RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia.

Several genetically distinct forms of cerebellar ataxia exist in Belgian shepherd dogs. We investigated a litter in which two puppies developed cerebellar ataxia. The clinical signs stabilized at around six weeks of age, but remained visible into adulthood. Combined linkage and homozygosity mapping delineated a 5.5 Mb critical interval. The comparison of whole-genome sequence data of one affected dog to 929 control genomes revealed a private homozygous ~4.8 kb deletion in the critical interval, Chr8:14,468,376_14,473,136del4761. The deletion comprises exon 35 of the RALGAPA1 gene, XM_038544497.1:c.6080-2893_6944+1003del. It is predicted to introduce a premature stop codon into the transcript, truncating ~23% of the wild-type open reading frame of the encoded Ral GTPase-activating protein catalytic subunit α 1, XP_038400425.1:(p.Val2027Glnfs*7). Genotypes at the deletion showed the expected co-segregation with the phenotype in the family. Genotyping additional ataxic Belgian shepherd dogs revealed three additional homozygous mutant dogs from a single litter, which had been euthanized at five weeks of age due to their severe clinical phenotype. Histopathology revealed cytoplasmic accumulation of granular material within cerebellar Purkinje cells. Genotyping a cohort of almost 900 Belgian shepherd dogs showed the expected genotype-phenotype association and a carrier frequency of 5% in the population. Human patients with loss-of-function variants in RALGAPA1 develop psychomotor disability and early-onset epilepsy. The available clinical and histopathological data, together with current knowledge about RALGAPA1 variants and their functional impact in other species, suggest the RALGAPA1 deletion is the likely causative defect for the observed phenotype in the affected dogs.

Phenotypic and genetic aspects of hereditary ataxia in dogs.

Hereditary ataxias are a large group of neurodegenerative diseases that have cerebellar or spinocerebellar dysfunction as core feature, occurring as an isolated sign or as part of a syndrome. Based on neuropathology, this group of diseases has so far been classified into cerebellar cortical degenerations, spinocerebellar degenerations, cerebellar ataxias without substantial neurodegeneration, canine multiple system degeneration, and episodic ataxia. Several new hereditary ataxia syndromes are described, but most of these diseases have similar clinical signs and unspecific diagnostic findings, wherefore achieving a definitive diagnosis in these dogs is challenging. Eighteen new genetic variants associated with these diseases have been discovered in the last decade, allowing clinicians to reach a definitive diagnosis for most of these conditions, and allowing breeding schemes to adapt to prevent breeding of affected puppies. This review summarizes the current knowledge about hereditary ataxias in dogs, and proposes to add a "multifocal degenerations with predominant (spino)cerebellar component" category regrouping canine multiple system degeneration, new hereditary ataxia syndromes that do not fit in 1 of the previous categories, as well as specific neuroaxonal dystrophies and lysosomal storage diseases that cause major (spino)cerebellar dysfunction.

Spinocerebellar ataxia in the Bouvier des Ardennes breed is caused by a KCNJ10 missense variant.

BACKGROUND: In Belgian Malinois, a KCNJ10 variant causes progressive spinocerebellar degeneration. HYPOTHESIS/OBJECTIVES: Describe the clinical, diagnostic, pathological and genetic features of spinocerebellar degeneration in the Bouvier des Ardennes breed. ANIMALS: Five affected Bouvier des Ardennes puppies with spinocerebellar ataxia (SCA), 8 healthy related dogs, and 63 healthy unrelated Bouvier des Ardennes. METHODS: Sequential case study. RESULTS: Clinical signs started at 6 weeks of age in 1 puppy with severe signs of cerebellar disease, and at 7 to 10 weeks of age in the 4 remaining puppies with milder signs of spinocerebellar disease. The first puppy displayed severe intention tremors and rapidly progressive generalized hypermetric ataxia, whereas the 4 others developed a milder progressive SCA. Euthanasia after progression to nonambulatory status was performed by 8 weeks of age in the first puppy, and before 11 months of age in the 4 remaining puppies. Histopathology revealed cerebellar spongy degeneration and a focal symmetrical demyelinating myelopathy. All cases were homozygous for KCNJ10 XM_545752.6:c.986T>C(p.(Leu329Pro)), which is pathogenic for SCA with (or without) myokymia, seizures or both (SAMS) and spongy degeneration and cerebellar ataxia (SDCA) 1 in Belgian Malinois dogs. All sampled parents were heterozygous and none of the healthy dogs were homozygous for this recessive variant. This variant has an allele frequency of 15% in the 63 healthy dogs studied. CONCLUSIONS AND CLINICAL IMPORTANCE: Inherited spinocerebellar degeneration also affects the Bouvier des Ardennes breed and is caused by a KCNJ10 variant. It can present with a spectrum of severity grades, ranging from severe cerebellar to milder spinocerebellar signs.

