Multiple Congenital Ocular Anomalies Research Articles

Multiple congenital ocular anomalies in three related litters of Jack Russell Terrier puppies.

To describe multiple congenital ocular anomalies in three litters of Jack Russell Terrier puppies. Seven purebred Jack Russell Terrier puppies from three related litters and their four parents. Medical records of the puppies and their parents were evaluated. All dogs underwent a complete ophthalmic examination, followed by bilateral ocular ultrasonography in two of the puppies with complete corneal opacity. One eye from an affected puppy was subjected to histopathology. A complete database of pedigrees was built, and individual inbreeding was evaluated. The most commonly diagnosed ocular anomalies in the puppies were: various anomalies of the fundus (12/14 eyes); microphthalmia (10/14 eyes); sclerocornea (8/14 eyes); and persistent pupillary membranes (7/14 eyes). Six out of seven puppies had at least two ocular abnormalities, and only one puppy was normal. Four out of seven puppies had sclerocornea, a particular corneal opacity to date described only in Spanish Podenco dogs. No ocular abnormalities were found in the parents examined (4/4). Analysis of the pedigrees showed that all the puppies and two parents were inbred, and the individual values of the inbreeding puppies were greater than 6.25% in two litters. Inbreeding with closely related Jack Russell Terriers may result in severe congenital eye abnormalities in puppies.

A pilot study about multiple congenital ocular anomalies in trait Comtois horse breed

The Silver gene is at the origin of the special coat color of the Trait Comtois Horse breed, but also predisposes carriers to Multiple Congenital Ocular Anomalies syndrome.
 The objective of this pilot study was to evaluate the awareness and knowledge of Comtois owners about this topic through their response to a questionnaire. After completing it, we offered documentation for them to keep and to refer to when they feel the need.
 The majority of the owners were aware about the gene, but still many are confused with its issues. Genetic testing is not systematically done when ocular problems are noticed, but willingness to pay more attention to genotypes is present in the common spirit. By developing a proper reproduction management and a proper genotyping of the Comtois horse breed population, conservation and enhancement of the breed will be possible. In this regard, Silver homozygous equines should not be discriminated, as they may possess desirable traits and may be able to perform as any other horse in their domain of activity. They should instead be encouraged to be mated with their bay peers, in order to obtain heterozygous foals. Genetic testing campaigns are increasingly offered during competitions and open to all categories of horses.
 This problematic should not divide breeders, but rather motivate them to work altogether to be able to perpetuate the Trait Comtois horse breed, flagship of the Franche-Comté region.

Multiple Congenital Ocular Anomalies in a silver coat Missouri Fox Trotter stallion.

This is the first description of Multiple Congenital Ocular Anomalies (MCOA) in a silver coat Missouri Fox Trotter determined to be heterozygous for the Silver PMEL17 missense mutation associated with MCOA and a silver coat in other breeds. The stallion was treated for meningoencephalitis and bilateral uveitis of unknown origin. A complete ophthalmic examination and ocular ultrasonography were performed. As an incidental finding, the patient exhibited bilateral cystic lesions restricted to the temporal anterior uvea consistent with the Cyst phenotype and was genotyped heterozygous for the Silver mutation. Additionally, 4 other non-silver colored Missouri Fox Trotters were genotyped homozygous for the wild-type allele. Screening for PMEL17 mutation in Missouri Fox Trotters accompanied by ophthalmic phenotype characterization is recommended to determine the allelic frequency and facilitate informed breeding decisions since the silver coat color is particularly popular.

