Published on March 13, 2014
Topic = Genetic Disorder “Hearing loss”. Presented By= M.Z.Arifeen Department Of Biotechnology University Of Malakand
Introduction Deafness, hearing impairment, or hearing loss is a partial or total inability to hear. Deafness affects 1 per 1000 children About 50% of childhood HL attributed to genetic factors, 20-25% environmental factors, and 25- 30% sporadic Hearing impairment is the world’s third leading chronic disease Recessive inherited deafness in Pakistan in high due to high rate of consanguineous marriages.
Causes of Hearing Loss: Hearing is a complex process, so it should be no surprise that the causes of hearing loss are also complex. Hearing loss can occur because of damage to the ear, especially the inner ear. For example, infants may be born with hearing loss caused by a viral infection that was acquired during pregnancy. At other times the cause is genetic and therefore due to changes in the genes involved in the hearing process. .
Sometimes, hearing loss is due to a combination of genetic and environmen-tal factors. There is, for example, a genetic change that makes some people more likely to develop hearing loss after taking certain antibiotic medications
Genetic • Infections • Structural What Causes Hearing Loss? • Unknown • Traumas/ Exposures Non-Genetic
How the ear works: • The ear has three main parts: the outer, middle and inner ear. • The outer ear (the part you can see) opens into the ear canal. • The eardrum separates the ear canal from the middle ear. • Small bones in the middle ear help transfer sound to the inner ear. (incus, malleus and stapes) • The inner ear contains the Cochlea, auditory (hearing) nerve, which leads to the brain.
Process of hearing • Any source of sound sends vibrations or sound waves into the air. • The funnel through the ear opening, down the ear, canal, and strike your eardrum, causing it to vibrate. • The vibrations are passed to the small bones of the middle ear, which transmit them to the hearing nerve in the inner ear. Here, the vibrations become nerve impulses and go directly to the brain, which interprets the impulses as sound (music, voice, etc.). Inner Ear The vibrations are changed into electrical impulses that are sent to the brain to create what we understand as “hearing.”
The different types of hearing loss are classified according to what part of the hearing system is affected. Sound is picked up by the outer ear and then passes through the ear canal to the middle ear. Problems in these places cause conductive hearing loss. After passing through the middle ear, the sound then travels to a part of the inner ear called the cochlea, where it is changed to a signal that can be sent down the hearing nerve to the brain. Problems here cause sensorineural hearing loss.
Types Of Hearing Loss Hereditary hearing loss is divided into syndromic and non-syndromic cases syndromic = a condition with various symptoms affecting multiple organ systems i.e deafness that is accompanied by other clinical features. Accounts for 30% of all cases of deafness non-syndromic = no other phenotypic abnormalities accompanying this type of deafness. Accounts for 70% is non-syndromic
Types of Hearing Loss congenital = Congenital means that a person was born with the hearing loss. acquired = Acquired hearing loss means that a person could hear when he or she was born, but developed hearing loss later in life. o prelingual = If hearing loss starts before the age when children usually begin talking, it is called “prelingual”, which means “before speaking”.
o Postlingual = If hearing loss starts after the age when children begin talking, it is called “postlingual”, which means “after speaking”. progressive= If the hearing loss gets worse over time, it is called “progressive”. nonprogressive= If the hearing loss does not change over time, it is “nonprogressive” or stable.
familial = If more than one person in a family has hearing loss, it is said to be “familial”. That is, it runs in the family. sporadic = If only one person in the family has hearing loss, it is called “sporadic”. That is, it does not run in the family. Conductive =“Conductive” hearing loss is caused by problems in the outer or middle ear. Sensorineural= “Sensorineural” hearing loss is caused by problems in the inner ear.
Classification of HHL Also divided into groups by mode of inheritance: Autosomal Dominant Autosomal Recessive X-Linked Disorder Mitochondrial Disorder
Etiology of Deafness
Autosomal Dominant Disorders 75-80% of genetic deafness attributed to AR inheritance, 18-20% to AD, with the remainder classified as X-linked or chromosomal disorders
Sex-Linked Disorders X-linked inheritance is rare Accounts for only 1% to 2% of cases of hereditary hearing loss May constitute about 6% of nonsyndromic profound losses in males X-linked congenital SNHL has been mapped to Xq X-linked dominant SNHL has been mapped to Xp
Mitochondrial Inheritance Hearing Loss Hearing LossHearing Loss Hearing Loss
Mitochondrial Genetics • Two genes are important for non-syndromic mitochondrial HL 1.MTRNR1: MTRNR1 gene encoding the 12S rRNA of Mt. Mutations in MT-RNR1 can be associated with predisposition to aminoglycoside ototoxicity and/or late-onset sensorineural hearing loss. •The MTRNR1 mutations probably alter the secondary structure of the 12S rRNA molecule, so that it resembles its bacterial counterpart, the 16S rRNA, more closely. As the bacterial 16S rRNA molecule is the target of aminoglycoside action, this might explain the cumulating effect of these MTRNR1 mutations and the use of aminoglycosides .
