Cerebellar Abiotrophy Across Domestic Species.

Cerebellar abiotrophy (CA) is a neurodegenerative disorder affecting the cerebellum and occurs in multiple species. Although CA is well researched in humans and mice, domestic species such as the dog, cat, sheep, cow, and horse receive little recognition. This may be due to few studies addressing the mechanism of CA in these species. However, valuable information can still be extracted from these cases. A review of the clinicohistologic phenotype of CA in these species and determining the various etiologies of CA may aid in determining conserved and required pathways necessary for proper cerebellar development and function. This review outlines research approaches of studies of CA in domestic species, compared to the approaches used in mice, with the objective of comparing CA in domestic species while identifying areas for further research efforts.

Genome sequencing reveals a splice donor site mutation in the SNX14 gene associated with a novel cerebellar cortical degeneration in the Hungarian Vizsla dog breed.

BACKGROUND: Cerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many dog breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several breeds, allowing screening for selective breeding to reduce the prevalence of these conditions. There have been no previous reports of CCD in Hungarian Vizslas. RESULTS: Two full-sibling Hungarian Vizsla puppies from a litter of nine presented with a history of progressive ataxia, starting around three months of age. Clinical signs included marked hypermetric and dysmetric ataxia, truncal sway, intention tremors and absent menace responses, with positional horizontal nystagmus in one dog. Routine diagnostic investigations were unremarkable, and magnetic resonance imaging performed in one dog revealed mild craniodorsal cerebellar sulci widening, supportive of cerebellar atrophy. Owners of both dogs elected for euthanasia shortly after the onset of signs. Histopathological examination revealed primary Purkinje neuron loss consistent with CCD. Whole genome sequencing was used to successfully identify a disease-associated splice donor site variant in the sorting nexin 14 gene (SNX14) as a strong causative candidate. An altered SNX14 splicing pattern for a CCD case was demonstrated by RNA analysis, and no SNX14 protein could be detected in CCD case cerebellum by western blotting. SNX14 is involved in maintaining normal neuronal excitability and synaptic transmission, and a mutation has recently been found to cause autosomal recessive cerebellar ataxia and intellectual disability syndrome in humans. Genetic screening of 133 unaffected Hungarian Vizslas revealed the presence of three heterozygotes, supporting the presence of carriers in the wider population. CONCLUSIONS: This is the first report of CCD in Hungarian Vizsla dogs and identifies a highly associated splice donor site mutation in SNX14, with an autosomal recessive mode of inheritance suspected.

PROGRESSIVE SYRINGOHYDROMYELIA AND DEGENERATIVE AXONOPATHY IN A BOBCAT (LYNX RUFUS) FOLLOWING SURGICAL CORRECTION OF A CHIARI-LIKE MALFORMATION.

A 3-yr-old male captive bobcat (Lynx rufus) presented with chronic ataxia and right-sided head tilt. Magnetic resonance imaging (MRI) revealed cerebellar crowding and compression consistent with Chiari-like malformation. The clinical signs did not improve after surgical occipital craniectomy, and 2 mo postoperatively a second MRI showed hydromyelia and continued cerebellar compression. The bobcat was euthanized, and necropsy showed chronic focal cerebellar herniation and chronic multifocal atlanto-occipital joint osteophyte proliferation. Histology confirmed the presence of a thick fibrous membrane along the caudal aspect of the cerebellar vermis, suggestive of postoperative adhesions, and axonal degeneration of the cervical spinal cord, even in sections without a central canal lesion. These lesions appear to have been complications associated with surgical correction of the Chiari-like malformation.

Congenital cerebellar dysplasia in White Leghorn chickens (Gallus gallus domesticus).

Congenital cerebellar anomalies have been rarely reported in birds. We examined cerebellums with disorganized folia from seven specific-pathogen-free White Leghorn chickens (Gallus gallus domesticus). Islands of heterotopic cortex were distributed from the deeper cortices to the medulla in the cerebellum. The characteristic lesions were composed of randomly admixed components of the cerebellar cortex, including Purkinje cells, a molecular layer and granular cells. Immunofluorescent analysis revealed Purkinje cells with haphazardly extended dendrites and a lack of Bergmann's glial fibres in the foci. Chicken parvovirus, Aino virus and avian retrovirus were not detected in the affected birds by polymerase chain reaction. This is the first report of cerebellar dysplasia in chickens possibly caused by a genetic abnormality.

