Cerebellar Abiotrophy Research Articles

Cerebellar abiotrophy in an Icelandic horse

BackgroundCerebellar abiotrophy (CA) is an uncommon hereditary neurodegenerative disorder affecting the cerebellar Purkinje cells. Equine CA has been reported in several breeds, but a genetic etiology has only been confirmed in the Arabian breed, where CA is caused by an autosomal recessive mutation.Case presentation.Clinical and histological findings consistent with CA are reported in an 8.5-month-old Icelandic filly. The filly showed a perceived sudden onset of marked head tremor, incoordination, ataxia, lack of menace response and a broad-based stance. Cerebrospinal fluid, hematological and biochemical findings were all within the normal range, ruling out several differential diagnoses. Post mortem histopathological examination revealed Purkinje cell degeneration accompanied by astrogliosis. Assessment of the filly’s pedigree revealed that its parents shared a common ancestor.ConclusionsTo the authors’ knowledge, this is the first report of CA in the Icelandic breed. The identification of a common parental ancestor makes autosomal recessive inheritance of CA in this filly possible, but this would need to be confirmed by further studies. Veterinarians and breeders working with Icelandic horses should be aware of this condition and report suspected cases in order to support genetic investigation.

Cerebellar Hypoplasia in Two Juvenile African Grey Parrots (Psittacus erithacus).

Two sibling 12-week-old DNA-sexed female African grey parrots (Psittacus erithacus) were presented for progressive whole-body tremors, proprioceptive deficits, and an inability to stand unassisted. A third bird in the clutch (DNA-sexed as a male) exhibited no clinical signs. Physical examination of the affected birds revealed ataxia, inability to stand without assistance, and a reliance on their beaks to assist with their mobility. Hematologic and biochemical analyses were normal, as were radiographic images of both birds. Cerebellar disease of unknown origin was diagnosed, and the birds were euthanized. Postmortem examinations of the brains of both parrots revealed marked reduction in cerebellar size and poor folia formation. Microscopic review of the cerebellums demonstrated decreased density of the granular layer and thinning of the molecular layer with poorly organized and differentiated Purkinje fibers, consistent with a diagnosis of cerebellar hypoplasia. There are limited clinical reports and experimental studies examining cerebellar disease in birds. Conditions described have included cerebellar hypoplasia, cerebellar abiotrophy, and cerebellar dysplasia. Although these terms are used interchangeably due to similar clinical signs, histopathology is needed to differentiate between the different disease conditions. This case describes cerebellar hypoplasia that suggested a developmental etiology in 2 African grey parrots.

Estudio histológico comparado de abiotrofia cerebelosa en un perro y un potrillo

A comparative histological study was performed in two cases of cerebellar abiotrophy in a dog (Canis lupus familiaris) and a foal (Equus ferus caballus) to assess whether the pathological changes differed in type and/or severity between these species. Samples of cerebellum (vermis, lateral hemispheres and flocculonodular lobe) from a female American Staffordshire terrier dog that developed signs of cerebellar abiotrophy at 6 years of age and was euthanized 6 months later due to poor prognosis, and a male Arabian foal that showed signs of cerebellar disease at 40 days of age and was euthanized 1 week later, were used. Samples were processed histologically, stained with hematoxylin and eosin, and examined microscopically to assess the types of lesions and their degree of severity using a 3-scale scoring system (mild, moderate, or severe). The main histological changes in both cases were a reduction in the number of cells in the granular layer, loss of Purkinje neurons, and thinning of molecular layer with astrogliosis. There were no qualitative differences of these lesions between species, although minor differences in the severity scores were observed for astrogliosis on the molecular layer, and reduction in the number of cells in the granular layer. We speculate that these differences could be attributed to differences in the clinical courses between cases, rather than to interspecific attributes.

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.

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.

Investigation of Cerebellar Abiotrophy (CA), Lavender Foal Syndrome (LFS), and Severe Combined Immunodeficiency (SCID) Variants in a Cohort of Three MENA Region Horse Breeds.

