A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog.

Dogs provide highly valuable models of human disease due to the similarity in phenotype presentation and the ease of genetic analysis. Seven Saluki puppies were investigated for neurological abnormalities including seizures and altered behavior. Magnetic resonance imaging showed a diffuse, marked reduction in cerebral cortical thickness, and symmetrical T2 hyperintensity in specific brain regions. Cerebral cortical atrophy with vacuolation (status spongiosus) was noted on necropsy. Genome-wide association study of 7 affected and 28 normal Salukis revealed a genome-wide significantly associated region on CFA 35. Whole-genome sequencing of three confirmed cases from three different litters revealed a homozygous missense variant within the aldehyde dehydrogenase 5 family member A1 (ALDH5A1) gene (XM_014110599.2: c.866G>A; XP_013966074.2: p.(Gly288Asp). ALDH5A1 encodes a succinic semialdehyde dehydrogenase (SSADH) enzyme critical in the gamma-aminobutyric acid neurotransmitter (GABA) metabolic pathway. Metabolic screening of affected dogs showed markedly elevated gamma-hydroxybutyric acid in serum, cerebrospinal fluid (CSF) and brain, and elevated succinate semialdehyde in urine, CSF and brain. SSADH activity in the brain of affected dogs was low. Affected Saluki dogs had striking similarities to SSADH deficiency in humans although hydroxybutyric aciduria was absent in affected dogs. ALDH5A1-related SSADH deficiency in Salukis provides a unique translational large animal model for the development of novel therapeutic strategies.

EVALUATION OF QUANTITATIVE THYROID SCINTIGRAPHY FOR DIAGNOSIS AND STAGING OF DISEASE SEVERITY IN CATS WITH HYPERTHYROIDISM: COMPARISON OF THE PERCENT THYROIDAL UPTAKE OF PERTECHNETATE TO THYROID-TO-SALIVARY RATIO AND THYROID-TO-BACKGROUND RATIOS.

Thyroid scintigraphy is commonly used for evaluation of cats with hyperthyroidism, with the thyroid-to-salivary ratio (T/S) being the most common method to quantify the degree of thyroid activity and disease. Calculation of thyroid-to-background ratios (T/B) or percent thyroidal uptake of (99m) TcO(-) 4 (TcTU) has only been reported in a few studies. The purpose of this prospective, cross-sectional study was to evaluate a number of quantitative scintigraphic indices as diagnostic tests for hyperthyroidism, including the T/S, three different T/B, TcTU, and estimated thyroid volume. Of 524 cats referred to our clinic for evaluation of suspected hyperthyroidism, the diagnosis was confirmed (n = 504) or excluded (n = 20) based on results of a serum thyroid panel consisting of thyroxine (T4 ), triiodothyronine (T3 ), free T4 (fT4 ), and thyroid-stimulating hormone (TSH) concentrations. In the hyperthyroid cats, median values for TcTU, T/S, and three T/B ratios were all significantly higher (P < 0.001) than values in euthyroid suspect cats or clinically normal cats. All scintigraphic parameters were relatively sensitive and specific as diagnostic tests for hyperthyroidism, but the T/S ratio had the highest test accuracy. The T/S ratio correlated strongly with the TcTU (r = 0.85). However, the TcTU had a higher and more significant correlation (P < 0.01) with serum T4 (r = 0.76 vs. 0.64), T3 (r = 0.77 vs. 0.64), and estimated thyroid volume (r = 0.62 vs. 0.38). Overall, calculation of TcTU is an accurate diagnostic test, but also appears to be the best parameter to predict the functional volume and metabolic activity of the feline adenomatous thyroid gland.

Prevalence and degree of thyroid pathology in hyperthyroid cats increases with disease duration: a cross-sectional analysis of 2096 cats referred for radioiodine therapy.

