GM1 gangliosidosis in a Japanese domestic cat: a new variant identified in Hokkaido,Japan

A male Japanese domestic cat with retarded growth in Hokkaido, Japan, showed progressive motor dysfunction, such as ataxia starting at 3 months of age and tremors, visual disorder and seizure after 4 months of age. Finally, the cat died of neurological deterioration at 9 months of age. Approximately half of the peripheral blood lymphocytes had multiple abnormal vacuoles. Magnetic resonance imaging showed bisymmetrical hyperintensity in the white matter of the parietal and occipital lobes in the forebrain on T2-weighted and fluid-attenuated inversion recovery images, and mild encephalatrophy of the olfactory bulbs and temporal lobes. The activity of lysosomal acid β-galactosidase in leukocytes was negligible, resulting in the biochemical diagnosis of GM1 gangliosidosis. Histologically, swollen neurons characterized by accumulation of pale, slightly granular cytoplasmic materials were observed throughout the central nervous system. Dysmyelination or demyelination and gemistocytic astrocytosis were observed in the white matter. Ultrastructually, membranous cytoplasmic bodies were detected in the lysosomes of neurons. However, genetic analysis did not identify the c.1448G>C mutation, which is the single known mutation of feline GM1 gangliosidosis, suggesting that the cat was affected with a new variant of the feline disease.     

GM2 Gangliosidosis Variant 0 (Sandhoff‐Like Disease) in a Family of Toy Poodles

Background: GM2 gangliosidosis variant 0 (human Sandhoff disease) is a lysosomal storage disorder caused by deficiencies of acid β‐hexosaminidase (Hex) A and Hex B because of an abnormality of the β‐subunit, a common component in these enzyme molecules, which is coded by the HEXB gene. Objective: To describe the clinical, pathological, biochemical, and magnetic resonance imaging (MRI) findings of Sandhoff‐like disease identified in a family of Toy Poodles. Animals: Three red‐haired Toy Poodles demonstrated clinical signs including motor disorders and tremor starting between 9 and 12 months of age. The animals finally died of neurological deterioration between 18 and 23 months of age. There were some lymphocytes with abnormal cytoplasmic vacuoles detected. Methods: Observational case study. Results: The common MRI finding was diffuse T2‐hyperintensity of the subcortical white matter in the cerebrum. Bilateral T2‐hyperintensity and T1‐hypointensity in the nucleus caudatus, and atrophic findings of the cerebrum and cerebellum, were observed in a dog in the late stage. Histopathologically, swollen neurons with pale to eosinophilic granular materials in the cytoplasm were observed throughout the central nervous system. Biochemically, GM2 ganglioside had accumulated in the brain, and Hex A and Hex B were deficient in the brain and liver. Pedigree analysis demonstrated that the 3 affected dogs were from the same family line. Conclusions and Clinical Importance: The Sandhoff‐like disease observed in this family of Toy Poodles is the 2nd occurrence of the canine form of this disease and the 1st report of its identification in a family of dogs.     

Hereditary cerebellar degeneration in three full sibling kittens

Two domestic shorthair littermate kittens had signs of cerebellar dysfunction, first observed between seven and eight weeks of age; a third littermate was unaffected. The signs were progressive and the more severely affected kitten was euthanased after six days. A postmortem examination revealed no gross lesions but the kitten had cerebellar cortical degeneration with extensive loss of Purkinje cells. The second kitten was euthanased at 10 months of age with similar, though more pronounced, changes. One of the two kittens in the next litter of the same parents had similar clinical signs and histopathological findings. The lesions in the cerebellum are interpreted as probably due to genetically determined abiotrophy. In addition, the two older kittens had medullary neuronal changes interpreted as probable neuraxonal dystrophy, and focal vacuolation of the neuropil in the medulla and cervical spinal cord.     

