchrony” (AN/AD) or “auditory neuropathies” to underline the
loss of temporal coding due to an abnormal synchronization at different levels of the peripheral neural
pathways [7,9–11].
More recently, studies of genetics and molecular biology on animal models have shown a wide
range of localization of the sites of impaired functioning, ranging from the area of inner hair cells (IHCs)
synapses to the auditory neural fibers [3,12,13]. As a consequence, the term “auditory synaptopathy”
has been used to distinguish ANSD due to a dysfunction of the IHCs ribbon synapses from the
“auditory neuropathy” due to neural fibers dysfunction [13–17].
The clinical profiles of ANSD are largely heterogeneous, according to the variety of possible
etiologies. ANSD may results from both syndromic and non-syndromic genetic anomalies,
environmental causes, as well as structural anomalies. Among these, cochlear nerve hypoplasia
or aplasia, variable lesion sites and congenital-neonatal or lately acquired dysfunctions have
been described.
Special attention must also be paid to the concept of hidden deafness or hidden hearing loss
(HHL), which corresponds to a hearing impairment in which speech discrimination in challenging
auditory conditions (noisy and/or reverberant environment, less or rapidly articulated speech) is
abnormally impaired as patients also display normal pure-tone and speech audiometry thresholds in
quiet. HHL is associated with well-synchronized ABRs. This auditory processing disorder may be
caused by a specific synaptopathy-neuropathy, limited to auditory fibers responding to high intensity
sounds with preservation of fibers responding to low intensity sounds [18,19]. This special kind of
auditory synaptopathy-neuropathy will be discussed separately because it does not correspond to
the currently accepted definition of ANSD where ABRs waves and speech audiometry in quiet are
severely deteriorated [20].
This article provides a literature review on ANSD management with a special focus on its etiologies,
audiological assessment and rehabilitation. In order to describe the variability of physiopathological
and clinical features of ANSD, we used a conceptual approach based on the site of the lesion, from the
more distal to the proximal site of the sensorineural pathway. Moreover, few own case reports have
been described.

2. Prevalence of ANSD
The prevalence of ANSD remains uncertain, and studies report prevalences ranging from less
than 1% of hearing impaired patients up to 10% [1,12,14,21–23]. This variability reflects the wide
heterogeneity of clinical profiles of ANSD patients across studies [12].
Newborns discharged from a neonatal intensive care unit (NICU), about 10%–15% of newborns,
have a higher prevalence of sensorineural hearing loss (SNHL), and particularly of ANSD [24,25].
The prevalence of SNHL in the NICU discharged population is around 1/50 compared to 1/1000 in
normal-term newborn children [26]. Similarly, their ANSD prevalence is also higher compared to
normal-term infants, as ANSD accounts for up to 30% of all SNHL in NICU discharged children [27–30].

3. Etiologies
A run-through of the normal process of cochlear transduction of an auditory signal into an
electrical impulse transmitted along the auditory nerve is essential for understanding the underlying
mechanisms implicated in ANSD as well as the heterogeneity of its clinical manifestations.
J. Clin. Med. 2020, 9, 1074 3 of 29

The IHCs are mechanosensory cells that convert mechanical deflections of the hair bundle at
their apex into a molecular signal suitable for triggering the electrical firing of neuronal fibers. The
deflection of the hair bundle of IHCs after the vibration of the tectorial membrane generates a cation
influx in the IHCs body. The consequent depolarizing potential allows a calcium influx through a
single or two voltage-gated calcium channels. The coupling of Ca2+ channels at the presynaptic site of
the ribbon synapse triggers a high rate synaptic vesicles fusion, leading to the release of glutamate
through the synaptic cleft. The presynaptic signal is transferred in a graded manner in order to respect
the rate code of the spike of the fibers of the spiral ganglion neurons (SGNs).
High levels of neurotransmitter liberation in the synapse enable the generation of an excitatory
postsynaptic potential that leads to the activation of a particular type of Ca2+ sensitive receptors, the
AMPA receptors, leading in turn to the generation of the neural spike at the level of SGNs fibers, that
travel along the axon to the SGN cell body. The effective encoding of auditory stimuli relies on rapid
and precise spike initiation in auditory nerve fibers. Preservation of the graded presynaptic signal,
of the high-rate kinetics of synaptic release and of the rapid restoration of postsynaptic membrane
activation, are primordial for the precise encoding of temporal features of auditory stimuli. Effective
frequency phase-locking of firing in the SGNs fibers to the frequency of the auditory signal is also an
essential element for pitch encoding of pure-tone sounds up to 1 kHz in frequency [31,32]. Furthermore,
high densities of voltage-gated ion channels, such as sodium (Nav 1.1, Nav 1.6), potassium (Kv 1.1, Kv 2.2,
Kv 3.1b, Kv 7.2 and Kv 7.3), ankyrin-G and Caspr channels on the auditory fibers, also contribute to the
accurate coupling of neural firing to the synaptic input [33]. From the synapse with IHCs, peripheral
axons of SGNs proceed in the modiolus of the cochlea and continue as proximal axons towards the
midbrain. SGNs are bipolar neurons, and frequency-tuned to a specific inner hair cell in order to
maintain the tonotopy during auditory stimuli processing [34]. The precise temporal coding is possible
due to a graded-fashion ionic influx along the axons, in particular of Na+ [35].
A dysfunction at any level of this complex transduction machinery may disturb the coding of
acoustic features, particularly of temporal cues. The potential sites of lesion and dysfunctions are
various: IHCs, synapses between IHCs and type I auditory fibers, neural fibers, synapses between the
fibers and their targets in the cochlear nucleus [36–43].
A wide range of etiologies has been reported, including prenatal factors (genetics, which
are discussed below; cochlear nerve malformation; fetal infection like measles, mumps or
cytomegalovirus—CMV; dysmaturity); postnatal factors (genetics with delayed onset of symptoms,
prematurity, perinatal disorders such as severe icterus and kernicterus, hypoxia with mechanical
ventilation, septicemia, ototoxic drugs, meningitis) [12,42,43].
In Figure 1, we report the audiological assessment of a 5-year-old child with ANSD caused by
neonatal hypoxia. Hearing aids were fitted at the age of 8 months. At first, his babbling developed
correctly. At the age of 2, he emitted low- and high-pitched phonemes, whereas an improvement of
language skills in the lexical and morphosyntactic fields was observed at the age of 3. At that time,
discrimination of environmental noise (such as animal sounds) remained poor. Besides speech therapy
support, teaching aids have been implemented. Hearing performances are still fluctuating and remain
poor in noise environment.
Moreover, studies reporting temporal bone analysis of premature and full-term infants admitted
to the NICU showed specific loss of IHCs in respectively 27% and 3% of the cases [27]. Magnetic
resonance imaging of auditory pathways have also shown structural abnormalities in up to half of
healthy newborn with ANSD [22]. Children fed on a poor thiamine diet leading to a thiamine-deficiency
may present with ANSD, which can be successfully treated with supplementary thiamine [44]. In this
case, individuals may show the peculiar pattern of preserved OAEs and abnormal ABRs, but absent
OAEs have also been reported in some cases, suggestive of a simultaneous impairment of OHCs.
J. Clin. Med. 2020, 9, 1074 4 of 29
J. Clin. Med. 2020, 9, x 4 of 31

Figure 1. Audiological assessment in a 5-year-old child with auditory neuropathy spectrum disorder
(ANSD) caused by neonatalneonatal hypoxia. Poor unaided pure-tone perception (a, gray line) was restored
with hearing
with hearing aids
aids ((a),
((a), black
black line). Panel (b) displays auditory brainstem responses (ABRs) evoked by
presented in rarefaction
clicks presented rarefaction (R) and condensation
condensation (C) polarities and the subtraction and summation
of RR and
andCC(R(R− C − and
C and
R +R C,+ C, respectively),
respectively), showing showing detectable
detectable cochlear
cochlear microphonic
microphonic (CM) and (CM) and
absence
absence
of wavesofV. waves V. Electrocochleography
Electrocochleography (ECochG)(ECochG) recorded
recorded throughthrough a transtympanic
a transtympanic electrode
electrode on
on the
the promontory
promontory wallwall
usingusing
10001000 Hz tone
Hz tone burstburst presented
presented in alternated
in alternated R andR and C polarities
C polarities at a rate
at a rate of
of 14.3
14.3 s (c) shows a large summating potential (SP). Auditory steady-state responses (ASSRs)
s (c) shows a large summating potential (SP). Auditory steady-state responses (ASSRs) thresholds (d) thresholds
(d)
are are present
present in the
in the leftleft
(X) (X) more
more thanthan in the
in the right
right (O)(O)
ear.ear.

Most deficits
Moreover, caused
studies by lesions
reporting of otherbone
temporal cochlear components,
analysis suchand
of premature as tectorial
full-termmembrane, OHCs,
infants admitted
IHCs,
to the supporting
NICU showed cellsspecific
or strialoss
vascularis
of IHCsimpairments, have
in respectively 27%not
andbeen
3% associated
of the caseswith ANSD-like
[27]. Magnetic
expression
resonance imaging of auditory pathways have also shown structural abnormalities in up to degree
because they impact not only IHCs but also OHCs functioning and respect a certain half of
of neuralnewborn
healthy synchronization.
with ANSD [22]. Children fed on a poor thiamine diet leading to a thiamine-
deficiency may present with ANSD, which can be successfully treated with supplementary thiamine
3.1. Genetic Etiologies
[44]. In this case, individuals may show the peculiar pattern of preserved OAEs and abnormal ABRs,
Various
but absent potential
OAEs have genetic
also beencauses of ANSD
reported have
in some been
cases, reported of
suggestive [12,13]. A genetic impairment
a simultaneous mutation may of
concern
OHCs. the synapses, the neural fibers or both sites. The distinction between these various lesion sites
is essential when studying
Most deficits caused by genetic causes
lesions of ANSD,
of other sincecomponents,
cochlear their impact such
on hearing outcomes
as tectorial differs,
membrane,
and
OHCs,may also supporting
IHCs, explain variability
cells or in cochlear
stria implantation
vascularis (CI) outcomes.
impairments, By directly
have not been stimulating
associated with ANSD- the
cochlear neural fibers,
like expression becauseCIthey
allows the bypassing
impact of disorders
not only IHCs but alsoinvolving IHCs synapses
OHCs functioning [13]. In acase
and respect of a
certain
degree of neural synchronization.

3.1. Genetic Etiologies

J. Clin. Med. 2020, 9, 1074 5 of 29

more central postsynaptic lesion involving the SGNs or more ascendant axons, the bypass implemented
by the CI may be insufficient, yielding lower hearing performances.

3.1.1. Presynaptic Synaptopathies

The first identified genetic cause of ANSD has been a mutation of the OTOF gene encoding
for Otoferlin, a protein of the Ferlin family involved in the mechanism of presynaptic membrane
fusion [45]. Otoferlin plays the important role of calcium sensor at the IHCs presynaptic site, as it
binds calcium and phospholipids at the final step of exocytosis of glutamatergic vesicles at the ribbon
synapse [37,46–51].
Mutations of OTOF are responsible for a form of nonsyndromic autosomal recessive sensorineural
deafness, DFNB9, defined by a severe to profound congenital or prelingual hearing impairment
but preserve vestibular functions [52–54]. Patients typically display normal OAEs but abnormal
ABRs [45]. However, OTOF mutations may produce heterogeneous clinical profiles with variable
speech discrimination scores and electrophysiological findings.
Some mutations in OTOF are responsible for a type of hearing loss sensitive to temperature [53,55].
When febrile, patients show a severe to profound hearing loss, while at normal body temperature
they present normal hearing or a mild hearing impairment affecting speech recognition, particularly
in background noise [56–58]. Most the OTOF subjects demonstrate good hearing outcomes with
CI [59,60].
According to the Deafness Variation Database, by the end of the year 2019, 7894 identified variants
of OTOF mutations have been reported, 113 of which accounted for being pathogenic, 17 were likely to
be pathogenic and 6298 remained of unknown pathogeny [61]. OTOF mutations were found in 2.4% of
individuals with hearing loss [62]. Virally mediated gene therapy has been put forward as a promising
prospect in restoring hearing in knock out mice with impaired OTOF [63].
Other gene mutations involving presynaptic proteins may potentially cause ANSD.
CACNA1D gene also plays an important role at the IHCs presynaptic sites [64]. It codes for a
subunit of Cav 1.3, a Ca2+ channel that works as the trigger for the glutamate release at the synaptic
site [65]. Since these channels are widely distributed across different compartments such as in OHCs,
IHCs, cardiomyocytes, neuroendocrine cells and neurons, this mutation may produce a syndrome
called “sinoatrial node dysfunction and deafness” (SANDD syndrome) in mice and in humans [64,66].
Severe to profound hearing loss is a common finding in these patients. These ion channels seem to also
play a role in calcium-mediated oxidative stress leading to age-related hearing loss in male mice [67]
and in inner ear differentiation [68].
CABP2 is another presynaptic protein that interacts with voltage-gated Cav channels for the
regulation of Ca2+ influx at the presynaptic site [69,70], leading to the vesicular release of synaptic
glutamate. Schrauwen et al. reported an autosomal-recessive nonsyndromic deafness in a family
presenting a mutation in the CABP2 gene at the DFNB93 locus, with a flat or cookie-bite moderate to
severe prelingual hearing impairment and with Marfanoid features [71].
SLC17A8 gene codes for the vesicular glutamate transporter type 3 (VGluT3), a protein responsible
for the glutamate uptake at the IHCs synapse [72,73].
In humans, an early report of a 12q22-q24 deletion associated with congenital deafness [74] was
later identified as an autosomal dominant nonsyndromic deafness at the DFNA25 locus associated
with mutations of SLC17A8 [75,76]. Affected individuals show a progressive sensorineural hearing
loss at high frequencies.
In animal models, mutations in SCL17A8 have been held responsible for a disruption of the
synaptic glutamate exocytosis form of ANSD, leading to a lack of excitatory synaptic transmission to
terminal dendrites synapses. Seizures may be associated with hearing loss, as an expression of central
nervous system damage [72].
However, good hearing outcomes have been observed after cochlear implantation in individuals
with SLC17A8 mutations, reinforcing the belief of a dysfunction at the synaptic site [77].
J. Clin. Med. 2020, 9, 1074 6 of 29

Virally mediated gene therapy has been shown to be a promising prospect in restoring hearing in
knock out mice with impaired VgluT3 function [78].