Genetic disorders in horses are mostly fatal or usually cause significant economic losses for breeders and owners. Here we studied a total of 177 Arabian, Barb and Arab-Barb horses from the Middle East and North Africa (MENA) using Sanger Sequencing and PCR-ACRS (polymerase chain reaction—artificially created restriction site) approaches to examine the genetic disorders in the studied horse breeds. We identified the genetic variations related to Cerebellar Abiotrophy (CA), Severe Combined Immunodeficiency (SCID) occurrence, and the studied population was free of the mutant allele determined Lavender Foal Syndrome (LFS). Overall, presented data showed that 15 of the studied horses are carriers of two genetic disorders; the investigated horse population showed that five Arabian horses were heterozygous for the CA-associated SNP (rs397160943). The SCID-deletion TCTCA within PRKDC was detected in ten horses (nine Arabian horses and one Arab-Barb horse). This investigation shows the importance of testing these breeds for genetic disorders to avoid further spread of deleterious variants

Estudio patológico de abiotrofia cerebelosa en American Staffordshire terrier - primer reporte en Uruguay

Cerebellar abiotrophy was observed in a female American Staffordshire terrier aged 6 years. The bitch showed tremors, weakness, ataxia as main clinical signs at the time of visit the Veterinary Hospital (FVET-UdelaR), and these signs were progressed slowly for 6 months. The dog was euthanatized due to owners offer, considering no possibility of recovery, and was examined pathologically. Grossly, the cerebellum was small, and the folia were thin, with expanded interfoliar sulci. Histologically, the three layers of the cerebellar cortex showed abnormal structure, characterized by decrease in number of cells in the granular layer, loss of Purkinje cells and thinning of molecular layer. From these pathological findings, this case was diagnosed as canine cerebellar abiotrophy. To our knowledge, this is the first case report of this disease in Uruguay.

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.

Apoptotic cell death in the mammalian central nervous system during development and in pathological conditions

Mammalian central nervous system (CNS) development involves genetically controlled, opposing processes, such as neuronal proliferation, migration, differentiation and death. The natural, developmental cell death is a ubiquitous phenomenon and is referred to as «programmed cell death» (PCD). Apoptosis, a type of PCD, is a central event in normal development of the CNS, playing an important role in the control of cell numbers and the establishment of neuronal circuitry. During embryogenesis, apoptosis takes place in proliferating cell populations and is involved in CNS morphogenesis. At later stages of development, apoptosis occurs in postmitotic neurons, because of the competition for limited supply of neurotrophic factors, that originally suppress the endogenous genetic death programme. Data concerning apoptotic cell death during normal CNS development of domestic mammals is lacking, therefore information about the developmental pattern of this phenomenon is restricted to rodents and rabbits. In these animals it has been suggested that apoptosis follows a mono- or biphasic time course and is completed duringan early, critical period of CNS development, that is characterized by morphological and functional neuronal maturation and synapse formation. Apart from its role in CNS development, apoptosis has also been implicated in neuronal loss accompanying neurodegenerative diseases and traumatic brain injuries in humans and animals. In the domestic canine brain, it has been shown that neurons die via apoptosis in Alzheimer's-like dementia, cerebellar abiotrophy, global and focal ischemia and virus-induced encephalopathies. In addition, cell death in ruminants with transmissible spongiform encephalopathy has been reported to be apoptotic in nature. A plethora of studies using animal models have been employed to elucidate the mechanisms than govern cell loss in neurological disorders. These studies provided strong evidence that experimental lesions of the connections between CNS areas and withdrawal of neurotrophic factors result in an increase of apoptosis, that is age-dependent. Specifically, developing neurons are more dependent on the integrity of their connections than mature ones. In addition, the response of neurons to apoptotic stimuli shows regional specificity. According to epidemiologic studies, CNS disorders are of major concern for animal and human public health, with a high socioeconomic impact. A major goal of neuroscientists is the development of therapeutic approaches for CNS repair. Contemporary strategies that are under trial include neurotrophic factor substitution and transplantation of stem cells. Investigation of the principles and mechanisms controlling cell loss in neurodegenerative diseases and traumatic brain injuries are universally considered of high priority and hopefully will lead to novel therapeutic approaches, with encouraging outcome. The present review summarises recent data on the molecular mechanisms and factors controlling neuronal apoptosis during development and in pathological conditions, describes popular animal models used in lesion studies and discusses therapeutic approaches aiming at preventing or restricting apoptotic cell death.

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.

Investigation of Known Genetic Mutations of Arabian Horses in Egyptian Arabian Foals with Juvenile Idiopathic Epilepsy.

