Download Guidelines for Assessment and Management of

Auditory Neuropathy/Dys-synchrony
Guidelines for Assessment and Management of
Children with Auditory
Neuropathy/Dys-synchrony
Linda J. Hood, Ph.D.
Professor, Vanderbilt University, Nashville, Tennessee
Honorary Professor, University of Queensland, Australia
Thierry Morlet, Ph.D.
Head, Auditory Physiology and Psychoacoustics Research Laboratory
Alfred I. duPont Hospital for Children, Wilmington, Delaware
Patients with outer hair cell responses and absent/abnormal
auditory brainstem responses, are classified as having:
- AN: auditory neuropathy*
- AN/AD: auditory neuropathy/dys-synchrony**
- ANSD: auditory neuropathy spectrum disorder***
Possible sites of abnormality:
- Partial or complete loss of inner hair cells, IHC malfunction
- Synaptic juncture of inner hair cells and VIIIth nerve
- Abnormal function of the VIIIth nerve
Charles I. Berlin, Ph.D.
Professor, University of South Florida
Former Director, Kresge Hearing Research Laboratory, New Orleans, Louisiana
* Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI. 1996. Auditory neuropathy. Brain, 119:741-753.
** Berlin C, Hood L, Rose K. 2001. On renaming auditory neuropathy as auditory dys-synchrony: Implications for a clearer
understanding of the underlying mechanisms and management options. Audiology Today 13:15-17.
*** Auditory neuropathy consensus conference. J Gravel, 2008, Como, Italy
Ten questions audiologists might
ask about AN/AD
AN/AD Question 1
• Assessment
– Test strategies and variation (Q1, Q2)
• With and without ABR
“What is the best test strategy for
accurately identifying AN/AD?”
– Differential diagnosis (Q3, Q4, Q5)
• EVA, cochlear nerve deficiency, imaging, central APD
• Neuromaturation
– Cortical responses and AN/AD (Q6)
“What kind of variation can I expect?”
• Management
–
–
–
–
Amplification and FM systems (Q7)
Cochlear implants (Q8)
Genetics and AN/AD (Q9)
Treating the patient (Q10)
Auditory Neuropathy
Auditory Neuropathy/Dys-synchrony
Auditory Neuropathy Spectrum Disorder
Demographic information
 Problems listening in noise, fluctuation, delayed speech/ language
development
Number of Subjects
50
 Physiologic Responses
 Hair Cell Responses
 Present otoacoustic emissions
 Present cochlear microphonics
 Neural Responses
 Variable audiometric configurations (detection)
 Variable but generally poor speech recognition (discrimination)
40
30
20
10
 Absent auditory brainstem responses
 Absent middle ear muscle reflexes
 Absent olivocochlear reflex (no suppression of otoacoustic emissions)
 Behavioral Responses
Male
Female
60
 Clinical Presentation
0
0-24m
25-48m
4-6y
7-12y
13-18y
19-30y
30+y
Age Group
Gender
Male
Female
Percent
55.7
44.3
Berlin, Hood, Morlet et al.,
International Journal of Audiology, 2010
1
ABR and Cochlear Microphonics
OAE test results
(CM - electrical responses generated in part by the outer hair cells)
Left Ear
Present
Absent
Partial/Questionable
76%
17%
7%
Right Ear
Present
Absent
Partial/Questionable
75%
16%
9%
From Berlin, Hood, Morlet et al., 2010
Auditory Brainstem Response
• The ABR is absent or
markedly abnormal
Normal ABR to condensation and
rarefaction clicks; CM inverts - neural
components do not.
AN/AD patient - all CM, no
neural response
•
•
•
Can CM presence alone, without OAEs, be used to diagnose AN/AD
Amplitude, duration characteristics
CM presence in an ABR trace is normal
Efferent Control of the Auditory Periphery
• Middle-ear muscle reflex
(MEMR)
– Controls the stapedius and tensor
tympani muscles of the middle
ear
Absent
Abn/High level
V only
• Recordings appear as:
From Berlin, Hood et al., 2010
– A “flat” ABR with no evidence of
any peaks or
– Poorly synchronized, but later
peaks (Wave V) that appear only
at high stimulus levels.