3.1.2. Postsynaptic Synaptopathies

The optic atrophy 1 gene (OPA1) codes for a mitochondrial protein [79,80] that plays an important
role in mitochondrial stability and energy output shaping [81,82].
Mutations in OPA1 result in progressive loss of visual acuity or in legal blindness. Visual
impairment may occur as an isolated clinical finding in the nonsyndromic dominant optic atrophy
(DOA) form or in the syndromic dominant optic atrophy (DOA+) form associated with hearing
impairment [83–86].
DOA+ occurs as a simultaneous onset of progressive visual impairment due to optic atrophy and
of an auditory postsynaptic hearing impairment, due to the degeneration of the terminal axons of
SGNs. Accordingly, OAEs and the receptor responses are preserved, but ABRs are abnormal [86].
Pure-tone audiometry shows moderate to severe hearing loss with high variability of the involved
frequencies among individuals within the same family. Individuals with DOA+ display in 60%
of cases a syndromic association of hearing impairment, sensorimotor neuropathy, myopathy and
ataxia [85–87].
ANSD may potentially be observed as an effect of other gene mutations involving
postsynaptic proteins.
ROR1 gene codes for a protein localized at the plasma membrane, the receptor tyrosine kinase-like
orphan receptor 1. ROR1 plays an important role in the NF-κB pathway for neural outgrowth. Mutated
variants of the gene in animal models have been correlated with deficiency of SGN axons and a lack of
innervation of the sensory hair cell synapses.
This mutation has been identified in two children from a consanguineous Turkish family presenting
profound SNHL, whose OAEs were preserved. Therefore, these combined animal and human findings
are suggestive of an auditory postsynaptic synaptopathy [88].
The ATP1A3 gene codes for the α3-subunit of the transmembrane Na/K-ATPase pump, implicated
in the regulation of intra- and extra-cellular ion levels [89].
Individuals with mutated variants of the ATP1A3 gene present a syndromic phenotype including
cerebellar ataxia, areflexia, pes cavus, optic atrophy and SNHL, summarized in the acronym CAPOS
syndrome [90]. In the ten families where CAPOS syndrome has been described to date, only the
specific heterozygous mutation c.2452G > A in exon 4 has been consistently reported [91–98].
Typically, affected individuals present slowly progressive ANSD and optic atrophy, but recurrent
acute exacerbation of the impairment from infancy has also been described. Moreover, hearing and
visual impairments may be associated with extensive acute neurological deterioration accompanied by
ataxia, areflexia, hypotonia, lethargy and ophthalmoplegia, with a possible partial post-crisis recovery.
It has been hypothesized that stressful events, such a febrile illness, may trigger the onset of such acute
episodes [95].
Pure-tone audiograms display various degrees of sensorineural hearing loss from moderate to
severe, along with poor speech discrimination. Distortion product Otoacoustic Emissions (DPOAEs)
responses are preserved, whereas ABRs are absent or abnormal. In accordance with the postsynaptic
role of ATP1A3 encoded protein, CAPOS syndrome is listed among the auditory synaptopathies with a
postsynaptic site of the lesion [99]. Overall good CI outcomes were reported [95] (Figure 2. For full
medical history of this case, see reference 95).
 J. Clin. Med. 2020, 9, 1074 7 of 29
J. Clin. Med. 2020, 9, x 7 of 31

Figure 2. Audiological assessment in 8-year-old patient with CAPOS syndrome. CAPOS is an acronym
for Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss. Unaided
pure tonal thresholds in both ears are shown in (a). The tonal hearing thresholds remain poor in
the right ear aided by an acoustical hearing aid ((b), gray line) but are clearly improved in the left
left ear by cochlear implant ((b), black line). Speech perception was poor in unaided condition ((c),
ear by cochlear implant ((b), black line). Speech perception was poor in unaided condition ((c), 10%
10% gray dot at 60dB), it was partially improved by acoustical hearing aids ((c), gray line) but became
gray dot at 60dB), it was partially improved by acoustical hearing aids ((c), gray line) but became
significantly better with cochlear implant ((c), black line). abnormal auditory brainstem responses
significantly better with cochlear implant ((c), black line). abnormal auditory brainstem responses
(ABRs) (d) show the responses evoked by clicks presented in rarefaction (R) and condensation (C)
phase and(d)
(ABRs) theshow the responses
subtraction of R and evoked by highlighting
C (R − C), clicks presented in rarefaction
the cochlear (R) and
microphonic (CM)condensation
and the (C)
phase and the subtraction of R and C (R − C), highlighting the cochlear microphonic (CM)
lack of waves V in the summation (R + C). Auditory steady-state responses (ASSRs) thresholds (e) are and the
lack ofinwaves
present the leftV(X)
in more
the summation
than in the(R + C).
right (O)Auditory
ear. steady-state responses (ASSRs) thresholds (e) are
present in the left (X) more than in the right (O) ear.
J. Clin. Med. 2020, 9, 1074 8 of 29

DIAPH3 gene codes for the diaphanous homolog 3 (DIAPH3), whose function at the synaptic
and neural sites remains unclear [100,101]. Clinical and electrophysiological findings along with
the good results obtained after cochlear implantation suggest a nonsyndromic autosomal dominant
auditory neuropathy 1 (AUNA1) via a synaptic lesion, listing DIAPH3 mutations as a postsynaptic
neuropathy [102,103].

3.1.3. Auditory Neuropathy

Auditory neuropathy is frequently associated with lesion of other peripheral neurons, leading to
syndromic phenotypes [13].
Charcot–Marie–Tooth disease (CMT) is one of the most prevalent inherited sensori-motor
neuropathies (HSMN), affecting approximately one in 2500 people in the United States [104]. Clinical
findings include a progressive motor and sensory neuropathy, with a variability in inheritance,
severity and neural damage localization, along with a SNHL with disproportionately poor speech
perception compared to the loss expected from the cochlear impairment [105]. For this reason, CMT
was included in the early description of auditory neuropathy [8]. Among several genes potentially
involved in CMT, mutations in the MPZ gene and the PMP22 gene have been correlated to the ANSD
phenotype. Histological temporal bone analysis of CMT patients demonstrated pronounced SGNs
fiber demyelination, whereas hair cells morphology was normal [106–108].
Speech perception scores of 54% after cochlear implantation in one subject with CMT suggest
poor results in this case of auditory neuropathy [83].
Friedreich ataxia is an HSMN which is thought to be caused by similar damage at the SGNs level,
resulting in auditory neuropathy [109].
The deafness–dystonia peptide-1/translocase of mitochondrial inner membrane 8A
(DDP1/TIMM8A) is a protein involved in the transfer of metabolites into the mitochondrial inner
membrane from the cytoplasm. A mutation of TIMM8A gene is responsible for an X-linked
recessive progressive neurodegenerative syndrome associated with auditory neuropathy, named
deafness–dystonia–optic neuropathy (DDON or Mohr–Tranebjaerg syndrome) [110].
Affected individuals also present dystonia and ataxia occurring in adolescence, progressive optic
atrophy starting in the third decade, and dementia after the age of 40, reflecting their progressive
degeneration of neurons [111,112].
AIFM1 codes for a flavin adenine of the mitochondrial intermembrane space, the
apoptosis-inducing factor mitochondria-associated-1, expressed in inner and outer hair cells and in
SGNs. This protein has a role in oxidative phosphorylation and in the apoptosis pathway [113,114].
Mutations of the AIFM1 gene are responsible for an X-linked auditory neuropathy associated
with a progressive neuromuscular degeneration and cognitive decline, known as Cowchock syndrome.
Clinical findings include numbness, unsteadiness and areflexia. In some patients with variants of the
AIFM1 gene, a delayed onset of cochlear nerve hypoplasia has been reported [115].
The mitochondrial asparaginyl-tRNA synthetase (NARS2) mutation has also been associated with
auditory neuropathy and Leigh syndrome, an early-onset progressive neurodegenerative disorders
characterized by symmetric, bilateral lesions in the basal ganglia, thalamus and brainstem.
Variants of NARS2 due to homozygous missense mutation cause mitochondrial respiratory
chain deficiency, leading to auditory neuropathy due to a cellular damage notably of the SGNs
(DFNB94) [116].

3.1.4. Synaptopathy and Neuropathy

Pejvakin, encoded by the DFNB59 gene, is expressed in hair cells and SGNs, where it acts as
a sensor and activates the autophagy mechanism to initiate the pexophagy or the degradation by
peroxisomes, in case of oxidative stress such as noise-induced damage [117–119].
The initial description of DFNB59 mutation-related deafness reported an ANSD phenotype
with pathological ABRs and preserved OAEs. However, following reports showed a lack of both
J. Clin. Med. 2020, 9, 1074 9 of 29

J. Clin. Med. 2020, 9, x 9 of 31

OAEs and ABRs in human and knock-in mice, due to a primary or secondary damage of the sensory
viral transduction
compartment andintomice withvulnerability
a higher a deficiency to of noise-induced
pejvakin has been demonstrated
damage to completely
[118,120–124]. restore
Interestingly, the
the disrupted peroxisomes proliferation triggered by pejvakin mutations, preventing
viral transduction in mice with a deficiency of pejvakin has been demonstrated to completely restore the damage
from oxidativeperoxisomes
the disrupted stress [117]. proliferation triggered by pejvakin mutations, preventing the damage from
Otherstress
oxidative proteins expressed in the auditory pathway may potentially lead to ANSD.
[117].
The transmembrane
Other proteins expressed serine
in protease
the auditory3 (TMPRSS3)
pathway may is apotentially
protein broadly
lead to expressed
ANSD. across the
human The transmembrane serine protease 3 (TMPRSS3) is a protein broadly expressed acrossinthe
peripheral hearing pathways [125,126], notably in type II SGNs, and is involved hair cells
human
and spiral ganglion
peripheral cells survival
hearing pathways in animal
[125,126], models
notably [126–128].
in type II SGNs,Mutations in TMPRSS3
and is involved geneand
in hair cells account
spiral
for autosomal recessive SNHL with both a postlingual onset (DFNB8) or with the congenital
ganglion cells survival in animal models [126–128]. Mutations in TMPRSS3 gene account for autosomal onset of
arecessive
severe SNHL
to profound hearing loss (DFNB10) with normal CM and smaller
with both a postlingual onset (DFNB8) or with the congenital onset of a severe toauditory nerve
neurophonic response, suggestivewith
profound hearing loss (DFNB10) of an auditory
normal neuropathy
CM and [129,130].nerve
smaller auditory However, variableresponse,
neurophonic speech
perception outcomes are reported after cochlear implantation in individuals
suggestive of an auditory neuropathy [129,130]. However, variable speech perception outcomes are with TMPRSS3
mutations. Depending
reported after cochlearon the degrees in
implantation of individuals
multisite lesions
with in various subjects,
TMPRSS3 mutations. auditory resultson
Depending vary
the
from good to poor [42,131–133].
degrees of multisite lesions in various subjects, auditory results vary from good to poor [42,131–133].

4.4.Psychoacoustic
PsychoacousticTests
Tests
Psychophysical
Psychophysicalevaluation
evaluationofofANSD
ANSDconsists
consistsof
ofadapted
adaptedbehavioral
behavioralpure-tone
pure-toneaudiometry
audiometryandand
speech
speechdiscrimination
discriminationininquiet and
quiet andnoise; moreover,
noise; supraliminal
moreover, testing
supraliminal suchsuch
testing as gap
as detection and
gap detection
sound localization,
and sound tonetone
localization, decay andand
decay frequency
frequencydiscrimination
discriminationshould
shouldcomplete
completethethe audiological
audiological
assessment.
assessment. Investigation should include the evaluation of language skills, global cognitive
should include the evaluation of language skills, global cognitive and motorand
motor development
development in children,
in children, as wellasaswell as attentional
attentional load
load and and psychological
psychological profilesprofiles in adults.
in adults.

4.1.Tonal
4.1. Tonaland
andSpeech
Speech Audiometry
Audiometry Thresholds
Thresholds
Evaluation of
Evaluation of hearing
hearing impairment
impairment in in ANSD
ANSD patients
patients with
with pure
pure tone
tone audiometry
audiometry maymay show
show
impairmentsranging
impairments rangingfrom
from normal
normal totoprofound
profound hearing
hearing loss
loss with
with no
nospecific
specific pattern.
pattern. Indeed,
Indeed,hearing
hearing
lossprofiles
loss profilesappear
appeartoto be
be variable:
variable: from
fromflat
flatto
tomore
moremarked
markedthresholds
thresholdsononlow
lowor
or high
high frequencies
frequencies
(Figure 33a).
(Figure (a)).

Distributionofofpure-tone
Figure3.3.Distribution
Figure pure-toneaudiometry
audiometrythreshold
threshold(a)(a)and
and(when
(whenpossible)
possible)speech
speechaudiometry
audiometry
threshold for disyllabic words (b) in 14 patients aged between 5 and 48 years withneuropathy
threshold for disyllabic words (b) in 14 patients aged between 5 and 48 years with auditory auditory
spectrum disorder
neuropathy (ANSD).
spectrum Etiologies
disorder (ANSD). of ANSD varyof
Etiologies among
ANSD patients. The figure
vary among is intended
patients. to show
The figure is
the large to
intended variability
show theinlarge
hearing ability in
variability among patients
hearing abilitywith ANSD.
among patients with ANSD.

