Fig 6 - uploaded by Brian Summers
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A–D Cerebellum. A Well-demarcated segmental atrophy affecting contiguous folia in the vermis (asterisks). The cortex in the most dorsal folium (top) is normal. Note also relative sparing of more lateral gray matter (arrows). B Higher magnification of an area in the most ventral folium in A demonstrating sparing of Purkinje neurons (arrows with p) within a moderately gliotic neuropil. There is subtotal atrophy of the granular cell layer with residual granule cells visible as dark dots. Thick arrows indicate the gray and white matter junction. A few hypertrophied astrocytes (arrows with a) are present in the atrophic gray matter and in the underlying white matter . C A quiescent lesion with profound atrophy of all cortical layers. Advanced fibrillary gliosis affects the molecular layer (M) and the depleted and attenuated granular layer (G) which are separated by a band of Bergmann's gliosis (B). Thick arrows indicate the gray and white matter junction. D A focus of subacute degeneration with numerous necrotic granule cell neurons seen as dark dots scattered throughout a gliotic and edematous granular layer. There is loss of all Purkinje neurons and Bergmann's gliosis (B). Note a surviving Golgi neuron (arrow with g) (M molecular layer). A, B Dog 2; C, D dog 4. A, B LFB; C, D H&E; A × 87.5, B–D × 175
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The gross and histopathological findings in the brain and spinal cord of five Alaskan Husky dogs with a novel incapacitating and ultimately fatal familial and presumed hereditary neurodegenerative disorder are described. Four dogs presented with neurological deficits before the age of 1 year (7-11 months) and one animal at 2.5 years old. Clinical s...
Citations
... Detailed neuropathological studies were carried out in five Alaskan husky dogs affected by canine neurodegenerative disorder resembling subacute necrotising encephalomyelopathy (Leigh-like Syndrome) (Brenner et al., 2000). The morphological studies showed bilateral and symmetrical cavitation in the thalamus, areas of progressive degenerations, and multifocal lesions in the cerebral cortex and in the grey matter (Brenner et al., 2000). ...
... Detailed neuropathological studies were carried out in five Alaskan husky dogs affected by canine neurodegenerative disorder resembling subacute necrotising encephalomyelopathy (Leigh-like Syndrome) (Brenner et al., 2000). The morphological studies showed bilateral and symmetrical cavitation in the thalamus, areas of progressive degenerations, and multifocal lesions in the cerebral cortex and in the grey matter (Brenner et al., 2000). Interestingly, it was suggested that canine neurodegenerative disorder resembling subacute necrotising encephalomyelopathy is a hereditary neurodegenerative mitochondrial disease, because four out of the five Alaskan husky dogs were affected (<1 year old). ...
... Moreover, similar clinical signs were found in other six dogs from five kennel clubs in the USA. Therefore, it is suspected that more dogs are affected by this condition, but most of them are euthanised after occurrence of characteristic neurological symptoms (Brenner et al., 2000). ...
Currently, the issue of the aetiology of mitochondrial diseases resulting from mitochondrial DNA (mtDNA) defects is underestimated. Genetic research is mostly focused on alterations in the nuclear genome (nDNA), and its impact on disease development as well as further health consequences without considering mtDNA abnormalities. However, in the case of energy-dependent diseases, it is important to understand the bioenergetic pathophysiology and its relation with mtDNA changes.
In the current animal research, there is limited data about mtDNA defects and their association with the development of bioenergetic diseases in the domestic dog (Canis lupus familiaris) in contrast to human medicine, where mitochondrial genetics research has recently increased. Molecular findings about mtDNA indicate that improper functioning of mitochondria resulting from genetic defects of mtDNA has a severe impact on cells and tissues, especially those that are heavily dependent on oxidative metabolism such as the brain, skeletal and cardiac muscles and, consequently, the whole organism.
The aim of this paper is to highlight the role of defects of mitochondria and mtDNA on the development and course of different diseases in the domestic dog. The field of canine mitochondrial genetics and genomics is definitely inexhaustible and it is worth drawing attention to the importance and consequences of the mitochondrial genome alterations. This review collects scientific data on mitochondrial DNA with special regard to the structure, features of canine mtDNA, and abnormalities in the mitochondrial genome and their association with the course and development of diseases, including mitochondrial myopathies, encephalopathies, and tumours.
... AHE, first characterized in the late twentieth century in sled dogs, is a degenerative brain condition that leaves dogs with extreme neurologic dysfunction [19,20]. The causative mutation, a 4 base pair insertion located on chromosome 25 within the thiamine transporter 2 (SLC19A3) gene, controls thiamine transportation in the central nervous system [21]. ...