Nonsense mutation of feline beta-hexosaminidase beta-subunit (HEXB) gene causing Sandhoff disease in a family of Japanese domestic cats

G(M2) gangliosidoses are inherited metabolic disorders and are caused by severely reduced enzymatic activity of lysosomal beta-hexosaminidase. In the present study, the open reading frame (ORF) of the HEXB gene in a family of Japanese domestic cats with G(M2) gangliosidosis variant 0 (Sandhoff disease) was determined. Two types of abnormal cDNA clones were obtained from the liver of an affected cat tissue. One showed a single nucleotide substitution from C to T at nucleotide position 667 of the HEXB ORF. In the deduced amino acid sequence, the codon of arginine was altered to a stop codon. The genotyping, using PCR-primer introduced restriction analysis confirmed that Sandhoff disease in this family is associated with this nonsense mutation. Discovery of the nonsense mutation will permit the confirmation of the clinical diagnosis of Sandhoff disease in conjugation with the already established enzyme-based test.     

GM2-gangliosidosis variant 0 (Sandhoff-like disease) in a family of Japanese domestic cats

A five-month-old, female Japanese domestic shorthair cat with proportionate dwarfism developed neurological disorders, including ataxia, decreased postural responses and generalised body and head tremors, at between two and five months of age. Leucocytosis due to lymphocytosis with abnormal cytoplasmic vacuolations was observed. The concentration of G(M2)-ganglioside in its cerebrospinal fluid was markedly higher than in normal cats, and the activities of beta-hexosaminidases A and B in its leucocytes were markedly reduced. On the basis of these biochemical data, the cat was diagnosed antemortem with G(M2)-gangliosidosis variant 0 (Sandhoff-like disease). The neurological signs became more severe and the cat died at 10 months of age. Histopathologically, neurons throughout the central nervous system were distended, and an ultrastructural study revealed membranous cytoplasmic bodies in these distended neurons. The compound which accumulated in the brain was identified as G(M2)-ganglioside, confirming G(M2)-gangliosidosis. A family study revealed that there were probable heterozygous carriers in which the activities of leucocyte beta-hexosaminidases A and B were less than half the normal value. The Sandhoff-like disease observed in this family of Japanese domestic cats is the first occurrence reported in Japan.     

Canine GM2‐Gangliosidosis Sandhoff Disease Associated with a 3‐Base Pair Deletion in the HEXB Gene

Background

GM2‐gangliosidosis is a fatal neurodegenerative lysosomal storage disease (LSD) caused by deficiency of either β‐hexosaminidase A (Hex‐A) and β‐hexosaminidase B (Hex‐B) together, or the GM2 activator protein. Clinical signs can be variable and are not pathognomonic for the specific, causal deficiency.

Objectives

To characterize the phenotype and genotype of GM2‐gangliosidosis disease in an affected dog.

Animals

One affected Shiba Inu and a clinically healthy dog.

Methods

Clinical and neurologic evaluation, brain magnetic resonance imaging (MRI), assays of lysosomal enzyme activities, and sequencing of all coding regions of HEXA, HEXB, and GM2A genes.

Results

A 14‐month‐old, female Shiba Inu presented with clinical signs resembling GM2‐gangliosidosis in humans and GM1‐gangliosidosis in the Shiba Inu. Magnetic resonance imaging (MRI) of the dog's brain indicated neurodegenerative disease, and evaluation of cerebrospinal fluid (CSF) identified storage granules in leukocytes. Lysosomal enzyme assays of plasma and leukocytes showed deficiencies of Hex‐A and Hex‐B activities in both tissues. Genetic analysis identified a homozygous, 3‐base pair deletion in the HEXB gene (c.618‐620delCCT).

Conclusions and Clinical Importance

Clinical, biochemical, and molecular features are characterized in a Shiba Inu with GM2‐gangliosidosis. The deletion of 3 adjacent base pairs in HEXB predicts the loss of a leucine residue at amino acid position 207 (p.Leu207del) supporting the hypothesis that GM2‐gangliosidosis seen in this dog is the Sandhoff type. Because GM1‐gangliosidosis also exists in this breed with almost identical clinical signs, genetic testing for both GM1‐ and GM2‐gangliosidosis should be considered to make a definitive diagnosis.     

