Solar radiation leads to increased collagenase gene expression (MMP1) in HERDA (Hereditary equine regional dermal asthenia) affected horses and may explain the typical dorsal distribution of their lesions.

BACKGROUND: Hereditary equine regional dermal asthenia (HERDA) is a genetic disease that alters collagen biosynthesis. Affected horses exhibit fragile, hyperextensible skin, especially over the dorsal region. Although ultraviolet (UV) radiation seems to contribute to the regional distribution of lesions and worsening of clinical signs, the molecular mechanisms involved are largely unknown. OBJECTIVES: To evaluate the effect of solar radiation on matrix metalloproteinase MMP1, MMP8 and MMP13 gene expression in the dorsal and ventral skin of HERDA-affected and HERDA-unaffected horses [wild-type (WT) horses]. ANIMALS: Six HERDA-affected and six unaffected Quarter horses (WT) were paired according to age, sex and coat colour. MATERIALS AND METHODS: Horses were submitted to 30 day sunlight restriction, followed by 15 day sunlight exposure. Dorsal and ventral skin biopsies were obtained at six sampling times over 45 days. The expression of MMP1, MMP8 and MMP13 genes was measured by quantitative PCR. RESULTS: Although solar radiation modulated MMP1, MMP8 and MMP13 expression, the effects were more pronounced on MMP1. Sun exposure for three days significantly upregulated MMP1 in the dorsal region when compared to the ventral skin in both unaffected and HERDA-affected horses. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows that solar irradiation leads to upregulation of skin collagenase genes particularly MMP1 in the dorsal, sun-exposed skin of horses. Furthermore, this was more marked in HERDA-affected horses. The increased activity of collagenases on the disorganised collagen present in HERDA affected horses would explain why UV radiation leads to deterioration of clinical signs in affected individuals.

Hereditary Equine Regional Dermal Asthenia homozygote adult working horse with mild signs - A Case Report.

Hereditary Equine Regional Dermal Asthenia (HERDA) is an autosomal recessive condition present in the American Quarter Horse and other related breeds. Resulting from a mutation in the peptidyl-prolyl cis-trans isomerase B (PPIB) gene, HERDA is homologous to Ehlers-Danlos syndrome in humans. Characterized by fragile, hyperelastic, skin, HERDA affected horses often present first with slow-healing wounds usually on the dorsum, and resulting in atrophic scars, seromas, and ulcers. As there is no treatment for the condition affected horses are typically reported to be unrideable, and if persistent wounds are sufficiently severe, may require euthanasia. This case report describes clinical presentation and genetic diagnostics of HERDA in an 8-year-old horse with notably mild clinical signs, previously undiagnosed. On recommendation from the referring veterinarian, the horse owners pursued genetic diagnostics for HERDA following development of painful dorsal skin lesions under the saddle area during a riding clinic. The individual was confirmed homozygous for HERDA c.115G>A missense mutation in the PPIB gene by commercial testing service (Etalon Diagnostics Inc.). Further objective studies on the severity and clinical presentation of HERDA are necessary to evaluate complex elements of this disease. Furthermore, mildly affected individuals may be underdiagnosed as a result of not demonstrating the clinical signs that commonly encourage genetic testing.

Evaluation of the Filum Terminale in Hereditary Equine Regional Dermal Asthenia.

The objectives of this study were to describe the anatomy, histology, and ultrastructure of the equine filum terminale (FT) and to describe the FT in hereditary equine regional dermal asthenia (HERDA), a model of human Ehlers-Danlos syndromes (EDS). Those humans suffer from tethered cord syndrome (TCS) caused by an abnormally structured FT wherein its attachment at the base of the vertebral column leads to long-term stretch-induced injury to the spinal cord. The pathophysiology of TCS in EDS is poorly understood, and there is a need for an animal model of the condition. Histopathologic and ultrastructural examinations were performed on FT from HERDA (n = 4) and control horses (n = 5) and were compared to FT from human TCS patients with and without EDS. Adipose, fibrous tissue, and neuronal elements were assessed. CD3 and CD20 immunohistochemistry was performed to clarify cell types (HERDA n = 2; control n = 5). Collagen fibrils were assessed in cross-section for fibril diameter and shape, and in longitudinal section for fibril disorganization, swelling, and fragmentation. The equine and human FT were similar, with both containing fibrous tissue, ependyma, neuropil, and nerve twigs. Hypervascularity was observed in both HERDA horses and human EDS-TCS patients and was not observed in equine or human controls. Moderate to severe abnormalities in collagen fibril orientation and architecture were observed in all HERDA horses and were similar to those observed in human EDS-TCS patients.