ANSD isis bilateral

ANSD bilateral in
in about
about 75%
75% of
of cases
cases and
and unilateral
unilateral in
in 25%
25% [134].
[134]. The
The hearing
hearing thresholds
thresholds
frequently fluctuate and could reach variations of over 40 dB. Hearing fatigue may be
frequently fluctuate and could reach variations of over 40 dB. Hearing fatigue may be presentpresent for high
for
intensities and/or long-duration tonal stimuli and may impede the threshold investigation.
high intensities and/or long-duration tonal stimuli and may impede the threshold investigation. Fluctuations
are more frequent
Fluctuations in children
are more frequentthan in adults.than
in children Someinchildren may show
adults. Some a spontaneous
children may showimprovement
a spontaneous in
improvement in hearing reactions, more frequently in the first year after diagnosis [134], therefore
special attention should be paid to tonal threshold evaluation in infants with ANSD caused by
J. Clin. Med. 2020, 9, 1074 10 of 29

hearing reactions, more frequently in the first year after diagnosis [134], therefore special attention
should be paid to tonal threshold evaluation in infants with ANSD caused by hyperbilirubinemia and
anoxia [135]. Otherwise, a slow hearing deterioration over time is frequently observed in children and
adults. Subjects with low frequencies hearing loss frequently show a deterioration overtime in their
high and middle frequencies [134,136]. The tonal hearing thresholds are variables within subjects, even
when accounted for by the same genetic mutation. For instance, subjects presenting an OTOF mutation
present a profound deafness in 75% of cases, whereas it is severe in 22% and moderate in 3% [60].
Hearing fluctuations over time explain why repetitive hearing assessment is imperative. Associated
cognitive impairments may also complicate the hearing thresholds estimation. The behavioral testing
must be adapted to the psychomotor age in children and to the attentional effort abilities in adults.
Speech perception tests show very poor speech discrimination abilities, even in subjects with
preserved tonal thresholds, as shown in Figure 3b. Impaired speech perception skills are typically out
of proportion compared to the tonal thresholds. Background noise further deteriorates residual speech
discrimination [1,7,134,137,138].

4.2. Supraliminal Tests

The supraliminal psychoacoustic tests study the auditory processing of complex sounds presented
at a comfortable level and not only around the hearing thresholds.
When short-duration stimuli (200 ms) are used, the psychoacoustic measures show that the
disrupted neural activity associated with ANSD has minimal effects on intensity-related perception,
such as discrimination of loudness changes and sound localization using interaural level differences or
on pitch discrimination at high frequencies [4].
In contrast, timing-related perception is impaired in ANSD subjects. They present poorer pitch
detection for low frequency, indexing a disturbed phase-locking, and a less efficient detection of shorter
stimuli and gaps between stimuli sounds. Moreover, they need larger changes to detect frequency
modulations and have an abnormal susceptibility to the masking effect that lasts longer in ANSD,
particularly for backward masking. Individuals with ANSD are disturbed largely by noises arriving
after the stimuli.
The abilities of sound localization using interaural time differences are also decreased [4].
The processing of short acoustic stimuli in ANSD shows an inverse pattern of what is observed in
nonsynaptic cochlear disorders, where intensity perception is impaired but temporal processing is
generally preserved.
When long-duration stimuli are used, ANSD subjects display abnormal loudness adaptation,
depending on the site of the lesion. If their abilities to detect brief changes of frequency or intensity
in continuous sounds are investigated, subjects with ribbon synapses disorders (e.g., in mutations of
otoferlin) report the disappearing of the background tone whereas the changes in intensity or frequency
are correctly detected, contrary to neuropathic subjects that do not report a loss of the steady tone [139].
The perception of loudness of sustained tones presented for 3 minutes is relatively preserved and
stable in normal hearing subjects, but it is decreased in ANSD as a function of frequencies. Ribbon
synapses’ ANSD shows an abnormal and rapid auditory fatigue, for both long-duration low and high
frequencies presented at comfortable levels, with loudness loss of more than 90% for 8 kHz at 90 s
and around 50% for 250 Hz. Individuals with neuropathic ANSD present a normal adaptation to low
frequencies but abnormal to high frequencies, even though less severe and less rapid than in ribbon
disorders. Abnormal adaptation may be associated with depletion of neurotransmission that may
exacerbate the abnormal speech perception in ANSD [54].

5. Objective Assessment of ANSD

Typical auditory patterns in ANSD include the preservation of OAEs and CM and absent or
altered neural waves of the ABRs [41] by loss of neural response synchronization or generation.
Therefore, objective assessment is essential in the correct diagnosis of ANSD. In Figure 4, we report the
J. Clin. Med. 2020, 9, 1074 11 of 29

audiological assessment in a 42-year-old woman with ANSD and bilateral atrophy of cochlear nerve.
Patient presents with Melkersson–Rosenthal syndrome, Ehler Danlos syndrome and Hashimoto’s
thyroiditis. She suffers from recurrent uveitis. Despite preserved hearing in quiet, patient complaints
of poor speech understanding in challenging hearing conditions, especially with background noise.
Besides OAEs and ABRs, a complete physiological assessment should also include impedance
and stapedial reflex evaluation, as well as other event-related potentials, such as electrocochleography
(ECochG), auditory steady-state responses (ASSRs) and cortical auditory evoked potentials (CAEPs).
OAE, first described by D. Kemp in 1978 [140], is the sound generated by the OHCs of the cochlea,
which can be recorded after a transient stimulation (transient-evoked, TEOAEs) or two simultaneous
pure-tone stimuli (distortion product, DPOAEs) with a sensitive probe placed in the external ear
canal [141]. This sound represents the cochlear amplifier energy that originates from the somatic
motility and the stereocilia bundle of OHCs, but multiple localizations and a more complex origins
have been speculated [142].
OAEs may decrease or disappear in 20 to 80% of the subjects with time, particularly after wearing
hearing aids [6,13,42]. Moreover, cases of recovering of ABRs synchronization in newborns with ANSD
have been described [143]. This recovery at the peripheral level may not concern more central levels,
resulting in supraliminal auditory processing disorders.
OHCs are the main contributors to the generation of an early evoked response, the cochlear
microphonic (CM), a short-latency potential occurring before wave I of the ABRs. It has been shown
that CM originates from the mechano-sensitive transduction channels in the stereocilia of both IHCs
and OHCs, with a predominance for the OHCs due to their greater number, and is produced by the
opening and closing of transduction channels in the hair bundle that follow the movement of the
basilar membrane [144,145]. The CM is an electrophysiological response that is polarity dependent.
CM is highlighted by the subtraction of the ABRs evoked by rarefaction and condensation stimuli. The
summation brings out the summating potential (SP) and neural responses like the compound action
potential (CAP) on ECochG or wave I on ABRs. Even when non-detectable at early neonatal stage, CM
could appear later in preterm infants. In Figure 5, we report a case of a 26-week preterm newborn with
ANSD of unknown etiology with no clinical history.
Transtympanic ECochG recorded at the promontory of the cochlea is a gold standard for the study
of the CM, SP and CAP, due to the proximity of the electrode with the basal portion of the cochlea and
a better signal-to-noise ratio compared to an extratympanic approach in which a probe is placed in the
external auditory canal [146–148].
ECochG may also be recorded intraoperatively during cochlear implantation, by means of the
intracochlear electrode of the implant, after acoustical stimulations [149–151].
Both OAEs and CM represent the physiological measures of the activity of OHCs. Therefore, the
presence of CM is crucial for the diagnosis of ANSD.
The origins of SP are more debated and remain unclear, but it is accepted that SP mainly reflects
the activity of IHCs [152]. More recently, the effects of ototoxins and neurotoxins in animal models
suggested a possible combined receptor and neural origin of the SP [144].
Another component of ECochG responses reflecting the neural activity is the auditory nerve
neurophonic (ANN), an auditory evoked potential representing the phase-locking activity of the neural
unit of the auditory nerve to low-frequency stimuli [153,154]. It is difficult to distinguish from the
cochlear microphonic.
In normal-hearing subjects, ECochG should consistently provide all the above-mentioned components.
The comparison of amplitudes of CM in normal hearing subjects and ANSD patients has shown
no significant difference [155], although the duration of CM can be longer in subjects with ANSD [146].
In auditory synaptopathy, the CM and the SP are preserved, while CAP is not detectable [11,12]
(Figure 1c). Most of the patients with ANSD display a prolonged negative deflection of ECochG
responses without separation between SP and CAP potentials.
J. Clin. Med. 2020, 9, x 11 of 31

Hashimoto’s thyroiditis. She suffers from recurrent uveitis. Despite preserved hearing in quiet,
patient
J. complaints
Clin. Med. of poor speech understanding in challenging hearing conditions, especially with
2020, 9, 1074 12 of 29
background noise.

Audiologicalassessment
Figure 4. Audiological assessmentininan anadult
adultpatient
patientwith
withauditory
auditoryneuropathy
neuropathyspectrumspectrum disorder
disorder
(ANSD) and
(ANSD) and bilateral
bilateral cochlear
cochlear nerve
nerve atrophy.
atrophy. Unaided
Unaidedthresholds
thresholdsforforpure-tone
pure-tone audiometry
audiometry ((a),
((a),
black
black line
linefor
forright
rightear,
ear,gray line
gray forfor
line leftleft
ear)ear)
and and
speech audiometry
speech ((b), black
audiometry ((b), line
black forline
right
forear, gray
right ear,
line
grayfor
lineleft
forear) in quiet
left ear) are are
in quiet good. Otoacoustic
good. Otoacoustic emissions (OAEs)
emissions areare
(OAEs) present
present bilaterally in in
bilaterally both
both
temporal/intensity
temporal/intensityrecordings
recordings(left
(leftpanel
panelinin(c)
(c)for
forright
rightear,
ear,left
leftpanel
panelinin(d)
(d)for
forleft
leftear) and
ear) and spectral
spectral
analysis (right panel in (c) for right ear, right panel in (d) for left ear); on the other hand, auditory
brainstem responses (ABRs) are abnormal with no clear cochlear microphonic (CM) ((e) for right ear, (f)
for left ear).
 basilar membrane [144,145]. The CM is an electrophysiological response that is polarity dependent.
CM is highlighted by the subtraction of the ABRs evoked by rarefaction and condensation stimuli.
The summation brings out the summating potential (SP) and neural responses like the compound
action potential (CAP) on ECochG or wave I on ABRs. Even when non-detectable at early neonatal
stage, CM could appear later in preterm infants. In Figure 5, we report a case of a 26-week preterm
J. Clin. Med. 2020, 9, 1074 13 of 29
newborn with ANSD of unknown etiology with no clinical history.

Auditory brainstem
Figure 5. Auditory brainstem responses
responses (ABRs)
(ABRs) in
in aa 26-week
26-week preterm
preterm newborn
newborn with auditory
neuropathy spectrum
spectrumdisorder (ANSD).
disorder Three-month
(ANSD). ABRsABRs
Three-month (a) show
(a) small
show early
smallcomponents, whereas
early components,
a cochlear
whereas microphonic
a cochlear (CM) was
microphonic detectable
(CM) 9 months
was detectable later (b),later
9 months suggesting a late, although
(b), suggesting partial,
a late, although
maturation. Auditory steady-state responses (ASSRs) remain absent in both ears.
partial, maturation. Auditory steady-state responses (ASSRs) remain absent in both ears.

Patients with ANSD

Transtympanic occurring
ECochG recordedwith
atpreservation of synaptic
the promontory functioning
of the cochlea may standard
is a gold show normal SP
for the
and CAP components (Figure 6c,d). In Figure 6, we report the audiological assessment in a 48-year-old
study of the CM, SP and CAP, due to the proximity of the electrode with the basal portion of the
woman with acquired ANSD caused by bilateral cochlear nerve hypotrophia of unknown etiology, with
no other medical history. She presents with a deterioration of speech discrimination despite partial
preservation of tonal perception. Detection of environmental noises remains fair, but discrimination of
sounds is absent.
However, the presence of neural activity recorded by ECochG is not sufficient for a diagnosis of
ANSD [38,40,156]. In fact, even in presynaptic lesions, some residual apical connections in the cochlea
may still be functional [43].
Therefore, the study of adaptation of the cochlear potentials is essential for the differential
diagnosis of ANSD [157]. Adaptation means a decrease in the amplitude of the electrophysiological
J. Clin. Med. 2020, 9, x 15 of 31
responses in the presence of stimuli repetition, representing a fatigue-like response.

Figure 6. Cont.
J. Clin. Med. 2020, 9, 1074 14 of 29

Figure 6. Audiological
Figure 6. Audiological assessment
assessmentin in adult with acquired
adult with acquiredauditory
auditory neuropathy
neuropathy spectrum
spectrum disorder
disorder
(ANSD)
(ANSD) caused by bilateral cochlear nerve hypotrophia of unknown etiology. Unaided pure tone ((a), ((a),
caused by bilateral cochlear nerve hypotrophia of unknown etiology. Unaided pure tone
blackblack lineright
line for for right
ear, ear,
graygray
lineline
for for
leftleft
ear)ear)
andand speech
speech ((b),
((b), bothears
both earsininfree
freefield)
field)thresholds
thresholds are
are poor,
with no improvement with hearing aids. Electrocochleography (ECochG) recorded afterafter
poor, with no improvement with hearing aids. Electrocochleography (ECochG) recorded clicks
clicks at 90 dB
and at a rate of 14.3 s ((c), grand average, above; superimposed, below) shows preserved summating
potential (SP) and compound action potential (CAP). ECochG responses to tone-burst stimuli at different
frequencies ((d), grand averages for 8, 4, 3, 2 and 1 kHz) show a large SP. Auditory brainstem responses
(ABRs) are absent, except for the cochlear microphonic (CM) (e). The 3-Tesla magnetic resonance
imaging of the right ear without contrast (f) shows the hypoplasia of the cochlear nerve.