Morphometric magnetic resonance imaging and genetic testing in cerebellar abiotrophy in Arabian horses.

BACKGROUND: Cerebellar abiotrophy (CA) is a rare but significant disease in Arabian horses caused by progressive death of the Purkinje cells resulting in cerebellar ataxia characterized by a typical head tremor, jerky head movements and lack of menace response. The specific role of magnetic resonance imaging (MRI) to support clinical diagnosis has been discussed. However, as yet MR imaging has only been described in one equine CA case. The role of MR morphometry in this regard is currently unknown. Due to the hereditary nature of the disease, genetic testing can support the diagnosis of CA. Therefore, the objective of this study was to perform MR morphometric analysis and genetic testing in four CA-affected Arabian horses and one German Riding Pony with purebred Arabian bloodlines in the third generation. RESULTS: CA was diagnosed pathohistologically in the five affected horses (2 months - 3 years) supported by clinical signs, necropsy, and genetic testing which confirmed the TOE1:g.2171G>A SNP genotype A/A in all CA-affected horses. On MR images morphometric analysis of the relative cerebellar size and relative cerebellar cerebrospinal fluid (CSF) space were compared to control images of 15 unaffected horses. It was demonstrated that in MR morphometric analyses, CA affected horses displayed a relatively smaller cerebellum compared to the entire brain mass than control animals (P = 0.0088). The relative cerebellar CSF space was larger in affected horses (P = 0.0017). Using a cut off value of 11.0% for relative cerebellar CSF space, the parameter differentiated between CA-affected horses and controls with a sensitivity of 100% and a specificity of 93.3%. CONCLUSIONS: In conclusion, morphometric MRI and genetic analysis could be helpful to support the diagnosis of CA in vivo.

Mapping of equine cerebellar abiotrophy to ECA2 and identification of a potential causative mutation affecting expression of MUTYH.

Equine Cerebellar Abiotrophy (CA) is a neurological disease found in Arabian horses. CA is characterized by post-natal degeneration of the Purkinje cells of the cerebellum. Signs of CA include ataxia, head tremors, and a lack of balance equilibrium. We have discovered a linkage of the CA phenotype to a microsatellite marker on ECA2 and identified a region of conserved homozygosity spanning approximately 142 kb. Complete sequencing of the four genes in this region identified one SNP found only in Arabian horses, located in exon 4 of TOE1 and approximately 1200 base pairs upstream of MUTYH, adjacent to a possible binding site for the transcription factor GATA2. qPCR analysis of cDNA from the cerebella of affected and unaffected horses suggested that MUTYH expression is down-regulated in affected horses. This SNP may therefore have a function effect on TOE1, or a regulatory effect on MUTYH by negatively affecting the binding affinity of GATA2.

Profiling of genetic markers useful for breeding decision in Selle Francais horse.

Genetic disorders are recognised as hereditary diseases with the most significant economic impact on horse breeding, causing important foal losses, costs of treatments of horses, and maintenance of the mare during the pregnancy. The Selle Francais horses are recognized in many countries and are showing great results in equestrian sports around the world (dressage, show jumping and eventing). The study aimed to detect the presence of three mutant alleles associated with inherited diseases including Fragile Foal Syndrome (FFS), Cerebellar Abiotrophy (CA), Polysaccharide Storage Myopathy (PSSM1) and variant impacting gait type in DMRT3. This trait is important for breeding decision in Selle Francais horses and sheds new light on genetic potential and risks on this breed. The genotyping was performed on 91 Selle Francais horses using PCR-RFLP (for POLD1; GYS1 and DMRT3 genes) and PCR-ACRS (TOE1 gene) methods. The presented report indicated the presence of mutant allele A casual for PSSM1 and allele T associated with FFS syndrome occurrence, in 4% and 6% of analysed horses, respectively. Regarding CA, the present survey did not register any cases of this genetic disorder in Selle Francais horses. Our results show also that about 1% of all the Sell Francais horses studied carry the A allele of DMRT3 gene. The present findings have provided data for these fulness of monitoring genetic diseases and gait type in the investigated breed to avoid losses of offspring.

Cerebellar Abiotrophy in Australian Working Kelpies Is Associated with Two Major Risk Loci.