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.

Dandy-Walker-Like Malformation in a Free-Ranging Atlantic Harbour Seal Pup (Phoca vitulina concolor).

An 88.5 cm long, 12.9 kg, 3-week-old stranded male Atlantic harbour seal (Phoca vitulina concolor) presented with cerebellar ataxia, delayed postural reactions, hyperaesthesia and nystagmus. The skull was enlarged and domed. Ultrasound through a persistent fontanelle in the frontal bone revealed hydrocephalus. Magnetic resonance imaging showed diffuse enlargement of the ventricular system, an absent cerebellar vermis, hypertrophy of the choroid plexus of the fourth ventricle and enlargement of the caudal fossa. Throughout rehabilitation, the seal failed to achieve milestones critical for successful release or placement in a managed care facility, including the ability to feed independently and haul out. Three months into rehabilitation it began to regurgitate and staff had difficulty administering food to the seal. The seal was euthanized due to a poor prognosis. Post-mortem examination confirmed a) aplasia of the dorsal cerebellar vermis and hypoplasia of the most dorsal portions of the right and left cerebellar hemispheres, b) severe, diffuse, congenital communicating hydrocephalus, and c) aplasia of the interthalamic adhesion and corpus callosum. This case represents the first report of Dandy-Walker-like malformation (DWLM) in a marine mammal and illustrates the importance of advanced imaging and thorough post-mortem examination in free-ranging pinnipeds that strand with evidence of neurological disease.

Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs.

A form of hereditary cerebellar ataxia has recently been described in the Norwegian Buhund dog breed. This study aimed to identify the genetic cause of the disease. Whole-genome sequencing of two Norwegian Buhund siblings diagnosed with progressive cerebellar ataxia was carried out, and sequences compared with 405 whole genome sequences of dogs of other breeds to filter benign common variants. Nine variants predicted to be deleterious segregated among the genomes in concordance with an autosomal recessive mode of inheritance, only one of which segregated within the breed when genotyped in additional Norwegian Buhunds. In total this variant was assessed in 802 whole genome sequences, and genotyped in an additional 505 unaffected dogs (including 146 Buhunds), and only four affected Norwegian Buhunds were homozygous for the variant. The variant identified, a T to C single nucleotide polymorphism (SNP) (NC_006585.3:g.88890674T>C), is predicted to cause a tryptophan to arginine substitution in a highly conserved region of the potassium voltage-gated channel interacting protein KCNIP4. This gene has not been implicated previously in hereditary ataxia in any species. Evaluation of KCNIP4 protein expression through western blot and immunohistochemical analysis using cerebellum tissue of affected and control dogs demonstrated that the mutation causes a dramatic reduction of KCNIP4 protein expression. The expression of alternative KCNIP4 transcripts within the canine cerebellum, and regional differences in KCNIP4 protein expression, were characterised through RT-PCR and immunohistochemistry respectively. The voltage-gated potassium channel protein KCND3 has previously been implicated in spinocerebellar ataxia, and our findings suggest that the Kv4 channel complex KCNIP accessory subunits also have an essential role in voltage-gated potassium channel function in the cerebellum and should be investigated as potential candidate genes for cerebellar ataxia in future studies in other species.