No MEMR
Some MEMR
Absent MEMRs
90%
(all absent)
Abnormal MEMRs 10%
(combination of elevated and absent)
• Medial olivocochlear reflex
(MOCR)
– Controls portions of the cochlea
Reference: Normal ABR
From Hood et al., 2003
Patient Variation:
A Continuum of AN/AD
No overt delays
or auditory
complaints
until adulthood
or
until first
MEMRs or ABR
Inconsistent auditory responses, can
be good in quiet, poorest in noise.
Audiograms can be misleading or
fluctuate. ABR desynchronized,
middle-ear muscle reflexes absent.
Visual phonetic language usually
works best until cochlear
implantation, unless family prefers
cultural Deafness.
Question 1:“What is the best test strategy for
accurately identifying AN/AD?”
• Physiologic Measures
– Presence of cochlear responses related to active cochlear
mechanisms (OAEs, cochlear microphonics)
Total lack of
sound
awareness
• OAEs affected by middle-ear problems
– Absent or highly abnormal neural responses
• Definitive measure is ABR
• MEMR and MOCR typically affected based on poor afferent input
• Changes over time
• Stable, fluctuating, progressive (changes in hair cell and/or neural
responses)
1
5
10
• Partial recovery of auditory ability (improved pure tone responses and
sound awareness despite continued dys-synchrony)
Berlin, Hood, Morlet et al., 2005, 2010
2
An Audiologic Test Strategy from
Kresge Hearing Research Laboratory
AN/AD Question 2
A triage for every new patient:
“What can I do to accurately evaluate
children with suspected AN/AD if I don’t
have access to ABR in my practice?”
– Tympanograms
– Ipsilateral and contralateral MEMRs
– Otoacoustic emissions
to quickly and objectively obtain information
that guides the remainder of evaluation.
Credit: C. Berlin et al.
Audiologic Test Strategy
Variation in Detection of Sound
Audiometric thresholds (n=258 Ears)
• Tymps abnormal, MEMRs elevated/absent, OAEs absent Conductive
20
18
• Tymps normal, MEMRs normal, OAEs absent - Thresholds
most likely between 35-60 dB HL
Percent of Ears
16
• Tymps normal, MEMRs normal, OAEs normal - Thresholds
< 35 dB HL
14
12
10
8
6
4
• Tymps normal, MEMRs elevated/absent, OAEs absent Thresholds > 60 dB HL or neural
2
N
M
ild
M
ild
-M
M od
ild
-S
M ev
ild
-P
ro
f
M
M od
od
-S
e
M
od v
-P
ro
f
S
Se ev
vPr
of
Pr
of
o
N
or rma
m
al l
-M
od
0
• Tymps normal, MEMRs absent, OAEs present - Auditory
neuropathy/dys-synchrony; neural disorder
Audiometric Threshold Range
From Berlin, Hood, Morlet et al., 2010
Variation in Discrimination of Sound
Auditory Neuropathy/Dys-synchrony
Word recognition in 68 patients age 4 years and older
Temporal Processing
A. 38 of 68 patients have 0% word recognition in quiet and hearing sensitivity ranging from mild to
severe.
C. 5 of 68 patients have good word
recognition in quiet and NO word recognition in
noise (+10 signal-noise ratio).
recognition in quiet and some word recognition
in noise, though below normal or SNHL.
100
Gap
No gap
Time
Gap detection (ms)
B. 25 of 68 patients have variable word
10
1
*
0
10
20
30
40
50
Sensation level (dB)
Gap Detection
Linear function for 98% of SNHL cases from Yellin, Jerger,
Fifer, 1989 study (n=324)
Data from Rance et al., 2007
*Kresge Lab
patients
AN/AD sound demo - Dr. F-G Zeng
3
Question 2: “What can I do to accurately evaluate children
with suspected AN/AD if I don’t have access to ABR in my
practice?”
AN/AD Question 3
• Physiologic Measures
– MEMRs with normal middle ear function
– Combination of OAEs and MEMRs
• MEMRs define neural abnormality in presence of normal middle
ear function
• Present OAEs consistent with normal middle ear function
•
“What other auditory problems might ‘look
like’ AN/AD, based on similar test results?”
Behavioral Measures
• Pure tone thresholds are not definitive.
