Exam 2 Flashcards
Syndrome
-a group of symptoms or traits that occur together
-can be from a chromosome abnormality, regulatory genes, genes, infection, environmental/chemical agent
-usually signs and symptoms are present at birth but may have a delayed onset
What are the 8 major forms of syndromic deafness? What are their inheritance? Prevalence in Deaf community?
-Pendred (AR, 5.0%)
-Usher (AR, 4.4%)
-Branchio-Oto-Renal (AD, 2%)
-Waardenburg (AD/AR, 1.4%)
-Alport (AR, SLR, 1%)
-Treacher-Collins (AD, 1%)
-Jervell, Lange-Nielsen (AR, 0.25%)
-Wolfram (AD, ?%)
Stickler type 3
-COL11A2
-syndromic
-HF SNHL with progression
-midfacial underdevelopment
-cleft palate (CHL), eye problems (myopia, cataract, retinal detachment), joint problems
-hypermobile ME
-possible vestibular hypofunction
-little temporal bone data
-under identified- may be identified in adulthood
-variable phenotypic expression
-1/7500-9000
-mostly AD, sometimes AR
-monitor, HAs, education and interdisciplinary revision
Waardenburg Syndrome
-mostly AD
-congenital SNHL
-white forelock, hair hypopigmentation
-pigmentation abnormality of the iris: heterochromia iridium, partial/segmental heterochromia (two difference colors in same iris, typically brown and blue), brilliant blue irides
-dystopia canthorum, W index > 1.95
-affected 1st degree relative
-less common: unibrow, premature greying, hypopigmentation-8 known genes
-four clinical types
-HL usually not progressive
-HL usually profound in WS1 but can be mild high frequency
-penetrance is about 80%
-1/20,000-40,000
-about 3% of congenitally deaf children
-expressivity is extremely variable
-may not be diagnosed
-may have temporal bone abnormalities including EVA, mondini
-ell number and migration affected
treatment and management
-depends on HL, family preference (monitor, HAs, CI, ASL, other manual)
-type of WS and specific mutation is important
Usher
-multiple related disorders that include vision loss, HL, and vestib dysfunction
-historically a clinical diagnosis
-historically associated with severe-profound SNHL
-3 clinical types but also atypical (classified by age of onset, severity, progression, vestib)
-most commonly occurring cause of combined neurosensory loss
-prevalence of USH in different general populations estimated 1/600-20000?
-AR, complete penetrance
-especially common in populations with consanguineous marriages- Israel, Pakistan, France, Northern Sweden, Finland, Acadians
Interactome/Usherome
-genetic advantages have provided the tools to understand the development and maintenance of the auditory system
-Usher syndrome and several nonsyndromic forms of HL
-proteins that interact to form scaffolding for development of stereocilia
-proteins that form the stereocilia
USH 1
-traditional type of Usher
-severe to profound SNHL at birth or within the first year
-vestibular areflexia (may not sit by 6 months, average age of walking 20 months, may be described as clumsy, swimming underwater potentially dangerous)
-night blindness and RP in late childhood- legal blindness by 30
-associated with higher risk of poor quality of life
-ERG (electroretinography) testing may not be abnormal for several years
Phenotype of USH1B
-by 5 months: severe bilateral HL
-18 mo: walk but all have vestib dysfunction
-13 years: night blindness
-16 years: decreased acuity
-40 years: legally blind
Usher type 2
-USH type 2 the most common, about 2/3 in US
-USH2A up to 85% of the phenotype but also responsible for NS retinitis pigmentosa
-Usherin- important in the basement membrane, maintenance
-phenotype: USH2A a little more severe than in other Usher type 2; there is more progression, more severe low frequency HL, earlier RP- lots of overlap
-phenotype-genotype: truncating alleles more severe phenotype
-non-distinctive HF sloping audiometric configuration, no vestibular – looks like NS SNHL, later vision issues
-progression faster than presbycusis
-more pronounced in low frequencies
-in some cases, profound HL by age 40 (looks like type 1
Usher 2 clinical presentation
-14 years: onset of bilateral HL
-21 years: night blindness
-37 years: poorer visual acuity
-USH2A: dysfunctional tactile and vibratory sensation
-USH2A: variable phenotype
Usher type 3
-CLRN1, 3q21-q25
-Clarin 1, a 232 amino cid protein
-finnish founder mutation (c.528 T>G) is a premature truncation
-progressive- stop and start
-age of onset varies, mean diagnosis is age 11
-may be diagnosed very late- 3rd-4th decade
-visual may precede hearing symptoms
-ultimate range from moderate to profound
-Finns, Ashkenazi
Diagnosis issues with USH