Among the other evoked potentials, auditory steady-state responses (ASSRs) best predict the pure
tone threshold in individuals with both normal and impaired hearing. ASSRs are evoked by rapid
and periodical auditory stimulation using frequency-specific stimuli, varying from 0.5 to 4 kHz [158].
They may be present in ANSD subjects and produced by the phase-locking to microphonic and/or
neurophonic responses [159].
Late auditory potentials recorded in children with ANSD have been correlated to cortical
maturation and behavioral outcomes and may be used as a good indicator of the disruption of cortical
development due to neural dys-synchrony [160].
Even with absent ABRs, cortical auditory evoked potentials (CAEPs) can be evoked in patients
with ANSD [161,162]. Abnormal or absent CAEPs have been observed in approximately one-third of
children with ANSD [139,160].
J. Clin. Med. 2020, 9, 1074 15 of 29

Among other CAEPs components, the P1 or N100 responses are significantly correlated with
auditory skills development [163].
N100 responses provides a fairly objective estimation of the psychoacoustic threshold for gap
detection and perceptual speech skills and may be useful for predicting significant benefits from
hearing amplification in patients with ANSD [1,138,161,162,164].
N100 differences in amplitude and latency may suggest the presynaptic or postsynaptic site of
the lesion. In presynaptic ANSD, N100 amplitudes in response to changes in frequency of 250 and
4000 Hz are larger than in postsynaptic disorders. Conversely, in postsynaptic ANSD, N100 latencies
evoked by frequency changes show more delayed latencies, whereas normal latencies are evoked in
individuals with presynaptic ANSD [139].
Mismatch Negativity (MMN) [165] and P300 (P3a and P3b) [166] are preattentive and
attention-targeted auditory cortical responses, respectively, to rare and unpredictable (deviant) stimuli
in repetitive sequences of standard sounds, called oddball paradigms. An example of those cognitive
evoked potentials is shown in Figure 7e, as a part of the audiological assessment in a 25-year-old girl
with ANSD and progressive Ponto-bulbar palsy syndrome (also called Brown–Vialetto–Van Laere
syndrome). This
J. Clin. Med. 2020,rare
9, xdegenerative familial disorder is caused by a riboflavin transporter deficiency.
17 of 31
The patient presents with neural impairment of the 8th and 12th cranial nerves and the optic nerves.
Without lip-reading, communication with others is possible only at low speech rate. Speech perception
increases when lip reading is available. Hearing aids did not improve significantly her auditory
perception skills.
J. Clin. Med. 2020, 9,However,
x speech perception was good after two months of CI experience. 17 of 31

Figure 7. Cont.
J. Clin. Med. 2020, 9, 1074 16 of 29

Figurein7.a Audiological
Figure 7. Audiological assessment assessment in a subject
subject with Brown–Vialetto–Van with
Laere Brown–Vialetto–Van Laere syndrome-re
syndrome-related
auditory neuropathy spectrumauditory
disorderneuropathy
(ANSD), resulting
spectrum in disorder
neural impairment of the 8th
(ANSD), resulting inand 12thimpairment of the 8th and
neural
cranial nerves and the optic nerves.
cranialUnaided
nerves andpure-tone
the opticaudiometry ((a), both
nerves. Unaided ears) shows
pure-tone bilateral((a), both ears) shows bil
audiometry
hearing loss mainly for low frequencies. Unaided
hearing loss mainlyfree
forfield
lowspeech discrimination
frequencies. Unaidedis free
poorfield
((b), speech
10% graydiscrimination is poor ((b)
dot at 80 dB). Aided tonal and gray
speech
dotperception
at 80 dB). outcomes
Aided tonal with
andacoustical hearing aids
speech perception remainwith
outcomes pooracoustical hearing aids re
and comparable to unaided perception. The latter clearly improves after cochlear implantation (CI) ((b),
black line). Otoacoustic emissions (OAEs) are present ((c), spectral analysis of OAEs in the white area,
compared to noise in the black area), whereas auditory brainstem responses (ABRs) synchronization
was abnormal with no wave V but a clear cochlear microphonic (CM) in both rarefaction (R) and
condensation (C) polarities and in the subtraction R − C (d). Cortical auditory evoked responses (e)
show a P3 complex after stimulation with an oddball paradigm and in selective attentive conditions
only, even if no recordable N100 or P200 waves are present in responses to the frequent stimuli (not
shown).

Cranial magnetic resonance imaging and genetic evaluation are recommended to detect potential
morphologic abnormalities of the cochlear nerve or peripheral and/or central nervous system
(Figure 6f) [42].

6. Therapy and Outcomes

The current management of individuals presenting with ANSD varies according to the severity of
the impairment. However, management remains challenging and is frequently tailored case-by-case. It
is based on bottom-up (auditory skills restoration by hearing aids) and top-down procedures (hearing
and speech training).
Generally, a multidisciplinary approach is favored.
Once the full workup is completed, two main therapeutic options may be offered. The first
relies on maximizing signal to noise ratio to improve listening in noise. The second consists of sound
amplification through conventional hearing aids or cochlear implant (CI).
Treatment modality should be chosen following intensive counselling of the patient or the pediatric
patient’s family. Clear information must be provided regarding the eventual outcome limits in the case
of postsynaptic or associated CNS lesions.

• Signal-to-noise ratio maximization

In milder forms of ANSD, patients may benefit from the use of “FM-listening” devices. Indeed,
speech comprehension in noise is one of the main difficulties encountered by ANSD patients, even in
milder forms with little audiometric threshold impact. The use of “FM-listening systems“ has been
extensively described in the classroom environment. Speech is detected directly from the speaker and
J. Clin. Med. 2020, 9, 1074 17 of 29

transmitted through radio signal to headphone receivers worn by the child, enhancing the speech
signal. Positive outcomes of this device have been described in several studies [167], as well as when
used in conjunction with CI [3], with reported improvement of speech in noise comprehension [168].

• Amplification: Hearing aids and cochlear implant

Conventional hearing aids may be proposed, although most studies report poor outcomes in the
case of ANSD [8,169]. Indeed, conventional hearing aids amplify the signal but fail to overcome the
neural dys-synchrony responsible for impaired speech comprehension. In a large multicentric study,
Berlin et al. reported the outcome of hearing aid use in 85 patients with confirmed ANSD as well as 49
patients with CI. Hearing aids were described as offering “good benefit” by 3.53% of patients, “some
benefit” by 10.59% of patients, “little benefit” by 24.71% of patients and “no benefit” by 61.17% of
patients. Conversely, CI recipients reported 85% of successful rehabilitation in speech recognition, with
an additional 8% of patients in the cohort being too recently implanted to obtain a correct evaluation of
their performance [3]. Similar positive results regarding CI in ANSD management have been reported
in both prospective and retrospective studies. Nevertheless, in the case of a more moderate hearing
loss, nerve malformation and/or syndromic forms of ANSD, acoustic hearing aids may be sufficient for
some ANSD children. [8,13,42,170,171]. However, if their auditory behavior and language skills do not
develop normally or within the expected outcomes, CI must be provided [172].
Indeed, CI appears to be an effective rehabilitation modality for ANSD patients. This may be
explained by the fact that the implanted electrode delivers synchronized electrical impulses directly to
the auditory nerve, bypassing the presynaptic IHCs and its synapse involved in the unsynchronized
firing of the auditory nerve described in ANSD [42].
Despite this evidence, CI outcomes in speech perception remain variable. Many biographical
factors (residual hearing, age at implantation, auditory privation duration, cognitive and socioeconomic
factors, anatomic morphology) have been reported to influence CI outcomes, but account for less than
25% of their variability [43]. In case of ANSD, the site of lesion along the auditory pathway seems
to also have a prognostic significance [173]. In two consecutive papers, Shearer et al. reported that
optimal CI outcome in ANSD with genetic etiology is reached in individuals affected by presynaptic
(IHCs) or synaptic dysfunction as opposed to patients with distal auditory nerve lesions. Shearer
argues that CI outcomes in ANSD may be partly predicted by the genetic site of lesion and their effect
on spiral ganglion function. In his studies, four ANSD gene mutations responsible for presynaptic or
postsynaptic cochlear dysfunction were examined (OTOF, SLC17A8, CACNA1D, CABP2). Patients
with these mutations had a significantly better outcome in speech recognition than patients with
mutations in the four studied genes responsible for spiral ganglion dysfunction (OPA1, DFNB59,
AIFM1, DIAPH3) [13,77].
The general rules for cochlear implantation must be promoted in children with isolated forms
of congenital or very early onset ANSD: early implantation must remain the standard of care in case
of severe to profound hearing loss with normal cochlear nerve anatomy. Otoferlin mutations are
associated with excellent CI outcomes and typically on par with individuals with genetic mutations
affecting the sensory partition of the cochlea [13]. Cochlear nerve malformation or associated disorders
are negative prognostic factors for CI outcomes but not contra-indications, and speech perception
impairment may be severe enough to indicate cochlear implantation [43] (Figures 8 and 9).
J. Clin. Med. 2020, 9, 1074 18 of 29
J. Clin. Med. 2020, 9, x 20 of 31

Audiological
Figure 8.Figure assessment
8. Audiological assessmentininaa 14-year-old child
14-year-old child withwith auditory
auditory neuropathy
neuropathy spectrum disorder
spectrum disorder
(ANSD) (ANSD)
features features occurring
occurring withwith severehearing
severe hearing loss. HerHer
loss. medical historyhistory
medical includesincludes
a 35-week a
preterm
35-week preterm
birth after an intrahepatic cholestasis of pregnancy, with normal birth weight but neonatal hypoxia
birth after an intrahepatic cholestasis of pregnancy, with normal birth weight but neonatal hypoxia
requiring 3 weeks of stay in neonatal intensive care unit. Hearing aids were fitted in early infancy.
requiring 3 weeks of stay in neonatal intensive care unit. Hearing aids were fitted in early infancy.
Besides poor sounds recognition and speech perception, speech development was good in the lexical
and morphosyntactic fields. Unaided tonal thresholds ((a), gray line for right ear, black line for left
ear) and unaided speech discrimination (b) are poor. Aided pure-tone audiometry (c) and speech
perception (d) with hearing aids are clearly improved, allowing a good development of language skills
and learning abilities. Auditory brainstem responses (ABRs) elicited by clicks at 90 dB show small
cochlear microphonic (CM) (e). Auditory steady-state responses (ASSRs) (f) are detected for 500 Hz at
the right ear.
 and morphosyntactic fields. Unaided tonal thresholds ((a), gray line for right ear, black line for left
ear) and unaided speech discrimination (b) are poor. Aided pure-tone audiometry (c) and speech
perception (d) with hearing aids are clearly improved, allowing a good development of language
skills and learning abilities. Auditory brainstem responses (ABRs) elicited by clicks at 90 dB show
small cochlear microphonic (CM) (e). Auditory steady-state responses (ASSRs) (f) are detected for 500
J. Clin. Med. 2020, 9, 1074 19 of 29
Hz at the right ear.

Figure9.
Figure Audiological assessment
9. Audiological assessmentinin a 14-years-old malemale
a 14-years-old with with
auditory neuropathy
auditory spectrum
neuropathy disorder
spectrum
(ANSD). His medical history includes neonatal hyperbilirubinemia and low birth
disorder (ANSD). His medical history includes neonatal hyperbilirubinemia and low birth weight. weight. Despite early
hearing aids fitting, speech development was delayed. He shows residual pure-tone
Despite early hearing aids fitting, speech development was delayed. He shows residual pure-tone hearing thresholds
((a), gray
hearing line) and((a),
thresholds poor speech
gray line) discrimination
and poor speech ((b), gray line) in((b),
discrimination the gray
left ear.
line)After left-ear
in the cochlear
left ear. After
implantation,
left-ear cochlearaided tonal ((a),aided
implantation, blacktonal
line)((a),
andblack
speech ((b),
line) andblack line)((b),
speech thresholds show
black line) good auditory
thresholds show
outcomes.
good Auditory
auditory brainstem
outcomes. Auditoryresponses (ABRs)
brainstem at left ear
responses are absent
(ABRs) at left(c). However,
ear are absent speech perception
(c). However,
in noise, such as during school activities, remains poor.
speech perception in noise, such as during school activities, remains poor.
7. Conclusions
7. Conclusions
The concept of ANSD is based on an operational definition: speech discrimination disorders
The concept of ANSD is based on an operational definition: speech discrimination disorders
and/or abnormal language development out of proportion with sound detection abilities, as well as
and/or abnormal language development out of proportion with sound detection abilities, as well as
preserved outer hair cell responses with very disturbed ABRs. ANSD may be caused by cochlear
preserved outer hair cell responses with very disturbed ABRs. ANSD may be caused by cochlear
presynaptic and postsynaptic lesions or by lesions to ascendant cochlear fibers from the auditory nerve
presynaptic and postsynaptic lesions or by lesions to ascendant cochlear fibers from the auditory
to the brainstem. Genetic, environmental, infectious, inflammatory and idiopathic causes may trigger
nerve to the brainstem. Genetic, environmental, infectious, inflammatory and idiopathic causes may
the symptoms since birth, during childhood or later in life. The clinical patterns of ANSD are very
heterogeneous. Hearing rehabilitation is more efficient in peri-synaptic disorders thanks to cochlear
implants. However, genetic studies that have proven to be essential in the knowledge of underlying
mechanisms of ANSD represent a promising therapeutic approach in the management of ANSD.