Industry Perceptions of HERDA in Performance Horses.

Hereditary equine regional derma asthenia (HERDA), an autosomal-recessive trait, found in Quarter Horses, causes abnormal collagen structure. Owing to current breeding practices, 3.5% of registered quarter horses and 28.3% of the cow horse population are heterozygote carriers. Research demonstrated homozygote horses develop hyperextensible skin susceptible to injury and other abnormal tissues containing high fibrillar collagen content. No research exists determining the effects of the disease in heterozygote carriers. Currently, 30% of cutting sires are HERDA carriers, potentially increasing the number of heterozygous individuals when bred. The objective of the present study is to gauge knowledge of the disease, perception, and concerns of the diseases' impact on horse performance and perceived value and breeding decisions. A Qualtrics link was distributed to horse owners via extension specialists and was available online on equine-related Facebook pages. Overall group means and standard deviations for constructs were reported. A total of 228 responses were collected. Most participants were involved in reining and cutting and 34.6% reported they were very familiar with the disease. Participants (78.5%) reported that HERDA status affects value of a breeding animal. Owners of HERDA carriers (62.5%) noticed no difference in performance or injury compared with noncarriers. Respondents (95.2%) believed that all breeding animals should have HERDA status available. Respondents are attempting to make informed breeding decisions based on HERDA status by pairing carriers with noncarriers; however, it remains to be seen if that is adequate to control the disease. Education regarding breeding practices and its impact on the genetic pool are warranted.

Cardiac findings in Quarter Horses with heritable equine regional dermal asthenia.

OBJECTIVE To compare biomechanical and histologic features of heart valves and echocardiographic findings between Quarter Horses with and without heritable equine regional dermal asthenia (HERDA). DESIGN Prospective case-control study. ANIMALS 41 Quarter Horses. PROCEDURES Ultimate tensile strength (UTS) of aortic and mitral valve leaflets was assessed by biomechanical testing in 5 horses with HERDA and 5 horses without HERDA (controls). Histologic evaluation of aortic and mitral valves was performed for 6 HERDA-affected and 3 control horses. Echocardiography was performed in 14 HERDA-affected and 11 control horses. Biomechanical data and echocardiographic variables of interest were compared between groups by statistical analyses, RESULTS Mean values for mean and maximum UTS of heart valves were significantly lower in HERDA-affected horses than in controls. Blood vessels were identified in aortic valve leaflets of HERDA-affected but not control horses. Most echocardiographic data did not differ between groups. When the statistical model for echocardiographic measures was controlled for body weight, mean and maximum height and width of the aorta at the valve annulus in short-axis images were significantly associated with HERDA status and were smaller for affected horses. CONCLUSIONS AND CLINICAL RELEVANCE Lower UTS of heart valves in HERDA-affected horses, compared with those of control horses, supported that tissues other than skin with high fibrillar collagen content are abnormal in horses with HERDA. Lack of significant differences in most echocardiographic variables between affected and control horses suggested that echocardiography may not be useful to detect a substantial loss of heart valve tensile strength. Further investigation is warranted to confirm these findings. Studies in horses with HERDA may provide insight into cardiac abnormalities in people with collagen disorders.