OBJECTIVES: Hyperthyroidism is common in cats, but there are no reports that evaluate its severity or underlying thyroid tumor disease based on disease duration (ie, time from original diagnosis). The objective of this study was to compare serum thyroxine (T4) concentrations and thyroid scintigraphic characteristics of cats referred for radioiodine treatment based on disease duration. METHODS: This was a cross-sectional study of 2096 cats with hyperthyroidism. Cats were divided into five groups based on time from diagnosis: ⩽1 year (n = 1773); >1-2 years (n = 169); >2-3 years (n = 88); >3-4 years (n = 35); and >4-6.1 years (n = 31). Methimazole, administered to 996 (47.5%) cats, was stopped at least 1 week prior to examination to allow for serum T4 testing. Each thyroid scintiscan was evaluated for pattern (unilateral, bilateral, multifocal), location (cervical, thoracic inlet, chest) and size (small, medium, large, huge) of the thyroid tumor, as well as features suggesting malignancy. RESULTS: Median serum T4 concentration increased with increasing disease duration from 100 nmol/l (⩽1 year) to 315 nmol/l (>4-6.1 years) (P <0.001). Prevalence of unilateral thyroid disease decreased, whereas multifocal disease (three or more tumor nodules) increased (P <0.001) with increasing disease duration. Median tumor volume in the five groups increased from 1.6 cm(3) (⩽1 year) to 6.4 cm(3) (>4-6.1 years). Prevalence of large (4-8 cm(3)) and huge (>8 cm(3)) thyroid tumors increased from 5.1% (⩽1 year) to 88.6% (>4-6.1 years), while the prevalence of intrathoracic tumor tissue increased from 3.4% (⩽1 year) to 32.3% (>4-6.1 years). Prevalence of suspected thyroid carcinoma (characterized by severe hyperthyroidism; huge, intrathoracic, multifocal tumors; refractory to methimazole treatment) increased with increasing disease duration from 0.4% (⩽1 year) to 19.3% (>4-6.1 years). CONCLUSIONS AND RELEVANCE: Our results indicate that the prevalence of severe hyperthyroidism, large thyroid tumors, multifocal disease, intrathoracic thyroid masses and suspected malignant disease all increase with disease duration in cats referred for radioiodine therapy.

Exogenous thyrotoxicosis in dogs attributable to consumption of all-meat commercial dog food or treats containing excessive thyroid hormone: 14 cases (2008-2013).

OBJECTIVE: To describe findings in dogs with exogenous thyrotoxicosis attributable to consumption of commercially available dog foods or treats containing high concentrations of thyroid hormone. DESIGN: Retrospective and prospective case series. ANIMALS: 14 dogs. PROCEDURES: Medical records were retrospectively searched to identify dogs with exogenous thyrotoxicosis attributable to dietary intake. One case was found, and subsequent cases were identified prospectively. Serum thyroid hormone concentrations were evaluated before and after feeding meat-based products suspected to contain excessive thyroid hormone was discontinued. Scintigraphy was performed to evaluate thyroid tissue in 13 of 14 dogs before and 1 of 13 dogs after discontinuation of suspect foods or treats. Seven samples of 5 commercially available products fed to 6 affected dogs were analyzed for thyroxine concentration; results were subjectively compared with findings for 10 other commercial foods and 6 beef muscle or liver samples. RESULTS: Total serum thyroxine concentrations were high (median, 8.8 µg/dL; range, 4.65 to 17.4 µg/dL) in all dogs at initial evaluation; scintigraphy revealed subjectively decreased thyroid gland radionuclide in 13 of 13 dogs examined. At ≥ 4 weeks after feeding of suspect food or treats was discontinued, total thyroxine concentrations were within the reference range for all dogs and signs associated with thyrotoxicosis, if present, had resolved. Analysis of tested food or treat samples revealed a median thyroxine concentration for suspect products of 1.52 µg of thyroxine/g, whereas that of unrelated commercial foods was 0.38 µg of thyroxine/g. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that thyrotoxicosis can occur secondary to consumption of meat-based products presumably contaminated by thyroid tissue, and can be reversed by identification and elimination of suspect products from the diet.

Thyroid scintigraphy findings in 2096 cats with hyperthyroidism.

Thyroid scintigraphy is currently the reference standard for diagnosing and staging cats with hyperthyroidism, but few studies describing the scintigraphic characteristics in a large number of cats have been reported. The objective of this study was to better characterize thyroid scintigraphy findings by evaluating 2096 consecutive cats with hyperthyroidism that were referred over a 3.5-year period. Of these cats, 2068 (98.7%) had a high thyroid-to-salivary ratio (>1.5), whereas 2014 (96.1%) were found to have a high thyroid-to-background ratio (>6.1). When the patterns of the cats' thyroid disease were recorded, 665 (31.7%) had unilateral disease, 1060 (50.6%) had bilateral-asymmetric disease (two thyroid lobes unequal in size), 257 (12.3%) had bilateral-symmetric disease (both lobes similar in size), and 81 (3.9%) had multifocal disease (≥3 areas of increased radionuclide uptake). The number of areas of (99m) TcO(-) 4 uptake in the 2096 cats ranged from 1 to 6 (median, 2), located in the cervical area in 2057 (98.1%), thoracic inlet in 282 (13.5%), and in the thoracic cavity in 115 (5.5%). Ectopic thyroid tissue (e.g. lingual or mediastinal) was diagnosed in 81 (3.9%) cats, whereas thyroid carcinoma was suspected in 35 (1.7%) of the cats. The results of this study support conclusions that most hyperthyroid cats have unilateral or bilateral thyroid nodules, but that multifocal disease will develop in a few cats that have ectopic thyroid disease or thyroid carcinoma. Both ectopic thyroid disease and thyroid carcinoma are relatively uncommon in hyperthyroid cats, with a respective prevalence of ∼4% and ∼2% in this study.