-historical acceptance of late diagnosis
-genetic and clinical heterogeneity, large genes
-early- not possible just from clinical symptoms
-history! importance of serial audios
-serial ERG in children with congenital or pre-lingual HL? vestib signs? or genetic testing for an early identification
Usher related minor findings
-bronchiectasis- accumulation of mucus in bronchi
-olfactory loss
-nasal ciliary beat frequency decreased
-tactile acuity/vibration sensitivity
-reduced sperm motility
Usher potential therapies
-gene replacement of MYO7A
-QR-421 antisense treatment
-C-18-04 antioxidant treatment
-CL-17-01 antioxidant treatment
-vitamin A- RP
-lutein supplements- RP
-omega 3 supplements- RP
-N-acetyl cysteine (NAC) supplements- RP
-sunglasses
Audiologic treatment/management of Usher
-monitor, HAs, CI, manual language, family support
-late diagnosis, counseling, recognition of grief process in both parents and child
Benefits of genetic diagnosis for Usher
-educational planning
-family planning
-delay the progression of the RP (diet and lifestyle, sunglasses, neuroprotectives, gene therapy trials)
Jervell and Lange-Nielson Syndrome (JLNS)
-form of Long QT Syndrome (Romano-Ward syndrome)
-profound congenital SNHL
-arrhythmia, syncope (fainting), sudden death
-triggers- physical activity, excitement, fear, stress
-prevalence: 1.6-6/1000000 worldwide but in norway 1/200000
-some carriers of the mutation may have heart trouble but no hearing loss
-associated with an increased risk of SIDS
-KCNQ1 is 90% of cases and a higher risk of arrhythmia
-KCNE1
-AR, homozygous for either gene or compound heterozygous (deletion, duplication, sequence change)
-testing identifies 95% of patients
-pathophysiology- bony and membranous cochlear abnormalities. animal models show atrophy of the stria vascularis, collapse of the endolymphatic compartments and surrounding membranes, complete degeneration of the organ of corti and associated degeneration of the spiral ganglion
Treatment for JLNS
-for hearing loss: CI
-for heart problems: pacemaker, implanted cardioverter/defibrillator, beta blockers, left cardiac sympathetic denervation
-sudden death exceeds 50% if untreated, 25% even with interventions
Lip and palate clefting
-cleft lip with or without CP, 13% of all congenital anomalies
-1 in 700, varies by race and sex (higher incidence in asian, hispanic, american indian population)
-associated with over 300 syndromes
-clinical implications- surgery, dentistry and orthodontry, audiology, speech, nutrition, social work, psychology, sometimes other medical
-multifactorial
Pierre Robin sequence
-1/8500-14000 births
-7 to 10 weeks jaw grow rapidly and if it does not it results in micrognathia (small jaw) so the tongue cannot lie flat it then rests in the back of the mouth which prevents the palate from closing (cleft palate)
-often respiratory and feeding problems
-isolated Pierre Robin sequence- the jaw of an affected child is often able to grow and catch up to normal size but often associated with other conditions
-60% have HL mainly conductive, often due to OM auricular anomalies in 75%, atresia 5%
Craniosynostosis
-occurs in Muenke, Crouzon, and Apert
-1/2000-3000
-premature fusion of neurocranial sutures
-craniofacial dysmorphologies
-85% nonsyndromic
-15%- 180 known craniosynothosis syndromes, mostly mendelian
-fibroblast growth factor receptors FGFR (modulators of bone and connective tissue growth)
-involve hands and feet
Muenke Syndrome
-1/30000
-61% incidence of HL
-may have normal cognitive function to mild ID, changes in extremities
-SNHL most common, CHL related to OME
-AD
-FGFR3- variable penetrance
Apert Syndrome
-1/65000
-up to 80% HL: stapedial fixation, middle ear structural anomalies, OME
-cleft palate, flat dished face, syndactyly, ID in about 50%
-heart and kidney issues
-primarily sporadic (paternal age effect)
-AD
-fibroblast growth factor receptor FGFR2
Crouzon
-1/25000
-74% HL, stenosis, atresia, microtia, CHL most common, ME structural anomalies rare, OME, SNHL more often than Apert and Pfeiffer
-usually no ID
-bulging eyes due to shallow orbits, broad flat head
-AD
-fibroblast growth factor receptor 2 (FGFR2)- gene on chromosome 10
-variable expressivity
Treacher Collins
-1/50000
-lower jaw and cheekbones smaller than normal, lower eyelid coloboma (notch), downward sloping eyes
-outer ear abnormalities (microtia, ear tags, ear pits, atresia), CHL, rarely SNHL
-cleft palate about 30% of cases
-about 60% cases are sporadic (advanced paternal age)
-AD
-100% penetrance, variable expressivity