Prevalence study of SNP c.421G>T in the ADAMTS2 gene responsible for dermatosparaxis in white dorper sheep in Brazil / Prevalência do SNP c.421G>T no gene ADAMTS2 responsável pela dermatosparaxia em ovinos white dorper no Brasil

Dermatosparaxis is an autosomal recessive disorder of connective tissue; the disorder is clinically characterized by skin fragility and hyperextensibility. Dermatosparaxis in White Dorper sheep is caused by a single nucleotide polymorphism (SNP) (c.421G>T) in the ADAM metalloproteinase with thrombospondin type 1 motif, 2 (ADAMTS2) gene. The aim of this study was to investigate the prevalence of this SNP in a White Dorper herd in São Paulo state, Brazil. In this study, we collected blood DNA samples from 303 White Dorper sheep and performed polymerase chain reaction to amplify the SNP region. The samples were sequenced to determine the presence of the SNP in the ADAMTS2 gene. The SNP prevalence in the studied population was 15.5%; this finding indicates that more effective control measures should be used to prevent the inheritance of SNP c.421G>T in the ADAMTS2 gene in Brazilian White Dorper herds.

A dermatosparaxia é uma doença autossômica recessiva do tecido conjuntivo, clinicamente caracaterizada pela fragilidade e hiperextensibilidade da pele. A dermatosparaxia em ovinos White Dorper é causada pelo polimorfismo de base única (SNP) c.421G>T no gene ADAM metalopeptidase com trombospondina tipo 1 motif, 2 (ADAMTS2). O objetivo deste estudo foi investigar a prevalência deste SNP em ovinos White Dorper no estado de São Paulo, Brasil. Foram coletadas amostras de sangue de 303 ovinos White Dorper. O DNA foi purificado destas amostras sanguíneas e utilizado em uma reação em cadeia da polimerase (PCR) para amplificação da região do gene contendo SNP c.421G>T. Os produtos das PCR foram sequenciados para determinar o genótipo dos animais. A prevalência do SNP na população estudada foi de 15,5%, estes achados indicam que medidas de controle efetivas devem ser utilizadas para prevenir a disseminação deste SNP no rebanho brasileiro de White Dorper.

Cutaneous asthenia (Ehlers-Danlos-like syndrome) of Burmese cats.

OF CASES: A 6-month-old Burmese kitten developed focal skin lesions following a routine ovariohysterectomy. These were eventually attributed to the patient struggling during catheter placement and induction of anaesthesia. The lesions were caused by fluid extravasation in the subcutis and ischaemic necrosis of the overlying dermis, giving rise to an eschar-like appearance. Such lesions have been seen previously in Burmese cats with cutaneous asthenia and it is thought that they arise due to poor collagenous support for dermal blood vessels. An increased skin extensibility index (>23%) supported a diagnosis of cutaneous asthenia (Ehlers-Danlos-like syndrome), which has been reported as an inherited condition of Burmese cats in Australia, New Zealand and Europe. An additional Burmese cat with cutaneous asthenia is presented in detail, with lifetime follow-up and further salient observations by the owner, a veterinarian. Photographs of three other affected Burmese cats are provided to illustrate the range of presentations encountered with this condition. All five affected cats were presented with eschars, atrophic alopecia and increased skin extensibility, while one cat also had skin ulcers. Routine histopathological examination, including use of special stains such as trichrome, was unhelpful in establishing the diagnosis. CLINICAL REVIEW: The clinical features of this genetic disease of Burmese cats are reviewed, especially in relation to the postulated 'vasculopathy' that gives rise to characteristic skin lesions. Long term management of this condition is discussed briefly.

Ocular dimensions, corneal thickness, and corneal curvature in quarter horses with hereditary equine regional dermal asthenia.

OBJECTIVES: The aim of this study was to compare ocular dimensions, corneal curvature, and corneal thickness between horses affected with hereditary equine regional dermal asthenia (HERDA) and unaffected horses. ANIMALS: Five HERDA-affected quarter horses and five healthy control quarter horses were used. METHODS: Schirmer's tear test, tonometry, and corneal diameter measurements were performed in both eyes of all horses prior to ophthalmologic examinations. Ultrasonic pachymetry was performed to measure the central, temporal, nasal, dorsal, and ventral corneal thicknesses in all horses. B-mode ultrasound scanning was performed on both eyes of each horse to determine the dimensions of the ocular structures and to calculate the corneal curvature. RESULTS: Each corneal region examined in this study was thinner in the affected group compared with the healthy control group. However, significant differences in corneal thickness were only observed for the central and dorsal regions. HERDA-affected horses exhibited significant increases in corneal curvature and corneal diameter compared with unaffected animals. The ophthalmologic examinations revealed mild corneal opacity in one eye of one affected horse and in both eyes of three affected horses. No significant between-group differences were observed for Schirmer's tear test, intraocular pressure, or ocular dimensions. CONCLUSIONS: Hereditary equine regional dermal asthenia-affected horses exhibit decreased corneal thickness in several regions of the cornea, increased corneal curvature, increased corneal diameter, and mild corneal opacity. Additional research is required to determine whether the increased corneal curvature significantly impacts the visual accuracy of horses with HERDA.

