Genetics Flashcards
DFNA9:
Genetics of the disorder: mode of inheritance, genetic locus (loci), mutations, proteins affected, including their role in the inner ear
DFNA9 is a nonsyndromic autosomal dominant cause of sensorineural hearing loss with vestibular dysfunction caused by heterozygous mutations in the COCH (coagulation factor C homology) gene, encoding the secreted protein cochlin (Frejo et al., 2016). The COCH gene has a cytogenetic locus of 14Q12. This gene is expressed in the mesodermal tissues of the cochlea and the vestibular labyrinth (Robertson et al., 1998). As of 2016, 21 mutations of the COCH gene have been reported (Kim et al., 2016). One example COCH mutation that has been identified in at least four Dutch families is the 208C→T mutation (de Kok et al., 1999). Its exact role in the ear is unknown, but it is thought to contribute to structural integrity of the cochlea and susceptibility to inner ear infection (Hildebrand et al., 2009; Smith, 2013). Prevalence of COCH mutations worldwide is unknown, as there is no systematic screening effort for late-onset hearing disorders; however, to date, COCH mutations have been found on four continents (Jones et al., 2010; Robertson et al., 2006).
NF2:
Genetics of the disorder: mode of inheritance, genetic locus (loci), mutations, proteins affected, including their role in the inner ear,
Neurofibromatosis 2 (NF2) is inherited in an autosomal dominant manner and is related to the NF2 gene with cytogenetic location 22q12.2. More than 400 mutations in the NF2 gene have been identified in people with NF2. Missense mutations usually cause mild symptoms and signs of NF2 (Baser et al., 2002). Most NF2 gene mutations result in an abnormally shortened version of the merlin protein. Research suggests that the loss of merlin’s function allows certain cells in the nervous system, especially Schwann cells, to multiply too frequently and form tumors. Nonsense/frameshift mutations produce a truncated protein, and tend to be associated with a more severe phenotype (Patronas et al., 2001). A study of 87 untreated NF2 CVSs showed that the presence of hearing loss strongly correlated with elevated intralabyrinthine protein in the inner ear (Asthagiri et al., 2012).
DFNA9:
Clinical presentation: signs and symptoms, typical history including age of onset of various signs and symptoms; epidemiology of the disorder
The phenotype associated with mutations in COCH includes both auditory and vestibular dysfunction, and some individuals may have symptoms suggestive of Meniere disease, including hearing loss fluctuations and asymmetry with accompanying episodes of vertigo or imbalance (Smith, 2013). Hearing loss from DFNA9 disorder is characterized as progressive and sensorineural in nature with onset in the high frequencies (Khetarpal, 2000). Vestibular symptoms occur in most people with DFNA9 and include imbalance, especially in the dark, and episodic vertiginous attacks ranging from paroxysmal to several hours in duration without aural fullness (Brewer & King, 2015). DFNA9 has an adult age onset for hearing loss and vestibular dysfunction which ranges from the second to the fifth decade of life depending on the specific mutation (Khetarpal, 2000). Despite different mutations in the COCH gene, American and European families both manifest auditory and vestibular dysfunction (Khetarpal, 2000).
NF2:
Clinical presentation: signs and symptoms, typical history including age of onset of various signs and symptoms; epidemiology of the disorder,
Neurofibromatosis type 2 (NF2) is characterized by bilateral cochleovestibular schwannomas (CVSs) and other nervous system tumors (Holliday et al, 2014). Patients with NF2 often present with hearing loss, which may be accompanied by tinnitus, dizziness, or imbalance (Asthagiri et al., 2009). The average age of onset is around 20 years (MacCollin & Mautner, 1998). Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. The incidence of NF2 is estimated to be between 1:25,000 and 1:40,000 (Radek et al., 2016) and prevalence is estimated as 1 in 100,000 (Evans et al., 1992). Hearing evaluation typically includes pure tone audiometry, speech intelligibility assessment and brainstem auditory evoked responses for clinical evaluation, with recommendations recently published regarding optimal outcomes for use in clinical trials (Plotkin et al., 2013). While audiologic assessment is important for management of patients with NF2, pure-tone audiometry may hold little diagnostic value. Hearing loss from NF2 occurs in an unpredictable manner and the underlying mechanisms are not known (Asthagiri et al., 2012). It is believed that hearing loss may develop as a result of cochlear aperture obstruction and accumulation of intralabyrinthine protein (Asthagiri et al., 2012). An NF2 natural history study revealed that increasing size correlated with worsening mid- and high-frequency averages, speech reception thresholds, and abnormal ABR (Lalwani et al., 1998). Word recognition testing may reveal PB max rollover when tumors are present on the auditory nerve. Vestibular findings can be variable as well. Some patients may demonstrate abnormal cervical vestibular evoked myogenic potential (cVEMP) if tumors have developed on or near the inferior portion of the vestibular nerve. Caloric testing may indicate a unilateral or bilateral peripheral weakness depending on if tumors are present unilaterally or bilaterally at the time of evaluation. Due to the bilateral nature of NF2, it is most expected to find significant bilateral vestibular dysfunction as tumor burden increases (Holliday et al., 2014). Abnormal cVEMP and caloric testing were significantly associated with larger tumor size (Holliday et al., 2014).