-TCOF1 gene on 5q32, treacle protein (directly affects RNA polymerase activity)
-P53 is a tumor suppressor gene
-stablization of p53 causes the high degree of neuroepithelial apoptosis- loss of neural crest cells
-mouse studies of antioxidant supplementation show a degree of reversal
Alport
-x-linked recessive 80% of cases, AD, AR
-1/5000
-kidney function-hematuria- in early childhood
-progressive HL, eye involvement (except AD)
-rare aneursyms in males
-bilateral HF SNHL in late childhood
-about 50% of male patients with x-linked Alport syndrome SNHL by 25
-about 90% of cases are deaf by 40
-less severe progress and outcomes in females
-highly variable
-COL4A3, COL4A4, COL4A5
Branchio Oto Renal (BOR)
-fistulas and cysts associated with 2nd brachial arch
-pits, tags, pinna abnormalities, ME and inner ear structural abnormalities, may be unilateral
-may have small or abnormal kidney(s), absent kidney, ultimately end stage renal disease possible
-may not be identified
-often confused with Alport
-about 1/40000
-HL in 95.4% of cases
-malformed auricles in about 86.8% of cases
-second branchial cleft anomalies in 86.5% of cases
-preauricular sinus in 87% of cases
-renal anomalies in 58.3% of cases
Conductive Otosclerosis
-youngest presentation around 5 but usually occurs in the 3rd decade
-0.2-1% prevalence in European studies
-AD based on pedigrees
-decreased penetrance (25-40%)
-multifactorial (bone, endocrine, inflammation, immune)
-may be mixed over time
-genes: loci identified but do not know what the genes do: OTSC1-OTSC10
-very little progress
-also COL1A1, TDF-beta (transforming growth factor)
MYO7A
-may cause DFNB2, DFNA11 and Usher I
-11q13.5, about 48 exons (some alternatively spliced), 559 pathogenic mutations
-Usher affects hearing, vestibular system and pigmentosa retinitis
-progression possible
-DFNB2 a precursor to Usher?
-low frequency SNHL is some cases
affects- stereocilia in hair cells and retinal pigmented cells
SLC26A4: Pendred Syndrome; DFNB4 and NSEVA
-AR, 7q22.3
-gene: SLC26A4 (majority), some evidence for digenic
-21 exons, 780 amino acid transmembrane anion transporter protein pendrin
-found in thyroid, inner ear and kidney
-localizes to apical membrane of cells in the spiral prominence and outer sulcus cells in cochlea; transitional cells of the cristae ampullaris, utriculi and sacculi, cells in the endolymphatic sac
-hearing loss, EVA and with syndrome sometimes Mondini
-syndrome 1896, 2 sisters with goiter and HL
DFNB4 (Pendred)
-fluctuating or progressive SNHL with EVA
-pre, peri or even postlingual onset, may pass NBHS
-severity, laterality, age of onset of SNHL variable
-ABG at low frequencies (3rd window)
-incomplete penetrance
-highly variable in severity and frequency
-abnormal testing frequent in patients but without subjective dizziness: carolis, rotational chair testing, cVEMP, vHIT
-vestib findings are not correlated with degree of HL
-pathophys: anion exchanger, loss of function, cytoplasmic accumulation; progression may be associated with changes in intracranial pressure
Genotype of DFNB4
-same gene as Pendred syndrome
-hundreds of variants
-mostly missense but an be deletions and duplications
-can be digenic
-likely additional genetic heterogenic
Pendred Syndrome and DFNB phenotype
-spectrum
for both: often congential, bilateral SNHL often mild to profound but can be mild to moderate, may be progressive or fluctuating, may have vesibular dysfunction, EVA
-pendred only: incompletely penetrant euthyroid goiter usually developing teens to 20s, often Mondini dysplasia
CDH23, DFNB12, Usher1D
-protein called Cadherin 23 (stereocilia interactome)
-major cause of HL in some populations
-nonsyndromic mostly- bilateral moderate to profound progressive SNHL, prelingual (20+ mutations)
-SNHL, retinitis pigmentosa and vestibular dysfunction in Usher (30+ mutations)
-do well with CI
TMC1 (DFNB7/11, DFNA36)
-prelingual moderate to severe to profound SNHL
-product is transmembrane protein localized to stereocilia channel complex
-common cause of recessive deafness in consanguineous Indian, Pakistani, Turkish and Tunisian families
-can be progressive
TMPRS33 (DFNB8/10)
-transmembrane protease
-progressive bilateral
-variable onset ages and progression rates
-sloping audio eventually becomes flat
OTOF
-DFNB9
-otoferlin, vesicle membrane fusion (IHC)
-2p23-24
-3-4% of NSSNHL
-ANSDE or profound HL
-correlates with ribbon synapses
-temperature sensitive allele in humans
-truncating mutation may cause severe to profound flat or gently sloping
-missense may cause moderate, flat to steeply sloping and is associated with ANSD
