Deafness in Dogs Causes, Prevalence, and Current Research George M. Strain Louisiana State University Baton Rouge, Louisiana USA

Forms of Deafness inherited or acquired congenital or later-onset sensorineural or conductive Result: eight possible combinations (i.e., acquired later-onset sensorineural deafness) There are many ways to look at deafness - this one seems to be helpful. Deafness can be classified by these three sets of descriptors. By combining them, 8 possible combinations result. The three forms most common in dogs are: 1. inherited, congenital, sensorineural 2. acquired, later-onset, sensorineural 3. acquired, later-onset, conductive I have not seen any inherited deafness that is later-onset, and I have not seen any inherited conductive deafness.

Definitions sensorineural deafness - loss of function because of loss of cochlear hair cells or cochlear nerve neurons conductive deafness - blockage of sound transmission through outer and/or middle ear without damage to cochlea Sensorineural deafness can result from direct damage to the hair cells, or indirectly from damage to the blood supply. Sensorineural deafness is not reversible in mammals. Conductive deafness may resolve or may be treatable in some cases.

Conductive deafness usually results from: 1) chronic otitis externa, where the canal tissues hypertrophy and a stenosis forms. 2) excess cerumen (ear wax) production. 3) pus residue after otitis media, which may take weeks or months for the body to clear up. These are less common in Dalmatians than some other breeds, and are not hereditary.

Inherited Congenital Sensorineural Deafness usually associated with the genes responsible for white hair piebald gene (sp) and extreme piebald (sw) gene merle (M) gene deafness develops at 3-4 weeks of age after the blood supply to the cochlea (stria vascularis) degenerates strial degeneration is thought to result from absence of pigment cells (melanocytes) other pigmentation effects are frequently seen We will focus today on inherited congenital sensorineural deafness. Dalmatians have the extreme piebald gene. In studies in my laboratory we have followed the development of hearing in Dal puppies, and found that they go deaf at 3-4 weeks of age. The function of melanocytes in the stria is not known. Similar pigment-associated hearing defects are seen in other species also (mouse, cat, etc.)

This dog (Demi Azure) demonstrates some of the common pigment changes seen in Dals. Half of the left iris is blue because the piebald gene suppressed pigmentation there, and pigment is missing from the back of the retina - this shows up as red from the blood vessels that are no longer covered by pigmentation. I will present this dog's pedigree later.

All children are taught in school that the ear consists of three chambers - the outer, middle, and inner ears. The outer ear and middle ear are air-filled chambers. The inner ear is encased in the mastoid bone, and is a fluid-filled structure with 3 parallel ducts. The three ducts are coiled, so it has the appearance of a snail.

In this cross section through one coil of the cochlea, the receptor nerve cells (hair cells) are located in the middle compartment (the scala media). Vibrations transmitted in the two outer compartments cause bending of the hair cell cilia, initiating nerve impulses. The special makeup of the fluid of the middle compartment is produced by the stria vascularis on the outside border. This tissue degenerates at 3 weeks of age. The other tissues then degenerate and collapse in on themselves.

Dog Breeds With Congenital Deafness reported in over 80 dog breeds prevalence (unilateral and bilateral) worst in: Dalmatian (n=5,333) 30% white Bull Terrier (n=346) 20% English Setter (n=3,656) 8% Australian Cattle Dog (n=296) 15% English Cocker Spaniel (n=1,136) 7% Jack Russell Terrier (n=56) 16%* Catahoula Leopard Dog (n=78) 63%* Congenital deafness (not necessarily hereditary) has been seen in over 60 breeds. This data is from the US only. The percentages include both unilateral and bilateral deafness. All of these breeds have the piebald gene. Other breeds with the piebald gene may have a similar problem, but are not routinely seeking hearing testing services.

Hearing Testing behavioral testing - sound stimuli outside of the animal's visual field cannot detect unilateral deafness animals quickly adapt to testing detected through other sensory modalities electrodiagnostic testing - brainstem auditory evoked response (BAER) objective, non-invasive detects unilateral deafness limited availability It might be useful to review how hearing testing is performed. Behavioral testing is not very reliable and does not detect unilaterally deaf dogs. Electrodiagnostic testing is objective and reliable, but not yet widely available.

Here is an example of a silent whistle used to test hearing. I use it sometimes to try to convince owners who question the results of a BAER test.

This is my electrodiagnostic testing machine - a Cadwell Sierra (brand) portable. Scalp electrodes are placed on the head and an auditory stimulus, a click, is transmitted to the ear. The computer records the responses through the electrodes, and averages many responses together to unmask the response which is hidden by muscle activity and EEG.

Some testers use headphones, but they are difficult to hold on the head and may actually compress the ear canal, producing a false conduction deafness. Insert earphones are held just outside the opening of the ear canal.

