w12

Question 1

Normal metabolism

Answer 1

maintains homeostasis, converts food to energy and removes waste products of metabolism

Question 2

Metabolic disorders can disrupt

Answer 2

the ability of enzyme/cell or organ to perform critical biochemical reactions

Question 3

Metabolic disorders can interfere with

Answer 3

1) growth (2) energy production & distribution to organs and tissues (3) waste product elimination

Question 4

consequences of metabolic imbalances

Answer 4

: brain dysfunction (intellectual disability or siezures) sensory and motor dysfunction (HL, blindness, decreased muscle tone) organ failure

Question 5

Metabolic pathways

Answer 5

: many including transporting or processing proteins (amino acids) carbohydrates (sugars and starches) or lipids (fatty acids)

Question 6

what causes metabolic disorders

Answer 6

Genetic: deficiency can be at molecular/cell level or organ/tissue level
Environment & lifestyle

Question 7

Hereditary metabolic disorders:

Answer 7

common disorder- as a group affect 1/1000 but individually rare >1300 different types of rare metabolic disorders
- Onset congenital or early childhood

Question 8

acquired metabolic disorders

Answer 8

diabetes mellitus type 2 * MOST common acquired disorder affecting >2 million Canadians

Question 9

metabolic disorder: complex

Answer 9

Genetic factors: inherited susceptibility
Environmental/lifestyle factors: lack of physical activity, smoking, excess alcohol consumption, nutrient deficits, toxic exposures
Organ/tissue disease affecting (liver, cardiovascular system, pancreas, endocrine gland, other organ involved in metabolism

Question 10

Site of lesion of metabolic disorders

Answer 10

cochlea, auditory nerve, CANS may be affected

Question 11

Primary auditory damage metabolic disorders

Answer 11

disease process which directly target both inner ear and another tissue/organ system
- Both are primary targets & share same underlying pathophysiology (e.g., gene mutation)

Question 12

Secondary auditory damage metabolic disorders

Answer 12

metabolic derangement primarily targeting non-auditory tissues/organs (e.g, hyperlipidemia: Cardiovascular & blood vessel disease)
- Metabolic derangement then has secondary effects disrupting auditory system

Question 13

mitochondrial disorders

Answer 13

damaged mitochondria cause loss of energy supply to cochlear cells (ATP) and excessive ROS generation- disrupts stria vascularis, hair cells & neurons leading to degeneration

Question 14

metabolic syndrome

Answer 14

• quite complex and a number of different factors: Genetics, Lifestyle
• rates of recovery from SSNHL were lower among patients with metabolic syndrome and prognosis is poorer in patients with a greater # of metabolic syndrome factors (central obesity, impaired glucose metabolism, insulin resistance, inflammation, dyslipidemia etc.)

Question 15

Type 1:

Answer 15

cause unknown (autoimmune & genetic factors) develops in childhood or adolescence, associated with peripheral and CAS dysfunction

Question 16

Type 2

Answer 16

acquired, develops in adulthood, ongoing research to examine effects on hearing

Question 17

Pathology responsible for permanent SNHL varied

Answer 17

• Generation of excess “free radicals” caused by metabolic disorder> damage cochlear and brain tissues
• Primary neuropathy affecting auditory nerve
• Small blood vessel disease: compromise vascular perfusion of cochlea
  o Ohc and stria vascularis very sensitive
• Central auditory damage and auditory processing (biological mechanisms poorly understood)

Question 18

Diabetes audiological assessment

Answer 18

Audiometry: abnormal thresholds especially high frequencies but low frequency decline also observed (ultra-high freq. range)
Objective tests: DPOAE and ABRs abnormal
Suprathreshold & auditory processing: SIN tests abnormal, temporal processing abnormal

Question 19

what is DNA

Answer 19

a double helix structure made up of A, T, C, G (A binds with T, C binds with G)

Question 20

dNA described

Answer 20

Each nucleus contains 23 pairs of chromosomes
22 autosomal (1-22) and 1 pair of sex chromosomes (XX= female XY=male)
- Autosomal tend to not be related to sex
- Most of information is on X chromosome, not lots on Y
- More males tend to be affected then it would be an X linked hearing loss