An autosomal recessive form of inherited cerebellar abiotrophy (CA) that is characterized by a degeneration of Purkinje and granule cells in the cerebellar cortex occurs in the Australian working kelpie dog breed. The clinical signs of CA include ataxia, head tremor, motor in-coordination, wide-based stance, and high-stepping gait. Investigation of clinical and pathological features indicated two closely related diseases with differences in age of onset. A genome-wide association study on 45 CA affected and 290 normal healthy Kelpies identified two significantly associated loci, one on CFA9 and a second on CFA20. Dogs homozygous for the risk haplotype on CFA20 (23 dogs) show clinical signs before ten weeks of age. Missense variants in the sixth exon of disruptor of telomeric silencing 1-like (DOT1Lp.R200Q) and in the only exon of Leucine Rich Repeat And Ig Domain Containing 3 (LINGO3p.R359C), both on CFA20, segregate with the associated risk marker which has incomplete penetrance (42%). Affected dogs homozygous for the risk haplotype on CFA9 have later onset ataxia. A missense variant in exon 5 of Vacuole Membrane Protein 1 (VMP1 p.P160Q) on CFA9 segregates as a fully penetrant Mendelian recessive with later-onset CA. Across mammals, the variety of causative loci so far identified as influencing cerebellar disorders reinforces the complexity of the pathways that contribute to cerebellar development and function, and to the pathophysiological mechanisms that may lead to cerebellar ataxia.

Mapping cerebellar abiotrophy in Australian Kelpies.

An autosomal recessive form of cerebellar abiotrophy occurs in Australian Kelpie dogs. Clinical signs range from mild ataxia with intention tremor to severe ataxia with seizures. A whole-genome mapping analysis was performed using Affymetrix Canine SNP array v2 on 11 affected and 19 control dogs, but there was no significant association with disease. A homozygosity analysis identified a three megabase region likely to contain the disease mutation. The region spans 29.8-33 Mb on chromosome 3, for which all affected dogs were homozygous for a common haplotype. Microsatellite markers were developed in the candidate region for linkage analysis that resulted in a logarithm of odds score suggestive of linkage. The candidate region contains 29 genes, none of which are known to cause ataxia.

Evidence of injury caused by gas bubbles in a live marine mammal: barotrauma in a California sea lion Zalophus californianus.

A yearling male California sea lion Zalophus californianus with hypermetric ataxia and bilateral negative menace reflexes was brought to The Marine Mammal Center, Sausalito, California, U.S.A., in late 2009 for medical assessment and treatment. The clinical signs were due to multiple gas bubbles within the cerebellum. These lesions were intraparenchymal, multifocal to coalescing, spherical to ovoid, and varied from 0.5 to 2.4 cm diameter. The gas composed 21.3% of the total cerebellum volume. Three rib fractures were also noted during diagnostic evaluation and were presumed to be associated with the gas bubbles in the brain. The progression of clinical signs and lesion appearance were monitored with magnetic resonance imaging, cognitive function testing and computed tomography. Gas filled voids in the cerebellum were filled with fluid on follow up images. Clinical signs resolved and the sea lion was released with a satellite tag attached. Post release the animal travelled approximately 75 km north and 80 km south of the release site and the tag recorded dives of over 150 m depth. The animal re-stranded 25 d following release and died of a subacute bronchopneumonia and pleuritis. This is the first instance of clinical injury due to gas bubble formation described in a living pinniped and the first sea lion with quantifiable cerebellar damage to take part in spatial learning and memory testing.

Paradoxical Vestibular Syndrome Caused by a Presumptive Cerebellar Infarction in a Rabbit.

A 6-year-old, female spayed rabbit (Oryctolagus cuniculus) presented with right paradoxical vestibular signs. Magnetic resonance imaging was performed and findings were consistent with an ischemic infarct of the cerebellum. The patient improved gradually and was free of clinical signs at the time this article was written. To the authors' knowledge this is the first case report of a paradoxical vestibular syndrome in a rabbit secondary to a presumptive ischemic infarct. Strokes should be included in the differential diagnosis of central vestibular syndrome in rabbits.

Neurologic disease in a pig.