Author Contributions: R.D.D.S. and N.D. designed the project. R.D.D.S. wrote the manuscript with the
contribution of F.R. and G.G. N.D., A.G. and R.D.D.S. provided own case reports. G.G. and R.D.D.S. designed
J. Clin. Med. 2020, 9, 1074 20 of 29

the figures. F.R. proofread the text. N.D. and P.R. supervised the project. All authors discussed the results and
contributed to the final manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations
ABRs Auditory Brainstem Responses
AN/AD Auditory Neuropathy/Auditory Dys-synchrony
ANN Auditory Nerve Neurophonic
ANSD Auditory Neuropathy Spectrum Disorder
ASSRs Auditory Steady-State Responses
C Condensation
CAEPs Cortical Auditory Evoked Potentials
CAP Compound Action Potential
CM Cochlear Microphonic
CMT Charcot–Marie–Tooth disease
CNS Central Nervous System
DOA Dominant Optic Atrophy
DPOAEs Distortion-Product Otoacoustic Emissions
ECochG Electrocochleography
HHL Hidden Hearing Loss
HSMN Hereditary Sensori-Motor Neuropathy
IHCs Inner Hair Cells
MMN Mismatch Negativity
NICU Neonatal Intensive Care Unit
OAEs Otoacoustic Emissions
OHCs Outer Hair Cells
R Rarefaction
SANDD Sinoatrial Node Dysfunction and Deafness
SGNs Spiral Ganglion Neurons
SNHL Sensorineural Hearing Loss
SP Summating Potential
TEOAEs Transient-Evoked Otoacoustic Emissions

References
1. Rance, G. Auditory Neuropathy/Dys-Synchrony and Its Perceptual Consequences. Trends Amplif. 2005, 9,
1–43. [CrossRef] [PubMed]
2. Berlin, C.I.; Morlet, T.; Hood, L.J. Auditory Neuropathy/Dyssynchrony: Its Diagnosis and Management.
Pediatr. Clin. N. Am. 2003, 50, 331–340. [CrossRef]
3. Berlin, C.I.; Hood, L.J.; Morlet, T.; Wilensky, D.; Li, L.; Mattingly, K.R.; Taylor-Jeanfreau, J.; Keats, B.J.B.;
John, P.S.; Montgomery, E.; et al. Multi-Site Diagnosis and Management of 260 Patients with Auditory
Neuropathy/Dys-Synchrony (Auditory Neuropathy Spectrum Disorder). Int. J. Audiol. 2010, 49, 30–43.
[CrossRef] [PubMed]
4. Zeng, F.G.; Kong, Y.Y.; Michalewski, H.J.; Starr, A. Perceptual Consequences of Disrupted Auditory Nerve
Activity. J. Neurophysiol. 2005, 93, 3050–3063. [CrossRef]
5. Fontenot, T.E.; Giardina, C.K.; Teagle, H.F.; Park, L.R.; Adunka, O.F.; Buchman, C.A.; Brown, K.D.;
Fitzpatrick, D.C. Clinical Role of Electrocochleography in Children with Auditory Neuropathy Spectrum
Disorder. Int. J. Pediatr. Otorhinolaryngol. 2017, 99, 120–127. [CrossRef]
6. Kitao, K.; Mutai, H.; Namba, K.; Morimoto, N.; Nakano, A.; Arimoto, Y.; Sugiuchi, T.; Masuda, S.; Okamoto, Y.;
Morita, N.; et al. Deterioration in Distortion Product Otoacoustic Emissions in Auditory Neuropathy Patients
with Distinct Clinical and Genetic Backgrounds. Ear Hear. 2019, 40, 184–191. [CrossRef]
J. Clin. Med. 2020, 9, 1074 21 of 29

7. Starr, A.; Picton, T.W.; Sininger, Y.; Hood, L.J.; Berlin, C.I. Auditory Neuropathy. Brain 1996, 119, 741–753.
[CrossRef]
8. Starr, A.; Dong, C.J.; Michalewski, H.J. Brain Potentials before and during Memory Scanning.
Electroencephalogr. Clin. Neurophysiol. 1996, 99, 28–37. [CrossRef]
9. Zeng, F.G.; Oba, S.; Garde, S.; Sininger, Y.; Starr, A. Temporal and Speech Processing Deficits in Auditory
Neuropathy. Neuroreport 1999, 10, 3429–3435. [CrossRef]
10. Berlin, C.I.; Hood, L.J.; Rose, K. On Renaming Audi- Tory Neuropathy as Auditory Dys-Synchrony. Audiol.
Today 2001, 13, 15–17.
11. Santarelli, R.; del Castillo, I.; Cama, E.; Scimemi, P.; Starr, A. Audibility, Speech Perception and Processing of
Temporal Cues in Ribbon Synaptic Disorders Due to OTOF Mutations. Hear. Res. 2015, 200–212. [CrossRef]
12. Moser, T.; Starr, A. Auditory Neuropathy-Neural and Synaptic Mechanisms. In Nature Reviews Neurology;
Nature Publishing Group: Berlin, Germany, 2016; pp. 135–149.
13. Shearer, A.E.; Hansen, M.R. Auditory Synaptopathy, Auditory Neuropathy, and Cochlear Implantation.
Laryngoscope Investig. Otolaryngol. 2019, 4, 429–440. [CrossRef]
14. Foerst, A.; Beutner, D.; Lang-Roth, R.; Huttenbrink, K.B.; von Wedel, H.; Walger, M. Prevalence of Auditory
Neuropathy/Synaptopathy in a Population of Children with Profound Hearing Loss. Int. J. Pediatr.
Otorhinolaryngol. 2006, 70, 1415–1422. [CrossRef]
15. Sergeyenko, Y.; Lall, K.; Charles Liberman, M.; Kujawa, S.G. Age-Related Cochlear Synaptopathy: An
Early-Onset Contributor to Auditory Functional Decline. J. Neurosci. 2013, 33, 13686–13694. [CrossRef]
16. Guest, H.; Munro, K.J.; Prendergast, G.; Millman, R.E.; Plack, C.J. Impaired Speech Perception in Noise with
a Normal Audiogram: No Evidence for Cochlear Synaptopathy and No Relation to Lifetime Noise Exposure.
Hear. Res. 2018, 364, 142–151. [CrossRef]
17. Kujawa, S.G.; Liberman, M.C. Adding Insult to Injury: Cochlear Nerve Degeneration after “Temporary”
Noise-Induced Hearing Loss. J. Neurosci. 2009, 29, 14077–14085. [CrossRef]
18. Chen, G.D. Hidden Cochlear Impairments. J. Otol. 2018, 13, 37–43. [CrossRef]
19. Xiong, B.; Liu, Z.; Liu, Q.; Peng, Y.; Wu, H.; Lin, Y.; Zhao, X.; Sun, W. Missed Hearing Loss in Tinnitus Patients
with Normal Audiograms. Hear. Res. 2019, 384, 107826. [CrossRef]
20. Iliadou, V.V.; Ptok, M.; Grech, H.; Pedersen, E.R.; Brechmann, A.A.; Deggouj, N.N.; Kiese-Himmel, C.;
Sliwinska-Kowalska, M.; Nickisch, A.; Demanez, L.; et al. A European Perspective on Auditory Processing
Disorder-Current Knowledge and Future Research Focus. Front. Neurol. 2017, 8, 622. [CrossRef]
21. Vignesh, S.S.; Jaya, V.; Muraleedharan, A. Prevalence and Audiological Characteristics of Auditory
Neuropathy Spectrum Disorder in Pediatric Population: A Retrospective Study. Indian J. Otolaryngol.
Head Neck Surg. 2016, 68, 196–201. [CrossRef]
22. Boudewyns, A.; Declau, F.; van den Ende, J.; Hofkens, A.; Dirckx, S.; Van de Heyning, P. Auditory Neuropathy
Spectrum Disorder (ANSD) in Referrals from Neonatal Hearing Screening at a Well-Baby Clinic. Eur. J.
Pediatr. 2016, 175, 993–1000. [CrossRef]
23. Penido, R.C.; Isaac, M.L. Prevalence of Auditory Neuropathy Spectrum Disorder in an Auditory Health Care
Service. Braz. J. Otorhinolaryngol. 2013, 79, 429–433. [CrossRef]
24. Robertson, C.M.T.; Howarth, T.M.; Bork, D.L.R.; Dinu, I.A. Permanent Bilateral Sensory and Neural Hearing
Loss of Children after Neonatal Intensive Care Because of Extreme Prematurity: A Thirty-Year Study.
Pediatrics 2009, 123, e797–e807. [CrossRef]
25. Vohr, B.R.; Widen, J.E.; Cone-Wesson, B.; Sininger, Y.S.; Gorga, M.P.; Folsom, R.C.; Norton, S.J. Identification of
Neonatal Hearing Impairment: Characteristics of Infants in the Neonatal Intensive Care Unit and Well-Baby
Nursery. Ear Hear. 2000, 21, 373–382. [CrossRef]
26. Schulman Galambos, C.; Galambos, R. Brain Stem Evoked Response Audiometry in Newborn Hearing
Screening. Arch. Otolaryngol. 1979, 105, 86–90. [CrossRef]
27. Amatuzzi, M.; Liberman, M.C.; Northrop, C. Selective Inner Hair Cell Loss in Prematurity: A Temporal Bone
Study of Infants from a Neonatal Intensive Care Unit. JARO J. Assoc. Res. Otolaryngol. 2011, 12, 595–604.
[CrossRef]
28. Berg, A.L.; Spitzer, J.B.; Towers, H.M.; Bartosiewicz, C.; Diamond, B.E. Newborn Hearing Screening in the
NICU: Profile of Failed Auditory Brainstem Response/Passed Otoacoustic Emission. Pediatrics 2005, 116,
933–938. [CrossRef]
J. Clin. Med. 2020, 9, 1074 22 of 29

29. Xoinis, K.; Weirather, Y.; Mavoori, H.; Shaha, S.H.; Iwamoto, L.M. Extremely Low Birth Weight Infants Are at
High Risk for Auditory Neuropathy. J. Perinatol. 2007, 27, 718–723. [CrossRef]
30. Bielecki, I.; Horbulewicz, A.; Wolan, T. Prevalence and Risk Factors for Auditory Neuropathy Spectrum
Disorder in a Screened Newborn Population at Risk for Hearing Loss. Int. J. Pediatr. Otorhinolaryngol. 2012,
76, 1668–1670. [CrossRef]
31. Fuchs, P.A. Time and Intensity Coding at the Hair Cell’s Ribbon Synapse. J. Physiol. 2005, 566, 7–12.
[CrossRef]
32. Moser, T.; Neef, A.; Khimich, D. Mechanisms Underlying the Temporal Precision of Sound Coding at the
Inner Hair Cell Ribbon Synapse. J. Physiol. 2006, 576, 55–62. [CrossRef]
33. Kim, K.X.; Rutherford, M.A. Maturation of Nav and Kv Channel Topographies in the Auditory Nerve
Spike Initiator before and after Developmental Onset of Hearing Function. J. Neurosci. 2016, 36, 2111–2118.
[CrossRef]
34. Nayagam, B.A.; Muniak, M.A.; Ryugo, D.K. The Spiral Ganglion: Connecting the Peripheral and Central
Auditory Systems. Hear. Res. 2011, 278, 2–20. [CrossRef]
35. Jeon, E.J.; Xu, N.; Xu, L.; Hansen, M.R. Influence of Central Glia on Spiral Ganglion Neuron Neurite Growth.
Neuroscience 2011, 177, 321–334. [CrossRef]
36. Jung, S.; Maritzen, T.; Wichmann, C.; Jing, Z.; Neef, A.; Revelo, N.H.; Al-Moyed, H.; Meese, S.; Wojcik, S.M.;
Panou, I.; et al. Disruption of Adaptor Protein 2µ (AP -2µ) in Cochlear Hair Cells Impairs Vesicle Reloading
of Synaptic Release Sites and Hearing. EMBO J. 2015, 34, 2686–2702. [CrossRef]
37. Pangšrič, T.; Lasarow, L.; Reuter, K.; Takago, H.; Schwander, M.; Riedel, D.; Frank, T.; Tarantino, L.M.;
Bailey, J.S.; Strenzke, N.; et al. Hearing Requires Otoferlin-Dependent Efficient Replenishment of Synaptic
Vesicles in Hair Cells. Nat. Neurosci. 2010, 13, 869–876. [CrossRef]
38. Khimich, D.; Nouvtan, R.; Pujol, R.; Diesk, S.T.; Egner, A.; Gundelfinger, E.D.; Moser, T. Hair Cell Synaptic
Ribbons Are Essential for Synchronous Auditory Signalling. Nature 2005, 434, 889–894. [CrossRef]
39. Parkinson, N.J.; Olsson, C.L.; Hallows, J.L.; Mckee-Johnson, J.; Keogh, B.P.; Noben-Trauth, K.; Kujawa, S.G.;
Tempel, B.L. Mutant β-Spectrin 4 Causes Auditory and Motor Neuropathies in Quivering Mice. Nat. Genet.
2001, 29, 61–65. [CrossRef]
40. Buran, B.N.; Strenzke, N.; Neef, A.; Gundelfinger, E.D.; Moser, T.; Liberman, M.C. Onset Coding Is Degraded
in Auditory Nerve Fibers from Mutant Mice Lacking Synaptic Ribbons. J. Neurosci. 2010, 30, 7587–7597.
[CrossRef]
41. Starr, A.; Sininger, Y.; Nguyen, T.; Michalewski, H. Cochlear Receptor and Auditory Pathway Activity in
Auditory Neuropathy. Ear Hear. 2001, 22, 91–99. [CrossRef]
42. Ehrmann-Müller, D.; Cebulla, M.; Rak, K.; Scheich, M.; Back, D.; Hagen, R.; Shehata-Dieler, W. Evaluation
and Therapy Outcome in Children with Auditory Neuropathy Spectrum Disorder (ANSD). Int. J. Pediatr.
Otorhinolaryngol. 2019, 127, 109618. [CrossRef]
43. Riggs, W.J.; Roche, J.P.; Giardina, C.K.; Harris, M.S.; Bastian, Z.J.; Fontenot, T.E.; Buchman, C.A.; Brown, K.D.;
Adunka, O.F.; Fitzpatrick, D.C. Intraoperative Electrocochleographic Characteristics of Auditory Neuropathy
Spectrum Disorder in Cochlear Implant Subjects. Front. Neurosci. 2017, 11, 416. [CrossRef] [PubMed]
44. Attias, J.; Raveh, E.; Aizer-Dannon, A.; Bloch-Mimouni, A.; Fattal-Valevski, A. Auditory System Dysfunction
Due to Infantile Thiamine Deficiency: Long-Term Auditory Sequelae. Audiol. Neurotol. 2012, 17, 309–320.
[CrossRef] [PubMed]
45. Yasunaga, S.; Grati, M.; Cohen-Salmon, M.; El-Amraoui, A.; Mustapha, M.; Salem, N.; El-Zir, E.; Loiselet, J.;
Petit, C. A Mutation in OTOF, Encoding Otoferlin, a FER-1-like Protein, Causes DFNB9, a Nonsyndromic
Form of Deafness. Nat. Genet. 1999, 21, 363–369. [CrossRef]
46. PangrŠič, T.; Reisinger, E.; Moser, T. Otoferlin: A Multi-C 2 Domain Protein Essential for Hearing. Trends
Neurosci. 2012, 35, 671–680. [CrossRef]
47. Roux, I.; Safieddine, S.; Nouvian, R.; Grati, M.; Simmler, M.C.; Bahloul, A.; Perfettini, I.; Le Gall, M.;
Rostaing, P.; Hamard, G.; et al. Otoferlin, Defective in a Human Deafness Form, Is Essential for Exocytosis at
the Auditory Ribbon Synapse. Cell 2006, 127, 277–289. [CrossRef]
48. Johnson, C.P.; Chapman, E.R. Otoferlin Is a Calcium Sensor That Directly Regulates SNARE-Mediated
Membrane Fusion. J. Cell Biol. 2010, 191, 187–197. [CrossRef]
J. Clin. Med. 2020, 9, 1074 23 of 29