DFNA9:
Clinical diagnosis: Expected findings on (a) auditory and vestibular tests (choose tests that are most appropriate to the diagnosis) (b) otologic examination (c) Supplemental tests critical to diagnosis (gene tests, laboratory tests, imaging studies)
Expected findings on an audiogram for DFNA9 include a moderate-to-severe high-frequency (3,000 Hz and above) hearing loss. Over time, DFNA9 hearing loss will be expected to progress to a severe-to-profound degree across the entire test frequency range (Hildebrand et al., 2009). Word recognition may be disproportionately reduced relative to pure tone thresholds (Bischoff et al., 2005). On a vestibular questionnaire, expected symptoms include vertiginous episodes, feeling clumsy in the dark, oscillopsia, and instability (Khetarpal, 2000). On the heel-to-toe walking test with eyes open or closed, patients with DFNA9 are expected to demonstrate mild-to-moderate ataxia and on the Romberg test patients are expected to demonstrate significant sway (Khetarpal, 2000). No spontaneous or gaze nystagmus is anticipated in these patients (Khetarpal, 2000). An evaluation of bilateral, bithermal caloric irrigations is expected to reveal a bilateral peripheral vestibular hypofunction (Robertson et al., 2006). Results of velocity step testing indicate that vestibular dysfunction starts at a younger age and progresses more rapidly than hearing loss; in some cases vestibular areflexia (absence of vestibular function) may be an early finding (Brewer & King, 2015).
NF2:
Clinical diagnosis: Expected findings on (a) auditory and vestibular tests (choose tests that are most appropriate to the diagnosis) (b) otologic examination (c) Supplemental tests critical to diagnosis (gene tests, laboratory tests, imaging studies)
Otoscopy with good visual inspection of the tympanic membrane is important for patients with NF2. Sone et al. (2007) described a case study patient with NF2, who was asymptomatic at a follow-up visit, during which otoscopic inspection of the tympanic membrane revealed a mass (later identified as a schwannoma) that had grown from the labyrinth into the entire middle ear space. Hearing evaluations, including brainstem auditory-evoked response (BAER) may demonstrate latency abnormalities before a mass is detectable on MRI. To establish the extent of disease in an individual diagnosed with NF2, an otolaryngologist may order a range of testing or referrals including head MRI, hearing evaluation, ophthalmologic evaluation, dermatologic evaluation, and genetic consultation. Diagnosis of NF2 is based on clinical criteria. Molecular genetic testing of NF2 that includes a combination of sequence analysis or scanning for pathogenic variants and duplication/deletion testing detects a pathogenic variant in most affected individuals who have a positive family history and are not the first individual in the family known to have the disorder.