Evaluation of intraorbital prosthetic pigmentation using 0.3 and 1.5 Tesla magnetic resonance imaging and computed tomography.

PURPOSE: To investigate the magnetic susceptibility artifact associated with pigmented intraorbital prosthetics when performing magnetic resonance imaging (MRI) and computed tomography (CT). Potential artifact reduction techniques were also investigated. STUDY DESIGN: Prospective study. METHODS: Five different-colored 20-millimeter small animal silicone intraorbital prosthetics and two equine prosthetics were evaluated using 0.3 and 1.5 Tesla (T) MRI and CT. MRI sequences included T1- (T1WI) and T2-weighted spin echo (T2WI), T2 gradient echo (T2*), short tau inversion recovery (STIR), and fluid-attenuated inversion recovery (FLAIR). When present, artifact size was measured using computerized software by three separate observers. Artifact reduction techniques included alterations in receiver bandwidth, field of view, slice thickness, and matrix size. RESULTS: The ferrous brown-pigmented prosthetic resulted in a magnetic susceptibility artifact with MRI. No artifact was observed on CT images. Interobserver variability was not statistically significant. For both the 0.3T and 1.5T MRI, the T2* sequence exhibited the largest artifact surface area followed by T2WI, T1WI, STIR, and FLAIR. Decreasing slice thickness showed a decrease in artifact size; however, this difference was not statistically significant. CONCLUSIONS: The ferrous substances in the brown intraorbital prosthetic resulted in a significant magnetic susceptibility artifact when performing MRI. Artifact reduction techniques did not significantly decrease artifact surface area. The use of ferrous brown-pigmented prosthetics and their potential to affect future MR imaging studies should be adequately discussed with pet owners.

MRI of a split cord malformation in a German shepherd dog.

A 9 yr old spayed female German shepherd dog was referred for MRI of the thoracic and lumbar spine because she had clinical signs of chronic neurogenic bladder dysfunction of an unknown cause. Transverse T2-weighted images identified a type II split cord malformation (i.e., diastematomyelia) in the thoracic spine. Split cord malformations are forms of spinal dysraphism where the abnormal development of spinal cord results in sagittal splitting of a portion of the cord into two hemicords. The location of the lesion in the thoracic spine was consistent with the dog's clinical signs of an upper motor neuron bladder. Split cord malformations that occur in humans have similar MRI characteristics and can result in similar clinical signs as those identified in the dog described in this report.

Thyroid scintigraphy in hyperthyroidism.

Thyroid scintigraphy is a nuclear medicine procedure that produces a visual display of functional thyroid tissue based on the selective uptake of various radionuclides by thyroid tissue. Thyroid scintigraphy provides valuable information regarding both thyroid anatomy and physiology and can play an integral role in the diagnosis and management of cats with hyperthyroidism. Thyroid scintigraphy allows the direct visualization of the functional adenomatous thyroid tissue responsible for the development of hyperthyroidism. For this reason, thyroid scintigraphy will allow the diagnosis of hyperthyroidism before laboratory tests are consistently abnormal. Thyroid scintigraphy can also exclude a diagnosis of hyperthyroidism in cats with thyroid hormone elevations of nonthyroidal origin. Thyroid scintigraphy provides an additional method for determining the relative severity of thyroid disease that is less affected by the presence of concurrent nonthyroidal illness than laboratory evaluations. When treating hyperthyroid cats with radioiodine, the lowest effective dose should be administered. In an effort to administer the lowest radioiodine dose possible, the volume of adenomatous thyroid tissue present in the individual hyperthyroid cat should be considered. Thyroid scintigraphy provides an excellent method for evaluating the size of hyperfunctional thyroid tissue that is not limited by the presence of ectopic or intrathoracic thyroid tissue. Thyroid scintigraphy also provides valuable information in the diagnosis and evaluation of hyperthyroid cats with thyroid carcinoma.