Background
This study describes the presence and frequency of health traits among three populations of dogs traditionally used for sledding and explores their ancestry and breed composition as provided by the commercially available Embark dog DNA test. The three populations include the purebred Siberian Husky and the admixed populations of Alaskan sled dogs and Polar Huskies. While the Siberian Husky represents a well-established breed with extensive historical and health data, the Alaskan sled dog is less studied but has been the subject of nutritional, physiological, and genetic studies related to ancestry and performance. In contrast, the Polar Husky is a relatively obscure and rare group of dogs used for arctic exploration with very little-known information. The three populations were compared using Embark results, providing new insight into the health traits circulating within the populations and the potential ancestral linkage of the health traits between the sledding populations. Embark results are based upon 228,588 single-nucleotide polymorphisms (SNPs) spanning the canine genome, characterized using a custom-designed Illumina beadchip array.
Results
Specifically, breed composition was summarized for the two admixed populations with most of the dogs being predominantly categorized as Alaskan husky- type dog or “Supermutt”. Mitochondrial and Y chromosome haplogroups and haplotypes were found with Alaskan sled dogs carrying most of the haplogroups and types found in Siberian and Polar Huskies. Genomic principal component analysis reflected population structure corresponding to breed and substructure within the Alaskan sled dogs related to sprint or distance competition. Genetic markers associated with Alanine Aminotransferase activity, Alaskan Husky Encephalopathy, dilated cardiomyopathy, Collie eye anomaly, degenerative myelopathy, ichthyosis, and factor VII deficiency were identified in the populations of sledding breeds.
Conclusion
These results provide a preliminary description of genetic characteristics found in sledding breeds, improving the understanding and care of working sled dogs.
... 11 The first report focused on a polioencephalomyelopathy resembling Leigh's syndrome in 3 Australian cattle dog puppies. 12 This report was followed by a number of reports in other breeds, [13][14][15][16][17][18][19][20][21] with the Alaskan Husky being most commonly represented. [19][20][21] Kittens affected by a suspected mitochondriopathy were identified once in 1979 22 and reported in 1995. ...
... 12 This report was followed by a number of reports in other breeds, [13][14][15][16][17][18][19][20][21] with the Alaskan Husky being most commonly represented. [19][20][21] Kittens affected by a suspected mitochondriopathy were identified once in 1979 22 and reported in 1995. 23 In humans, however, PMDs show great heterogeneity in clinical presentation and lesion distribution, and lack pathognomonic patterns. ...
... If distribution of the brain lesions in this cat did not overlap any specific human or canine PMD pattern, involvement of cerebral white matter and cerebellar cortex resembles that observed in Pearson/Kerns-Sayre syndrome (P/KSS) in humans, 29 whereas involvement of the thalamus and brain stem is similar to what is observed in Leigh syndrome in humans, 8 necrotizing AHE and subacute necrotizing encephalopathy in Yorkshire Terriers. 14,20 Indeed, compared to SSNE of these dog breeds, subcortical white matter lesions in our cat were much more severe whereas thalamic and brain stem lesions did not occur with a V-shaped pattern. 14 Similar to a previous study, 20 we identified active degeneration in the caudate nuclei, thalamus, and brainstem, primarily characterized by gliosis and prominent blood vessel reactivity. ...
A 2‐year‐old female cat was referred for progressive neurological signs indicative of involvement of the prosencephalon, cerebellum, and brainstem. Magnetic resonance imaging identified multifocal, bilateral, symmetrical lesions with strong contrast enhancement, affecting multiple areas of the brain. Neuropathology at necropsy showed demyelination, necrotic lesions, spongiosis, and neuropil edema with reactive astrogliosis and neovascularization. Ultrastructural study indicated mitochondrial polymorphism. Genetic investigations outlined 2 polymorphisms within the tRNA‐Leu(UUR) gene of mitochondrial DNA. Imaging and neuropathological findings were consistent with selective symmetrical necrotizing encephalopathy, for which genetic investigations support mitochondrial pathogenesis.
... 6,7 A mutation (c.624 insTTGC, c.625 C>A) in the thiamine transporter 2 (SLC19A3) gene is the cause of Alaskan (Siberian) husky encephalopathy (AHE). [8][9][10] This gene controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein, THTR2. 8 Affected dogs are unable to produce THTR2, so thiamine uptake into the CNS is significantly reduced. ...