• Speech recognition in quiet is highly variable; speech recognition in
noise typically poorer than found in SNHL.
• Poorer than expected speech recognition in noise may be a possible
indicator to refer for physiologic testing.
Associated Disorders and Differential
Diagnosis
• Cochlear Nerve Deficiency
AI duPont Database
Absent or hypoplastic auditory nerves are not uncommon and these
cases usually resemble ANSD when OHC are present and functioning.
• 24 children (out of 150+) were identified with MRI
evidence of cochlear nerve dysplasia (CND).
• Three were affected bilaterally.
• 60% of unilateral cases occurred on the left side.
• Other inner ear anomalies were found in 50% of
patients including all patients with bilateral CND.
• Of the 24 patients tested, more than 75% had an
audiometric profile of ANSD (absent MEMR, present
OAEs/CM, absent ABR). ANSD feature couldn’t be
confirmed in 4 patients.
4
Imaging studies
• Imaging studies are useful in evaluating hearing loss
to diagnose inner ear malformations as well as to
check for presence and size of the auditory nerve.
• Absent or hypoplastic auditory nerves are not
uncommon (Buchman et al., 2006) and these cases
usually resemble ANSD when OHC are present and
functioning.
• Audiological management in these patients is
problematic because a cochlear implant cannot work
when the nerve is absent and might not work well
when the nerve is hypoplastic.
• An MRI does not give the full picture!
Associated Disorders and Differential
Diagnosis
• Cochlear Nerve Deficiency
• Friedreich Ataxia
Rance et al., 2010
Constellation of findings compatible
with cochlear hypoplasia including nonpartitioned cochlea, absent
visualization of the modiolus,
decreased size of the internal auditory
canal and absent visualization of
cochlear nerve and cochlea aperture.
Friedreich Ataxia may look like ANSD
• Dys-synchrony
• Gap detection affected as well
• Brain still able to process language for a while
(but in good conditions only, i.e., without
background noise).
• Dys-synchrony occurs after acquisition of
language (ANSD which mostly affects preverbal infants).
Associated Disorders and Differential
Diagnosis
• Cochlear Nerve Deficiency
• Friedreich Ataxia
• Enlarged Vestibular Aqueduct
5
ANSD Pattern LE EVA
EVA: Definition
• EVA is the most common radiological abnormality seen in
children with SNHL: 5-15% of children with SNHL have
EVA.
• EVA can be associated with other congenital ear
anomalies, such as a hypoplastic cochlea.
• Studies suggest that most children with EVA will develop
some degree of hearing loss.
• SNHL onset may occur from birth to adolescence, usually
during childhood and may be precipitated by various
factors such as head trauma. Hearing loss is often
progressive and can fluctuate.
• Vestibular and balance disorders can also be associated.
• Children with an EVA present with a wide variety of
audiometric thresholds and physiologic measurements.
Subject 004
ANSD Pattern LE EVA
Present CM, Absent ABR
Subject 037
EVA
• Phenotypic expressions associated with EVA
are heterogeneous to include the following
possibilities:
– normal hearing
– total deafness
– progressive sensorineural hearing loss
– fluctuating sensorineural hearing loss or sudden
sensorineural hearing loss, sometimes subsequent
to head trauma.
– There is not always agreement between OAEs,
ABRs, MEMRs, PTA & speech scores.
AN/AD Question 4
“What about neuromaturation?”
“How often does it happen and is there a way to
predict this?”
6
Can we predict which children
will have neuromaturation?
Neuromaturation
Hyperbilirubinemia.
Exchange Transfusion
Present TEOAEs
Normal thresholds by 7
months
•
NO!
•
Medical review of all children
with neuromaturation was
inconclusive
•
One of the children in the
database who had the most risk
factors for hearing loss had
definite neuromaturation
•
Children with neuromaturation
had regions of present DPOAEs
•
Neuromaturation typically occurs
prior to 12 months of age
Attias and Raveh, 2007
ANSD and CAPD
AN/AD Question 5
“I thought a child had central auditory processing
disorder (APD), but it turned out to be AN/AD.”
“How are these two problems similar and different?”
“Is the management different?”