Microphthalmia With Multiple Anterior Segment Defects in Portuguese Water Dogs

Portuguese Water Dog breeders and veterinary ophthalmologists recognize microphthalmia with multiple congenital ocular anomalies. Fifteen Portuguese Water Dog puppies (<8 weeks of age; 8 females, 7 males) and 1 adult (5 years old; castrated male) with microphthalmia were examined. The 2 most common abnormalities were microphthalmia (31/32 eyes; 97%) and lens abnormality (congenital cataract or aphakia; 32/32 eyes; 100%). Other common histologic lesions included lack of both a ciliary cleft and trabecular meshwork (15/32 eyes; 47%) and abnormal relationship of anterior segment structures (15/32 eyes; 47%). Many of the observed lesions were similar to those described in various types of anterior segment dysgenesis in humans. Our findings define the histologic lesions in affected Portuguese Water Dogs and suggest a genetic defect that causes anterior segment malformation early in development.

The refractive state of the eye in Icelandic horses with the Silver mutation

BackgroundThe syndrome Multiple Congenital Ocular Anomalies (MCOA) is a congenital eye disorder in horses. Both the MCOA syndrome and the Silver coat colour in horses are caused by the same missense mutation in the premelanosome protein (PMEL) gene. Horses homozygous for the Silver mutation (TT) are affected by multiple ocular defects causing visual impairment or blindness. Horses heterozygous for the Silver mutation (CT) have less severe clinical signs, usually cysts arising from the ciliary body iris or retina temporally. It is still unknown if the vision is impaired in horses heterozygous for the Silver mutation. A recent study reported that Comtois horses carrying the Silver mutation had significantly deeper anterior chambers of the eye compared to wild-type horses. This could potentially cause refractive errors. The purpose of the present study was to investigate if Icelandic horses with the Silver mutation have refractive errors compared to wild-type horses. One hundred and fifty-two Icelandic horses were included in the study, 71 CT horses and five TT horses. All horses were genotyped for the missense mutation in PMEL. Each CT and TT horse was matched by a wild-type (CC) horse of the same age ± 1 year. Skiascopy and a brief ophthalmic examination were performed in all horses. Association between refraction and age, eye, genotype and sex was tested by linear mixed-effect model analysis. TT horses with controls were not included in the statistical analyses as they were too few.ResultsThe interaction between age and genotype had a significant impact on the refractive state (P = 0.0001). CT horses older than 16 years were on average more myopic than wild-type horses of the same age. No difference in the refractive state could be observed between genotypes (CT and CC) in horses younger than 16 years. TT horses were myopic (−2 D or more) in one or both eyes regardless of age.ConclusionOur results indicate that an elderly Icelandic horse (older than 16 years) carrying the Silver mutation is more likely to be myopic than a wild-type horse of the same age.

Post mortem magnetic resonance imaging of multiple congenital ocular anomalies in a Comtois mare

SummaryMultiple congenital ocular anomalies syndrome consists of several abnormalities mainly localised to the anterior segment of the eye. This condition, comprising iridal or ciliary cysts with or without iridal hypoplasia, an excessively protruding cornea (‘cornea globosa’), miotic pupils, retinal dysplasia, cataract, and other lesions, has been reported in several breeds and is strongly related to the silver coat colour, as a result of a dominant mutant allele at the PMEL17 locus. This report describes the macroscopic, ultrasonographic, histological and magnetic resonance imaging findings of the ocular abnormalities in a Comtois mare with multiple congenital ocular anomalies syndrome.

Equine Multiple Congenital Ocular Anomalies and Silver Coat Colour Result from the Pleiotropic Effects of Mutant PMEL

Equine Multiple Congenital Ocular Anomalies (MCOA) syndrome is a heritable eye disorder mainly affecting silver colored horses. Clinically, the disease manifests in two distinct classes depending on the horse genotype. Horses homozygous for the mutant allele present with a wide range of ocular defects, such as iris stromal hypoplasia, abnormal pectinate ligaments, megaloglobus, iridociliary cysts and cataracts. The phenotype of heterozygous horses is less severe and predominantly includes iridociliary cysts, which occasionally extend into the temporal retina. In order to determine the genetic cause of MCOA syndrome we sequenced the entire previously characterized 208 kilobase region on chromosome 6 in ten individuals; five MCOA affected horses from three different breeds, one horse with the intermediate Cyst phenotype and four unaffected controls from two different breeds. This was performed using Illumina TruSeq technology with paired-end reads. Through the systematic exclusion of all polymorphisms barring two SNPs in PMEL, a missense mutation previously reported to be associated with the silver coat colour and a non-conserved intronic SNP, we establish that this gene is responsible for MCOA syndrome. Our finding, together with recent advances that show aberrant protein function due to the coding mutation, suggests that the missense mutation is causative and has pleiotrophic effect, causing both the horse silver coat color and MCOA syndrome.