PJVK
-DFNB59 2q31.2
-pejvakin (function related to gene at DFNA5 7q18.3)
-AR
-pre or post lingual mild-profound HL
-ANSD
-expressed in spiral ganglion neurons
-truncating mutation will cause profound SNHL and vestibular hypofunction
Charcot Marie Tooth
-most common peripheral neurological syndrome’-2 main forms, much genetic heterogeniety- genes usually affect axon function, often myelination
-GJB1 Xq13.1 affects hearing (x-linked dominant)
TECTA
-DFNA12, DFNB21
-alpha-tectorin- non-collagenous extracellular matrix
-11q23.3
4% of prelingual HL in Iran, about 4% ADNSHL
-most frequently: prelingual, often mid-frequency loss, may be severe to profound, heterozygous less severe
-less frequently HF SNHL or postlingual or progressive (missense)
-expressed weeks 12-20
-tectorial membrane core is collagen embedded in striated sheet of tectorin
-otoconial membrane
-pathophysiology: interaction between basal membrane and tectorial membrane traveling wave may affect spatial extent and timing of OHC excitation
-audiologic measures: loudness growth curves normal, suprathresholds normal, DPOAEs present at higher stimulus levels, more like CHL than SN
Genotype/phenotype of TECTA for AD missense
-dominant and varied
-mid frequency, progressive, sometimes HF
-mutations in the zona pellucida domain would cause mid frequency U-shaped HL
-mutations in the zonadhesin-like domain may cause HF HL
Genotype/phenotype of TECTA for loss of function AR
-recessive
-stable prelingual HL
-moderate to severe across all frequencies
-more pronounced in the mid frequency range
OTOG
-otogelin, glycoprotein
-moderate SNHL similar to TECTA
-not thought to be progressive
-DFNB18B
-AR
-11q15.1
-may have vestib (unlike TECTA)- anchors otoconia
-normal imaging likely
DFNA2
-1p34, KCNNQ4
-potassium voltage gated channel, KQT like subfamily, member 4
-regulates K+ current (excitability)
-isoforms
-complete penetrance
-present in hair cells
-nonsyndromic, symmetric, progressive predominantly HF SNHL
-may be identified through school screenings but likely congenital, most aware by teens, can be as late as 40s
-clinical testing available
DFNA6/14/38; WFS1
-4q16.1, wolframin
-also syndrome, very rare nonsymdromic recessive
-heterozygous for missense mutations
-transmembrane protein, 8 exons, expressed highly in the brain and the heart
-progressive low frequency SNHL, good speech unless ARHL
-often not identified until early childhood
-no profound HL
-referrals: should be checked out for optic atrophy
-testing available
Wolfram syndrome
-neurodegenerative spectrum disorder
-4p16, 8 exons: wolframin, transmembrane glycoprotein
-pathophysiology: post translational protein folding ER
-progressive
-onset of diabetes mellitus and optic atrophy by age 16
-HL often low frequency, variable, can be profound
-diabetes insipidus
-neurologic and psychiatric abnormalities
-may be initially diagnosis with diabetes type 1
-high morbidity and early mortality
-AR
COL11A2, DFNA13 (DFNB53)
-6p21
-nonsyndromic postlingual HL
-may be mid or low frequency
-progressive HL beginning in the second to fourth decades
USH1
-traditional Usher type
-severe to profound SNHL at birth or within 1st year
-vestibular areflexia (may not sit by 6 mo, average age of walking around 20 mo, may be described as clumsy, swimming underwater potentially dangerous)
-night blindness and RP in late childhood- legal blindness by age 30
-associated with higher risk of poor QoL
-ERG testing may not be abnormal for several years
Define multifactorial HL
-non-mendelian inheritance
-clefting and syndromes involving craniofacial
-ARHL
-mitochondrial
-NIHL
-speech/language
-genes + environment
Issues with genome-wide association study
-very large numbers
-meaningful definitions
-consistent and appropriate phenotyping
Specific genes associated with NIHL
-catalase: breakdown of superoxide anions
-glutathione S-transferase (GST) enzymes: catalyse the conjugation of glutathione with xenobiotics, compounds foreign to human metabolism
-N-acetyltransferases (NAT): detoxify harmful substances
-Sirt3 (mitochondrial): promotes glutathione-mediated mitochondrial antioxidant defense system in mice, activated in calorie reduction
Mitochondrial genes
-16569 base pairs, no histones
-well characterized genes: oxidative phosphorylation, rRNA and tRNA mutations
-requires nuclear genome products
-maternal inheritance or de novo
-10-20 times more prone to mutation
-pleiotropic effects
-penetrance, tissue specificity
-regular screening of newborns for most common mutations in China
-ethnicity important for specific mutation, prevalence
