Week 8: Epilepsy and Hearing Disorders

Conductive Hearing Loss (CHL)

Blockage of sound into the ear (structural defects, impaction, build-up)

Sensorineural Hearing Loss (SNHL)

Nerve of hair cell damage to cochlea

Mixed Hearing Loss

Both sensorineural and conductive hearing loss

Prelingual hearing loss

Hearing loss that occurs before the development of language

• Usually caught on NBS

• Speech delay

Postlingual hearing loss

Occurs after the development of speech

Characteristics of hearing loss

• pre/postlingual

• decade of onset

• stable/progressive

• syndromic/nonsyndromic

• severity

• frequency

Severity

The sound level, decibels that you can hear

Frequency

Loss at what specific sound frequencies

Audiometry

• subjective testing to determine severity/frequency of hearing loss

• O = right ear

• X = left ear

Auditory brain stem response (ABR or BAER)

measures the nerve reception (determining electrophysiologic responses)

Evoked otoacoustic emissions (EOAE)

measure activity of the outer hair cells of the cochlea

Immitance testing (tympanometry)

measures pressure in the middle eay to determine mobility and function

How many newborns have prelingual hearing loss?

1 in 500 newborns

What percent of prelingual hearing loss is acquired vs. genetic?

20% acquired/environmental, 80% genetic

Of genetic causes, what percent is syndromic vs. nonsyndromic?

20% syndromic, 80% nonsyndromic

AD Nonsyndromic Hearing Loss Genetic Causes

DIAPH1, GJB2/3/6, KCNQ4, TECTA, WFS1, COCH, POU4F3, ACTG1

AD Nonsyndromic Hearing Loss Phenotype

most progressive with postlingual onset, varying ages at presentation

Waardenburg Syndrome (WS) Genetic Cause

AD: pathogenic variants in PAX3, MITF, EDNRB, EDN3, SOX10

Waardenburg Syndrome Symptoms/Presentation

• varying SNHL

• hypopigmentation of skin, hair, and eyes

• heterochromia

• white forelock

Types of Waardenburg Syndrome

• Type 1: PAX3 - congenital SNHL, neural tube defects, canthus dystopia (inner eye corner displaced inward)

• Type 2: MITF - no dystopia canthorum

• Type 3: more severe, musculoskeletal/neuro symptoms

• Type 4: EDNRB or EDN3 - Hirschprung disease,

Branchiootorenal Spectrum Disorder (BOR) Genetic Cause

AD: pathogenic variants in EYA1 or SIX1

Branchiootorenal Spectrum Disorder (BOR) Symptoms/Presentation

• conductive, sensorineural, mixed hearing loss

• branchial cleft abnormalities

• preauricular pits

• external ear malformations

• renal anomalies

Schwannomatosis Genetic Cause

AD: pathogenic variants in NF2

Schwannomatosis Symptoms/Presentation

• schwannomas

• hearing loss (3rd decade)

  • secondary to bilateral vestibular schwannomas

• balance dysfunction, tinnnitus

Stickler Syndrome Genetic Cause

AD: pathogenic variants in COL2A1, COL1A1, COL11A2

Stickler Syndrome Symptoms/Presentation

• progressive SNHL/conductive HL

• Pierre-Robin sequence (cleft palate)

• spondyloepiphyseal dysplasia

• precocious arthritis

• severe myopia (retinal detachment)

AR Nonsyndromic Hearing Loss Genetic Causes

AR: biallelic pathogenic variants in GJB2, SLC26A4, MYO15A, OTOF, TMC1, CDH23, TMPRSS3

AR Nonsyndromic Hearing Loss Phenotype

most severe to profound, stable hearing loss

• some moderate and progressive

Usher Syndrome Genetic Cause

AR: biallelic pathogenic variants in MYO7A, USH1C, USH2A, CDH23, PCDH15, USH1G, and CIB2

Usher Syndrome Phenotype

SNHL and retinitis pigmentosa (retina deterioration)