49. Padmanarayana, M.; Hams, N.; Speight, L.C.; Petersson, E.J.; Mehl, R.A.; Johnson, C.P. Characterization of
the Lipid Binding Properties of Otoferlin Reveals Specific Interactions between PI(4,5)P2 and the C2C and
C2F Domains. Biochemistry 2014, 53, 5023–5033. [CrossRef]
50. Fuson, K.; Rice, A.; Mahling, R.; Snow, A.; Nayak, K.; Shanbhogue, P.; Meyer, A.G.; Redpath, G.M.I.;
Hinderliter, A.; Cooper, S.T.; et al. Alternate Splicing of Dysferlin C2A Confers Ca2+-Dependent and
Ca2+-Independent Binding for Membrane Repair. Structure 2014, 22, 104–115. [CrossRef]
51. Jiménez, J.L.; Bashir, R. In Silico Functional and Structural Characterisation of Ferlin Proteins by Mapping
Disease-Causing Mutations and Evolutionary Information onto Three-Dimensional Models of Their C2
Domains. J. Neurol. Sci. 2007, 260, 114–123. [CrossRef]
52. Dulon, D.; Safieddine, S.; Jones, S.M.; Petit, C. Otoferlin Is Critical for a Highly Sensitive and Linear
Calcium-Dependent Exocytosis at Vestibular Hair Cell Ribbon Synapses. J. Neurosci. 2009, 29, 10474–10487.
[CrossRef]
53. Varga, R.; Avenarius, M.R.; Kelley, P.M.; Keats, B.J.; Berlin, C.I.; Hood, L.J.; Morlet, T.G.; Brashears, S.M.;
Starr, A.; Cohn, E.S.; et al. OTOF Mutations Revealed by Genetic Analysis of Hearing Loss Families Including
a Potential Temperature Sensitive Auditory Neuropathy Allele. J. Med. Genet. 2006, 43, 576–581. [CrossRef]
54. Wynne, D.P.; Zeng, F.G.; Bhatt, S.; Michalewski, H.J.; Dimitrijevic, A.; Starr, A. Loudness Adaptation
Accompanying Ribbon Synapse and Auditory Nerve Disorders. Brain 2013, 136, 1626–1638. [CrossRef]
55. Marlin, S.; Feldmann, D.; Nguyen, Y.; Rouillon, I.; Loundon, N.; Jonard, L.; Bonnet, C.; Couderc, R.;
Garabedian, E.N.; Petit, C.; et al. Temperature-Sensitive Auditory Neuropathy Associated with an Otoferlin
Mutation: Deafening Fever! Biochem. Biophys. Res. Commun. 2010, 394, 737–742. [CrossRef]
56. Wang, D.Y.; Wang, Y.C.; Weil, D.; Zhao, Y.L.; Rao, S.Q.; Zong, L.; Ji, Y.B.; Liu, Q.; Li, J.Q.; Yang, H.M.; et al.
Screening Mutations of OTOF Gene in Chinese Patients with Auditory Neuropathy, Including a Familial
Case of Temperature-Sensitive Auditory Neuropathy. BMC Med. Genet. 2010, 11, 79. [CrossRef]
57. Romanos, J.; Kimura, L.; Fávero, M.L.; Izarra, F.A.R.; De Mello Auricchio, M.T.B.; Batissoco, A.C.; Lezirovitz, K.;
Abreu-Silva, R.S.; Mingroni-Netto, R.C. Novel OTOF Mutations in Brazilian Patients with Auditory
Neuropathy. J. Hum. Genet. 2009, 54, 382–385. [CrossRef]
58. Matsunaga, T.; Mutai, H.; Kunishima, S.; Namba, K.; Morimoto, N.; Shinjo, Y.; Arimoto, Y.; Kataoka, Y.;
Shintani, T.; Morita, N.; et al. A Prevalent Founder Mutation and Genotype-Phenotype Correlations of OTOF
in Japanese Patients with Auditory Neuropathy. Clin. Genet. 2012, 82, 425–432. [CrossRef]
59. Runge, C.L.; Erbe, C.B.; Mcnally, M.T.; Van Dusen, C.; Friedland, D.R.; Kwitek, A.E.; Kerschner, J.E. A Novel
Otoferlin Splice-Site Mutation in Siblings with Auditory Neuropathy Spectrum Disorder. Audiol. Neurotol.
2015, 18, 374–382. [CrossRef]
60. Iwasa, Y.; Nishio, S.; Sugaya, A.; Kataoka, Y.; Kanda, Y.; Taniguchi, M.; Nagai, K.; Naito, Y.; Ikezono, T.;
Horie, R.; et al. OTOF Mutation Analysis with Massively Parallel DNA Sequencing in 2,265 Japanese
Sensorineural Hearing Loss Patients. PLoS ONE 2019, 14, e021593. [CrossRef]
61. Deafness Variation Database. Available online: http://deafnessvariationdatabase.org/ (accessed on 10 January
2020).
62. Sloan-Heggen, C.M.; Bierer, A.O.; Shearer, A.E.; Kolbe, D.L.; Nishimura, C.J.; Frees, K.L.; Ephraim, S.S.;
Shibata, S.B.; Booth, K.T.; Campbell, C.A.; et al. Comprehensive Genetic Testing in the Clinical Evaluation of
1119 Patients with Hearing Loss. Hum. Genet. 2016, 135, 441–450. [CrossRef]
63. Tertrais, M.; Bouleau, Y.; Emptoz, A.; Belleudy, S.; Sutton, R.B.; Petit, C.; Safieddine, S.; Dulon, D. Viral
Transfer of Mini-Otoferlins Partially Restores the Fast Component of Exocytosis and Uncovers Ultrafast
Endocytosis in Auditory Hair Cells of Otoferlin Knock-out Mice. J. Neurosci. 2019, 39, 3394–3411. [CrossRef]
64. Baig, S.M.; Koschak, A.; Lieb, A.; Gebhart, M.; Dafinger, C.; Nürnberg, G.; Ali, A.; Ahmad, I.;
Sinnegger-Brauns, M.J.; Brandt, N.; et al. Loss of Ca v 1.3 (CACNA1D) Function in a Human Channelopathy
with Bradycardia and Congenital Deafness. Nat. Neurosci. 2011, 14, 77–86. [CrossRef]
65. Brandt, A.; Striessnig, J.; Moser, T. Cav1.3 Channels Are Essential for Development and Presynaptic Activity
of Cochlear Inner Hair Cells. J. Neurosci. 2003, 23, 10832–10840. [CrossRef]
66. Platzer, J.; Engel, J.; Schrott-Fischer, A.; Stephan, K.; Bova, S.; Chen, H.; Zheng, H.; Striessnig, J. Congenital
Deafness and Sinoatrial Node Dysfunction in Mice Lacking Class D L-Type Ca2+ Channels. Cell 2000, 102,
89–97. [CrossRef]
J. Clin. Med. 2020, 9, 1074 24 of 29

67. Qi, F.; Zhang, R.; Chen, J.; Zhao, F.; Sun, Y.; Du, Z.; Bing, D.; Li, P.; Shao, S.; Zhu, H.; et al. Down-Regulation
of Cav1.3 in Auditory Pathway Promotes Age-Related Hearing Loss by Enhancing Calcium-Mediated
Oxidative Stress in Male Mice. Aging 2019, 11, 6490–6502. [CrossRef]
68. Eckrich, S.; Hecker, D.; Sorg, K.; Blum, K.; Fischer, K.; Münkner, S.; Wenzel, G.; Schick, B.; Engel, J.
Cochlea-Specific Deletion of Cav1.3 Calcium Channels Arrests Inner Hair Cell Differentiation and Unravels
Pitfalls of Conditional Mouse Models. Front. Cell. Neurosci. 2019, 13, 225. [CrossRef]
69. Haeseleer, F.; Imanishi, Y.; Sokal, I.; Filipek, S.; Palczewski, K. Calcium-Binding Proteins: Intracellular Sensors
from the Calmodulin Superfamily. In Biochemical and Biophysical Research Communications; Academic Press
Inc.: Cambridge, MA, USA, 2002; pp. 615–623.
70. Christel, C.; Lee, A. Ca 2 +-Dependent Modulation of Voltage-Gated Ca 2 + Channels. Biochim. Biophys. Acta
Gen. Subj. 2012, 1820, 1243–1252. [CrossRef]
71. Schrauwen, I.; Helfmann, S.; Inagaki, A.; Predoehl, F.; Tabatabaiefar, M.A.; Picher, M.M.; Sommen, M.;
Seco, C.Z.; Oostrik, J.; Kremer, H.; et al. A Mutation in CABP2, Expressed in Cochlear Hair Cells, Causes
Autosomal-Recessive Hearing Impairment. Am. J. Hum. Genet. 2012, 91, 636–645. [CrossRef]
72. Seal, R.P.; Akil, O.; Yi, E.; Weber, C.M.; Grant, L.; Yoo, J.; Clause, A.; Kandler, K.; Noebels, J.L.; Glowatzki, E.;
et al. Sensorineural Deafness and Seizures in Mice Lacking Vesicular Glutamate Transporter 3. Neuron 2008,
57, 263–275. [CrossRef]
73. Ruel, J.; Emery, S.; Nouvian, R.; Bersot, T.; Amilhon, B.; Van Rybroek, J.M.; Rebillard, G.; Lenoir, M.;
Eybalin, M.; Delprat, B.; et al. Impairment of SLC17A8 Encoding Vesicular Glutamate Transporter-3,
VGLUT3, Underlies Nonsyndromic Deafness DFNA25 and Inner Hair Cell Dysfunction in Null Mice. Am. J.
Hum. Genet. 2008, 83, 278–292. [CrossRef]
74. Petek, E.; Windpassinger, C.; Mach, M.; Rauter, L.; Scherer, S.W.; Wagner, K.; Kroisel, P.M. Molecular
Characterization of a 12q22-Q24 Deletion Associated with Congenital Deafness: Confirmation and Refinement
of the DFNA25 Locus. Am. J. Med. Genet. Part A 2002, 117, 122–126. [CrossRef]
75. Ryu, N.; Sagong, B.; Park, H.J.; Kim, M.A.; Lee, K.Y.; Choi, J.Y.; Kim, U.K. Screening of the SLC17A8 Gene as
a Causative Factor for Autosomal Dominant Non-Syndromic Hearing Loss in Koreans. BMC Med. Genet.
2016, 17, 6. [CrossRef]
76. Ryu, N.; Lee, S.; Park, H.J.; Lee, B.; Kwon, T.J.; Bok, J.; Park, C.I.; Lee, K.Y.; Baek, J.I.; Kim, U.K. Identification
of a Novel Splicing Mutation within SLC17A8 in a Korean Family with Hearing Loss by Whole-Exome
Sequencing. Gene 2017, 627, 233–238. [CrossRef]
77. Shearer, A.E.; Eppsteiner, R.W.; Frees, K.; Tejani, V.; Sloan-Heggen, C.M.; Brown, C.; Abbas, P.; Dunn, C.;
Hansen, M.R.; Gantz, B.J.; et al. Genetic Variants in the Peripheral Auditory System Significantly Affect
Adult Cochlear Implant Performance. Hear. Res. 2017, 348, 138–142. [CrossRef]
78. Akil, O.; Lustig, L. AAV-Mediated Gene Delivery to the Inner Ear. In Methods in Molecular Biology; Humana
Press Inc.: Totowa, NJ, USA, 2019; Volume 1950, pp. 271–282.
79. Alexander, C.; Votruba, M.; Pesch, U.E.A.; Thiselton, D.L.; Mayer, S.; Moore, A.; Rodriguez, M.; Kellner, U.;
Leo-Kottler, B.; Auburger, G.; et al. OPA1, Encoding a Dynamin-Related GTPase, Is Mutated in Autosomal
Dominant Optic Atrophy Linked to Chromosome 3q28. Nat. Genet. 2000, 26, 211–215. [CrossRef]
80. Delettre, C.; Lenaers, G.; Griffoin, J.M.; Gigarel, N.; Lorenzo, C.; Belenguer, P.; Pelloquin, L.; Grosgeorge, J.;
Turc-Carel, C.; Perret, E.; et al. Nuclear Gene OPA1, Encoding a Mitochondrial Dynamin-Related Protein, Is
Mutated in Dominant Optic Atrophy. Nat. Genet. 2000, 26, 207–210. [CrossRef]
81. Kasahara, A.; Scorrano, L. Mitochondria: From Cell Death Executioners to Regulators of Cell Differentiation.
Trends Cell Biol. 2014, 24, 761–770. [CrossRef]
82. Bansal, D.; Miyake, K.; Vogel, S.S.; Groh, S.; Chen, C.C.; Williamson, R.; McNeil, P.L.; Campbell, K.P. Defective
Membrane Repair in Dysferlin-Deficient Muscular Dystrophy. Nature 2003, 423, 168–172. [CrossRef]
83. Ferré, M.; Bonneau, D.; Milea, D.; Chevrollier, A.; Verny, C.; Dollfus, H.; Ayuso, C.; Defoort, S.; Vignal, C.;
Zanlonghi, X.; et al. Molecular Screening of 980 Cases of Suspected Hereditary Optic Neuropathy with a
Report on 77 Novel OPA1 Mutations. Hum. Mutat. 2009, 30, E692–E705. [CrossRef]
84. Davies, V.J.; Hollins, A.J.; Piechota, M.J.; Yip, W.; Davies, J.R.; White, K.E.; Nicols, P.P.; Boulton, M.E.;
Votruba, M. Opa1 Deficiency in a Mouse Model of Autosomal Dominant Optic Atrophy Impairs Mitochondrial
Morphology, Optic Nerve Structure and Visual Function. Hum. Mol. Genet. 2007, 16, 1307–1318. [CrossRef]
J. Clin. Med. 2020, 9, 1074 25 of 29

