Genetics of Hearing Loss Dr Nayyar

7/31/2019 Genetics of Hearing Loss Dr Nayyar

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By:- Dr. Supreet Singh Nayyar, AFMC

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7/22/2012www.nayyarENT.com

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Genetics of hearing loss
http://www.nayyarent.com/http://www.nayyarent.com/http://www.nayyarent.com/http://www.nayyarent.com/


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Overview


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Introduction

Types of genetic hearing impairment

Common types of syndromic deafness

Common types of non-syndromic deafness Genetic evaluation

Genetic counseling

Recent advances in genetic treatment
http://www.nayyarent.com/http://www.nayyarent.com/


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Introduction

7/22/2012www.nayyarENT.com3

Gregor Mendel - father of modern genetics

Human genome project

Otolaryngologist role in genetic hearing loss

Hearing impairment possibilities


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HEARING LOSS


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Syndromic Deafness


Over 400 syndromes

Two syndromes by different mutations of same

gene

Mutations of more than one gene can cause thesame clinical phenotype

Mode of inheritance


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Autosomal Dominant Syndromic

Hearing Impairment


Waardenburg Syndrome

Branchio-oto-renal Syndrome

Stickler Syndrome

Neurofibromatosis II

Treacher Collins Syndrome

Goldenhar Syndrome


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Petrus J. Waardenburg - 1951

Aggregate prevalence 1:10,000 to 20,000

Usually autosomal dominant

Sensorineural hearing loss Pigmentary abnormalities

Hair

Iris Skin

4 clinical subtypes


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Type 1: With dystopia canthorum

Penetrance 36% to 58%

PAX3

Type 2:

Like type 1 but without dystopia canthorum Hearing loss penetrance as high as 87%

MITF


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Type 3 (Klein-Waardenburg syndrome): Type 1 clinical features + hypoplastic muscles

and contractures of the upper limbs

PAX3

Type 4 ( Shah-Waardenburg syndrome): Type 2 clinical features + Hirschsprungs

disease EDN3 , EDNRB , SOX10

Autosomal recessive


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Branchio-oto-renal syndrome


Melnick - 1975

Penetrance is nearly 100%

Prevalence 1 in 40, 000

2% of profoundly deaf children

EYA1 , 1q31


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Otologic findings

External ear

Middle ear

Inner ear


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PTA

Branchial anomalies

Renal anomalies

Less common phenotypic anomalies


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Major and Minor Diagnostic Criteria for Branchiootorenal Syndrome

Major Criteria Minor Criteria

Second branchial arch anomalies External auditory canal anomalies

Deafness Middle ear anomaliesPreauricular pits Inner ear anomalies

Auricular deformity Preauricular tags

Renal anomaliesOther: facial asymmetry, palate

abnormalities

Chang EH, Menezes M, Meyer NC, Cucci RA, Vervoort VS, Schwartz CE, Smith RJ. Branchio-oto-renal

syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat2004;23:582-9

Branchio-oto-renal syndrome



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Stickler Syndrome


Dr. Gunner Stickler - 1965

Prevalence 1:10,000

Mutations - type II and type XI collagen

Snead and Yates criteria (1) Congenital vitreous anomaly (2) Any three of

Sensorineural hearing loss Myopia with onset before age 6 years Midline clefting Joint hypermobility with abnormal beighton score Rhegmatogenous retinal detachment


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Stickler Syndrome


SS type I COL2A1

Classical ocular findings with a "membranous" vitreous

Normal hearing or only a mild impairment

SS type II

COL11A2

Minimal ocular abnormalities

Mild to moderate hearing loss

SS type III

COL11A1

Vitreous - irregularly thickened fiber

Moderate-to-severe hearing loss

Hearing loss Conductive- eustachian tube dysfunction that commonly occurs

with palatal clefts

Sensorineural Alterations in the pigmented epithelium of the inner ear

Abnormalities of inner ear collagen

Mixed


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Hallmark hearing loss secondary to bilateralvestibular schwannomas

Incidence 1:40,000 to 1:90,000

Hearing loss usually begins in the third decade

Generally unilateral and gradual

Risk of other tumors including meningiomas,astrocytomas, ependymomas, and

meningioangiomatosis


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Diagnostic criteria

Bilateral CN VIII schwannomas on MRI or CT scan (no biopsynecessary) (age


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Treacher Collins Syndrome


Incidence - 1/50,000 live births

Gene TCOF

Clinical features

Maldevelopment of the maxilla and mandible Downward slanting palpebral fissures

(anti mongoloid fissure)

Lower lid colobomas

Choanal atresia

Cleft palate

Conductive hearing loss Ossicular fixation


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Goldenhar syndrome


Maurice Goldenhar 1952 OAV - Gorlin 1990

Incidence 1/3500 to 1/26000

Etiology

Possible vascular insult to 1st and 2nd branchial arches Mostly sporadic & multifactorial