DFNA9:
Prognosis, treatment and management
Currently, DFNA9 is clinically diagnosed through genetic testing. The test is completed using a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies. NGS uses disease-targeted exon-capture approaches restrict sequencing to the COCH (American College of Medical Genetics and Genomics, 2014). Single-gene testing, which is available for DFNA9, is warranted in cases in which the medical or family history, or presentation of the hearing loss, suggests the DFNA9 etiology (American College of Medical Genetics and Genomics, 2014). Temporal bone imaging by computed tomography or magnetic resonance imaging should be considered as a complement to genetic testing in cases of progressive hearing loss such as DFNA9 (American College of Medical Genetics and Genomics, 2014). Visual otological examination of a patient with DFNA9 does not indicate any specific or unique signs. Post mortem histopathology studies have demonstrated the a unique acidophilic deposit in the membranous labyrinths of affected individuals (Khetarpal, 2000). Additionally, electron microscopic analysis showed the spiral ligament to be enriched for a highly branched non-banded microfibrillar substance that is decorated with glycosaminoglycan granules, and the spiral ligament lacks the 67-nm-thick straight periodically banded bundles of type II collagen that are normally abundant in this structure.(Khetarpal, 2000). Identifying prognosis for patients with DFNA9 requires an in-depth person-specific clinical analysis combined with molecular analysis. There is no cure for DFNA9 currently. However, in the future, gene therapy offers the possibility of restoring hearing by overcoming the functional deficits created by the underlying genetic mutations (Chien et al., 2015). Management for the symptoms of DFNA9 include regular monitoring of auditory and balance function. Interventions may include hearing aids or other hearing assistive technology as warranted by audiologic candidacy criteria and vestibular therapy for balance and instability concerns.
NF2:
Prognosis, treatment and management
There is no standard approach to management of CVs related to NF2. Treatment is individualized to the patient and specific ear. In the absence of brainstem compression, the approach is often watchful waiting, but there is no consensus regarding timing of treatment with surgery, chemotherapy, or radiation therapy. It is still unclear whether to wait until further tumor growth, hearing loss, or both to pursue surgery for smaller tumors (Blakeley et al., 2012). Hearing aids may be helpful early in the course of the disease. High levels of speech recognition, including high levels of open-set speech recognition, are possible with auditory brainstem implants even in patients with NF2 and large tumors (Behr et al., 2014). As such, a brainstem implant may be a viable option for some patients, for which the peripheral auditory system has been compromised greatly. Patients experiencing balance problems may benefit from physical therapy and/or vestibular training exercises. While individuals with NF2 typically experience progressive symptoms and signs of disease, the clinical course varies between individuals, depending on age of onset, genotype, tumor burden, complications and management (Ardern-Holmes, Fisher, & North, 2016). Risk of early mortality from brainstem compression and other complications is significant (Ardern-Holmes, Fisher, & North, 2016). Life expectancy for patients with NF2 is estimated to be around 40 years with one study reporting a range of ages at death from 16-67 years old (Evans et al., 1992). There is no cure for NF2, but drug therapies are currently under clinical investigation.
(Frejo et al., 2016)
DFNA9 is a nonsyndromic autosomal dominant cause of sensorineural hearing loss with vestibular dysfunction caused by heterozygous mutations in the COCH (coagulation factor C homology) gene, encoding the secreted protein cochlin (Frejo et al., 2016).
(Robertson et al., 1998).
This gene is expressed in the mesodermal tissues of the cochlea and the vestibular labyrinth (Robertson et al., 1998).
(de Kok et al., 1999)
One example COCH mutation that has been identified in at least four Dutch families is the 208C→T mutation
Hildebrand et al., 2009; Smith, 2013
COCH protein’s exact role in the ear is unknown, but it is thought to contribute to structural integrity of the cochlea and susceptibility to inner ear infection (Hildebrand et al., 2009; Smith, 2013).
Jones et al., 2010; Robertson et al., 2006).
Prevalence of COCH mutations worldwide is unknown, as there is no systematic screening effort for late-onset hearing disorders; however, to date, COCH mutations have been found on four continents
Smith, 2013)
The phenotype associated with mutations in COCH includes both auditory and vestibular dysfunction, and some individuals may have symptoms suggestive of Meniere disease, including hearing loss fluctuations and asymmetry with accompanying episodes of vertigo or imbalance
Khetarpal, 2000) #1
Hearing loss from DFNA9 disorder is characterized as progressive and sensorineural in nature with onset in the high frequencies
Brewer King #1
Vestibular symptoms occur in most people with DFNA9 and include imbalance, especially in the dark, and episodic vertiginous attacks ranging from paroxysmal to several hours in duration without aural fullness
