Genetic-HL-slides-2004-0317 - Genetic Hearing Loss Jing...

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Unformatted text preview: Genetic Hearing Loss Jing Shen M.D. Ronald Deskin M.D. UTMB Dept of Otolaryngology March 2004 1 Epidemiology Hearing loss occurs in 1 out of every 1,000 births 50 % are hereditary Syndromic vs. nonsyndromic 2 30% syndromic 70% nonsyndromic Autosomal dominant vs. autosomal recessive vs. x­linked vs. mitochondrion 3 4 5 Methods Linkage mapping Mouse model Difficulties: 6 Families too small for linkage analysis Assortive mating introducing various genes into one single pedigree Incomplete penetrance Syndromic deafness 7 Has other abnormalities About 20­30% of genetic hearing loss Two syndromes can be caused by different mutations of the same gene Mutations of more than one gene can cause the same clinical phenotype Alport syndrome At least 1% of congenital hearing loss X­linked inheritance (80%), autosomal recessive as well as dominant Sensorineural hearing loss: mostly affect high tone Renal dysfunction 8 Microscopic hematuria Man are more severely affected than woman Onset in early childhood and progress to renal failure in adulthood increased risk of developing anti­GBM nephritis after renal transplantation Alport syndrome Ocular abnormalities 9 Lenticulus Retina flecks Defective collagen type 4 causes abnormalities in the basement membrane 3 genes: COL4A5, COL4A3, COL4A4 These collagens found in the basilar membrane, parts of the spiral ligament, and stria vascularis Exact mechanism of hearing loss is unknown Branchio­oto­renal syndrome 2% of profoundly deaf children Autosomal dominant disorder Otologic anomalies: 10 variable hearing loss (sensorineural, conductive or mixed) malformed pinna, preauricular pits Branchial derived abnormalities: cyst, cleft, fistula Renal malformation: renal dysplasia with anomalies of the collecting system, renal agenesis Sometimes with lacrimal duct abnormalities: aplasia, stenosis EYA1 gene mutation – knockout­mice showed no ears and kidneys because apoptotic regression of the organ primordia Jervell and Lange­Nielsen syndrome Autosomal recessive 0.25% of profound congenital hearing loss Prolonged QT interval, sudden syncopal attacks Severe to profound sensorineural hearing loss 2 genes identified: 11 KVLQT1: expressed in the stria vascularis of mouse inner ear KCNE1 Both gene products form subunits of a potassium channel involved in endolymph homeostasis Norrie syndrome 12 X­linked inheritance Ocular symptoms with congenital blindness: pseudotumor of the retina, retinal hyperplasia, hypoplasia and necrosis of the inner layer of the retina, cataracts, phthisis bulbi Progressive sensorineural hearing loss Mental deficiency Norrin gene: encodes a protein related to mucins Pendred Syndrome Most common form of syndromal deafness­ 4­10 % Autosomal recessive disorder Sensorineural hearing loss 13 bilateral, severe to profound, and sloping in the higher frequencies incomplete partition of the cochlear Pendred syndrome Vestibular dysfunction: Thyroid goiter: 14 enlargement of the vestibular aqueducts, the endolymphatic sac and duct usually euthyroid, can be hypothyroid defective organic binding of iodine positive potassium perchlorate discharge test Pendred syndrome PDS gene mutations: PDS knockout mouse: 15 on chromosome 7q31 encodes pendrin: an anion transporter in inner ear, thyroid, kidney complete deaf endolymph­containing spaces enlargement inner and outer hair cell degeneration no thyroid abnormality Stickler syndrome Autosomal dominant Variable sensorineural hearing loss Ocular symptoms: progressive myopia, resulting in retina detachment and blindness Arthropathy: premature degenerative changes in various joints Orofacial features: midface hypoplasia Three genes: COL2A1, COL11A1, COL11A2 16 Associated with defective collagen protein Each gene mutation corresponding to a phenotype Treacher­collins syndrome Autosomal dominant with variable expression Conductive hearing loss Craniofacial abnormalities: TCOF1 gene: 17 Coloboma of the lower lids, micrognathia, microtia, hypoplasia of zygomatic arches, macrostomia, slanting of the lateral canthi Involved in nucleolar­cytoplasmic transport mutation results in premature termination of the protein product Usher syndrome 18 Autosomal recessive disorder Sensorineural hearing loss Progressive loss of sight due to retinitis pigmentosa Three different clinical types 11 loci