Question 21

What is a gene

Answer 21

Approx 30 000 genes in the human body
- Portion of DNA that code for proteins
- Different etiologies have different forms of inheritance

Question 22

RNA and proteins

Answer 22

Information gets translated from DNA to RNA
RNA is single stranded and contains Uracil (U) instead of thymine (T)

Question 23

Mutation in promotor-

Answer 23

part of gene that initiates transcription: possible outcome ‘;transcription process may not be initiated or may have up regulation if binds with additional affinity; results in change in protein level (can have none, too much or not enough)

Question 24

Mutation in exon

Answer 24

wrong peptide coded, change protein, can have premature stop, can result sometimes in no change

Question 25

Mutation in intron

Answer 25

• will get spliced out often, no issues, can occasionally change splicing, can have truncated or elongated MRNA transcript which would then change the peptide and protein function

Question 26

Gene expression

Answer 26

• Every cell contains 100% of genetic information
• Approx.. 20% of genes are expressed in each cell type (not always on or off can have different levels of expression)_
• Can have mutations causing HL, syndromes or HL + other impairments

Question 27

types of mutation

Answer 27

Substitution
Inversion
Deletion
Insertion

Question 28

autosomal traits

Answer 28

• Traits controlled by 1 gene
• Inherited by dominant or recessive pattern
  Dominant: 1 copy of the allele required to show trait
  Recessive: 2 copies of the allele required to show trait

Question 29

Polygenic traits

Answer 29

multiple alleles that contribute to phenotype
Shows different probabilities of exhibiting certain phenotypes
Ex., 6 copies of darker skin allele - more likely to have darker skin vs 6 copies of lighter skin allele more likely to have lighter skin

Question 30

genetics and hearing

Answer 30

• Approx.. 50% hearing impairments due to genetic factors
• Genetic HL categorized into 2 major forms: (1) syndromic 30% (2) non-syndromic 70%
• Genetic HL caused by various mutations in various genes, resulting in various phenotypic presentations. Over 100 genes identified (ex. GJB2, Cadherin 23, Otoferlin)

Question 31

1997 DFNB1: GJB2

Answer 31

• DNA codes for connexin 26 protein – protein in gap junctions which connect adjacent cells and regulate the flow of small molecules between cochlear cells (not present in hair cells)
• Most common form of non-syndromic deafness
• GJB2 mutations: different errors in gene code >100 identified

Question 32

Cadherin 23

Answer 32

Function: allows cells to stick together
Expression: stereocilia, retina
Phenotype: deafness or Deafness and blindness
- Difference depends on type of mutation in cdh23

Question 33

Cadherin 23 mutation 1

Answer 33

nonsense mutation (premature stop-shorter protein) Phenotype1: hearing loss + vision impairment

Question 34

Cadherin 23 Mutation 2

Answer 34

missense mutation (Change in amino acid) Phenotype 2: hearing loss only

Question 35

Otoferlin (OTOF)

Answer 35

Function: unknown
Expression: brain, cochlea
Phenotype: auditory neuropathy
16 different mutations identified within OTOF
- Unique mutation (deletion) results in “deafening fever” severe- profound HL only when fever present, only mild HL when no fever present

Question 36

Why bother familiarize with genetics

Answer 36

HL can have genetic etiology, improved counselling, better understanding of HL, potential for new treatments (e.g., gene therapy)

Question 37

X-linked in newfoundland family

Answer 37

mutation on X chromosome causes HL phenotype
WFs1: autosomal dominant mutation 28 affected individuals
KNCQ4: autosomal dominant mutation 13-16 affected individuals
FOXL1: autosomal dominant otosclerosis

Question 38

future opportunity for audiology

Answer 38

1. Identification (do I have genetic HL and what type)
2. Surveillance (have gene but hl fine, or have HL will it get worse)
3. Counselling
4. Treatment/monitoring