Dermatological and morphological findings in quarter horses with hereditary equine regional dermal asthenia.

BACKGROUND: Hereditary equine regional dermal asthenia (HERDA) is an autosomal recessive disorder affecting quarter horses (QHs); affected horses exhibit characteristic skin abnormalities related to abnormal collagen biosynthesis. HYPOTHESIS/OBJECTIVES: To characterize the thickness and morphological abnormalities of the skin of HERDA-affected horses and to determine the interobserver agreement and the diagnostic accuracy of histopathological examination of skin biopsies from horses with HERDA. ANIMALS: Six affected QHs, confirmed by DNA testing, from a research herd and five unaffected QHs from a stud farm. METHODS: The skin thickness in 25 distinct body regions was measured on both sides in all affected and unaffected horses. Histopathological and ultrastructural evaluation of skin biopsies was performed. RESULTS: The average skin thickness in all of the evaluated regions was thinner in the affected horses. A statistically significant difference between skin thickness of the affected and unaffected animals was observed only when the average magnitude of difference was ≥38.7% (P = 0.038). The interobserver agreement for the histopathological evaluation was fair to substantial. The histopathological sensitivity for the diagnosis of HERDA was dependent on the evaluator and ranged from 73 to 88%, whereas the specificity was affected by the region sampled and ranged from 35 to 75%. CONCLUSIONS AND CLINICAL IMPORTANCE: Despite the regional pattern of the cutaneous signs, skin with decreased thickness was not regionally distributed in the HERDA-affected horses. Histopathological evaluation is informative but not conclusive for establishing the diagnosis. Samples of skin from the neck, croup or back are useful for diagnosis of HERDA. However, the final diagnosis must be confirmed using molecular testing.

Allele frequency of hereditary equine regional dermal asthenia in American Quarter horses in Brazil determined by quantitative real-time PCR with high resolution melting analysis.

Hereditary equine regional dermal asthenia (HERDA) is a genetic disorder that occurs in the American Quarter horse (AQH) and is caused by a c.115G>A missense mutation in the peptidylprolyl isomerase B (PPIB) gene. Using a quantitative real-time PCR high resolution melting analysis genotyping assay for the PPIB mutation, the estimated HERDA allele and carrier frequencies in a sample of Brazilian AQHs were 2.9% and 5.8%, respectively.

Heritable equine regional dermal asthenia.

Hereditary equine regional dermal asthenia is a form of Ehlers-Danlos syndrome, and has an autosomal recessive mode of inheritance. Affected horses are typically born normal and develop lesions within the first 2 years of life. The most common symptoms of the disease include stretchy, loose skin that feels doughy or mushy. More severely affected horses experience spontaneous skin sloughing and extensive lacerations, hematomas, and seromas from minor trauma. Affected horses have a higher than expected incidence of corneal ulcers. DNA testing can normal, establish carrier and affected status. Palliative therapy is available, but no curative treatment exists.

Assessment of growth performance, immune responses, serum metabolites, and prevalence of leg weakness in broiler chicks submitted to early-age water restriction.