2. MTTS1: MTTS1 gene encodes transfer RNA for serine both of which are important in mitochondrial protein synthesis. • Individuals with an MTTS1 mutation generally have an onset of sensorineural hearing loss during childhood.
Waardenburg Syndrome Accounts for 3% of childhood hearing impairment Most common form of inheritable congenital deafness Incidence is 1 in 4000 live births sensorineural hearing loss iris pigmentary abnormality (two eyes different color or iris bicolor or characteristic brilliant blue iris) hair hypopigmentation (white forelock or white hairs at other sites on the body) skin hypopigmentation(congenital leukoderma/white skin patches) medial eyebrow flare (unibrow synophrys) broad nasal root premature graying of the hair (before age 30). All features are variable in appearance
Waardenburg Syndrome Types 1 and 3 caused by mutation of PAX3 gene on chromosome 2q; Type 2 is caused by mutation of MITF gene on chromosome 3q (The 'q' refers to the long arm of the chromosome) Also linked to other genes -EDN3, EDNRB, and SOX10
Stickler Syndrome Characterized by cleft palate, micrognathia, severe myopia and retinal detachments Severe HL in 15%; less severe HL in 80% Most cases attributed to mutations in COL2A1 gene on chromosome 12
Branchio-oto-renal Syndrome Estimated to occur in 2% of children with congenital hearing loss Involves ear pits/tags or cup ear and renal involvement ranging from agenesis and renal failure to minor dysplasia 75% of affected patients have significant hearing loss Gene felt to be responsible is located on chromosome 8q in humans
Nonsyndromic Hearing Loss Nonsyndromic deafness is hearing loss that is not associated with other signs and symptoms. Most forms of nonsyndromic deafness are associated with permanent hearing loss caused by damage to structures in the inner ear. The inner ear consists of three parts: a snail-shaped structure called the cochlea that helps process sound, nerves that send information from the cochlea to the brain, and structures involved with balance. Loss of hearing caused by changes in the inner ear is called sensorineural deafness.
Hearing loss that results from changes in the middle ear is called conductive hearing loss. Some forms of nonsyndromic deafness, particularly a type of deafness called DFN3, involve changes in both the inner ear and the middle ear. This combination is called mixed hearing loss. The causes of nonsyndromic deafness are complex. Researchers have identified more than 30 genes that, when mutated, may cause nonsyndromic deafness; however, some of these genes have not been fully characterized Many genes related to deafness are involved in the development and function of the inner ear. Mutations in these genes result in hearing loss by interfering with critical steps in processing sound
What are GJB2 and Connexin 26? Autosomal Recessive Non-syndromic Hearing loss: –Connexin 26 mutations are the most common cause of autosomal recessive, non-syndromic hearing loss Mutations in the GJB2 gene causes prelingual nonsyndromic deafness This gene provides instructions for making a protein called connexin 26 These proteins form parts (subunits) of channels called gap junctions, which allow communication between neighboring cells. Mutations in connexin proteins that make up gap junctions may affect the function or survival of cells that are needed for hearing. Gap junction are present inside cochlea. The cochlea is a very complex and specialized part of the body that needs many instructions to guide its development and functioning
The GJB2gene contains the instructions for a protein called Connexin 26; this protein plays an important role in the functioning of a part of the ear called the cochlea.
Deafness Type 3 (DFN3) DFN3 deafness is caused by mutations in the POU3F4 gene, which is located on the X chromosome. (Xq21) In people with this condition, one of the small bones in the middle ear (the stapes) cannot move normally, which interferes with hearing. This characteristic sign of DFN3 is called stapes fixation At least four other regions of the X chromosome are involved in hearing loss, but the responsible genes have not been discovered
Nonsyndromic AD Hearing Loss
Recessive Nonsyndromic Hearing Loss
Nonsyndromic X-Linked Hearing Loss
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