Type 1 Usher Syndrome Symptoms/Presentation

• congenital severe-to-profound SNHL

• abnormal vestibular dysfunction

Type 2 Usher Syndrome Symptoms/Presentation

• congenital mild-to-severe SNHL

• normal vestibular function

Type 3 Usher Syndrome Symptoms/Presentation

• progressive hearing loss

• deterioration of vestibular function

Pendred Syndrome Genetic Cause

AR: biallelic pathogenic variants in SLC26A4

Pendred Syndrome Symptoms/Presentation

• congenital SNHL (severe to profound)

• thyroid goiter

• puberty or adulthood (10s-20s)

Jervell and Lange-Nielsen Syndrome Genetic Cause

AR: biallelic pathogenic variants in KCNQ1 or KCNE1

Jervell and Lange-Nielsen Syndrome Symptoms/Presentation

• congenital profound SNHL

• Long QT syndrome

  • syncopal episodes, potentially sudden death

Biotinidase Deficiency Genetic Cause

AR: biallelic pathogenic variants in BTD

Biotinidase Deficiency Symptoms/Presentation

• deficient biotinidase enzyme

• some degree of SNHL

• cutaneous features (rash, alopecia)

• hypotonia

• seizures

• developmental delay

Refsum Disease Genetic Cause

AR: biallelic pathogenic variants in PHYH or PEX7

Refsum Disease Symptoms/Presentation

• faulty phytanic acid metabolism

• severe progressive SNHL

• early retinitis pigmentosa

• anosmia

• ataxia

• ichthyosis

X-linked Nonsyndromic Hearing Loss Genetic Cause

X-linked: pathogenic variants in PRPS1, POU3F4, or SMPX

X-linked Nonsyndromic Hearing Loss Phenotype

progressive mixed hearing loss, mild to profound

MPS II or Hunter Syndrome Genetic Cause

X-linked: pathogenic variants in IDS

MPS II or Hunter Syndrome Symptoms/Presentation

• macrocephaly w/ hydrocephalus

• hearing loss and recurrent ear infections

• CNS involvement: DD, speech delay

• dysmorphic features

• heart valve issues

Alport Syndrome Genetic Causes

X-linked: pathogenic variants in COL4A5

AR/AD: pathogenic variants in COL4A3, COL4A4

Alport Syndrome Symptoms/Presentation

• progressive SNHL

• progressive glomerulonephritis (renal failure)

• ophthalmologic problems

Mohr-Tranebjaerg Syndrome (Deafness-dystonia-optic atrophy syndrome) Genetic Cause

X-linked: pathogenic variants in TIMM8A

• contiguous gene deletion

Mohr-Tranebjaerg Syndrome (Deafness-dystonia-optic atrophy syndrome) Symptoms/Presentation

• SNHL hearing loss (pre/postlingual)

• impaired vision

• dystonia/ataxia in teens

• fractures

• ID

TIMM8A contiguous deletion symptoms

X-linked agammaglobulinemia with SNHL

22q11 Deletion Syndrome Symptoms/Presentation

• CATCH (cardiac, abnormal facies/autism, thymic aplasia, cleft palate, hypocalcemia)

• hearing loss

16p12.2 Microdeletion Syndrome Symptoms/Presentation

• sometimes hearing loss

• DD, speech delay, hypotonia

• heart malformations

• epilepsy

Mitochondrial Nonsyndromic Genetic Cause

Mitochondrial: pathogenic variants in MT-RNR1 and MT-TS1

MELAS Genetic Cause

Mitochondrial: pathogenic variants in MT-TL1 and MT-ND5

m. 3243 A>G

Japanese founder variant (diabetes mellitus and SNHL)

What percent of epilepsy is considered genetic?