BackgroundThe carrier status of lavender foal syndrome (LFS), cerebellar abiotrophy (CA), severe combined immunodeficiency (SCID), and occipitoatlantoaxial malformation (OAAM1) in foals with juvenile idiopathic epilepsy (JIE) is unknown.Hypothesis/ObjectivesTo determine the carrier status of LFS, CA, SCID, and OAAM1 in foals with JIE.AnimalsTen foals with JIE.Materials and MethodsArchived DNA samples were tested for known genetic mutations causing LFS, CA, SCID, and OAAM1. The inclusion criteria consisted of having been diagnosed with JIE by ruling out other causes of seizures in foals and supported by electroencephalographic examination.ResultsTen Egyptian Arabian horses (5 females and 5 males) were phenotyped as foals with JIE by electroencephalography (EEG). All foals were negative for the genetic mutations that cause LFS, CA, SCID, and OAAM1 except for 1 foal that was a carrier of CA.Conclusions and Clinical ImportanceJuvenile idiopathic epilepsy of Egyptian Arabian foals and LFS appear to be phenotypically and genetically distinct disorders. There was no apparent association between JIE and LFS, CA, SCID, and OAAM1.

Variation in MUTYH expression in Arabian horses with Cerebellar Abiotrophy

Cerebellar Abiotrophy (CA) is a neurodegenerative disease in Arabian horses affecting the cerebellum, more specifically the Purkinje neurons. Although CA occurs in several domestic species, CA in Arabian horses is unique in that a single nucleotide polymorphism (SNP) has been associated with the disease. Total RNA sequencing (RNA-seq) was performed on CA-affected horses to address the molecular mechanism underlying the disease. This research expands upon the RNA-seq work by measuring the impact of the CA-associated SNP on the candidate gene MutY homolog (MUTYH) and its regulation, isoform-specific expression and protein localization. We hypothesized that the CA-associated SNP compromises the promoter region of MUTYH, leading to differential expression of its isoforms. Our research demonstrates that the CA-associated SNP introduces a new binding site for a novel transcription factor (Myelin Transcription Factor-1 Like protein, MYT1L). In addition, CA-affected horses show differential expression of a specific isoform of MUTYH as well as different localization in the Purkinje and granular neurons of the cerebellum.

Exclusion of known gene loci for cerebellar abiotrophy in the Australian Working Kelpie.

Exclusion of known gene loci for cerebellar abiotrophy in the Australian Working Kelpie.

Cerebellar Cortical Abiotrophy in Young Labrador-Retrievers

Cerebellar abiotrophy is a hereditary degenerative disorder of the central nervous system in humans and animals. Four male and one female Labrador-retriever pups were presented with clinical signs of head swaying with intention tremor, loss of target oriented movement, wide base stance, forelimb hypermetria, and hindlimb ataxia leading to falling off during ambulation. On histopathologic examination of cerebellum, cerebellar cortical abiotrophy was confirmed with extensive loss of Purkinje cells, diminution of granular layer, relative thickening and foliar gliosis in white matter. This is the first reported case of cerebellar abiotrophy in Labrador-retriever to our knowledge.

Defining Trends in Global Gene Expression in Arabian Horses with Cerebellar Abiotrophy.

Equine cerebellar abiotrophy (CA) is a hereditary neurodegenerative disease that affects the Purkinje neurons of the cerebellum and causes ataxia in Arabian foals. Signs of CA are typically first recognized either at birth to any time up to 6months of age. CA is inherited as an autosomal recessive trait and is associated with a single nucleotide polymorphism (SNP) on equine chromosome 2 (13074277G>A), located in the fourth exon of TOE1 and in proximity to MUTYH on the antisense strand. We hypothesize that unraveling the functional consequences of the CA SNP using RNA-seq will elucidate the molecular pathways underlying the CA phenotype. RNA-seq (100bp PE strand-specific) was performed in cerebellar tissue from four CA-affected and five age-matched unaffected horses. Three pipelines for differential gene expression (DE) analysis were used (Tophat2/Cuffdiff2, Kallisto/EdgeR, and Kallisto/Sleuth) with 151 significant DE genes identified by all three pipelines in CA-affected horses. TOE1 (Log2(foldchange)=0.92, p=0.66) and MUTYH (Log2(foldchange)=1.13, p=0.66) were not differentially expressed. Among the major pathways that were differentially expressed, genes associated with calcium homeostasis and specifically expressed in Purkinje neurons, CALB1 (Log2(foldchange)=-1.7, p<0.01) and CA8 (Log2(foldchange)=-0.97, p<0.01), were significantly down-regulated, confirming loss of Purkinje neurons. There was also a significant up-regulation of markers for microglial phagocytosis, TYROBP (Log2(foldchange)=1.99, p<0.01) and TREM2 (Log2(foldchange)=2.02, p<0.01). These findings reaffirm a loss of Purkinje neurons in CA-affected horses along with a potential secondary loss of granular neurons and activation of microglial cells.