This shows the placement of the scalp electrodes and the positioning of the insert earphone. The computer records the electrical activity between the vertex (top) and the stimulated ear. A ground wire is between the eyes. Anesthesia or sedation are not required for testing. I have only sedated one dog in the ~7,000 dogs I have tested.

Brainstem Auditory Evoked Response This shows BAER responses for 4 Dal puppies. Peak I is produced by the cochlea and auditory nerve. The other peaks are produced in the brain. If the cochlea is destroyed the first peak cannot be produced, so the later peaks cannot be produced either. Puppy 1 was normal. Puppies 2 and 3 were uni's. Puppy 4 was bilaterally deaf.

Genetics of Congenital Deafness Doberman - simple autosomal recessive pigment-associated deafness in dogs - most likely polygenic, incomplete penetrance, or other mechanism – NOT simple autosomal recessive merle gene - dominant; homozygous dogs have additional health problems piebald genes - recessive, but all dogs in the breed are homozygous The inheritance of deafness is not understood in most breeds. For the Doberman it hasbeen shown to be simple recessive. For Dal it appears that more than one gene is involved. Incomplete penetrance may also be involved - in this situation, an animal inherits a syndrome but does not show all aspects of it. So, a dog may "inherit deafness" but not actually go deaf. This is what probably happens with the good ear in unilateral deafness.

Demi Azure Pedigree 6 (5) 12 (11) To show the complexity of deafness inheritance in Dals, this is the pedigree of Demi Azure. Born from two accidentally bred uni parents, she was one of only two affected in a litter of 8. She was bred in my laboratory to a deaf male (Bubba) twice. The first litter had 1 deaf from 5 survivors. The second litter had 8 deaf from 11 survivors. This does not resemble simple recessive or dominant inheritance. If it was simple recessive, all should have been deaf. If deafness is simple dominant, half of all Dalmatians should be deaf. 6 (5) 12 (11)

Dalmatian Deafness Prevalence in the US 70.1% (3,740) This graph shows the prevalence of deafness in Dalmatians in the US that I have tested - 4,871 animals. 70.1% heard in both ears. 21.9% were deaf in one ear. 8.0% were deaf in both ears. So, 29.9% of US Dals were deaf in one or both ears. 21.9% (1,167) 8.0% (426)

Prevalence of Deafness In Dalmatians By Country United States 30% (G Strain, N=5,333)) United Kingdom 21% (M Greening, N=2,282) Holland 18% (B Schaareman, N=1,208) By contrast to the 30% in the US, other countries have reported lower prevalence rates. 21% in the UK. 18% in the Netherlands. I will discuss later why I think these differences result.

Effect of Parent Hearing Status On Deafness Prevalence B-B Parents (N=2,320) B-U Parents (N=728) 73% 59% If deafness is hereditary in the Dalmatian, puppies bred from parents who both hear in both ears (B-B) should have a lower prevalence of deafness than those where one parent was unilaterally deaf (B-U). That was true, providing support for a hereditary component to Dalmatian deafness. This does not mean, however, that other factors do not play a role. 31% 21% 11% 6%

Effect of Sex On Deafness Prevalence Male (N=2,459) Female (N=2,424) 71% 69% There is considerable controversy on whether one sex is more likely to be deaf than another. Studies in England, Norway, the Netherlands, and one study in the US found more deafness in females; this difference was statistically significant in two studies. I found no statistical difference between males and females in my studies. I do not know why we get different results. 22% 22% 7% 9%

Coat Pigmentation Genes In The Dalmatian Base coat - underlying coat color B - black (dominant) b - liver (recessive) Extreme piebald gene - sw - white covering, recessive but homozygous in all Dalmatians (hair is white if it contains no pigment granules [melanin] or other substances which absorb light) Ticking gene - T - dominant, produces holes in white to show underlying coat color Is pigmentation a factor in deafness? Three pigment genes determine the appearance of Dalmatians. Normal white hair (with the piebald gene) results from an absence of pigment granules because melanocytes are missing. It is not the same as albinism, where melanocytes are present but there is a total absence of pigment resulting from absence of the enzyme needed to make melanin. The extreme piebald gene appears to be the one associated with deafness, based on studies in many species.

Effect of the Extreme Piebald Gene Weak gene expression: failure of the piebald gene to completely suppress the underlying coat color (black or liver) results in a patch Strong gene expression: suppresses pigmentation in the iris (blue eyes) and tapetum (red eye), and in the stria vascularis (deafness) It appears that several factors or genes influence how strongly the extreme piebald gene is expressed in the Dalmatian. When it is weakly expressed patches result. When it is strongly expressed blue eyes result and deafness may occur. Not all blue-eyed dogs are deaf. but there is a strong relationship.