30%

AD Nocturnal Frontal Lobe Epilepsy (ADNFLE) Symptoms/Presentation

• frontal lobe epilepsy

• occurs only at night

• feeling of being choked/strangled

  • first familial epilepsy identified

AD Nocturnal Frontal Lobe Epilepsy (ADNFLE) Genetic Cause

AD: pathogenic variants in CHRNA4, CHRNA2, CHRNB2

• mutations in nicotinergic acetylcholine receptors

Most common epilepsy genes

SCN1A, KCNQ2, SCN2A, PCDH19, STXBP1

30/10 Rule

Diagnostic yield of genetic testing/actionability of treatment

Epilepsy genes - ion channels

• epilepsy caused by channelopathy

• SCN1A, SCN2A, KCNQ2, CACNA1A

Epilepsy genes - synaptic transmission

• epilepsies caused by synaptopathies

• important in epileptic encephalopathies

• DNM1, SNAP25, STXBP1, STX1B, SYNGAP1

Diagnostic yield of neonatal epileptic encephalopathies

50%

KCNQ2 Related Epilepsy - Protein Truncating Variants

Self-limiting neonatal epilepsy (limited to early in life)

KCNQ2 Related Epilepsy - Dominant Negative Missense Variants

Neonatal epileptic encephalopathy

KCNQ2 Related Epilepsy

one of the most common genetic neonatal epilepsies, can be treated with carbamazepine

Ohtahara Syndrome Genetic Cause

AD: pathogenic variants in STXBP1, KCNQ2, SCN2A

Ohtahara Syndrome Symptoms/Presentation

• Neonatal onset

• Tonic seizures

• Burst suppression on EEG

Epilepsy of Infancy with Migrating Focal Seizures Genetic Cause

AD: pathogenic variants in KCNT1, SCN2A

Epilepsy of Infancy with Migrating Focal Seizures Symptoms/Presentation

• neonatal onset

• refractory focal seizures, migrate from one region to another

West Syndrome Genetic Cause

AD: pathogenic variants in CDKL5, STXBP1, ARX, DNM1

West Syndrome Symptoms/Presentation

• infantile spasms

• hypsarrhythmia on EEG

Dravet Syndrome Genetic Cause

AD: pathogenic variants in SCN1A

• common splice site variant: c.1377+1delG

Dravet Syndrome Symptoms/Presentation

• infantile onset

• prolonged febrile/afebrile seizures

• focal hemiclonic

• regression

Lennox-Gastaut Syndrome Genetic Cause

AD: pathogenic variants in CDKL5, DNM1

Lennox-Gastaut Syndrome Symptoms/Presentation

• onset 1-8y/o

• refractory seizures (tonic)

• generalized slow-spike wave on EEG

Myoclonic-atonic epilepsy/Doose Syndrome Genetic Cause

AD: pathogenic variants in SLC2A1, SLC6A1

Myoclonic-atonic epilepsy/Doose Syndrome Symptoms/Presentation

• onset 1-8y/o

• febrile seizures

• myoclonic-atonic seizures

• regression

Landau-Kleffner Syndrome Genetic Cause

AD: pathogenic variants in GRIN2A

Landau-Kleffner Syndrome Symptoms/Presentation

• onset 2-10y/o

• acquired aphasia after previously normal development

• potential seizures

• electrical status epilepticus during slow wave sleep

SCN1A-related epilepsies

• most common genetic epilepsies

• mild, familial epilepsies: genetic epilepsy with febrile seizures plus (GEFS+)

• severe epilepsies: Dravet syndrome

GLUT1 Deficiency Syndrome Genetic Cause

AD: pathogenic variants in SLC2A1

GLUT1 Deficiency Syndrome Symptoms/Presentation

• classic: neonatal epileptic encephalopathy, microcephaly, ID

• milder: refractory GGE, absence epilepsy

GLUT1 Deficiency Syndrome Treatment

• ketogenic diet

• issued with glucose uptake due to transporter deficiency - use ketones instead

Genetic Testing for Epliepsy Considerations

• low diagnostic yield (ex. absence seizures - besides GLUT1)

• known pathology (ex. lesional epilepsies)