A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals.

Idiopathic hypocalcemia in Thoroughbred (TB) foals causes tetany and seizures and is invariably fatal. Based upon the similarity of this disease with human familial hypoparathyroidism and occurrence only in the TB breed, we conducted a genetic investigation on two affected TB foals. Familial hypoparathyroidism was identified, and pedigree analysis suggested an autosomal recessive (AR) mode of inheritance. We performed whole-genome sequencing of the two foals, their unaffected dams and four unaffected, unrelated TB horses. Both homozygosity mapping and an association analysis were used to prioritize potential genetic variants. Of the 2,808 variants that significantly associated with the phenotype using an AR mode of inheritance (P<0.02) and located within a region of homozygosity, 1,507 (54%) were located in a 9.7 Mb region on chr4 (44.9-54.6 Mb). Within this region, a nonsense variant (RAPGEF5 c.2624C>A,p.Ser875*) was significantly associated with the hypoparathyroid phenotype (Pallelic = 0.008). Affected foals were homozygous for the variant, with two additional affected foals subsequently confirmed in 2019. Necropsies of all affected foals failed to identify any histologically normal parathyroid glands. Because the nonsense mutation in RAPGEF5 was near the C-terminal end of the protein, the impact on protein function was unclear. Therefore, we tested the variant in our Xenopus overexpression model and demonstrated RAPGEF5 loss-of-function. This RAPGEF5 variant represents the first genetic variant for hypoparathyroidism identified in any domestic animal species.

HEPATIC OSTEODYSTROPHY IN A GOLDEN LION TAMARIN (LEONTOPITHECUS ROSALIA).

An 8-yr-old, captive, female golden lion tamarin ( Leontopithecus rosalia ) with a 6-yr history of hyperbilirubinemia was examined for inappetence and weight loss. Physical examination and blood pressure monitoring under anesthesia revealed hypothermia and hypotension, and blood work revealed hypoglycemia, markedly elevated liver enzymes, including serum alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase, and confirmed the hyperbilirubinemia. A complete blood count suggested chronic lymphoid leukemia. The animal's condition deteriorated during recovery, and the animal died despite aggressive treatment. Grossly, there was micronodular cirrhosis of the liver, severe icterus, and diffuse osteopenia of all examined bones. Microscopic examination of the liver confirmed the micronodular cirrhosis and bone lesions were compatible with diffuse osteopenia and osteomalacia. This brief communication presents a case of chronic liver disease and lesions indicative of metabolic bone disease, also known as hepatic osteodystrophy. To the authors' knowledge, this is the first documented case of hepatic osteodystrophy in the veterinary literature.

Imaging diagnosis--meningoencephalitis secondary to suppurative rhinitis and meningoencephalocele infection in a dog.

Nasal encephaloceles (meningoceles or meningoencephaloceles) are rare and not reported to be infected or coupled with a facial deformity in dogs. This report describes an older dog with acute worsening of seizures due to suppurative meningoencephalitis with coexisting suppurative rhinitis and infection of a meningoencephalocele. Additionally, the dog had a facial deformity for at least 5 years. The results of necropsy, computed tomography, and postmortem magnetic resonance imaging are compared. The development of nasal encephaloceles is discussed, including the potential role of early trauma, and whether separation of neural ectoderm from the surface ectoderm is part of the pathogenesis.

Intra-Articular Administration of a Synthetic Lubricin in Canine Stifles.

OBJECTIVE: The aim of this study was to evaluate the functional, systemic, synovial and articular changes after intra-articular administration of a synthetic lubricin within healthy canine stifles. STUDY DESIGN: A prospective randomized blinded placebo-controlled study composed of 10 dogs equally divided into either a treatment group (intra-articular synthetic lubricin injection, n = 5) or control group (saline, n = 5). Clinical (orthopaedic examination, gait observation, gait analysis), biochemical (complete blood count and biochemistry profile) and local tissue outcomes (joint fluid analysis, joint capsule and articular cartilage histopathology) were evaluated over a time period of 3 months. RESULTS: No significant differences between the treatment group and control group were identified with regard to baseline patient parameters. No clinically significant orthopaedic examination abnormalities, gait abnormalities, biochemical alterations, joint fluid alterations or histopathological alterations were identified over the course of the study. CONCLUSION: The synthetic lubricin studied herein is both biocompatible and safe for a single administration within the canine stifle joint. Further research is necessary to evaluate the clinical efficacy of the synthetic lubricin in canine osteoarthritic joints.

Differences in the magnetic resonance imaging parameter T2* may be identified during the course of canine patellar tendon healing: a pilot study.

BACKGROUND: Previous studies have utilized ultrashort echo (UTE) magnetic resonance imaging (MRI), and derived T2* maps, to evaluate structures with highly ordered collagen structures such as tendon. T2* maps may provide a noninvasive means to assess tendon damage and healing. This pilot study evaluated the longitudinal relationship of an induced mechanical strain on the patellar tendon with corresponding UTE T2* metrics, histologic and biomechanical evaluation at two post-operative time points. METHODS: A total of 27 patellar tendons in male Beagles were surgically subjected to stretching by a small diameter (SmD) or a large diameter (LgD) diameter rod to induce damage due to strain, and evaluated at 4- and 8-week intervals using quantitative MRI (qMRI), biomechanical testing, and histology. A separate set of 16 limbs were used as controls. RESULTS: The tendons experienced a 67% and 17% prolongation of short T2* values as compared to controls at 4 and 8 weeks post-operatively, respectively. Histologic analysis displayed a trend of increased collagen disruption at 4 weeks followed by presence of greater organization at 8 weeks. Biomechanical evaluation found a reduction of tendon modulus and failure strain at both time points, and an increase in cross-sectional area at 4 weeks as compared to controls. CONCLUSIONS: These findings display tendon healing in response to an imposed strain and present the utility of qMRI to evaluate longitudinal differences of patellar tendon T2* values in a model of induced subclinical tendon damage. The qMRI technique of UTE provides a means to non-invasively evaluate the healing process of a mechanically damaged tendon.