Three 4-week-old Yorkshire-Hampshire cross piglets from a litter of 9 (7 liveborn) developed convulsions the day of weaning. They were subsequently obtunded, ataxic, and hypermetric and had intention tremors. An affected male pig was presented live for necropsy on day 5 postweaning. This animal was euthanatized and necropsied. No significant grossly visible postmortem lesions were found. Histologic examination of the brain disclosed laminar necrosis of the submeningeal cerebral and cerebellar cortices with replacement by broad sheets of gitter cells. Occasional cerebral and cerebellar leptomeningeal and parenchymal vessels were surrounded by lymphocytes with fewer eosinophils. The morphologic diagnosis was severe multifocal subcortical cerebral and cerebellar laminar necrosis with moderate multifocal lymphocytic and eosinophilic cerebral and cerebellar leptomeningeal and parenchymal perivasculitis. The history and histologic findings are consistent with an etiologic diagnosis of sodium ion intoxication.

Parvovirus-associated cerebellar hypoplasia and hydrocephalus in day old broiler chickens.

Cerebellar hypoplasia and hydrocephalus were identified in day old broiler chickens showing nervous signs, impaired mobility, and diarrhea. At postmortem examination, brains of chickens were misshapen and cerebellums were smaller than normal. Microscopically, cerebellar folia were reduced in size and irregularly shaped, and the ventricles were widely distended. Affected cerebellums had focal areas along the base of folia where the internal granular cell layer had been lost, and Purkinje cells were disorganized and located within the molecular layer. Parvovirus DNA was detected by polymerase chain reaction in three of nine brains with oligonucleotide primers designed for amplification of chicken and turkey parvoviruses. On the basis of phylogenetic analyses, the detected virus was most closely related to chicken parvoviruses. These findings suggest that a chicken parvovirus might cause a neurologic disease of young chickens characterized by cerebellar hypoplasia and hydrocephalus; however, its role as the cause of the disease remains to be confirmed.

Necrotizing cerebellitis and cerebellar atrophy caused by Neospora caninum infection: magnetic resonance imaging and clinicopathologic findings in seven dogs.

BACKGROUND: Adult dogs with neosporosis can develop a variety of neurologic signs. No area of predilection within the nervous system so far has been identified in adult dogs. OBJECTIVES: To document neosporosis as a cause of progressive cerebellar ataxia and cerebellar atrophy in dogs. ANIMALS: Seven client-owned dogs. METHODS: Retrospective, descriptive study. RESULTS: Age at diagnosis ranged from 1 year 6 months to 9 years 11 months. Neuroanatomic localization indicated cerebellar and brainstem disease in 6 dogs and a central vestibular lesion in 1 dog. In all 7 dogs, there was moderate to marked bilaterally symmetrical cerebellar atrophy, with the atrophied cerebellum being surrounded by a region of T2-weighted hyperintense and T1-weighted hypointense signal. Cerebrospinal fluid (CSF) analysis in all but 1 dog showed mononuclear pleocytosis and high protein concentration. Polymerase chain reaction testing for Neospora caninum performed on the CSF was positive in 4/5 dogs tested and there was a high titer of serum antibodies to N. caninum (> or = 1 : 800) in all 6 dogs tested. Postmortem examination in 1 dog confirmed cerebellar atrophy and multifocal nonsuppurative encephalitis with areas of malacia and leptomeningitis. All of the remaining 6 dogs were treated with some combination of clindamycin, trimethoprim, sulfadiazine, and pyrimethamine. Two dogs were euthanized because of deterioration or relapse of neurologic signs, but treatment of the remaining 4 dogs resulted in improvement (3 dogs) or resolution (1 dog) of neurologic signs. CONCLUSIONS AND CLINICAL IMPORTANCE: Neosporosis is an important cause of progressive cerebellar ataxia and cerebellar atrophy in adult dogs.

Feline Phaeohyphomycotic Cerebellitis Caused by Cladosporium cladosporioides-complex: Case Report and Review of Literature.

Cerebellar phaeohyphomycosis was diagnosed in an 8-year-old neutered male domestic cat. Gross lesions were limited to the cerebellum, which had a focally extensive dark brown-black, soft, irregular area affecting the cortex and white matter of the left hemisphere and extending to the reticular formation. Microscopically, multifocal pyogranulomatous meningoencephalitis with intralesional pigmented fungal hyphae effaced the cerebellar grey and white matter. Fungal hyphae were 3-6 µm in diameter, septate and non-dichotomously branched, with parallel, thin and slightly bulbous walls. Polymerase chain reaction for the internal transcribed spacer 1-2 ribosomal RNA genes was performed on tissue samples from formalin-fixed and paraffin wax-embedded sections of cerebellum. Nucleotide sequence analysis of the amplified fragment identified the fungal agent as Cladosporium cladosporioides. This is the first confirmed report of cerebellar phaeohyphomycosis attributable to C. cladosporioides-complex in a domestic cat.