85. Yu-Wai-Man, P.; Griffiths, P.G.; Gorman, G.S.; Lourenco, C.M.; Wright, A.F.; Auer-Grumbach, M.; Toscano, A.;
Musumeci, O.; Valentino, M.L.; Caporali, L.; et al. Multi-System Neurological Disease Is Common in Patients
with OPA1 Mutations. Brain 2010, 133, 771–786. [CrossRef]
86. Santarelli, R.; Rossi, R.; Scimemi, P.; Cama, E.; Valentino, M.L.; La Morgia, C.; Caporali, L.; Liguori, R.;
Magnavita, V.; Monteleone, A.; et al. OPA1-Related Auditory Neuropathy: Site of Lesion and Outcome of
Cochlear Implantation. Brain 2015, 138, 563–576. [CrossRef]
87. Huang, T.; Santarelli, R.; Starr, A. Mutation of OPA1 Gene Causes Deafness by Affecting Function of Auditory
Nerve Terminals. Brain Res. 2009, 1300, 97–104. [CrossRef]
88. Diaz-Horta, O.; Abad, C.; Sennaroglu, L.; Ii, J.F.; DeSmidt, A.; Bademci, G.; Tokgoz-Yilmaz, S.; Duman, D.;
Cengiz, F.B.; Grati, M.; et al. ROR1 Is Essential for Proper Innervation of Auditory Hair Cells and Hearing in
Humans and Mice. Proc. Natl. Acad. Sci. USA 2016, 113, 5993–5998. [CrossRef]
89. Holm, T.H.; Lykke-Hartmann, K. Insights into the Pathology of the A3 Na+/K+-ATPase Ion Pump in
Neurological Disorders; Lessons from Animal Models. Front. Physiol. 2016, 7, 209. [CrossRef]
90. Nicolaides, P.; Appleton, R.E.; Fryer, A. Cerebellar Ataxia, Areflexia, Pes Cavus, Optic Atrophy, and
Sensorineural Hearing Loss (CAPOS): A New Syndrome. J. Med. Genet. 1996, 33, 419–421. [CrossRef]
91. Demos, M.K.; van Karnebeek, C.D.; Ross, C.J.; Adam, S.; Shen, Y.; Zhan, S.H.; Shyr, C.; Horvath, G.; Suri, M.;
Fryer, A.; et al. A Novel Recurrent Mutation in ATP1A3 Causes CAPOS Syndrome. Orphanet J. Rare Dis.
2014, 9, 15. [CrossRef]
92. Rosewich, H.; Weise, D.; Ohlenbusch, A.; Gärtner, J.; Brockmann, K. Phenotypic Overlap of Alternating
Hemiplegia of Childhood and CAPOS Syndrome. Neurology 2014, 83, 861–863. [CrossRef]
93. Tranebjærg, L.; Strenzke, N.; Lindholm, S.; Rendtorff, N.D.; Poulsen, H.; Khandelia, H.; Kopec, W.;
Lyngbye, T.J.B.; Hamel, C.; Delettre, C.; et al. Correction to: The CAPOS Mutation in ATP1A3 Alters
Na/K-ATPase Function and Results in Auditory Neuropathy Which Has Implications for Management. Hum.
Genet. 2018, 137, 111–127. [CrossRef]
94. Heimer, G.; Sadaka, Y.; Israelian, L.; Feiglin, A.; Ruggieri, A.; Marshall, C.R.; Scherer, S.W.; Ganelin-Cohen, E.;
Marek-Yagel, D.; Tzadok, M.; et al. CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and
Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene. J. Child Neurol. 2015, 30,
1749–1756. [CrossRef]
95. Paquay, S.; Wiame, E.; Deggouj, N.; Boschi, A.; De Siati, R.D.; Sznajer, Y.; Nassogne, M.-C. Childhood Hearing
Loss Is a Key Feature of CAPOS Syndrome: A Case Report. Int. J. Pediatr. Otorhinolaryngol. 2018, 104,
191–194. [CrossRef]
96. Potic, A.; Nmezi, B.; Padiath, Q.S. CAPOS Syndrome and Hemiplegic Migraine in a Novel Pedigree with the
Specific ATP1A3 Mutation. J. Neurol. Sci. 2015, 358, 453–456. [CrossRef]
97. Duat Rodriguez, A.; Prochazkova, M.; Santos Santos, S.; Rubio Cabezas, O.; Cantarin Extremera, V.;
Gonzalez-Gutierrez-Solana, L. Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia—Review of
the Literature and a New Family. Pediatr. Neurol. 2017, 71, 60–64. [CrossRef]
98. Maas, R.P.P.W.M.; Schieving, J.H.; Schouten, M.; Kamsteeg, E.J.; Van De Warrenburg, B.P.C. The Genetic
Homogeneity of CAPOS Syndrome: Four New Patients with the c.2452G>A (p.Glu818Lys) Mutation in the
ATP1A3 Gene. Pediatr. Neurol. 2016, 59, 71–75. [CrossRef]
99. Han, K.H.; Oh, D.Y.; Lee, S.; Lee, C.; Han, J.H.; Kim, M.Y.; Park, H.R.; Park, M.K.; Kim, N.K.D.; Lee, J.; et al.
ATP1A3 Mutations Can Cause Progressive Auditory Neuropathy: A New Gene of Auditory Synaptopathy.
Sci. Rep. 2017, 7, 1–11. [CrossRef]
100. Schoen, C.J.; Burmeister, M.; Lesperance, M.M. Diaphanous Homolog 3 (Diap3) Overexpression Causes
Progressive Hearing Loss and Inner Hair Cell Defects in a Transgenic Mouse Model of Human Deafness.
PLoS ONE 2013, 8, e56520. [CrossRef]
101. Schoen, C.J.; Emery, S.B.; Thorne, M.C.; Ammana, H.R.; Śliwerska, E.; Arnett, J.; Hortsch, M.; Hannan, F.;
Burmeister, M.; Lesperance, M.M. Increased Activity of Diaphanous Homolog 3 (DIAPH3)/Diaphanous
Causes Hearing Defects in Humans with Auditory Neuropathy and in Drosophila. Proc. Natl. Acad. Sci.
USA 2010, 107, 13396–13401. [CrossRef]
102. Kim, T.B.; Isaacson, B.; Sivakumaran, T.A.; Starr, A.; Keats, B.J.B.; Lesperance, M.M. A Gene Responsible for
Autosomal Dominant Auditory Neuropathy (AUNA1) Maps to 13q14-21. J. Med. Genet. 2004, 41, 872–876.
[CrossRef]
J. Clin. Med. 2020, 9, 1074 26 of 29

103. Starr, A.; Isaacson, B.; Michalewski, H.J.; Zeng, F.G.; Kong, Y.Y.; Beale, P.; Paulson, G.W.; Keats, B.J.B.;
Lesperance, M.M. A Dominantly Inherited Progressive Deafness Affecting Distal Auditory Nerve and Hair
Cells. JARO J. Assoc. Res. Otolaryngol. 2004, 5, 411–426. [CrossRef]
104. Charcot-Marie-Tooth Disease Fact Sheet|National Institute of Neurological Disorders and Stroke. Available
online: https://www.ninds.nih.gov/Disorders/Patient-caregiver-education/Fact-sheets/Charcot-Marie-Tooth-
Disease-Fact-Sheet (accessed on 31 December 2019).
105. Goswamy, J.; Bruce, I.A.; Green, K.M.J.; O’Driscoll, M.P. Cochlear Implantation in a Patient with
Sensori-Neural Deafness Secondary to Charcot-Marie-Tooth Disease. Cochlear Implants Int. 2012, 13,
184–187. [CrossRef]
106. Verhagen, W.I.M.; Huygen, P.L.M.; Gabreëls-Festen, A.A.W.M.; Engelhart, M.; Van Mierlo, P.J.W.B.; Van
Engelen, B.G.M. Sensorineural Hearing Impairment in Patients with Pmp22 Duplication, Deletion, and
Frameshift Mutations. Otol. Neurotol. 2005, 26, 405–414. [CrossRef]
107. Varga, R.; Kelley, P.M.; Keats, B.J.; Starr, A.; Leal, S.M.; Cohn, E.; Kimberling, W.J. Non-Syndromic Recessive
Auditory Neuropathy Is the Result of Mutations in the Otoferlin (OTOF) Gene [2]. J. Med. Genet. 2003, 40,
45–50. [CrossRef]
108. Kabzińska, D.; Korwin-Piotrowska, T.; Drechsler, H.; Drac, H.; Hausmanowa-Petrusewicz, I.; Kochański, A.
Late-Onset Charcot-Marie-Tooth Type 2 Disease with Hearing Impairment Associated with a Novel Pro105Thr
Mutation in the MPZ Gene. Am. J. Med. Genet. Part A 2007, 143, 2196–2199. [CrossRef]
109. Rance, G.; Fava, R.; Baldock, H.; Chong, A.; Barker, E.; Corben, L.; Delatycki, M.B. Speech Perception Ability
in Individuals with Friedreich Ataxia. Brain 2008, 131, 2002–2012. [CrossRef]
110. Tranebjærg, L. Deafness-Dystonia-Optic Neuronopathy Syndrome. In GeneReviews®[Internet]; Adam, M.P.,
Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Stephens, K., Amemiya, A., Eds.; University of
Washington: Seattle, WA, USA, 2003.
111. Bahmad, F.; Merchant, S.N.; Nadol, J.B.; Tranebjærg, L. Otopathology in Mohr-Tranebjærg Syndrome.
Laryngoscope 2007, 117, 1202–1208. [CrossRef]
112. Brookes, J.T.; Kanis, A.B.; Tan, L.Y.; Tranebjærg, L.; Vore, A.; Smith, R.J.H. Cochlear Implantation in
Deafness-Dystonia-Optic Neuronopathy (DDON) Syndrome. Int. J. Pediatr. Otorhinolaryngol. 2008, 72,
121–126. [CrossRef]
113. Kawarai, T.; Yamazaki, H.; Yamakami, K.; Tsukamoto-Miyashiro, A.; Kodama, M.; Rumore, R.; Caltagirone, C.;
Nishino, I.; Orlacchio, A. A Novel AIFM1 Missense Mutation in a Japanese Patient with Ataxic Sensory
Neuronopathy and Hearing Impairment. J. Neurol. Sci. 2020, 409, 116584. [CrossRef]
114. Joza, N.; Pospisilik, J.A.; Hangen, E.; Hanada, T.; Modjtahedi, N.; Penninger, J.M.; Kroemer, G. AIF: Not Just
an Apoptosis-Inducing Factor. Ann. N. Y. Acad. Sci. 2009, 1171, 2–11. [CrossRef]
115. Zong, L.; Guan, J.; Ealy, M.; Zhang, Q.; Wang, D.; Wang, H.; Zhao, Y.; Shen, Z.; Campbell, C.A.; Wang, F.;
et al. Mutations in Apoptosis-Inducing Factor Cause X-Linked Recessive Auditory Neuropathy Spectrum
Disorder. J. Med. Genet. 2015, 52, 523–531. [CrossRef]
116. Simon, M.; Richard, E.M.; Wang, X.; Shahzad, M.; Huang, V.H.; Qaiser, T.A.; Potluri, P.; Mahl, S.E.; Davila, A.;
Nazli, S.; et al. Mutations of Human NARS2, Encoding the Mitochondrial Asparaginyl-TRNA Synthetase,
Cause Nonsyndromic Deafness and Leigh Syndrome. PLoS Genet. 2015, 11, e1005097. [CrossRef]
117. Defourny, J.; Aghaie, A.; Perfettini, I.; Avan, P.; Delmaghani, S.; Petit, C. Pejvakin-Mediated Pexophagy
Protects Auditory Hair Cells against Noise-Induced Damage. Proc. Natl. Acad. Sci. USA 2019, 116, 8010–8017.
[CrossRef]
118. Delmaghani, S.; Del Castillo, F.J.; Michel, V.; Leibovici, M.; Aghaie, A.; Ron, U.; Van Laer, L.; Ben-Tal, N.;
Van Camp, G.; Weil, D.; et al. Mutations in the Gene Encoding Pejvakin, a Newly Identified Protein of the
Afferent Auditory Pathway, Cause DFNB59 Auditory Neuropathy. Nat. Genet. 2006, 38, 770–778. [CrossRef]
119. Schwander, M.; Sczaniecka, A.; Grillet, N.; Bailey, J.S.; Avenarius, M.; Najmabadi, H.; Steffy, B.M.; Federe, G.C.;
Lagler, E.A.; Banan, R.; et al. A Forward Genetics Screen in Mice Identifies Recessive Deafness Traits and
Reveals That Pejvakin Is Essential for Outer Hair Cell Function. J. Neurosci. 2007, 27, 2163–2175. [CrossRef]
120. Borck, G.; Rainshtein, L.; Hellman-Aharony, S.; Volk, A.; Friedrich, K.; Taub, E.; Magal, N.; Kanaan, M.;
Kubisch, C.; Shohat, M.; et al. High Frequency of Autosomal-Recessive DFNB59 Hearing Loss in an Isolated
Arab Population in Israel. Clin. Genet. 2012, 82, 271–276. [CrossRef]
J. Clin. Med. 2020, 9, 1074 27 of 29