Retrospective diagnosis of feline GM2 gangliosidosis variant 0 (Sandhoff-like disease) in Japan: possible spread of the mutant allele in the Japanese domestic cat population

GM2 gangliosidosis variant 0 (human Sandhoff disease) is a lysosomal storage disease caused by simultaneous deficiencies of acid beta-hexosaminidase (Hex) A and Hex B due to an abnormality of beta-subunit, a common component in these enzyme molecules, which is coded by the HEXB gene. In the present study, a retrospective diagnosis was performed in 2 previous suspected cases of feline Sandhoff-like disease using a DNA test to detect the causative mutation identified previously in 4 cats in 2 other families of Japanese domestic cats. Enzymic analysis was also performed using stored leukocytes and plasma collected from the subject families in order to investigate the usefulness of enzymic diagnosis and genotyping of carriers. The DNA test suggested that the 2 cases were homozygous recessive for the mutation. Consequently, 6 cats homozygous for the same mutation have been found in 4 separate locations of Japan, suggesting that this mutant allele may be spread widely in the Japanese domestic cat populations. In enzymic analysis, Hex A and Hex B activities in leukocytes and plasma measured using 4-methylumbelliferyl N-acetyl-beta-D-glucosaminide as a substrate were negligible in affected cats, compared with those in normal and carrier cats. However, there was a wide overlap in enzyme activity between normal and carrier cats. Therefore, it was concluded that enzymic analysis is useful for diagnosis of affected cats, but is not acceptable for genotyping of carriers.     

IMAGING DIAGNOSIS—MAGNETIC RESONANCE IMAGING FINDINGS IN A CAT WITH SYSTEMIC REACTIVE ANGIOENDOTHELIOMATOSIS

A 10‐year‐old, castrated male domestic short‐haired cat was presented with an acute history of seizures, lethargy, anorexia, vomiting, and dyspnea. Magnetic resonance imaging of the brain showed multifocal areas of gray matter T2‐weighted hyperintensity. The lesions did not enhance with intravenous contrast. The cat was diagnosed at necropsy with feline systemic reactive angioendotheliomatosis, a rare vascular proliferative disorder for which a treatment has not yet been identified. This report is the first to describe associated magnetic resonance imaging changes for this disease.     

Hypertrophic cardiomyopathy in two kittens.

Two 2-month-old kittens presented with a loud cardiac murmur. One cat showed severe signs of heart failure such as respiratory effort and exercise intolerance. Echocardiography revealed left ventricular concentric hypertrophy and severe left ventricular outflow obstruction. They died at 5 and 12 months of age, respectively. Necropsy and histopathology confirmed hypertrophic cardiomyopathy.     

Attempted transmission of Toxoplasma gondii infection from pregnant cats to their kittens

Sixteen 1- to 7-week-old pregnant specific-pathogen free cats were inoculated orally with Toxoplasma gondii cysts. Fetuses and neonatal kittens were examined for toxoplasma infection by inoculating suspensions of their tissues into mice. Toxoplasma gondii was not isolated from 23 fetuses and 16 newborn kittens from 13 queens. Six (3 litters) of the 15 kittens from the 3 remaining queens were killed on the day of or a day after birth, and the remaining 9 kittens were housed with their mothers for 7 to 33 days. None of the 9 kittens from the 2 litters examined between 0 and 33 days of age was infected with T gondii. In the other litter, T gondii was isolated from 3 kittens killed at 9, 16, and 22 days of age but not from 3 littermates killed on days 1, 1, and 22. Internal organs from the 3 kittens with proved toxoplasma infectivity in mice were examined histologically. Multifocal granulomatous encephalitis, hepatitis, nephritis, myocarditis, myositis, and interstitial pneumonia were found in all 3 kittens. Toxoplasma forms were demonstrated histologically in the tissues of 2 of these kittens. The mode of toxoplasma infection in newborn kittens was not determined but did not appear to be either transplacental or via fecal contamination from oocysts excreted by the mother cat. Evidence obtained in these experiments suggests that transplacental toxoplasma infection in the cat is not an important epidemiologic factor in perpetuation of the disease in the feline population.     