A retrospective study of quadrigeminal arachnoid cysts diagnosed by Magnetic Resonance Imaging and Computed Tomography in 26 dogs / Estudo retrospectivo de cistos aracnoides da cisterna quadrigeminal diagnosticados pela ressonância magnética e tomografia computadorizada em 26 cães

Arachnoid cysts are accumulations of cerebrospinal fluid that occur within the arachnoid membrane due to the splitting or duplication of this structure. The aim of this retrospective study is to report the occurrence of this condition in 26 dogs, as well as to describe the findings of computed tomography imaging and magnetic resonance image scans and to correlate these with the clinical signs. A prevalence of the condition was observed in males, predominantly in the small breeds Miniature Pinscher and Shih Tzu, with age raging from 2 months to 9 years. The mainly clinical signs observed in these dogs were seizures and cerebellar ataxia. The study concluded that in 17 dogs the quadrigeminal arachnoid cyst was regarded as an incidental finding, in 6 dogs this condition was regarded as the determinant cause of the clinical signs, and in 3 dogs some clinical signs were associated with arachnoid cyst, but they also presented clinical signs involving others sites of intracranial lesion. (AU)

Cistos aracnoide são acúmulos de líquido cefalorraquidiano que ocorre dentro da membrana aracnoide devido à divisão ou duplicação desta estrutura. O objetivo desse estudo retrospectivo é relatar a ocorrência dessa condição em 26 cães, assim como descrever os aspectos de imagem pela tomografia computadorizada e ressonância magnética e correlacionar com os sinais clínicos. No estudo observamos a prevalência em machos, em raças de pequeno porte, com predomínio de Pinscher miniatura e Shih Tzu, com idade variando de dois meses a nove anos. Os principais sinais neurológicos observados nestes animais foram crises epiléticas e ataxia cerebelar. Foi possível concluir que em 17 cães o cisto aracnoide quadrigeminal foi considerado um achado incidental, em seis cães essa condição foi considerada a causa determinante dos sinais clínicos, e em três cães alguns sinais estavam associados com o cisto aracnoide, porém esses animais apresentaram sinais clínicos relacionados a outros sítios de lesão intracraniana.

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.

A SINE Insertion in ATP1B2 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2).

Spongy degeneration with cerebellar ataxia (SDCA) is a genetically heterogeneous neurodegenerative disorder with autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. Using a combined linkage and homozygosity mapping approach we identified an ∼10.6 Mb critical interval on chromosome 5 in a Malinois family with four puppies affected by cerebellar dysfunction. Visual inspection of the 10.6 Mb interval in whole-genome sequencing data from one affected puppy revealed a 227 bp SINE insertion into the ATP1B2 gene encoding the ß2 subunit of the Na+/K+-ATPase holoenzyme (ATP1B2:c.130_131insLT796559.1:g.50_276). The SINE insertion caused aberrant RNA splicing. Immunohistochemistry suggested a reduction of ATP1B2 protein expression in the central nervous system of affected puppies. Atp1b2 knockout mice had previously been reported to show clinical and neurohistopathological findings similar to the affected Malinois puppies. Therefore, we consider ATP1B2:c.130_131ins227 the most likely candidate causative variant for a second subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia subtype 2 (SDCA2). Our study further elucidates the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population in Malinois and the other varieties of the Belgian Shepherd breed. ATP1B2 thus represents another candidate gene for human inherited cerebellar ataxias, and SDCA2-affected Malinois puppies may serve as a naturally occurring animal model for this disorder.

A Missense Variant in KCNJ10 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1).