• Different etiologies
• But both share similarities
• Can be confused unless appropriate testing is
used
• Treatment is not the same
Auditory Processing Disorders
• In children, auditory processing disorder (APD) presents as
difficulty processing speech despite audiometrically
normal hearing.
• Commonly, this difficulty is most pronounced in the
presence of competing background noise, which,
unfortunately, represents most typical real-world listening
situations.
• The causes of (C)APD are not known, and in all likelihood,
(C)APD as broadly defined represents a family of auditory
processing deficits stemming from multiple causes.
Clinical Presentation
•
•
•
•
•
•
•
MEMR present and in the normal range
OAE present
Suppression of OAEs present
Normal ABR (to a click)
Normal speech in quiet
Impaired speech in noise
Deficits related to auditory percepts
dependent in temporal cues
7
APD suspected: Importance of the
triage
Illustrative Case
•
•
•
•
•
•
•
•
•
•
Normal birth and medical history
11 months: ENT for ear infections
Babbling at 12 months
14 months: 1st set of tubes
1st true word at 18 months
22 months: 2nd set of tubes
3 years: ENT for speech delay. Failed most of her 1st grade classes
Soundfield audiogram indicated normal hearing thresholds in at least the
better ear. Speech therapy recommended
7 years: Audiology for CAPD evaluation
Fluctuations in achievement (good/bad weeks)`
Auditory Neuropathy Spectrum
Disorder or (C)APD?
ANSD vs APD
ANSD
APD
Normal
Normal
Abnormal or absent
Present
OAE
Present or absent (over
time)
Present
ABR
Abnormal or absent
Normal
Normal
Word recognition (quiet)
Normal to
severe/profound
Excellent to poor
Excellent
Word recognition (noise)
Poor
Fair to poor
• Auditory Neuropathy Spectrum Disorder
Tympanogram
MEMR
Pure-tone thresholds
AN/AD Question 6
“What about cortical responses – can they
help in figuring out what a child hears and
help in planning management?”
– ABR, MEMR absent
– Cortical potentials can be present
– Cochlear implants a management option
• Central APD
– Peripheral synchrony usually within normal limit
– ABR, MEMR usually normal
– Cortical potentials present
– Cochlear implant not useful
Cortical Potentials
• Normal maturation and functioning of auditory
cortical areas is a precondition for normal
development of speech and oral language skills.
• Disruption of normal maturational processes will
result in diminished capacity for speech/language
acquisition.
• Cortical potentials are useful in assessing
maturation and function of the auditory cortical
areas.
8
P1
/da/ 7 year old
Martin et al., 1996
Sharma et al., 2011
Cortical Potentials
• P1 latency seems to be a strong predictor of behavioral
outcome.
• Children with ANSD show distinct patterns of central
auditory maturation (i.e., different morphology, latency and
amplitude of the cortical potentials).
• Cortical potentials can (and should) be used to monitor
auditory cortical development before AND during
management (can help assess benefit of hearing aids, CI,
etc...).
Cortical Potentials
•
•
•
P1-N1-P2 complex provides information regarding the arrival of sound to the
auditory cortex.
It does not provide information regarding discrimination.
Other cortical potentials or more complex sounds could/should be
considered in evaluating the cortical processing of speech in infants.
Martin et al., 1996
9
AN/AD Management:
Protocols and Outcomes
AN/AD Question 7
• Outcomes data are based on three AN/AD patient databases:
“Do hearing aids and FM systems help?”
– Kresge Hearing Research Laboratory, Louisiana State University Health
Sciences Center, New Orleans, LA
• Charles Berlin PhD, Linda Hood PhD, Thierry Morlet PhD et al. (1988-2005)
“How do I know if hearing aids are helping – or if it’s
time to try something else?”
– Vanderbilt University, Vanderbilt Bill Wilkerson Center, Nashville, TN
• Linda Hood PhD, Cathi Hayes AuD et al. (2005-present)
– A.I. DuPont Medical Center/Nemours Children’s Hospital, Wilmington,
DE
• Thierry Morlet PhD et al. (2005-present)
Children with Diagnosis of ANSD
(n=44)
Neuromaturation
(n=5)
Amplification Trial Recommended
(n=39)
FM, based on normal thresholds
(n=1)
Management of Vanderbilt
AN/AD Patients with
Hearing Aids
Outcomes with Amplification
n=198 AN/AD patients from three sites
Good benefit = functional interaction,
facilitates speech/language
development
Hearing Aids recommended
(n=38)
When should hearing aids be fit?