Phenotypic description of multiple congenital ocular anomalies in Comtois horses

SummaryMultiple congenital ocular anomalies (MCOA) and their relation to coat colour genotype have not yet been described in Comtois horses, unlike in Rocky Mountain Horses. The objectives of the study were to describe prevalence, nature and severity of congenital ocular anomalies relating to the PMEL17 (Silver) mutation in Comtois horses. Seventy‐four purebred Comtois and one half‐cross Comtois horses, aged 10 days to 18 years, were examined by transillumination, direct ophthalmoscopy and ultrasonography. Hair samples were collected from 34 horses for coat colour genotyping. Sixty‐six horses (88%) revealed cysts (65 horses) or abnormal thickness (one horse) of the ciliary bodies, most of them only diagnosed by ultrasonography. Cysts were localised in the nasal part of the eye in 8 horses. All these horses presented the silver phenotype with mane and tail being white or flaxen, or were chestnut with genetic testing confirming PMEL17 mutation. Of these, 39 (58%) showed MCOA‐syndrome with iridal hypoplasia (100%), cataract (85%), cornea globosa (56%) and lens luxation (8%). Only 8 bay mature horses (11%) were classified as being disease‐free. Genetic testing confirmed that cyst‐phenotype horses were heterozygous carriers for the Silver mutation, MCOA‐phenotype horses were homozygous carriers, and bay horses were noncarriers. Bay homozygous carriers had significantly lighter coat colour than heterozygous carriers. One foal with heterozygous mutation had normal eyes. Thus, MCOA‐syndrome related to PMEL17 mutation is overrepresented in Comtois horses, and should be taken into consideration for breeding purposes. Ultrasonography permitted detection of cysts in all Silver carriers apart from one, some of them being localised in the nasal part of the eye.

Icelandic horses with the Silver coat colour show altered behaviour in a fear reaction test

The colour of a horse's coat has long been discussed to reflect its temperament. One opinion is that Silver coloured horses are nervous, difficult to handle and react more strongly to different fear stimuli. The objective with the present study was to investigate if mutations associated with the Silver coat colour affect fear reactions in Icelandic horses. The hypothesis was that horses with the Silver mutation Arg618Cys in PMEL show stronger fear reactions than horses without the mutation (e.g. Black/Brown or Chestnut horses). Twenty-seven Icelandic horses (nine Silver, nine Chestnuts and nine Black/Brown) matched for sire, were exposed to the fear stimulus (a suddenly moving plastic bag) while feeding from a container. The test was repeated five times and behavioural responses and latency to return to the feed container were recorded. All horses were genotyped for the Silver mutation. The proportion of Silver horses that were hesitant to approach the test set-up before each trial was significantly higher (P<0.05) than the proportion of non-Silver horses and this difference was most pronounced before the first two trials. No differences in reaction vigour or latency to resume feeding were found between the differently coloured horses. The results suggest that Silver horses are more cautious in novel situations rather than more reactive in fearful situations. One likely explanation for this difference is that the Silver mutation is associated with multiple congenital ocular anomalies (MCOA) syndrome and visual impairment. Furthermore, offspring (regardless of coat colour) from sires with a Best Linear Unbiased Prediction (BLUP, an index indicating which traits a horse will pass on to its offspring) value above 100 for the temperament trait ‘Spirit’, showed a greater fear reaction (P<0.01) and reacted for a longer time (P<0.01) than horses from sires with a lower (<100) index. These results indicate that horses with a high BLUP value for ‘Spirit’ seem to express stronger fear reactions. Breeding for Silver coat colour and the ‘Spirit’ trait, as it is currently defined, may need to be reconsidered if these results are confirmed in a larger cohort.