Prognostic significance of specific magnetic resonance imaging features in canine nasal tumours treated by radiotherapy

Objectives : To investigate the prognostic significance of the magnetic resonance (MR) findings of meningeal hyperintensity of the olfactory bulbs and tumour extension into the caudal nasal recess (CNR) in dogs with nasal tumours treated by radiotherapy. Methods : MR images of 41 dogs with nasal tumours treated with radiotherapy were reviewed. The occurrence of neurological signs and survival of patients with and without meningeal hyperintensity of the olfactory bulbs and tumour extension into the CNR were analysed together with possible confounding factors including intracranial extension and patient age. Results : There was no significant association between the presence of meningeal hyperintensity or CNR involvement and the occurrence of neurological signs. Although there was a tendency towards shorter survival in dogs with tumour extension into the CNR, multivariable analysis showed no significant difference in survival between dogs with/without CNR involvement, meningeal hyperintensity or intracranial tumour extension (P=0·12, 0·50 and 0·57, respectively). Clinical Significance : In dogs with nasal tumours treated with radiotherapy, tumour extension into the cranium is not necessarily associated with shorter survival in patients without neurological signs at time of diagnosis. Although a definite influence of CNR involvement on case outcome could not be demonstrated, studies with a larger population are warranted.     

Rostral cerebellar arterial infarct in two cats

A 10-year-old female neutered domestic shorthair (DSH) cat and a 6-year-old female neutered Siamese cat were presented following a peracute onset of decerebellate rigidity and a cerebellar vestibular syndrome, respectively. In both cats, physical examination and routine blood tests were unremarkable, as was routine analysis of cerebrospinal fluid obtained from the DSH cat. Based on the magnetic resonance imaging (MRI) features - focal wedge-shaped lesion in the cerebellum characterised by hyperintensity in T2-weighted, T2( *)-gradient echo and fluid attenuated inversion recovery (FLAIR) images - a presumptive diagnosis of cerebellar infarct was made in both cases. In the DSH cat, the post-mortem examination confirmed the diagnosis of cerebellar infarct and additionally found acute renal infarcts and a pulmonary neoplasia. In the Siamese cat, ultrasonographic evaluation of the heart revealed a probable low-grade chronic valvular endocarditis which was thought to be a potential source of thromboembolism. This paper describes the first two cases - one confirmed and the other suspected - of cerebellar infarct in the cat. The in vivo potential diagnostic value of the MRI study is highlighted. Cerebellar infarcts should be included in the differential diagnosis of cat with a peracute onset of cerebellar signs regardless of the severity of neurological deficits.     

Clinical and clinico-pathologic characteristics of Shiba dogs with a deficiency of lysosomal acid beta-galactosidase: a canine model of human GM1 gangliosidosis

The present study was conducted to determine the clinical and clinico-pathologic characteristics of Shiba dogs with GM1 gangliosidosis, which is due to an autosomal recessively inherited deficiency of lysosomal acid beta-galactosidase activity. Clinical and clinico-pathological features were investigated in 10 homozygous Shiba dogs with GM1 gangliosidosis. The age at onset was 5 to 6 months and the dogs manifested progressive neurologic signs including loss of balance, intermittent lameness, ataxia, dysmetria and intention tremor of the head. The dogs were unable to stand by 10 months of age due to a progression of ataxia and spasticity in all limbs. Corneal clouding, a visual defect, generalized muscle rigospasticity, emotional disorder and a tendency to be lethargic were observed at 9 to 12 months. The dogs became lethargic from 13 months of age. The survival period seemed to be 14 to 15 months. As a clinico-pathologic feature, lymphocytes with abnormally large vacuoles were observed in peripheral blood (30 to 50% of total lymphocytes) through the lifetime of the dogs. The clinical and clinico-pathologic characteristics of this animal model are useful for not only the development and testing of potential methods of therapy, but also the diagnosis of affected homozygous Shiba dogs in veterinary clinics.     