and 6 genes have been identified Usher syndrome Type 1: Type 2: Sloping congenital deafness, normal vestibular response, onset of retinitis pigmentosa in first or second decade of life Type 3: 19 Profound congenital deafness, absent vestibular response, onset of retinitis pigmentosa in the first decade of life Progressive hearing loss, variable vestibular response, variable onset of retinitis pigmentosa Type I II 20 III Locus name USH1A USH1B USH1C USH1D USH1E USH1F USH1G USH2A USH2B USH2C USH3 gene unknown MYO7A USH1C CDH23 unknown PCDH15 unknown USH2A unknown unknown USH3 Usher syndrome 21 MYO7A: encodes for myosin 7A, molecular motor for hair cells USH1C: encodes for harmonin, bundling protein in stereocilia CDH23: encodes cadherin 23, an adhesion molecule may be important for crosslinking of stereocilia, also may be involved in maintaining the ionic composition of the endolymph Myosin 7A, harmonin, and cadherin 23 form a transient functional complex in stereocilia Waardenburg syndrome 22 About 2% of congenital hearing loss Usually autosomal dominant Dystonia canthorum Pigmentary abnormalities of hair, iris and skin Sensorineural hearing loss 4 clinical subtypes Waardenburg syndrome Type 1: Type 2: 23 With dystopia canthorum Penetrance for hearing loss 36% to 58% Wide confluent eyebrow, high broad nasal root, heterochromia irides, brilliant blue eyes, premature gray of hair, eyelashes, or eyebrows, white forelock, vestibular dysfunction like type 1 but without dystopia canthorum Hearing loss penetrance as high as 87% Waardenburg syndrome Type 3 (Klein­Waardenburg syndrome): Type 4 ( Shah­Waardenburg syndrome): 24 Type 1 clinical features + hypoplastic muscles and contractures of the upper limbs Type 2 clinical features + Hirschsprung’s disease Five genes on five chromosomes have been identified Waardenburg syndrome Type 1 and type 3: Type 2: 25 all associated with PAX3 gene mutation Associated with dominant mutations of MITF gene Associated with homozygous deletion of SLUG gene MITF was found to activate the SLUG gene Waardenburg syndrome Type 4: 26 EDNRB gene – encodes endothelin­b receptor, development of two neural crest derived­cell lineages, epidermal melanocytes and enteric neurons EDN3 gene – encodes endothelin­3, ligand for the endothelin­b receptor SOX10 gene – encodes transcription factor Non­syndromic deafness About 70­80% of hereditary hearing loss Autosomal dominant (15%): Autosomal recessive (80%): 33 loci (DFNB) and 21 genes identified Usually prelingual onset, non­progressive Severity from severe to profound All frequencies affected X­linked (2­3%): 27 41 loci (DFNA) and 20 genes identified Usually postlingual onset, progressive Severity from moderate to severe Majority of the hearing loss in middle, high or all frequencies 4 loci (DFN) and 1 gene identified Either high or all frequencies affected Non­syndromic deafness Identified genes encode: 28 Unconventional myosin and cytoskeleton proteins Extracellular matrix proteins Channel and gap junction components Transcription factors Proteins with unknown functions More than one gene found in the same loci (DFNA2 and DFNA3) Some genes cause autosomal dominant and autosomal recessive hearing loss Some genes cause non­syndromic and syndromic hearing loss Ion homeostasis Potassium recycling to maintain high potassium concentration in endolymph KCNQ4: encodes a potassium channel SLC26A4: encodes an anion transporter, pendrin 4 gap junction genes: GJB2, GJB3, DJB6, GJA1 29 Encode connexin proteins Function of gap junctions: molecular pores connecting two adjacent cells allowing small molecules and metabolites exchange GJB2 (Gap Junction Beta 2) The first non­syndromic sensorineural deafness gene to be discovered On chromosome 13q11 50% of recessive non­syndromic hearing loss Encodes connexin 26 80 recessive and 6 dominant mutations 35delG mutation 30 Expressed in stria vascularis, basement membrane, limbus, spiral prominence of cochlea Recycling of potassium back to the endolymph after stimulation of the sensory hair cell One guanosine residue deletion from nucleotide position 35 Results in protein truncation High prevalence in Caucasian population Screening test available 31 32 Transcription factors POU3F4 POU4F3 33 X­linked mixed hearing loss Stapes fixation causing conductive hearing loss Increased perilymphatic pressure Causing the typical “gusher” during stapes footplate surgery – stapes­gusher syndrome Autosomal