Multiple congenital ocular anomalies syndrome in a family of Shetland and Deutsches Classic ponies in Belgium

Summary The multiple congenital ocular anomalies (MCOA) syndrome has been associated with the Silver phenotype only in a few equine breeds. This report describes the phenotypic and genotypic characteristics of MCOA in a family of Silver-coated Shetland ponies including a 20-year-old stallion, 17-year-old mare and their 1.5-year-old female offspring. Another 7-year-old Silver female Deutsches Classic Pony descending from the same dam but from a different sire, was also examined. Each pony underwent a complete ophthalmic examination, tonometry, ocular ultrasonography and genotyping for the silver coat colour. The stallion had a thickened iris, temporal retinal atrophy and bilateral iridociliary and peripheral retinal cysts. All females presented more severe anomalies: cornea globosa, iridocorneal adhesions, miosis, hypoplastic granula iridica and poorly responsive pupils to light and to pharmacological mydriasis. Iris hypoplasia, anterior cortical cataracts and temporal retinal atrophy were detected in 2 mares. One female presented bilateral lens subluxation. Supero-temporal cystic structures were confirmed ultrasonographically in all ponies. The stallion was heterozygous for the Silver mutation, whereas all females were homozygous. This is the first report of the MCOA syndrome in a family of Shetland ponies and a Deutsches Classic Pony in association with the Silver phenotype, in Europe.

Ultrasonographic features ofPMEL17(Silver) mutant gene-associated multiple congenital ocular anomalies (MCOA) in Comtois and Rocky Mountain horses

(1) To describe the ultrasonographic appearance of multiple congenital ocular anomalies (MCOA) in the eyes of horses with the PMEL17 (Silver) mutant gene. (2) To compare the accuracy of B-mode ocular ultrasound to conventional direct ophthalmoscopy. Sixty-seven Comtois and 18 Rocky Mountain horses were included in the study. Horses were classified as being carriers or noncarriers of the PMEL17 mutant allele based on coat color or genetic testing. Direct ophthalmoscopy followed by standardized ultrasonographic examination was performed in all horses. Seventy-five of 85 horses (88.24%) carried at least one copy of the Silver mutant allele. Cornea globosa, severe iridal hypoplasia, uveal cysts, cataracts, and retinal detachment could be appreciated with ultrasound. Carrier horses had statistically significantly increased anterior chamber depth and decreased thickness of anterior uvea compared with noncarriers (P < 0.05). Uveal cysts had a wide range of location and ultrasonographic appearances. In 51/73 (69.86%) carrier horses, ultrasound detected ciliary cysts that were missed with direct ophthalmoscopy. In this study, ultrasonography was useful to identify uveal cysts in PMEL17 mutant carriers and to assess anterior chamber depth.

Equine Multiple Congenital Ocular Anomalies (MCOA) syndrome inPMEL17(Silver) mutant ponies: five cases

To describe the clinical phenotype and genetics of equine Multiple Congenital Ocular Anomalies (MCOA) syndrome in PMEL17 (Silver) mutant ponies. Five presumably unrelated ponies. The ponies were examined under field conditions in their barn by slit lamp biomicroscopy, indirect ophthalmoscopy, and applanation tonometry. Blood was collected and genomic DNA extracted for MCOA genotyping using the PMEL17ex11 marker. One pony solely presented with temporal ciliary body cysts, suggestive of the less severe Cyst phenotype of MCOA; the animal was heterozygous at the MCOA locus. Multiple bilateral anterior segment anomalies were identified in four ponies, consistent with the more severe MCOA phenotype characterized by cornea globosa, iris hypoplasia, encircling granula iridica along the pupillary ruff, and cataracts. These animals were homozygous for the mutant MCOA allele. Four of the ponies had a silver dapple or chocolate coat color with white or flaxen manes and tails. Silver dappling was masked by the palomino coloring of a 5th pony that was homozygous at the MCOA locus. The MCOA syndrome can be seen in ponies. The results of both clinical evaluation and genotyping resembled the previously described MCOA of both Rocky Mountain and Kentucky Mountain Saddle horses.