CLINICAL,IMAGING, AND PATHOLOGIC CHARACTERISTICS OF GURLTIA PARALYSANS MYELOPATHY IN DOMESTIC CATS FROM CHILE

Gurltia paralysans is a rare metastrongylid nematode of domestic cats that is found mainly in the veins of the spinal cord subarachnoid space and parenchyma. Endemic regions for G. paralysans mainly include Chile and Argentina. The ante mortem diagnosis of gurltiosis is difficult and based primarily on neurological signs, epidemiological factors, and the exclusion of other causes of feline myelopathies. The purpose of this retrospective case series was to describe clinical, imaging, and pathologic characteristics in nine domestic cats naturally infected with G. paralysans. Imaging tests included radiography, myelography, computed tomographic myelography (myelo‐CT), and magnetic resonance imaging (MRI). Neurological signs included paraparesis, paraplegia, pelvic limb ataxia and proprioceptive deficits, pelvic limb tremors, lumbosacral hyperesthesia, and tail trembling or atony. Complete blood count findings included a decrease in the mean corpuscular hemoglobin concentration value in eight cats. Eosinophilia in peripheral blood was observed in three cats, and thrombocytopenia was observed in three cats. Cerebrospinal fluid analysis revealed mononuclear pleocytosis in five cases. Myelo‐CT showed diffuse enlargement of the spinal cord at the midthoracic, lumbar, and sacral regions in all cats. Magnetic resonance image findings in the thoracic and lumbar region demonstrated multiple small nodular areas of T2 hyperintensity in the periphery of the spinal cord parenchyma. Localized intraparenchymal areas of increased T2 intensity were also observed in the thoracolumbar spinal cord and lumbosacral conus medullaris. In conclusion, G. paralysans should be considered as a differential diagnosis for domestic cats in endemic regions that have this combination of clinical and imaging characteristics.     

Congenital portosystemic shunts in the cat: A report of nine cases

The clinical features, diagnosis, management and outcome of nine cases of congenital portosystemic shunt in the cat are reported. Neurological signs associated with hepatic encephalopathy and ptyalism were the main clinical signs. Six cases were presented as kittens less than six months of age and the remaining three cases were presented as adults, although in one of these signs were first noted at eight to 12 weeks of age. Fasting hyperammo-naemia was the only consistent abnormal biochemical finding. Medical management was instituted in all cases and surgical partial ligation was later performed in four with recanalisation of the ligated vessel occurring in three cases. The condition in the cat is compared and contrasted with that in the dog.     

Gastrointestinal parasites of domestic cats in Perth, Western Australia

A study was conducted to determine the prevalence of gastrointestinal parasites in a sample of domestic cats in Perth and the knowledge of their owners about the control and potential for zoonotic transmission of these parasites. Faecal samples (418), collected from cats originating from five sources, were examined by microscopy and questionnaires administered to cat owners. Forty randomly selected samples were also screened using PCR in order to detect cysts of Giardia and oocysts of Cryptosporidium that may have been present in a faecal sample at very low levels. The overall prevalence of gastrointestinal parasites in domestic cats by microscopy was 8.6%. Pet shop kittens had the highest parasite prevalence (34.3%), followed by cats and kittens from breeding establishments (15.8%), refuge cats and kittens (8.3%), privately owned cats (2.3%), and boarding cats and kittens (1.6%). Surprisingly, 80% of the 40 cats tested by PCR were positive for Giardia duodenalis and 10% for Cryptosporidium. None of these cats were positive on microscopy. After adjusting for other factors with multiple logistic regression, kittens less than 6 months of age, and cats living in households with more than one cat or with a dog were significantly more likely to be parasitised. In the logistic regression model, the presence of parasitism was also significantly influenced by the number of anthelmintic doses administered in the 12 month period prior to the study. The majority (64.5%) of cat owners were aware that feline parasites could be transmitted to humans, however less than half (42.8%) were aware of the modes of transmission to humans.     