121. Ebermann, I.; Walger, M.; Scholl, H.P.N.; Issa, P.C.; Lüke, C.; Nürnberg, G.; Lang-Roth, R.; Becker, C.;
Nürnberg, P.; Bolz, H.J. Truncating Mutation of the DFNB59 Gene Causes Cochlear Hearing Impairment and
Central Vestibular Dysfunction. Hum. Mutat. 2007, 28, 571–577. [CrossRef]
122. Chaleshtori, M.H.; Simpson, M.A.; Farrokhi, E.; Dolati, M.; Hoghooghi Rad, L.; Geshnigani, S.A.; Crosby, A.H.
Novel Mutations in the Pejvakin Gene Are Associated with Autosomal Recessive Non-Syndromic Hearing
Loss in Iranian Families. Clin. Genet. 2007, 72, 261–263. [CrossRef]
123. Collin, R.W.J.; Kalay, E.; Oostrik, J.; Çaylan, R.; Wollnik, B.; Arslan, S.; Den Hollander, A.I.; Birinci, Y.;
Lichtner, P.; Strom, T.M.; et al. Involvement of DFNB59 Mutations in Autosomal Recessive Nonsyndromic
Hearing Impairment. Hum. Mutat. 2007, 28, 718–723. [CrossRef]
124. Delmaghani, S.; Defourny, J.; Aghaie, A.; Beurg, M.; Dulon, D.; Thelen, N.; Perfettini, I.; Zelles, T.; Aller, M.;
Meyer, A.; et al. Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of
Peroxisomes. Cell 2015, 163, 894–906. [CrossRef]
125. Guipponi, M. The Transmembrane Serine Protease (TMPRSS3) Mutated in Deafness DFNB8/10 Activates the
Epithelial Sodium Channel (ENaC) in Vitro. Hum. Mol. Genet. 2002, 11, 2829–2836. [CrossRef]
126. Fasquelle, L.; Scott, H.S.; Lenoir, M.; Wang, J.; Rebillard, G.; Gaboyard, S.; Venteo, S.; François, F.;
Mausset-Bonnefont, A.L.; Antonarakis, S.E.; et al. Tmprss3, a Transmembrane Serine Protease Deficient in
Human DFNB8/10 Deafness, Is Critical for Cochlear Hair Cell Survival at the Onset of Hearing. J. Biol. Chem.
2011, 286, 17383–17397. [CrossRef]
127. Shrestha, B.R.; Chia, C.; Wu, L.; Kujawa, S.G.; Liberman, M.C.; Goodrich, L.V. Sensory Neuron Diversity in
the Inner Ear Is Shaped by Activity. Cell 2018, 174, 1229–1246. [CrossRef]
128. Li, Y.; Peng, A.; Ge, S.; Wang, Q.; Liu, J. MiR-204 Suppresses Cochlear Spiral Ganglion Neuron Survival
Invitro by Targeting TMPRSS3. Hear. Res. 2014, 314, 60–64. [CrossRef]
129. Scott, H.S.; Kudoh, J.; Wattenhofer, M.; Shibuya, K.; Berry, A.; Chrast, R.; Guipponi, M.; Wang, J.; Kawasaki, K.;
Asakawa, S.; et al. Insertion of β-Satellite Repeats Identifies a Transmembrane Protease Causing Both
Congenital and Childhood Onset Autosomal Recessive Deafness. Nat. Genet. 2001, 27, 59–63. [CrossRef]
130. Bonne-Tamir, B.; DeStefano, A.L.; Briggs, C.E.; Adair, R.; Franklyn, B.; Weiss, S.; Korostishevsky, M.;
Frydman, M.; Baldwin, C.T.; Farrer, L.A. Linkage of Congenital Recessive Deafness (Gene DFNB10) to
Chromosome 21q22.3. Am. J. Hum. Genet. 1996, 58, 1254–1259.
131. Weegerink, N.J.D.; Schraders, M.; Oostrik, J.; Huygen, P.L.M.; Strom, T.M.; Granneman, S.; Pennings, R.J.E.;
Venselaar, H.; Hoefsloot, L.H.; Elting, M.; et al. Genotype-Phenotype Correlation in DFNB8/10 Families with
TMPRSS3 Mutations. JARO J. Assoc. Res. Otolaryngol. 2011, 12, 753–766. [CrossRef]
132. Miyagawa, M.; Nishio, S.Y.; Sakurai, Y.; Hattori, M.; Tsukada, K.; Moteki, H.; Kojima, H.; Usami, S.I. The
Patients Associated with TMPRSS3 Mutations Are Good Candidates for Electric Acoustic Stimulation. Ann.
Otol. Rhinol. Laryngol. 2015, 124, 193S–204S. [CrossRef]
133. Eppsteiner, R.W.; Shearer, A.E.; Hildebrand, M.S.; DeLuca, A.P.; Ji, H.; Dunn, C.C.; Black-Ziegelbein, E.A.;
Casavant, T.L.; Braun, T.A.; Scheetz, T.E.; et al. Prediction of Cochlear Implant Performance by Genetic
Mutation: The Spiral Ganglion Hypothesis. Hear. Res. 2012, 292, 51–58. [CrossRef]
134. Meleca, J.B.; Stillitano, G.; Lee, M.Y.; Lyle, W.; Carol Liu, Y.C.; Anne, S. Outcomes of Audiometric Testing in
Children with Auditory Neuropathy Spectrum Disorder. Int. J. Pediatr. Otorhinolaryngol. 2020, 129, 109757.
[CrossRef]
135. Haustein, M.D.; Read, D.J.; Steinert, J.R.; Pilati, N.; Dinsdale, D.; Forsythe, I.D. Acute Hyperbilirubinaemia
Induces Presynaptic Neurodegeneration at a Central Glutamatergic Synapse. J. Physiol. 2010, 588, 4683–4693.
[CrossRef]
136. Chandan, H.S.; Prabhu, P. Audiological Changes over Time in Adolescents and Young Adults with Auditory
Neuropathy Spectrum Disorder. Eur. Arch. Oto-Rhino-Laryngol. 2015, 272, 1801–1807. [CrossRef]
137. Rance, G.; Beer, D.E.; Cone-Wesson, B.; Shepherd, R.K.; Dowell, R.C.; King, A.M.; Rickards, F.W.; Clark, G.M.
Clinical Findings for a Group of Infants and Young Children with Auditory Neuropathy. Ear Hear. 1999, 20,
238–252. [CrossRef]
138. Kraus, N.; Bradlow, A.R.; Cheatham, M.A.; Cunningham, J.; King, C.D.; Koch, D.B.; Nicol, T.G.; McGee, T.J.;
Stein, L.K.; Wright, B.A. Consequences of Neural Asynchrony: A Case of Auditory Neuropathy. JARO J.
Assoc. Res. Otolaryngol. 2000, 1, 33–45. [CrossRef]
J. Clin. Med. 2020, 9, 1074 28 of 29

139. Dimitrijevic, A.; Starr, A.; Bhatt, S.; Michalewski, H.J.; Zeng, F.G.; Pratt, H. Auditory Cortical N100 in Pre-
and Post-Synaptic Auditory Neuropathy to Frequency or Intensity Changes of Continuous Tones. Clin.
Neurophysiol. 2011, 122, 594–604. [CrossRef]
140. Kemp, D.T. Stimulated Acoustic Emissions from within the Human Auditory System. J. Acoust. Soc. Am.
1978, 64, 1386–1391. [CrossRef]
141. Prieve, B.; Fitzgerald, T. Otoacoustic Emissions. In Handbook of Clinical Audiology; Katz, J., Ed.; Wolters
Kluwer Health: Philadelphia, PA, USA, 2015.
142. Glattke, T.J. Otoacoustic Emissions—Clinical Applications, 2nd ed.; Thieme: New York, NY, USA, 2002.
143. Uus, K. Transient Auditory Neuropathy in Infants: How to Conceptualize the Recovery of Auditory Brain
Stem Response in the Context of Newborn Hearing Screening? Semin. Hear. 2011, 32, 123–128. [CrossRef]
144. Pappa, A.K.; Hutson, K.A.; Scott, W.C.; David Wilson, J.; Fox, K.E.; Masood, M.M.; Giardina, C.K.; Pulver, S.H.;
Grana, G.D.; Askew, C.; et al. Hair Cell and Neural Contributions to the Cochlear Summating Potential. J.
Neurophysiol. 2019, 121, 2163–2180. [CrossRef]
145. Dallos, P.; Cheatham, M.A. Production of Cochlear Potentials by Inner and Outer Hair Cells. J. Acoust. Soc.
Am. 1976, 60, 510–512. [CrossRef]
146. do Amaral Soares, I.; de Lemos Menezes, P.; Carnaúba, A.T.L.; de Andrade, K.C.L.; Lins, O.G. Estudo Do
Microfonismo Coclear Na Neuropatia Auditiva. Braz. J. Otorhinolaryngol. 2016, 82, 722–736. [CrossRef]
147. Santarelli, R. Information from Cochlear Potentials and Genetic Mutations Helps Localize the Lesion Site in
Auditory Neuropathy. Genome Med. 2010, 2, 91. [CrossRef]
148. Santarelli, R.; Arslan, E. Electrocochleography in Auditory Neuropathy. Hear. Res. 2002, 170, 32–47.
[CrossRef]
149. Abbas, P.J.; Brown, C.J. Assessment of Responses to Cochlear Implant Stimulation at Different Levels of the
Auditory Pathway. Hear. Res. 2015, 322, 67–76. [CrossRef]
150. Fitzpatrick, D.C.; Campbell, A.T.; Choudhury, B.; Dillon, M.P.; Forgues, M.; Buchman, C.A.; Adunka, O.F.
Round Window Electrocochleography Just before Cochlear Implantation: Relationship to Word Recognition
Outcomes in Adults. Otol. Neurotol. 2014, 35, 64–71. [CrossRef]
151. Formeister, E.J.; McClellan, J.H.; Merwin, W.H.; Iseli, C.E.; Calloway, N.H.; Teagle, H.F.B.; Buchman, C.A.;
Adunka, O.F.; Fitzpatrick, D.C. Intraoperative Round Window Electrocochleography and Speech Perception
Outcomes in Pediatric Cochlear Implant Recipients. Ear Hear. 2015, 36, 249–260. [CrossRef]
152. Durrant, J.D.; Wang, J.; Ding, D.L.; Salvi, R.J. Are Inner or Outer Hair Cells the Source of Summating
Potentials Recorded from the Round Window? J. Acoust. Soc. Am. 1998, 104, 370–377. [CrossRef]
153. Snyder, R.L.; Schreiner, C.E. The Auditory Neurophonic: Basic Properties. Hear. Res. 1984, 15, 261–280.
[CrossRef]
154. Henry, K.R. Auditory Nerve Neurophonic Recorded from the Round Window of the Mongolian Gerbil. Hear.
Res. 1995, 90, 176–184. [CrossRef]
155. Santarelli, R.; Scimemi, P.; Dal Monte, E.; Arslan, E. Cochlear Microphonic Potential Recorded by
Transtympanic Electrocochleography in Normally-Hearing and Hearing-Impaired Ears. Acta Otorhinolaryngol.
Ital. 2006, 26, 78–95.
156. Wichmann, C.; Moser, T. Relating Structure and Function of Inner Hair Cell Ribbon Synapses. Cell Tissue Res.
2015, 361, 95–114. [CrossRef]
157. Santarelli, R.; Arslan, E. Electrocochleography. In Handbook of Clinical Audiology, 7th ed.; Katz, J., Ed.; Wolters
Kluwer Health Adis (ESP): London, UK, 2014.
158. Korczak, P.; Smart, J.; Delgado, R.; Strobel, T.M.; Bradford, C. Auditory Steady-State Responses. J. Am. Acad.
Audiol. 2012, 23, 146–170. [CrossRef]
159. Lu, P.; Huang, Y.; Chen, W.-X.; Jiang, W.; Hua, N.-Y.; Wang, Y.; Wang, B.; Xu, Z.-M. Measurement of Thresholds
Using Auditory Steady-State Response and Cochlear Microphonics in Children with Auditory Neuropathy.
J. Am. Acad. Audiol. 2019, 30, 672–676. [CrossRef]
160. Sharma, A.; Cardon, G.; Henion, K.; Roland, P. Cortical Maturation and Behavioral Outcomes in Children
with Auditory Neuropathy Spectrum Disorder. Int. J. Audiol. 2011, 50, 98–106. [CrossRef] [PubMed]
161. Michalewski, H.J.; Starr, A.; Zeng, F.G.; Dimitrijevic, A. N100 Cortical Potentials Accompanying Disrupted
Auditory Nerve Activity in Auditory Neuropathy (AN): Effects of Signal Intensity and Continuous Noise.
Clin. Neurophysiol. 2009, 120, 1352–1363. [CrossRef]
J. Clin. Med. 2020, 9, 1074 29 of 29

162. Michalewski, H.J.; Starr, A.; Nguyen, T.T.; Kong, Y.Y.; Zeng, F.G. Auditory Temporal Processes in
Normal-Hearing Individuals and in Patients with Auditory Neuropathy. Clin. Neurophysiol. 2005, 116,
669–680. [CrossRef]
163. Emami, S.F.; Abdoli, A. Cortical Auditory Evoked Potentials in Children with Auditory
Neuropathy/Dys-Synchrony. Indian J. Otolaryngol. Head Neck Surg. 2019, 71, 238–242. [CrossRef]
164. Narne, V.K.; Vanaja, C.S. Speech Identification and Cortical Potentials in Individuals with Auditory
Neuropathy. Behav. Brain Funct. 2008, 4, 15. [CrossRef]
165. Näätänen, R. The Mismatch Negativity: A Powerful Tool for Cognitive Neuroscience. Ear Hear. 1995, 16,
6–18. [CrossRef]
166. Squires, N.K.; Squires, K.C.; Hillyard, S.A. Two Varieties of Long-Latency Positive Waves Evoked by
Unpredictable Auditory Stimuli in Man. Electroencephalogr. Clin. Neurophysiol. 1975, 38, 387–401. [CrossRef]
167. Kumar, A.U.; Jayaram, M. Auditory Processing in Individuals with Auditory Neuropathy. Behav. Brain Funct.
2005, 1, 21. [CrossRef]
168. Rance, G.; Starr, A. Pathophysiological Mechanisms and Functional Hearing Consequences of Auditory
Neuropathy. Brain 2015, 138, 3141–3158. [CrossRef]
169. Walker, E.; McCreery, R.; Spratford, M.; Roush, P. Children with Auditory Neuropathy Spectrum Disorder
Fitted with Hearing AIDS Applying the American Academy of Audiology Pediatric Amplification Guideline:
Current Practice and Outcomes. J. Am. Acad. Audiol. 2016, 27, 204–218. [CrossRef]
170. Giraudet, F.; Avan, P. Auditory Neuropathies. Curr. Opin. Neurol. 2012, 25, 50–56. [CrossRef]
171. Breneman, A.I.; Gifford, R.H.; Dejong, M.D. Cochlear Implantation in Children with Auditory Neuropathy
Spectrum Disorder: Long-Term Outcomes. J. Am. Acad. Audiol. 2012, 23, 5–17. [CrossRef]
172. Teagle, H.F.B.; Roush, P.A.; Woodard, J.S.; Hatch, D.R.; Zdanski, C.J.; Buss, E.; Buchman, C.A. Cochlear
Implantation in Children with Auditory Neuropathy Spectrum Disorder. Ear Hear. 2010, 31, 325–335.
[CrossRef]
173. Crispino, G.; Di Pasquale, G.; Scimemi, P.; Rodriguez, L.; Ramirez, F.G.; de Siati, R.D.; Santarelli, R.M.;
Arslan, E.; Bortolozzi, M.; Chiorini, J.A.; et al. BAAV Mediated GJB2 Gene Transfer Restores Gap Junction
Coupling in Cochlear Organotypic Cultures from Deaf Cx26Sox10Cre Mice. PLoS ONE 2011, 6, e23279.
[CrossRef]

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