Some benefit = some help in
language acquisition
- Once frequency specific/ear specific thresholds are obtained through behavioral
testing, typically at about 6 months.
Little benefit = environmental sounds
only
- Fit using pediatric hearing aid fitting protocol (DSL 5.0: Desired Sensation Level).
No benefit = no help in
communication or speech/language
development
- Monitor closely and adjust as needed.
What if a child cannot perform reliable behavioral
testing due to delays in development?
Proceed with a conservative hearing aid fitting if the following criteria are met:
1. Speech evaluation shows delayed receptive and/or expressive language skills.
2. Parent auditory questionnaire identifies areas of concern.
Kresge Lab (n=85)
Vanderbilt (n=27)
A.I.DuPont (n=86)
4%
8%
26%
62%
Adapted from Hayes et al., 2010
Management of AN/AD: FM Systems
AN/AD Question 8
• AN/AD patients generally have very poor ability to
understand speech in background noise.
• Vanderbilt AN Patients: FM used with amplification in all
patients, but one who uses FM only (normal threshold
sensitivity)
“Who are candidates for cochlear implants?”
“And what are the outcomes?”
• Efferent feedback function (middle-ear and olivocochlear
reflexes) is disabled
• Thought to assist in listening in noise (e.g., Liberman and Guinan,
1998)
10
Outcomes with Cochlear Implants
Management of Vanderbilt
AN/AD Patients with
Cochlear Implants
Children with ANSD, unsuccessful
with amplification, cochlear implant
recommended
n=100 AN/AD patients from three sites
Success = functional
interaction, facilitates
speech/language
development
Lack of responsiveness to sound
•
GOAL: Three months progress in three months
time (preferably more)
•
Percent Patients
Lack of progress in speech/language
development
Re-evaluate every 3 months to
verify 3 months progress in 3
months time
If progressing, continue to
evaluate every 3 months.
If NOT progressing, initiate
cochlear implant work up and
continue monitoring
progress.
Cochlear implant recommendation
- Lack of progress with amplification
- Continuing delays in speech and language development
NOTE: Vanderbilt unsuccessful
patient has generalized neural
disease, poor neural responses
across modalities, abnormal
adaptation to sound, resulting in
non-use of CI.
Kresge Lab (n=49)
- Approximately ½ of the Vanderbilt ANSD CI patients have bilateral CIs, by
successive or simultaneous implantation.
Vanderbilt (n=20)
A.I.DuPont (n=31)
Successful
78%
Successful
Too soon to tell
(recent CI)
15%
Too soon to tell
(recent CI)
Insufficient information
7%
74%
6%
Insufficient information 20%
Adapted from Hayes et al., 2010
Auditory Neuropathy/Dys-synchrony and
Cochlear Implants
Success with cochlear implants has been
demonstrated in infants, children and adults
with AN/AD.
•
Post-implant neural response telemetry, EABR,
MEMR reflexes are comparable to responses in
non-AN/AD implant patients (Shallop et al.,
2001)
Photo: Cochlear Corporation
•
Inner hair cell, neurotransmitter, synaptic losses
could leave neural function intact.
•
AN patients with conditions associated with
VIIIth nerve dysfunction and demyelinating
conditions have demonstrated benefit from CI.
•
Matched 35 ANSD and 35 SNHL
children with cochlear implants
•
No significant difference in word
recognition between groups
•
80% of ANSD and 69% of SNHL
patients achieved open-set word
recognition scores >80%.
Word Recognition
Percent Correct
•
Cochlear Implant Performance
Breneman AI, Gifford R, DeJong MD. 2012. Cochlear implantation of children with auditory
neuropathy neuropathy spectrum disorder: Long-term outcomes.
J Amer Acad Audiol. 25:5-17.
– 32 of 35 ANSD had some open-set
word recognition.