Targeted analysis of four breeds narrows equine Multiple Congenital Ocular Anomalies locus to 208 kilobases

The syndrome Multiple Congenital Ocular Anomalies (MCOA) is the collective name ascribed to heritable congenital eye defects in horses. Individuals homozygous for the disease allele (MCOA phenotype) have a wide range of eye anomalies, while heterozygous horses (Cyst phenotype) predominantly have cysts that originate from the temporal ciliary body, iris, and/or peripheral retina. MCOA syndrome is highly prevalent in the Rocky Mountain Horse but the disease is not limited to this breed. Affected horses most often have a Silver coat color; however, a pleiotropic link between these phenotypes is yet to be proven. Locating and possibly isolating these traits would provide invaluable knowledge to scientists and breeders. This would favor maintenance of a desirable coat color while addressing the health concerns of the affected breeds, and would also provide insight into the genetic basis of the disease. Identical-by-descent mapping was used to narrow the previous 4.6-Mb region to a 264-kb interval for the MCOA locus. One haplotype common to four breeds showed complete association to the disease (Cyst phenotype, n = 246; MCOA phenotype, n = 83). Candidate genes from the interval, SMARCC2 and IKZF4, were screened for polymorphisms and genotyped, and segregation analysis allowed the MCOA syndrome region to be shortened to 208 kb. This interval also harbors PMEL17, the gene causative for Silver coat color. However, by shortening the MCOA locus by a factor of 20, 176 other genes have been unlinked from the disease and only 15 genes remain.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-011-9325-7) contains supplementary material, which is available to authorized users.

Multiple congenital ocular anomalies in Icelandic horses

BackgroundMultiple congenital ocular anomalies (MCOA) syndrome is a hereditary congenital eye defect that was first described in Silver colored Rocky Mountain horses. The mutation causing this disease is located within a defined chromosomal interval, which also contains the gene and mutation that is associated with the Silver coat color (PMEL17, exon 11). Horses that are homozygous for the disease-causing allele have multiple defects (MCOA-phenotype), whilst the heterozygous horses predominantly have cysts of the iris, ciliary body or retina (Cyst-phenotype). It has been argued that these ocular defects are caused by a recent mutation that is restricted to horses that are related to the Rocky Mountain Horse breed. For that reason we have examined another horse breed, the Icelandic horse, which is historically quite divergent from Rocky Mountain horses.ResultsWe examined 24 Icelandic horses and established that the MCOA syndrome is present in this breed. Four of these horses were categorised as having the MCOA-phenotype and were genotyped as being homozygous for the PMEL17 mutation. The most common clinical signs included megaloglobus, iris stromal hypoplasia, abnormal pectinate ligaments, iridociliary cysts occasionally extending into the peripheral retina and cataracts. The cysts and pectinate ligament abnormalities were observed in the temporal quadrant of the eyes. Fourteen horses were heterozygous for the PMEL17 mutation and were characterized as having the Cyst-phenotype with cysts and occasionally curvilinear streaks in the peripheral retina. Three additional horses were genotyped as PMEL17 heterozygotes, but in these horses we were unable to detect cysts or other forms of anomalies.One eye of a severely vision-impaired 18 month-old stallion, homozygous for the PMEL17 mutation was examined by light microscopy. Redundant duplication of non-pigmented ciliary body epithelium, sometimes forming cysts bulging into the posterior chamber and localized areas of atrophy in the peripheral retina were seen.ConclusionsThe MCOA syndrome is segregating with the PMEL17 mutation in the Icelandic Horse population. This needs to be taken into consideration in breeding decisions and highlights the fact that MCOA syndrome is present in a breed that are more ancient and not closely related to the Rocky Mountain Horse breed.