dominant hearing loss Knockout mice fail to develop hair cells with subsequent loss of spiral and vestibular ganglia EYA4 TFCP2L3 Cytoskeleton proteins Associated with actin­rich stereocilia of hair cells Myosin: actin­dependent molecular motor proteins Otoferlin: calcium triggered synaptic vesicle trafficking USH1C (also in Usher type 1c) Cadherin: important for stereocilia organization 34 OTOF one particular mutation accounts for 4.4% of recessive prelingual hearing loss negative for GJB2 mutation Actin­polymerization protein: HDIA1 Harmonin: organize multiprotein complexes in specific domains (tight junction, synaptic junction) MYH9 MYO3A, MYO6, MYO7A, MYO15 – all have vestibular dysfunction CDH23 ( also in Usher type 1d) Extracellular matrix components TECTA COL11A2 Encodes collage type XI polypeptide subunit 2 Knockout mice with atypical and disorganized collagen fibrils of the tectorial membrane COCH 35 Encodes alpha tectorin­ component of the tectorial membrane Knockout mice with detachment of tectorial membrane from the cochlear epithelium Encodes COCH (coagulation factor C homologue) protein Expressed in cochlear and vestibular organs Associated with vestibular problems Unknown function genes WFS1 36 Dominant sensorineural hearing loss Responsible for 75% of low frequency nonsyndromic progressive hearing Responsible for up to 90% of cases of Wolfram syndrome, a recessive disorder with diabetes mellitus, diabetes insipidus, optic atrophy, and deafness Mitochondrial disorders 2­10 mitochondrial chromosomes in each mitochondrion Transmitted only through mothers With syndromic hearing loss With non­syndromic hearing loss With aminoglycoside ototoxic hearing loss 37 Associated with systemic neuromuscular syndromes: such as Kearns­Sayre syndrome, MELAS, MERRF Also in families with diabetes and sensorineural hearing loss Associated with skin condition: palmoplantar keratoderma A1555G mutation in the 12S ribosomal RNA gene Maternally transmitted predisposition to aminoglycoside ototoxicity Accounts for 15% of all aminoglycoside induced deafness Evaluation History Prenatal: infection, medication Perinatal: risk factors Postnatal: infection, speech and language milestones Family: 38 hearing loss in first and second degree relatives Hearing loss occurred before age 30 Consanguinity or common origin from ethnically isolated areas Evaluation Physical exam: features of syndromic hearing loss 39 Hair color: white forelock, premature graying Facial shape Skull shape Eye: color, position, intercanthal distance, cataracts, retinal findings Ear: preauricular pit, skin tags, shape and size of pinna, abnormality of EAC and TM Oral cavity: cleft Neck: brachial anomalies, thyroid enlargement Skin: hyper/ hypopigmentation, café­au­lait spots Digits: number, size, shape Neurological exam: gait, balance Evaluation Audiologic evaluation Lab testing: based on history and physical exam Torch titers CBC and electrolytes Urinalysis thyroid function test (perchlorate discharge test) EKG Radiological study: CT temporal bone is the test of choice 40 Dilated vestibular aqueduct (>1.5mm at middle third or >2mm anywhere along its length) Mondini malformation Semicircular canal absence or dysplasia Internal auditory canal narrowing or dilation Renal ultrasound Genetic screening GJB2 41 most common cause of severe to profound nonsyndromic recessive deafness High prevalence of 35delG mutation Small size of GJB2 gene SLC26A4­ most common cause of Mondini dysplasia or dilated vestibular aqueduct syndrome EYA1­ 30­40% of families with a branchio­oto­ renal phenotype Genetic counseling Goal: 42 Cause of deafness Other medical implication Chance of recurrence in future children Implications for other family members Assist family in making choices that are appropriate for them Team approach including clinical/medical geneticist, genetic counselor, social worker, psychologists Consent need to be obtained for genetic testing Cochlear gene therapy Adenoid associated virus as vector Routes of delivery Safety concern 43 Hearing loss Regional and distal dissemination 44 Resources for hereditary hearing loss 45 Hereditary hearing loss home page Online Mendelian Inheritance in Man ...
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This note was uploaded on 12/28/2011 for the course STEP 1 taught by Professor Dr.aslam during the Fall '11 term at Montgomery College.

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