AD and AR variants reported

Incomplete development Ear Nose Soft palate,lip, and mandible

Usually one side of the body


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Goldenhar syndrome


Clinical features Epibulbar dermoids

Upper eyelid colobomas

Mandibular hypoplasia

Microtia, preauricular appendages FN involvementfacial muscle hypoplasia

Hemifacial microsomia 90% unilateral

Lateral facial clefts/Macrosomia

Hemi vertebrae anomalies

Cardiac, renal, pulmonary, CNS, skeletal

OMENS ocular, mandibular, ear, FN, soft tissue


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Autosomal Recessive Syndromic

Hearing Impairment


Usher Syndrome

Pendred Syndrome

Jervell and Lange-Nielsen Syndrome

Biotinidase Deficiency

Refsum Disease


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Usher Syndrome


Prevalence 4.4 per 100,000

3% to 6% of congenitally deaf persons

Cause of 50% of deaf-blindness

Characterized by Sensorineural hearing loss

Retinitis pigmentosa

Vestibular dysfunction

11 loci and 6 genes have been identified


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Usher Syndrome


Type 1 Type 2 Type 3Hearing loss Profound since

birth

Moderate-to-

severe ,

sloping curve

Progressive

Vestibularresponse

Absent Normal Variable

Onset ofretinitispigmentosa

First decade of

life

First or second

decade of life

Variable onset

Timing of cochlear implantation in Usher Syndrome


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Pendred Syndrome


Vaughan Pendred - 1896

Prevalence 7.5 to 10 per 100,000

SLC26A4, encodes pendrin

Functions as a chloride/iodide transporter

Expressed in inner ear, thyroid, and kidney

Hearing loss

SNHL

Prelingual

Bilateral

Profound


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Pendred Syndrome


Mondini dysplasia

Enlargement of Vestibular aqueducts

Endolymphatic sac

NormalDilated

endolymphatic sac


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Pendred Syndrome


Thyroid goiter

Second decade

Euthyroid

Perchlorate discharge test >10% radioactivity +ve test

Sensitivity low

Genetic testing


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Jervell and Lange-Nielsen Syndrome


Jervell and Lange-Nielsen - 1957 Prevalence 0.21%

Syndrome characterized by Congenital deafness

Prolonged QT interval Syncopal attacks

KVLQT1 , KCNE1

Encode for K+ channel expressed in the heart and

inner ear Hearing impairment

Due to changes in endolymph homeostasis

Congenital, bilateral, and severe to profound


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Leads to deficiency in biotin Neurologic features

Seizures, hypertonia

Developmental delay,ataxia

Visual problems and conjunctivitis

Mild to moderate SNHL

Cutaneous features

Alopecia Skin rash


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With biotin treatment Neurologic and cutaneous manifestations resolve

Hearing loss and optic atrophy usually irreversible


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Refsum Disease


Refsum 1946

Faulty phytanic acid metabolism

Phytanoyl-CoA hydroxylase

Clinical features Severe progressive SNHL

Scaly skin (icthyosis)

Neurologic damage, cerebellar ataxia

Peripheral neuropathy

Night blindness

Cataracts

Retinitis pigmentosa

Diagnosis High serum concentration of phytanic acid

Treatment Dietary modification

Plasmapharesis


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X-Linked Syndromic Hearing

Impairment


Alport Syndrome Mohr-Tranebjaerg Syndrome


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Alport Syndrome


Progressive sensorineural hearingloss of varying severity

Progressive glomerulonephritisleading to end-stage renal disease

Variable ophthalmologic findings(e.g. anterior lenticonus)

Autosomal dominant,autosomal recessive and x-linked

X-linked 85%


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Alport Syndrome


COL4A5, COL4A3, COL4A4

Type IV collagen

Found in Basilar membrane

Parts of the spiral ligament

Stria vascularis

Loss of integrity due to defective collagen


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Mohr-Tranebjaerg Syndrome


Deafness-dystonia-optic atrophy syndrome

Progressive, post-lingual SNHL

Other findings

Visual disability

Dystonia

Multiple fractures

Mental retardation

TIMM8A

Involved in translocation of proteins across inner mitochondrial

membrane


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Mitochondrial Syndromic Hearing

Impairment


2-10 mitochondrial chromosomes in each mitochondrion

Transmitted only through mothers

Affect tissues with high energy demands

Syndromic mitochondrial diseases MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke

like episodes) syndrome

MERRF (myoclonic epilepsy and red ragged fibers) syndrome

Kearns-Sayre syndrome (KS)

Maternally inherited diabetes and deafness

0.5% to 2.8% of diabetic patients

Hearing loss occurs late and is progressive, bilateral, and high frequency;

Presence is correlated with the level of heteroplasmy for 3243 a-to-g mt dna

mutation


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But are all children actually gifted totaste this food of love !!