Pleiotropic effects of pigmentation genes in horses

Horses are valued for the beauty and variety of colouration and coat patterning. To date, eleven different genes have been characterized that contribute to the variation observed in the horse. Unfortunately, mutations involving pigmentation often lead to deleterious effects in other systems, some of which have been described in the horse. This review focuses on six such pleiotropic effects or associations with pigmentation genes. These include neurological defects (lethal white foal syndrome and lavender foal syndrome), hearing defects, eye disorders (congenital stationary night blindness and multiple congenital ocular anomalies), as well as horse-specific melanoma. The pigmentation phenotype, disorder phenotype, mode of inheritance, genetic or genomic methods utilized to identify the genes involved and, if known, the causative mutations, molecular interactions and other susceptibility loci are discussed. As our understanding of pigmentation in the horse increases, through the use of novel genomic tools, we are likely to unravel yet unknown pleiotropic effects and determine additional interactions between previously discovered loci.

Equine Multiple Congenital Ocular Anomalies maps to a 4.9 megabase interval on horse chromosome 6

BackgroundEquine Multiple Congenital Ocular Anomalies (MCOA) syndrome consists of a diverse set of abnormalities predominantly localized to the frontal part of the eye. The disease is in agreement with a codominant mode of inheritance in our horse material. Animals presumed to be heterozygous for the mutant allele have cysts originating from the temporal ciliary body, peripheral retina and/or iris. In contrast, animals predicted to be homozygous for the disease-causing allele possess a wide range of multiple abnormalities, including iridociliary and/or peripheral retinal cysts, iridocorneal angle abnormalities, cornea globosa, iris hypoplasia and congenital cataracts. MCOA is most common in the Rocky Mountain horse breed where it occurs at a high frequency among Silver colored horses. The Silver coat color is associated with mutations in PMEL17 that resides on ECA6q23. To map the MCOA locus we analyzed 11 genetic markers on ECA6q and herein describe a chromosome interval for the MCOA locus.ResultsWe performed linkage analysis within 17 paternal half-sib families of the Rocky Mountain horse breed. More than half of the 131 offspring had the Cyst phenotype and about one third had MCOA. Segregation data were obtained by genotyping 10 microsatellite markers most of which are positioned on ECA6q22-23, as well as the missense mutation for the Silver phenotype in PMEL17. Significant linkage was found between the MCOA locus and eight of the genetic markers, where marker UPP5 (Theta = 0, z = 12.3), PMEL17ex11 (Theta = 0, z = 19.0) and UPP6 (Theta = 0, z = 17.5) showed complete linkage with the MCOA locus. DNA sequencing of PMEL17 in affected and healthy control individuals did not reveal any additional mutations than the two mutations associated with the Silver coat color.ConclusionThe MCOA locus can with high confidence be positioned within a 4.9 megabase (Mb) interval on ECA6q. The genotype data on UPP5, PMEL17ex11 and UPP6 strongly support the hypothesis that horses with the Cyst phenotype are heterozygous for the mutant allele and that horses with the MCOA phenotype are homozygous for the mutant allele.

Bilateral Renal Agenesis with Multiple Congenital Ocular Anomalies

A 920-g male infant born with features of Potter's syndrome had multiple ocular anomalies. Ocular abnormalities included absence of keratocytes in the inner central corneal stroma, cataract with retention of cell nuclei in the nucleus of the lens, hypoplasia of the ganglion cell and nerve fiber layers of the retina, and absence of nerve bundles in the optic nerve. Other ocular findings including microphthalmos, fetal chamber angle, persistent pupillary membrane , retinal avascularity, and prominent Bergmeister's papilla may have been related to the prematurity of the child.