Spongy degeneration with cerebellar ataxia (SDCA) is a severe neurodegenerative disease with monogenic autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. We performed a genetic investigation in six families and seven isolated cases of Malinois dogs with signs of cerebellar dysfunction. Linkage analysis revealed an unexpected genetic heterogeneity within the studied cases. The affected dogs from four families and one isolated case shared a ∼1.4 Mb common homozygous haplotype segment on chromosome 38. Whole genome sequence analysis of three affected and 140 control dogs revealed a missense variant in the KCNJ10 gene encoding a potassium channel (c.986T>C; p.Leu329Pro). Pathogenic variants in KCNJ10 were reported previously in humans, mice, and dogs with neurological phenotypes. Therefore, we consider KCNJ10:c.986T>C the most likely candidate causative variant for one subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia 1 (SDCA1). However, our study also comprised samples from 12 Malinois dogs with cerebellar dysfunction which were not homozygous for this variant, suggesting a different genetic basis in these dogs. A retrospective detailed clinical and histopathological analysis revealed subtle neuropathological differences with respect to SDCA1-affected dogs. Thus, our study highlights the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population. These dogs represent an animal model for the human EAST syndrome.

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.

A deletion in the VLDLR gene in Eurasier dogs with cerebellar hypoplasia resembling a Dandy-Walker-like malformation (DWLM).

Dandy-Walker-like malformation (DWLM) is the result of aberrant brain development and mainly characterized by cerebellar hypoplasia. DWLM affected dogs display a non-progressive cerebellar ataxia. Several DWLM cases were recently observed in the Eurasier dog breed, which strongly suggested a monogenic autosomal recessive inheritance in this breed. We performed a genome-wide association study (GWAS) with 9 cases and 11 controls and found the best association of DWLM with markers on chromosome 1. Subsequent homozygosity mapping confirmed that all 9 cases were homozygous for a shared haplotype in this region, which delineated a critical interval of 3.35 Mb. We sequenced the genome of an affected Eurasier and compared it with the Boxer reference genome and 47 control genomes of dogs from other breeds. This analysis revealed 4 private non-synonymous variants in the critical interval of the affected Eurasier. We genotyped these variants in additional dogs and found perfect association for only one of these variants, a single base deletion in the VLDLR gene encoding the very low density lipoprotein receptor. This variant, VLDLR:c.1713delC is predicted to cause a frameshift and premature stop codon (p.W572Gfs*10). Variants in the VLDLR gene have been shown to cause congenital cerebellar ataxia and mental retardation in human patients and Vldlr knockout mice also display an ataxia phenotype. Our combined genetic data together with the functional knowledge on the VLDLR gene from other species thus strongly suggest that VLDLR:c.1713delC is indeed causing DWLM in Eurasier dogs.

A case of Murray Valley encephalitis in a 2-year-old Australian Stock Horse in south-east Queensland.

CASE REPORT: This report summarises the findings from a case of naturally-occurring Murray Valley encephalitis in a 2-year-old filly presenting with acute onset of depression and weakness. Serum samples tested at the onset of clinical signs were negative for Hendra and Kunjin virus antibodies, but positive for Murray Valley encephalitis virus (MVEV) using IgM-capture ELISA (1 : 300 dilution). A virus neutralisation assay performed 4 weeks later confirmed a titre of 1 : 160. Sera collected in the weeks preceding neurological signs returned a negative titre for MVEV 2 weeks prior followed by a titre of 1:80 in the week prior to illness. Serological surveillance conducted on 67 co-located horses returned a positive titre of 1 : 20 in one in-contact horse. There was no history of clinical disease in that horse. At 3 months after the onset of clinical signs in the index case, the filly continued to show mild facial paresis and hypermetria; the owners elected euthanasia and gave permission for necropsy. Histopathological analysis of the brain showed a mild meningoencephalitis. CONCLUSION: The progression of a naturally-occurring MVEV infection in a horse has been documented in this case.

Cerebellar ataxia suspected to be caused by Oxytropis glabra poisoning in western Mongolian goats.

In the last five years in western Mongolia, a neurological disorder and resultant economic loss have developed in goats, sheep, cattle and horses: association of the disease with ingestion of Oxytropis glabra, a toxic plant, was suggested. Affected goats showed neurological signs, including ataxia, incoordination, hind limb paresis, fine head tremor and nystagmus. Three goats, one with moderate clinical signs and the other two with severe clinical signs, were necropsied and examined to describe and characterize the histologic, immunohistochemical and ultrastructural lesions. Although no gross pathological changes were observed in a variety of organs including the central nervous system of these goats, microscopic examination of the cerebellum demonstrated degenerative changes in all these goats, such as vacuolar changes and loss of Purkinje cells, torpedo formation in the granular layer, increased number of spheroids in the cerebellar medulla, and loss of axons and myelin sheaths of Purkinje cells. The chemical analysis of the dried plant detected 0.02-0.05% (dry weight basis) of swainsonine. This is the first report describing the clinical and pathological findings in Mongolian goats suspected to be affected by O. glabra poisoning.