... AHE and SNE closely resemble Leigh syndrome in children. 10,11 Mutations in mtDNA are also incriminated in the development of spongiform leukoencephalomyelopathy in the Australian cattle dog, Shetland sheepdog, and border terrier. 11 For more information on the disorder in these breeds, see the Canine VINcyclopedia chapter on Spongiform Leukodystrophy and other Leukodystrophies. ...
... 6,7 Advanced Imaging: Magnetic resonance imaging can reveal bilaterally symmetrical T1weighted hypointense and T2-weighted hyperintense lesions in many different areas of the brain. [8][9][10][11] Lesions are noncontrast enhancing, and preferentially affect grey matter, especially of the basal nuclei, caudate, thalamus, and brainstem nuclei. [8][9][10][11] Lesions can be cavitated and cyst like. ...
Mitochondrial diseases are a type of metabolic disorder involving the respiratory chain that is under the control of both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Mitocondriopathies can also be clinically classified as neurodegenerative diseases when they affect the central nervous system (CNS). Mitochondrial defects cause encephalopathy, encephalomyelopathy, neuropathy, and myopathies in dogs.
The author review the currently known canine syndromes describing clinical signs, breed predilection, advanced imaging findings (on MRI and CT), treatment and outcome. Up to date genetic mutations related to these syndromes are also described.
... Rare forms of SNE were described e.g., in cattle [5][6][7] and dogs (OMIA 001097-9615). The first report of this disorder was described in Alaskan huskies [8,9] and subsequently, a similar form of SNE was reported in Yorkshire terriers [10] and American Staffordshire bull terriers [11]. Neuropathologically, SNE in Yorkshire terriers is nearly identical to the Alaskan husky form and very similar to human Leigh syndrome [10]. ...
Sporadic occurrence of juvenile-onset necrotizing encephalopathy (SNE) has been previously reported in Yorkshire terriers. However, so far, no causative genetic variant has been found for this breed-specific form of suspected mitochondrial encephalomyopathy. Affected dogs showed gait abnormalities, central visual defects, and/or seizures. Histopathological analysis revealed the presence of major characteristics of human Leigh syndrome and SNE in Alaskan huskies. The aim of this study was to characterize the genetic etiology of SNE-affected purebred Yorkshire terriers. After SNP genotyping and subsequent homozygosity mapping, we identified a single loss-of-function variant by whole-genome sequencing in the canine SLC19A3 gene situated in a 1.7 Mb region of homozygosity on chromosome 25. All ten cases were homozygous carriers of a mutant allele, an indel variant in exon 2, that is predicted to lead to a frameshift and to truncate about 86% of the wild type coding sequence. This study reports a most likely pathogenic variant in SLC19A3 causing a form of SNE in Yorkshire terriers and enables selection against this fatal neurodegenerative recessive disorder. This is the second report of a pathogenic alteration of the SLC19A3 gene in dogs with SNE.
... En la necropsia se hallaron lesiones similares al síndrome de encefalomielopatía mitocondrial con acidosis láctica y episodios símil-stroke de los humanos (de su sigla en inglés, MELAS) (Gruber et al. 2002). En Springer Spaniel los signos clínicos comenzaron a los 15 meses de edad, y consistieron en ausencia de la respuesta de amenaza con deficiencias visuales, nistagmo vertical posicional e hipermetría y pérdida del balance inducido por la excitación (Brenner et al. 1997). También se ha descrito en una perra mestiza de 14 meses (Chai et al. 2015). ...
... However, due to THTR-2 not being affected by this mechanism, the risk of developing thiamine deficiency as a result of FeLV may be low. In dogs, Alaskan Husky Encephalopathy (AHE) is a generally fatal neurological disease that manifests in juvenile Alaskan Huskies, and the genomes of affected dogs have been found to contain a mutation in the gene that produces THTR-2, SLC19A3 [99,100]. Dogs with AHE have a novel defect in one of two SLC19A3 paralogs that has been found to lead to poor expression of this gene [19,100]. ...
Recent pet food recalls for insufficient dietary thiamine have highlighted the importance of adequate thiamine intake in dogs and cats, as thiamine is an essential dietary nutrient with a critical role in energy metabolism. Prolonged thiamine deficiency leads to clinical signs that can span several organ systems, and deficiency can be fatal if not reversed. In this review, the current knowledge of thiamine metabolism will be summarized. Dietary recommendations for dogs and cats will be discussed, and the risk factors and clinical signs associated with thiamine deficiency will be examined.