Magnetic resonance imaging and histologic features of the supraspinatus tendon in nonlame dogs.

OBJECTIVE To characterize the MRI and histologic features of the supraspinatus tendon in nonlame dogs. ANIMALS 7 cadavers (14 shoulder joints) of nonlame 2-year-old sexually intact male Beagles. PROCEDURES Multiple MRI fluid-sensitive pulse sequences were obtained for both shoulder joints of each cadaver, and the thickness, volume, and signal intensity of each supraspinatus tendon were assessed. After MRI scanning was complete, the shoulder joints were processed for histologic examination. Tissue specimens were stained with various stains to determine tendon morphology and composition. Histologic and MRI findings were correlated and described. RESULTS All supraspinatus tendons had a trilaminar appearance on sagittal and transverse MRI images, which was characterized by a thick, hyperintense center layer (central substance) sandwiched between thin hypointense superficial and deep margins. The mean ± SD central substance-to-superficial margin and central substance-to-deep margin thickness ratios were 8.4 ± 1.2 and 9.0 ± 0.9, respectively; supraspinatus tendon-to-triceps brachii muscle signal intensity ratio was 1.3 ± 0.2; and tendon volume was 445 ± 20 mm3. The superficial and deep margins histologically resembled other tendons with highly ordered collagen fibers. The central substance was comprised of water-rich glycosaminoglycans interspersed among haphazardly arranged collagen bundles. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated histologically normal canine supraspinatus tendons have a trilaminar appearance on MRI images. In dogs, a diagnosis of supraspinatus tendinosis should not be based solely on the tendon having a hyperintense signal on MRI images; other MRI evidence of shoulder joint disease and diagnostic findings are necessary to support such a diagnosis.

Magnetic Resonance Imaging T2 Values of Stifle Articular Cartilage in Normal Beagles.

OBJECTIVES: The purpose of this study was to evaluate regional differences of canine stifle articular cartilage using the quantitative magnetic resonance imaging (MRI) technique of T2 mapping. METHODS: Fourteen stifle joints from seven juvenile male Beagle dogs with no evidence or prior history of pelvic limb lameness were imaged ex vivo using standard of care fast spin echo MRI and quantitative T2 mapping protocols. Regions of interest were compared between the femoral, patellar and tibial cartilages, as well as between the lateral and medial femorotibial compartments. Limbs were processed for histology with standard stains to confirm normal cartilage. RESULTS: The average T2 value of femoral trochlear cartilage (37.5 ± 2.3 ms) was significantly prolonged (p < 0.0001) as compared with the femoral condylar, patellar and tibial condylar cartilages (33.1 ± 1.5 ms, 32.8 ± 2.3 ms, and 28.0 ± 1.7 ms, respectively). When comparing medial and lateral condylar compartments, the lateral femoral condylar cartilage had the longest T2 values (34.8 ± 2.8 ms), as compared with the medial femoral condylar cartilage (30.9 ± 1.9 ms) and lateral tibial cartilage (29.1 ± 2.3 ms), while the medial tibial cartilage had the shortest T2 values (26.7 ± 2.4 ms). CLINICAL SIGNIFICANCE: As seen in other species, regional differences in T2 values of the canine stifle joint are identified. Understanding normal regions of anticipated prolongation in different joint compartments is needed when using quantitative imaging in models of canine osteoarthritis.

Quantitative Magnetic Resonance Imaging and Histological Comparison of Normal Canine Menisci.

OBJECTIVE: The purpose of this observational study was to establish normative data for the canine menisci using magnetic resonance imaging (MRI). METHODS: Ten fresh stifles from five normal male Beagles were obtained from animals with no known lameness. Conventional MRI and ultrashort echo time (UTE) imaging were performed and T2* values calculated. Five stifles were assessed histologically. RESULTS: The caudal horn of the medial meniscus had significantly prolonged T2* values (4.6 ± 1.27 ms; p = 0.002) as compared with the cranial horn of the medial meniscus (3.25 ± 0.86 ms), and the cranial (3.06 ± 0.54 ms) and caudal (3.64 ± 0.72 ms) horns of the lateral meniscus. Histology demonstrated normal tibial, femoral, interior and peripheral meniscal margins, and normal cellularity. The medial meniscus was noted to be obliquely oriented to the scan plane compared with the relatively perpendicular orientation of the lateral meniscus as compared with the bore of the magnet in a limb-extended orientation. CLINICAL SIGNIFICANCE: Variability of MRI UTE T2* is seen in the normal canine meniscus, with prolongation of the caudal horn, medial meniscus. Prolongation may be due to magic angle effects, as the medial meniscus of the Beagle is not perpendicular to the axis of the main magnetic field. Canine meniscal injury is a common sequela to cruciate tear, and detecting meniscal damage is important for directing patient care. The non-invasive quantitative MRI technique of UTE imaging can be used for the evaluation of collagen orientation, while acknowledging inherent regions of prolongation.