The objective of this study was to evaluate the effects of two methods of early-age water restriction on performance, some immune responses, serum metabolites, and prevalence of leg weakness in broiler chicks. One-hundred-eighty-seven-day-old chicks (Ross 308) were allocated to three treatments with four replicates based on a completely randomized design. Treatments included the control group, where birds had free access to water, and water-restricted groups, where access to water was limited to three 2-h periods (WRT1) or a 12-h period (WRT2) per day from days 7 to 17. Chicks in the control group were significantly heavier (P < 0.05) at 17 and 46 days of age compared to the restricted birds. In the WRT2 group, feed intake decreased significantly over the 17- to 28-day period while feed conversion ratio was poorer during water restriction (P < 0.05). Antibody titers against Newcastle and SRBC were higher (P < 0.05) for chicks with ad libitum access to water. Birds in the restricted groups exhibited a higher heterophil to lymphocyte ratio compared to the control group (P < 0.05). The treatments had no significant impact on serum metabolites including protein, triglyceride, total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterols, calcium, and phosphorus concentrations. Walking ability, tibial dyschondroplasia, foot pad, hock burn, and valgus/varus angulation were not significantly influenced by water restriction. In conclusion, the current results indicate that early-age water restriction negatively influenced productive traits and immunological responses of broiler chicks and failed to have any favorable impacts on leg health.

Cutaneous asthenia in a Warmblood foal.

A 6-week-old Warmblood colt foal was presented for investigation of multiple haematoma formation in various locations, poor wound healing and abnormal scar formation. Based on the history and clinical presentation of hyperextensible skin with prolonged skin tenting, the foal was diagnosed with cutaneous asthenia and euthanased because of the poor prognosis. Histopathological and electron microscopic findings were inconclusive. This is the first case report of cutaneous asthenia in a Warmblood horse in Australia. Cutaneous asthenia is reviewed with particular reference to hereditary equine regional dermal asthenia and its similarities and differences to the case presented.

Prevalence of the mutation in cyclophilin B (PPIB), a causal candidate gene for HERDA, among Quarter Horses in France.

Hereditary equine regional dermal asthenia (HERDA) in Quarter Horses is an inherited degenerative skin disease. Initially reported as hyperelastosis cutis, HERDA has a phenotype of hyperextensible, fragile skin, with secondary seromas, haematomas, ulcers and scarring. It primarily affects the dorsal aspect of the body. An autosomal recessive mode of inheritance is considered likely, with affected horses more at risk to produce affected offspring. A mutation in cyclophilin B (PPIB) as a novel, causal candidate gene for HERDA has been described, and verified as segregating with carriers and affected horses. Screening of control Quarter Horses in the USA has indicated a 3.5% carrier frequency. The prevalence of this mutation among Quarter Horses in France was determined to be 1.6%.

Ocular findings in Quarter Horses with hereditary equine regional dermal asthenia.

OBJECTIVE: To compare ocular structures of Quarter Horses homozygous for hereditary equine regional dermal asthenia (HERDA) with those of Quarter Horses not affected by HERDA (control horses) and to determine the frequency of new corneal ulcers for horses with and without HERDA during a 4-year period. DESIGN: Cohort study of ocular structures and retrospective case series of horses with and without HERDA. ANIMALS: The cohort portion of the study involved 10 Quarter Horses with HERDA and 10 Quarter Horses without HERDA; the retrospective case series involved 28 horses with HERDA and 291 horses without HERDA. PROCEDURES: Ophthalmic examinations, Schirmer tear tests, tonometry, corneal pachymetry, histologic examinations, and scanning electron microscopy (SEM) were performed in cohorts of Quarter Horses with and without HERDA. Records were reviewed to determine the incidence of corneal ulcers in horses with and without HERDA during a 4-year period. RESULTS: Corneal thickness of horses with HERDA was significantly less than that of control horses, but tear production of horses with HERDA was significantly greater than that of control horses. Results of SEM revealed zones of disorganized, haphazardly arranged collagen fibrils in corneas of horses with HERDA that were not evident in corneas of control horses. The incidence of corneal ulcers was significantly greater for horses with HERDA than for horses without HERDA during the 4-year period. CONCLUSIONS AND CLINICAL RELEVANCE: Alterations in corneal thickness, arrangement of collagen fibers, and incidence of corneal ulcers indicated that abnormalities in horses with HERDA were not limited to the skin.

[Swiss warmblood horse with symptoms of hereditary equine regional dermal asthenia without mutation in the cyclophylin B gene (PPIB)]. / Schweizer Warmblutfohlen mit Symptomen von hereditärer dermaler Asthenie (HERDA) ohne Mutation im Cyclophilin B-Gen (PPIB).