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.

Unilateral cerebellar hypoplasia and mesencephalic malformation in a Hanoverian foal.

Neurological cases, especially in foals, are rare in the daily practical work. The most common causes are traumata and infectious diseases of the central nervous system (CNS). This case report provides further insights into the wide spectrum of possible neuropathological lesions by detailing a complex malformation with unilateral neurological signs that occurred later post natum. Thus, clinicians should also be aware of malformations in case of respective neurological patients. A Hanoverian foal was presented with progressive ataxia. General and blood examination revealed no further alterations. By neurologic examination, a unilateral hypermetria was diagnosed and a cysternography of the head was performed. A cerebellar malformation was assumed and the foal was euthanized due to poor prognosis. At necropsy, a unilateral absence of a cerebellar hemisphere and vermis accompanied by contralateral malformation of the mesencephalon was diagnosed. The missing areas of the right cerebellar hemisphere were replaced by a cystic formation. The left part of the mesencephalic lamina quadrigemina was reduced in size and the corpus callosum was hypoplastic. Additional microscopical findings were most obvious near the cyst formation and included angiofibrosis in remaining cerebellar and mesencephalic parenchyma and leptomeninges, heterotopia of cerebellar neurons, sclerosis in cerebellar cortex, focal proliferation of meningeal cells and mild mononuclear perivascular infiltrates. Occassional irregular neuronal arrangement in the mesencephalon was also present. Infectious agents such as Borna disease virus, rabies virus, and equine herpesvirus were not detected. Therefore, the complex malformation in this foal might have been caused by a destructive, possibly ischemic event, or could represent a sequel of a primary retrocerebellar cyst with accompanying compression of adjacent parenchyma.

A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery.

Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (p(raw) = 1.1x10(-7), p(genome) = 7.5x10(-4)). Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L), revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD-mediated neurodegenerative disease model, and proposes SEL1L as a new candidate gene in progressive childhood ataxias. Furthermore, our results have enabled the development of a genetic test for breeders.

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.

Spongy degeneration with cerebellar ataxia in Malinois puppies: a hereditary autosomal recessive disorder?

BACKGROUND: There is a high incidence of hereditary degenerative diseases of the central nervous system in purebred dogs. HYPOTHESIS: Cerebellar ataxia in Malinois puppies, caused by degenerative changes that predominate in cerebellar nuclei and the granular cell layer, is a hereditary disorder that is distinct from cerebellar cortical abiotrophies. ANIMALS: Thirteen Malinois puppies with cerebellar ataxia. METHODS: Retrospective study. Records of Malinois puppies with spongy degeneration of the cerebellar nuclei were analyzed including clinical signs, histopathological changes, and pedigree data. RESULTS: Signs of cerebellar dysfunction were observed in puppies of both sexes from 5 different litters (1995-2009) of phenotypically normal parents. Clinical signs started before the age of 2 months and resulted in euthanasia of all puppies by the age of 13 weeks. Histopathology disclosed marked bilateral spongy degeneration of the cerebellar nuclei and vacuoles in the granular cell layer and foliate white matter of the cerebellum. In some puppies, discrete vacuoles in gray and white matter were present in other parts of the brain. Furthermore, spheroids and dilated myelin sheaths were observed. Pedigree data and segregation frequency support an autosomal recessive hereditary disorder. CONCLUSIONS AND CLINICAL IMPORTANCE: Malinois suffer from a hereditary spongiform degeneration that predominates in the cerebellum and causes an early onset of clinical signs with unfavorable prognosis. Future efforts should increase awareness among veterinarians and breeders and aim to identify underlying metabolic mechanisms and the affected genes.