If music be the food of love,Play on, give me excess of it

William

Shakespeare


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Non-syndromic deafness (NSHL)


70-80% of hereditary hearing loss Specific nomenclature

Different gene loci - DFN

Autosomal dominant - DFNA

Autosomal recessive - DFNB

X-linked - DFN

Number following these reflects order of gene

mapping and/or discovery


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Non-syndromic deafness


Autosomal dominant Autosomal recessive

Percentage 15% 80%

Loci identified 41 loci (DFNA) 39 loci (DFNB)

Genes identified 20 genes 21 genes

Hearing loss onset Postlingual Prelingual

Progression ProgressiveNon-

progressive

SeverityModerate tosevere SNHL

Severe to

profound

FrequenciesMiddle & high

frequenciesAll frequencies


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Autosomal Recessive


DFNB1 locus on chromosome 13q11

50% of AR NSHL

connexin26 (Cx26, gene symbol GJB2)

connexin30 (Cx30, GJB6).

Extensive genotype-phenotype studies


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Connexin 26


Vertebrate gap junction proteins

connexin

connexon

gapjunction


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Connexin 26 Inner ear


Supporting cells, stria vascularis,

basement membrane, limbus, and

spiral prominence of the cochlea

Mechanosensory transduction

Passage of K+

Recycling of K+ ions


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Connexin 26


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More than 90 mutations described Specific ethnic groups

35delG ,167delT, 235delC , W24X

Moderate-to-profound deafness Symmetric

Non-progressive

Genetic testing importance

Prognostic information - cochlear implant


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X-linked


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2-3% of Non syndromic hearing loss

5 loci (DFN) and 2 genes identified

Either high or all frequencies affected

X Li k d C it l St Fi ti


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X-Linked Congenital Stapes Fixation

with Perilymph Gusher


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DFN3 - POU3F4

Progressive mixed hearing loss

Reduced vestibular responses

Radiologic findings

Widening of the lateral IAM

Dilation of the vestibule

Widening of labyrinthine portion

of FN

Large cochlea

Thin separation b/w IAM &

vestibule

Stapedectomy - perilymph

Mit h d i l N S d i


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Mitochondrial Non Syndromic

Hearing Impairment


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Familial Progressive Sensorineural Deafness

Susceptibility to aminoglycoside ototoxicity

1555 A-to-G mutation

Changes the 12S ribosomal RNA gene

Altering its structure to make it more similar to bacterial rRNA Hearing loss even at normal doses

Can even be seen months after aminoglycoside exposure

Outer hair cells in the basal turn of the cochlea are affected first

Damage eventually extends to include apical outer hair cells and inner hair cells

Presbycusis and genes !!

Mit h d i l S d i H i


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Mitochondrial Syndromic Hearing

Impairment


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Molecular Genetic Testing


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GJB2, GJB6

SLC26A4(Pendred syndrome)

EYA1 (BOR syndrome)

Issues

Large size of many (MYO7A, MYO15)

Low relative contribution to deafness (DFNB9, HDIA1,

TECTA, COCH, POU4F3)


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Genetic Counseling


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Goal: Cause of deafness Other medical implication Chance of recurrence in future children Implications for other family membersAssist family in making choices that are appropriate

for them

Team approach including clinical/medical

geneticist, genetic counselor, social worker,psychologist

R t Ad i G ti


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Recent Advances in Genetic

Manipulation


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Therapeutic insertion of genetic material intoinner ear

Hope

Prevent, arrest, reverse or cure

Number of vectors studied in vivo


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Cochlear gene therapy

Adenoid associated

virus as vector

Routes of delivery Safety concern

Hearing loss

Regional and distal

dissemination



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Stem cell & Gene therapy


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Potential of twin technologies of stem cell andgene therapy.

Hair cells of cochlea very vulnerable

Once dead not naturally replaced

Trigger regeneration of cochlear hair cells

Combined dual treatment of stem cell insertion

and gene transfer


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Drug Therapy


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To exploit alternative pathways to carry out the taskthat is affected by mutation

E.g. connexin 26 mutation

Another connexin may be capable of substituting ingap junction, but its gene may not normally beexpressed in the cochlea

A drug might therefore be developed to activateexpression of the alternative connexin gene in cellsneeding to form gap junction


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Conclusion


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Know the roots

May be the future

Researches required


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References


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Scott Bown 7th

Edition Cummings 4th Edition

Article Genetics of Hearing Loss by Dr Michelle Vas, MD

(Paed), PGDDN from Hearsay July 2009

Hereditary hearing loss homepage -

http://hereditaryhearingloss.org

Connexin deafness homepage - http://davinci.crg.es/deafness/

Familial Progressive Sensorineural Deafness Is Mainly Due to

the mtDNA A1555G Mutation and Is Enhanced by Treatment with

Aminoglycosides byXavier Estivill et al

GJB2 Gene Mutations in Cochlear Implant Recipients -

Prevalence and Impact on Outcome Lawrence et al. ,ARCHOTOLARYNGOL HEAD NECK SURG/VOL 130, MAY 2004

Various Journal Articles from internet
http://hereditaryhearingloss.org/http://davinci.crg.es/deafness/http://davinci.crg.es/deafness/http://hereditaryhearingloss.org/


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Thank You

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visit www.nayyarENT.com

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Genetics of Hearing Loss Dr Nayyar

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