Test Results (Age 15 years)
Case Study: Detection versus Discrimination in
Cochlear Implant Decision-making
Normal OAEs
Frequency (Hz)
250
-10
500
1000
2000
4000
8000
0
10
Female, age: 15 years
•
Increased listening difficulty,
particularly in noise
•
Difficulty in school, losing interest
20
dB Hearing Level
•
30
40
50
60
70
80
Absent ABRs, CM only present
90
100
110
1
•
3
4
5
6
7
8
9
10
11
B
C
Vision problems, progressively
worsening
– Optic nerve atrophy
•
2
H,V
Other affected family members
– Autosomal dominant inheritance
H,V
pattern
H,V
V
H,V
V
Word Recognition Quiet (40 SL):
W22*: 8% R / 10% L
CID Sentences*: 19% R / 36% L
Word Recognition Noise (+10):
W22*: 0% R / 0% L
SIN*: 0% R / 0% L
Tymps: Type A R&L
MEMRs: Ipsi and contra absent R&L
*recorded stimuli
11
Post Cochlear Implant
Speech Recognition Results
AN/AD Question 9
(Age 16 years)
• Hearing In Noise Test (HINT) stimuli at 60 dB HL
“Can AN/AD be inherited?”
• In quiet: 96%
• CID Everyday Sentences at 60 dB HL
“What genes are associated with AN/AD?”
• In noise: 74% at +10 S/N
• Pre-implant performance in noise: 0% at +10 S/N
Genetics and AN/AD
• Affected siblings or other family members suggests genetic
forms of AN/AD
– Recessive, dominant, and mitochondrial inheritance patterns
• AN/AD can be part of a syndrome or non-syndromic
Candidate Genes (gene name, loci or protein product):
• OTOF
• PJVK
• 13q14-21 (AUNA1)
• Xq23-27.3 (AUNX)
• 12SrRNA (mtDNA)
• SLC19A2
• FXN
• ERG2
• PMP22
• MPZ
• Cx26 (GJB2), Cx29, Cx30 (GJB6), Cx31 (GJB3), Cx32 (GJB1)
Genetics: Non-Syndromic Recessive Auditory Neuropathy
Genetics: Non-Syndromic Dominant Auditory Neuropathy
AUNA1: AUDITORY NEUROPATHY, AUTOSOMAL DOMINANT, 1
Non-syndromic
Localized to to chromosome 13q (13q14-21) by Kim et al. (2004)
Mutation in the DIAPH3 gene on chromosome 13q identified by Schoen et al.
(2010)
Clinical Features
• Multigenerational U.S. family of European descent segregating autosomal
dominant auditory neuropathy. Hearing loss had an average age of onset
of 18.6 years (Kim et al., 2004).
• Benefit from cochlear implants in family members reported by Starr et al.,
(2004)
Van Camp G, Smith RJH. Hereditary Hearing Loss Homepage.
URL: http://hereditaryhearingloss.org
Online Mendelian Inheritance in Man (omim.org)
Genetics: Non-Syndromic Recessive Auditory Neuropathy
DFNB9: NON-SYNDROMIC RECESSIVE DEAFNESS 9
AUNB1: AUDITORY NEUROPATHY, AUTOSOMAL RECESSIVE, 1
DFNB9: NON-SYNDROMIC RECESSIVE DEAFNESS 9
AUNB1: AUDITORY NEUROPATHY, AUTOSOMAL RECESSIVE, 1
[AUDITORY NEUROPATHY, NONSYNDROMIC RECESSIVE; NSRAN]
[AUDITORY NEUROPATHY, NONSYNDROMIC RECESSIVE; NSRAN]
DFNB9 and AUNB1 are caused by homozygous or compound heterozygous mutations in the gene
encoding otoferlin (OTOF) [Gene map locus: 2p23]
DFNB9:
• Lebanese family with nonsyndromic autosomal recessive SNHL. Deafness at birth or before 2
years. Audiometry showed profound hearing loss and no ABR. Parents, who were obligate
carrier heterozygotes, had normal audiometric tests (Chaib et al., 1996).
Nonsyndromic Recessive Auditory Neuropathy:
• Varga et al. (2003) defined 'nonsyndromic recessive auditory neuropathy' (NSRAN). Varying
degrees of hearing loss with poor speech reception out of proportion to the degree of hearing
loss. Most not helped by hearing aids, but may be helped by cochlear implants
• Tekin et al. (2005) reported 3 Turkish sibs, born of consanguineous parents, with NSRAN
confirmed by genetic analysis. Severe to profound pre-lingual SNHL. Acoustic middle ear
reflexes and ABR absent. OAEs present.