Effect of Patch On Deafness Prevalence Patched (N=436) Not Patched (N=4,404) 90% 68% This appears to be born out by the results shown in this graph. Dals with a patch had much less deafness than Dals without a patch. 23% 9% 8% 2%

Effect of Eye Color (Brown or Blue) On Deafness Prevalence BR-BR (N=4,246) BR-BL (N=372) BL-BL (N=143) 73% 49% 50% Also, Dals with one or two blue eyes had more deafness than Dals with only brown eyes. 33% 33% 21% 18% 17% 7%

Effect of Retinal Pigmentation On Deafness Prevalence Pigmented (N=2,611) Not Pigmented (N=623) 71% 56% Also, Dals missing pigment from the retina had more deafness than Dals with pigmented retinal tissue. 29% 22% 15% 7%

Impact Of Breed Standards United States: allows blue eyes Canada: does not allow blue eyes Europe: does not allow blue eyes Efforts through breedings to reduce blue eyes in Norwegian Dalmatians also reduced deafness prevalence. So, what accounts for the difference in deafness prevalence between the US and Europe? Enough animals have been tested to assure that accurate rates have been measured. First, the blue eye is allowed in the breed standard in the US. This would seem to favor deafness. Second, the patch is not allowed. Third, and perhaps most important, breeding of unilaterally deaf dogs is not forbidden. This will guarantee high numbers of deaf Dalmatians.

Breeding Recommendations best advice: don't breed affected animals a unilaterally deaf animal is genetically the same as a bilaterally deaf animal, and SHOULD NOT BE BRED! it is unwise to repeat breedings that produced large numbers of deaf animals avoid breeding to animals with a history of producing many deaf offspring I recommend the following: 1. Don't breed unilaterally deaf animals. 2. Do not repeat breedings that produced many deaf. 3. Avoid breeding to lines that have produced many deaf.

Breeding Recommendations (cont.) do not totally breed away from patches - possibly accept in the breed standard avoid breedings to blue eyed animals ALWAYS KNOW THE HEARING STATUS OF DOGS YOU BREED TO! BREEDING DECISIONS SHOULD ALWAYS TAKE INTO CONSIDERATION THE OVERALL GOOD OF THE BREED 4. Do not eliminate patched dogs. 5. Do not breed blue-eyed dogs. Make breeding decisions thinking about what is best for the breed, not what might be best for your kennel.

Possible Impact of Selective Breeding a recent study by Wood & Lakhani* suggested that selective breeding against unilaterally and bilaterally deaf animals could reduce deafness to below 15% and 4% respectively. *The Veterinary Journal 154:121, 1997 4-5 generations of selective breeding would probably be necessary for a detectable impact on overall prevalence. This epidemiological study took into account a litter effect - animals from the same litter should have a similar genetic makeup. The number of generations before an effect is seen is just a guess. It will depend in part on whether participation is total in a region or country.

Current Research

Study: Molecular Genetics of Deafness AKC/CHF: Murphy, Strain "Genetics of Hereditary Deafness in the Domestic Dog" candidate genes mitf c-kit DNA collection from affected pedigrees Dalmatian English Cocker Spaniel English Setter determination of mode of inheritance

mitf Study: Molecular Genetics of Deafness human homolog of the mouse microphthalmia (mi) gene responsible for >20% of cases of Waardenburg Syndrome type 2 in humans regulates the expression of several pigment genes necessary for transition of precursor cells to melanoblasts (which become melanocytes)

c-kit Study: Molecular Genetics of Deafness tyrosine kinase receptor activation of the c-kit receptor regulates mitf function mutations result in the absence of melanocytes and functional mast cells, as well as defects in ova and sperm development and blood cell formation gene defects in mice produce dominant white spotting and deafness gene defects in humans produce piebaldism and occasionally deafness

Results: mitf – not causative for deafness Study: Molecular Genetics of Deafness Results: mitf – not causative for deafness c-kit – not causative for deafness mode of inheritance: NOT simple autosomal recessive best modeled as being inherited as a single “locus” but one that does not follow Mendelian genetics

Other Ongoing Molecular Genetic Studies AKC/CHF: Murphy, Strain: "Whole genome screens using microsatellite markers in genetic analyses of hereditary deafness in the Dalmatian and English Setter“ pedigree of >200 Dalmatians with DNA English setter pedigree being assembled whole-genome screens underway further funding being sought from NIH & CHF

References: Strain GM. Deafness in Dogs & Cats web page: www.lsu.edu/deafness/deaf.htm Strain GM. 1996. Aetiology, prevalence and diagnosis of deafness in dogs and cats. British Veterinary Journal 152 (1): 17-36. Little CC. 1957. The Inheritance Of Coat Color in Dogs. Howell Book House: New York. 194 pp. Searle AG. 1968. Comparative Genetics of Coat Colour In Mammals. Logos Press/ Academic Press: London. 310 pp. These references provide further information. The first is an Internet web page I created that has much of this information on it.

This cartoon shows just how important hearing can be for a dog. (Gerold - I may not use this - I don't know if people would understand the humor from another language: the rhyme of neuter and tutor.)

Deafness in Dogs & Cats Web Site: www.lsu.edu/deafness/deaf.htm strain@lsu.edu