A Novel Inherited Cerebellar Abiotrophy in a Cohort of Related Goats

Cerebellar abiotrophies, also known as cerebellar ataxias, are characterized by premature post-natal degeneration of cerebellar neurons. This report describes the clinical, magnetic resonance imaging (MRI), gross, histopathological and immunohistochemical features of a novel inherited cerebellar abiotrophy in a cohort of three closely related mixed-breed goats (Capra aegagrus hircus) in the southeastern USA. The animals all presented with early juvenile-onset ataxia, hypermetria, wide-based stance, head tremors and nystagmus. On MRI and at gross examination, there was moderate thinning of the cerebellar vermis and sharpening of the folia. Histologically, the vermis, paravermis and flocculonodular lobe had moderate to severe segmental loss of Purkinje cells with sparing of the hemispheres and secondary loss of granule cells and astrogliosis. Heritable cerebellar ataxias have been reported in many domestic animal species, but not, to the authors' knowledge, as a heritable condition in goats.

Morphometric analysis of progressive changes in hereditary cerebellar cortical degenerative disease (abiotrophy) in rabbits caused by abnormal synaptogenesis.

We previously investigated rabbit hereditary cerebellar cortical degenerative disease, called cerebellar cortical abiotrophy in the veterinary field, and determined that the pathogenesis of this disease is the result of failed synaptogenesis between parallel fibers and Purkinje cells. In this study, longitudinal changes in the development and atrophy of the cerebellum of rabbits with hereditary abiotrophy after birth were morphometrically examined (postnatal day [PD] 15 and 42) using image analysis. Although development of the cerebellum in rabbits with abiotrophy was observed from PD 15 to PD 42, the growth rate of the cerebellum was less than that in normal rabbits. In rabbits with abiotrophy, the number of granular cells undergoing apoptosis was significantly higher at PD 15 and dramatically decreased at PD 42. The number of granular cells did not increase from PD 15 to 42. The synaptogenesis peak at PD 15 occurred when the largest number of apoptotic granular cells in rabbits with abiotrophy was observed. Although 26% to 36% of parallel fiber terminals formed synaptic junctions with Purkinje cell spines, the remainder did not at PD 15 and 42. The rate of failure of synaptogenesis in the present study might be specific to this case of abiotrophy. Morphometric analysis revealed detailed changes in development and atrophy in animals with postnatal cerebellar disease occurring soon after birth.

Erratum

Aust Vet J 2014; 92: 339– 342. doi: 10.1111/avj.12211 Late-onset cerebellar abiotrophy in a Labrador Retriever by Bertalan, A, Glass, EN, Kent, M, De LaHunta, A and Bradley, C The editors wish to correct two errors in the Introduction. Lines 5–7 of the second paragraph of this section should read: Affected dogs are classified based on the age of onset into three groups: early (2–4 weeks of age), intermediate (5–6 weeks of age), or late-onset (5 months or older).

Late‐onset cerebellar abiotrophy in a Labrador Retriever

A 5-year-old female spayed Labrador Retriever was examined for a hindlimb gait abnormality. Initial neurological examination was consistent with vestibular dysfunction. Over the course of 1 year, signs progressed to reflect cerebellar ataxia, vertical nystagmus and delayed postural reactions in all limbs. At the initial examination, subjective evaluation of magnetic resonance imaging scan of the brain was considered normal. Repeat imaging at 1 year after initial examination revealed a reduction in the size of the cerebellum. Retrospectively, the size of the cerebellum on the initial MRI was small when assessed using an objective measurement algorithm. Postmortem histopathological evaluation of the brain showed diffuse degeneration of Purkinje cell neurones with secondary granule cell loss in the cerebellum, in addition to pigment inclusions in brainstem neurones. The clinical history and clinicopathological data are consistent with late-onset cerebellar abiotrophy, which has not previously been described in this breed.

Cerebellar cortical abiotrophy in a Samoyed dog

Cerebellar abiotrophies have a non-sex-linked, autosomal, recessively inherited basis in anumber of animal species, and lesions typically reflect progressive loss of Purkinje cells. In this report, ataxia was observed in a one-week-old male Samoyed puppy with no history of trauma or any other illness. Physical examination revealed uncoordinated movements, mild trunkal ataxia and intensive head tremors, so the dog had trouble eating, evacuating and difficulties in standing and walking without falling. The complete cell count, cerebrospinal fluid analysis and cerebral radiographs were normal. Treatment with diazepam, vitamin B1 and glucocorticoids had no effect on clinical signs and the dog died after a month. According to clinical signs and histopathological features, cerebellar cortical abiotrophy was diagnosed. This is the first report of a cerebellar cortical abiotrophy in a Samoyed puppy.