Hereditary equine dermal asthenia (HERDA) is an autosomal recessive skin disease that affects predominantly Quarter Horses and related breeds. Typical symptoms are easy bruising and hyperextensible skin on the back. The prognosis is guarded, as affected horses cannot be ridden normally and are often euthanised. In the Quarter Horse, HERDA is associated with a mutation in cyclophilin B (PPIB), an enzyme involved in triple helix formation of collagen. Here we describe the case of a Swiss Warmblood filly with symptoms of HERDA without PPIB-mutation and in which we also could exclude Ehlers-Danlos syndrome Type IV, VI, VIIA, VIIB and VIIC (dermatosparaxis type) as etiological diseases.

Increased elastic microfibrils and thickening of fibroblastic nuclear lamina in canine cutaneous asthenia.

Cutaneous asthenia is a hereditary connective tissue disease, primarily of dogs and cats, resembling Ehlers-Danlos syndrome in man. Collagen dysplasia results in skin hyperextensibility, skin and vessel fragility, and poor wound healing. The purpose of this study was to describe the histological findings in a dog with a collagenopathy consistent with cutaneous asthenia. An 8-month-old crossbreed female dog presented with lacerations and numerous atrophic and irregular scars. The skin was hyperextensible and easily torn by the slightest trauma. Ultrastructurally, the dermis was comprised of elaunin and oxytalan microfibrils. These are immature fibres in which the fibrillar component is increased but elastin is reduced. Collagen fibres were profoundly disorganized. The fibrils had a highly irregular outline and a corroded appearance when viewed in cross-section, and were spiralled and fragmented in a longitudinal view. Dermal fibroblasts displayed a conspicuous thickening of the nuclear lamina. Nuclear lamins form a fibrous nucleoskeletal network of intermediate-sized filaments underlying the inner nuclear membrane. Mutations in lamins or lamin-associated proteins cause a myriad of genetic diseases collectively called laminopathies. Disruption of the nuclear lamina seems to affect chromatin organization and transcriptional regulation of gene expression. A common link among all laminopathies may be a failure of stem cells to regenerate mesenchymal tissue. This could contribute to the connective tissue dysplasia seen in cutaneous asthenia.

Evaluation of allele frequencies of inherited disease genes in subgroups of American Quarter Horses.

OBJECTIVE: To estimate allele frequencies of the hyperkalaemic periodic paralysis (HYPP), lethal white foal syndrome (LWFS), glycogen branching enzyme deficiency (GBED), hereditary equine regional dermal asthenia (HERDA), and type 1 polysaccharide storage myopathy (PSSM) genes in elite performance subgroups of American Quarter Horses (AQHs). DESIGN: Prospective genetic survey. ANIMALS: 651 elite performance AQHs, 200 control AQHs, and 180 control American Paint Horses (APHs). PROCEDURES: Elite performance AQHs successful in 7 competitive disciplines (barrel racing, cutting, halter, racing, reining, western pleasure, and working cow horse) were geno- typed for 5 disease-causing alleles. Age-matched control AQHs and APHs were used to establish comparative whole-breed estimates of allele frequencies. RESULTS: Highest allele frequencies among control AQHs were for type 1 PSSM (0.055) and GBED (0.054), whereas HERDA (0.021) and HYPP (0.008) were less prevalent. Control APHs uniquely harbored LWFS (0.107) and had high prevalence of HYPP (0.025), relative to AQHs. Halter horse subgroups had significantly greater allele frequencies for HYPP (0.299) and PSSM (0.155). Glycogen branching enzyme deficiency, HERDA, and PSSM were found broadly throughout subgroups; cutting subgroups were distinct for HERDA (0.142), and western pleasure subgroups were distinct for GBED (0.132). Racing and barrel racing subgroups had the lowest frequencies of the 5 disease genes. CONCLUSIONS AND CLINICAL RELEVANCE: Accurate estimates of disease-causing alleles in AQHs and APHs may guide use of diagnostic genetic testing, aid management of genetic diseases, and help minimize production of affected foals.