Late onset of cerebellar cortical degeneration in a Magellanic penguin (Spheniscus magellanicus).

An 8-year-old female Magellanic penguin (Spheniscus magellanicus) started to show epilepsy-like seizures. Subsequent magnetic resonance imaging (MRI) examinations did not reveal any responsible lesions. The neurological symptoms worsened at the age of 10. This penguin became recumbent and died 6 months later after the apparition of the recumbency. At necropsy, only multiple yellowish necrotic lesions in the air sacs and lungs were found. Histopathological evaluation of the brain showed a marked loss of Purkinje cells and many hypertrophied parvalbumin-positive basket/stellate cells were seen in the cerebellar cortex. Calbindin immunohistochemistry demonstrated disrupted arrangement of dendrites in the Purkinje cells. This case was diagnosed as cerebellar cortical degeneration with a very late onset and a slow progression in a Magellanic penguin.

Genetic screening for cerebellar abiotrophy, severe combined immunodeficiency and lavender foal syndrome in Arabian horses in Poland.

The highly selective breeding of Arabian horses results in inbreeding depression and genetic disorders, thereby causing significant economic loss. The Polish population of Arabians has a great impact on many breeding programmes. The aim of the current study was to monitor genetic variants involved in the most common genetic disorders of this breed. A total of 808 elite Arabian horses were screened for cerebellar abiotrophy (CA), severe combined immunodeficiency (SCID) and lavender foal syndrome (LFS) genetic disorders by Sanger sequencing and allelic discrimination methods. The investigated population was clear of LFS. The unfavourable SCID allele was detected in three heterozygous horses (q = 0.00185). Regarding CA, the minor allele frequency was q = 0.04029. This is the first report of SCID carriers in Poland. This investigation demonstrates the value of genetic testing to support breeding decisions and to facilitate genetic disease monitoring.

Computer-assisted magnetic resonance imaging brain morphometry in American Staffordshire Terriers with cerebellar cortical degeneration.

BACKGROUND: Cerebellar cortical degeneration exists in American Staffordshire Terriers. Magnetic resonance imaging (MRI) can be suggestive, but a definitive diagnosis requires histopathology. HYPOTHESIS: Computer-assisted MRI morphometry can be used to distinguish between American Staffordshire Terriers with or without cerebellar cortical degeneration. ANIMALS: Normal American Staffordshire Terriers (n = 17) and those with clinical signs of cerebellar cortical degeneration (n = 14). METHODS: This was a partly retrospective and partly prospective study. Causes of cerebellar disease were ruled out with brain MRI, cerebrospinal fluid (CSF) analysis, CBC, blood biochemistry, and clinical follow-up. On T2-weighted midsagittal MR images, the following parameters were calculated: size of the cerebellum relative to the entire brain, size of the CSF space surrounding the cerebellum relative to the cerebellum, and 2 threshold-dependent cerebellar CSF indices (with and without surrounding CSF). RESULTS: Statistical analyses indicated a significantly lower relative cerebellar size (P < .001) and a larger relative cerebellar CSF space (P < .001) in dogs with cerebellar cortical degeneration. The measurement of relative cerebellar size could distinguish between affected and nonaffected dogs with a sensitivity and a specificity of 93 and 94%, respectively, using a cut-off of 13.3%. Using a cut-off of 12.8%, the measurement of relative CSF space could distinguish between both groups with a sensitivity of 93% and a specificity of 100%. There was a significant difference in 1 of the 2 CSF indices between affected and normal dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Relative cerebellar size and relative CSF space calculated from MRI are effective in American Staffordshire Terriers to differentiate between normal animals and those with cerebellar cortical degeneration.

Cerebellar vascular hamartoma in a British Shorthair cat.

Cerebellar vascular hamartoma was diagnosed in a 16-month-old cat following magnetic resonance imaging and incisional biopsy. The clinical features were consistent with the cerebellar site of the lesion accompanied by signs attributable to cerebellar herniation through the foramen magnum and increased intra-cranial pressure. A lesion of this type represents a previously unreported differential diagnosis for central nervous system lesions in young cats.