... Gliosis in affected brain regions, which recapitulates human LS pathology, is observed in Alaskan Husky dogs with LS-like encephalopathy (38,39) and in the Ndufs4 KO mouse model of LS (Table) (40Y46). The Ndufs4 KO mouse is an ideal model for determining whether gliosis is a driver or a secondary effect of the disease. ...
Leigh syndrome (LS) is the most common pediatric presentation of a defined mitochondrial disease. This progressive encephalopathy is characterized pathologically by the development of bilateral symmetrical lesions in the brainstem and basal ganglia that show gliosis, vacuolation, capillary proliferation, relative neuronal preservation, and by hyperlacticacidemia in the blood and/or cerebrospinal fluid. Understanding the molecular mechanisms underlying this unique pathology has been challenging, particularly in view of the heterogeneous and not yet fully determined genetic basis of LS. Moreover, animal models that mimic features of LS have only been created relatively recently. Here, we review the pathology of LS and consider what might be the molecular mechanisms underlying its pathogenesis. Data from a wide range of sources, including patient samples, animal models, and studies of hypoxic-ischemic encephalopathy (a condition that shares features with LS), were used to provide insight into the pathogenic mechanisms that may drive lesion development. Based on current data, we suggest that severe ATP depletion, gliosis, hyperlacticacidemia, reactive oxygen species, and potentially excitotoxicity cumulatively contribute to the neuropathogenesis of LS. An intimate understanding of the molecular mechanisms causing LS is required to accelerate the development of LS treatments.
... P olioencephalomyelopathy in dogs with morphologic similarities to subacute necrotizing encephalomyelopathy (SNE), or Leigh's disease in humans, has previously been reported in various pure breeds (1)(2)(3)(4)(5)(6)(7)(8). The pathologic findings of SNE-like diseases in dogs are limited to the central nervous system (CNS). ...
... Microscopic changes are often more widespread and may be found in the basal nuclei, midbrain, pons, and medulla. Multifocal lesions may also be found at the base of the cerebral sulci and in the gray matter of the cerebellum and spinal cord, depending on the breed (1)(2)(3)(4)(5)(6)(7)(8). Here, we report for the first time polioencephalomyelopathy resembling Leigh's disease in a mixed-breed dog. ...
... In the medulla oblongata, lesions were limited to the olivary nucleus with probable early lesions in the reticular formation. In the Alaskan huskies (2,3,7) and Yorkshire terriers (4), the medulla and thalamus were the main areas affected. ...
A 14-month-old mixed-breed dog was presented with acute onset of exercise intolerance that quickly progressed to quadriparesis. Gross and microscopic autopsy findings indicated a type of degenerative polioencephalomyelopathy resembling subacute necrotizing encephalomyelopathy in dogs or Leigh's disease in humans. This syndrome has previously been reported only in purebred dogs.
... Metabolic and nutritional diseases that are described to cause bilateral symmetrical lesions of the brain are osmotic myelinolysis (O'Brien et all., 1994)., hepatic encephalopathy (Torisu et al., 2005) and thiamine deficiency . Subacute necrotizing polioencephalopathy of Alaskan Huskies (Brenner et al., 2000;) or L-2-hydroxyglutaric aciduria in Staffordshire terrier (Abramson et al., 2003) and Yorkshire Terriers (Baiker et all., 2009) are examples of degenerative disorders associated with symmetric lesions of either gray or white matter of the nervous system. Clinical fi ndings, bloodwork and CSF examination were suggestive for a infl amatory CNS disease making meningoencephalomyelitis of autoimmune or infectious origin most important clinical differential diagnosis; however, they tend to have more asymmetric distribution. ...
Tick borne encephalitis virus (TBE) is an endemic infectious agent in northeastern Switzerland causing mainly meningoencephalomyelitis in dogs. We report a canine case of tick born meningoencephalomyelitis resulting in flaccid tetraplegia and, subsequently, fatal respiratory failure. Magnetic resonance imaging (MRI) demonstrated intra-axial bilateral, symmetric, and hyperintense lesions in T2-weighted and Fluid Attenuated Inversion Recovery (FLAIR) sequences affecting thalamus, basal nuclei, cerebral white matter and ventral horns of the caudal cervical spine. These radiological findings overlap those described during flavivirus encephalitis affecting human beings. These lesions in MRI and diffusion weighted images correlated with areas of vasogenic edema detected histopathologically. In endemic regions, clinicians should be aware that bilateral, symmetrical hyperintense thalamic lesions in T2WI can be suggestive of flavivirus infection in dogs with encephalitis.