Van Camp G, Smith RJH. Hereditary Hearing Loss Homepage.
URL: http://hereditaryhearingloss.org
Online Mendelian Inheritance in Man (omim.org)
Nonsyndromic Recessive Auditory Neuropathy, Temperature-Sensitive
• Varga et al. (2006) reported 2 sibs with a temperature-sensitive auditory neuropathy
phenotype.
• Matsunaga et al. (2012) reported a 26-year-old Japanese man with temperaturesensitive auditory neuropathy associated with a homozygous mutation in the OTOF
gene
• Roux et al., 2006 reported connection of otoferlin to the ribbon synapse.
Van Camp G, Smith RJH. Hereditary Hearing Loss Homepage.
URL: http://hereditaryhearingloss.org
Online Mendelian Inheritance in Man (omim.org)
12
Genetics and AN/AD
Genetics and AN/AD
– Otoferlin is expressed at the inner hair cells, possible roles in
membrane trafficking and/or IHC synaptic vesicle fusion
AN/AD occurs as part of a syndrome with various
inheritance patterns
– In mice, otoferlin has been localized to IHC associated ribbon
synaptic vesicles
• Accompanying other hereditary motor sensory
neuropathies - HMSN (e.g., Butinar et al., 1999; Starr et al.,
– Associated with temperature sensitive AN (e.g., Varga et al., 2003;
Marlin et al., 2010; Wang et al., 2010; Matsunaga et al., 2012)
2004)
– Multiple mutations; influence of other genes and processes on
phenotype not yet known
• Charcot-Marie-Tooth disease
• Friedreich’s ataxia
• AN and optic nerve abnormalities
Van Camp G, Smith RJH. Hereditary
Hearing Loss Homepage.
URL: http://hereditaryhearingloss.org
Summary: Evaluation and Management
AN/AD Question 10
•
Effect, directly or indirectly, is on neural processing of auditory stimuli
– Physiologic measures are needed to accurately identify AN/AD
– Important to differentiate detection from discrimination when evaluating outcomes
“I hear about ‘treating the patient, not the test
results’ – what do you mean by that?”
Resources
• Listserve for parents and professionals interested in AN/AD
[email protected]
• Our Website for information and links: www.kresgelab.com
•
Distinguish AN/AD from neuromaturation, EVA, central auditory processing
disorders
•
Without good auditory input, visual information is critical for auditory
communication and speech/language development.
•
Many patients benefit from CI, including some with demyelinating conditions;
variation is similar to non-AN/AD.
•
Follow patients closely and consider the possibility of change in auditory function
over time.
Colleagues at Kresge Hearing Research Laboratory and the Audiology Clinic,
Department of Otolaryngology, Louisiana State University Health Sciences
Center, New Orleans, Louisiana, USA
Charles I. Berlin, PhD
Jill Bordelon, MCD
Leah Goforth-Barter, MS
Jennifer Taylor-Jeanfreau, MCD
Li Li, MD
Thierry Morlet, PhD
Patti St. John, MCD
Melanie Thibodeaux, MCD
Diane Wilensky, MS
Harriet Berlin, MS
Shanda Brashears, AuD
Annette Hurley Larmieu, PhD
Bronya Keats, PhD
Elizabeth Montgomery, MS
Kelly Rose Mattingly, MA
Sonya Tedesco, MCD
Han Wen, MSBE
• Contributions to our database are welcome.
The Vanderbilt Auditory Neuropathy Team: Mary Edwards AuD, Jill
Gruenwald AuD, Cathi Hayes AuD, Andrea Hedley-Williams AuD, Lindsey Rentmeester
AuD, Devin McCaslin PhD, Geniene Snell MS, Dale Tylor MD, Linsey Sunderhaus AuD
Research supported by the NIH-NIDCD, Oberkotter Foundation, Deafness Research Foundation, American
Hearing Research Foundation, National Organization for Hearing Research, Marriott Foundation, Kam’s Fund for
Hearing Research, Vanderbilt University Development Funds
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