Prognostic value of magnetic resonance imaging in dogs with paraplegia caused by thoracolumbar intervertebral disk extrusion: 77 cases (2000-2003)

OBJECTIVE: To determine whether magnetic resonance imaging findings in dogs with paraplegia caused by thoracolumbar intervertebral disk extrusion were predictive of clinical outcome. DESIGN: Retrospective case series. ANIMALS: 77 dogs. PROCEDURE: Medical records and magnetic resonance images were reviewed; clinical outcome was classified as successful (regained ability to walk with no more than mild neurologic deficits) or unsuccessful (severe neurologic deficits persisted). The prognostic value of magnetic resonance imaging was compared with prognostic value of deep pain perception, duration of clinical signs, and rate of onset of clinical signs. RESULT: 33 (43%) dogs had areas of hyperintensity of the spinal cord greater than or equal to the length of the L2 vertebral body on T2-weighted magnetic resonance images. All 44 dogs without areas of hyperintensity on T2-weighted images had a successful outcome, but only 18 of the 33 (55%) dogs with an area of hyperintensity did. Only 5 of 16 dogs with an area of hyperintensity that had also lost deep pain perception had a successful outcome. The odds ratio for an unsuccessful outcome for a dog with an area of hyperintensity (29.87) was higher than the odds ratio for a dog that had lost deep pain perception (5.24). Duration and rate of onset of clinical signs were not associated with clinical outcome. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggest that results of magnetic resonance imaging can be used to predict clinical outcome in dogs with paraplegia caused by intervertebral disk extrusion.     

Fibrodysplasia ossificans progressiva-like condition in a cat

Fibrodysplasia ossificans progressiva (FOP)-like condition was diagnosed in a Japanese domestic cat with stiffness, marked atrophy of the muscles, and limited mobility of all joints in both the pelvic limbs. Etretinate, a retinoid, was used for medical management; however, no improvement in the clinical signs was observed. Inheritance of the disorder has not yet been demonstrated. Furthermore, the clinical signs and histopathological findings of feline FOP-like condition in the present case differed from those of the previously reported cases.     

IMAGING DIAGNOSIS—CONVENTIONAL AND FUNCTIONAL MAGNETIC RESONANCE IMAGING OF A BRAIN ABSCESS IN A GOAT

A 2‐month‐old female goat was presented for depressed mental status and multifocal central neurologic signs 3 weeks after hot‐iron disbudding. Conventional magnetic resonance imaging (MRI) findings included a large intra axial mass in the left frontal lobe that was T2 hyperintense and T1 hypointense centrally with a contrast‐enhancing peripheral capsule and perilesional T2 hyperintensity. A restrictive pattern was present in diffusion‐weighted imaging. Magnetic resonance spectroscopy demonstrated an increased amount of succinate, acetate, amino acids, lipids; minimal amounts of lactate; and decreased amounts of N‐acetyl aspartate and choline. A cerebral abscess due to Trueperella pyogenes was confirmed from necropsy and tissue culture.     

Multiple meningiomas: clinical, radiological, surgical, and pathological findings with outcome in four cats

The present report describes the clinical signs, magnetic resonance imaging (MRI) findings, surgical procedure, pathological findings and follow-up in four cats with multiple meningiomas; three castrated male and one spayed female domestic shorthair indoor cats, ranging in age from 11 to 14 years. In three of four cats, clinical signs at presentation were suggestive of a focal lesion. Three cats had two meningiomas and one had four meningiomas. Most of the tumours were supratentorial, one arose from the tentorium and one was infratentorial. The duration of presenting signs before surgery ranged from 10 days to 11 months. Postoperative MRI revealed complete gross tumour removal in three cases. In one cat with two cranial fossa meningiomas, subtotal excision with a small basal remnant (2 x 2 mm) of the ventral part of one meningioma lying on the floor of the skull, was observed. Based on histopathological architecture, six tumours revealed features of a transitional subtype meningioma, and four of a meningotheliomatous meningioma. In each cat, the multiple meningiomas were all assigned to the same histopathological group. The preoperative presenting signs had resolved by the follow-up examinations 4 weeks after surgery in two cats. Long-term follow-up evaluation revealed that surgically-induced or exacerbated neurological deficits in two cats had completely or almost completely resolved within 8 weeks of surgery. All patients are still alive 12 to 21 months after surgery and no clinical signs of recurrence could be detected at that time.