Leigh-like subacute necrotising encephalopathy in Yorkshire Terriers: neuropathological characterisation, respiratory chain activities and mitochondrial DNA
Alaskan Husky encephalopathy – a canine neurodegenerative disorder resembling subacute necrotizing encephalomyelopathy (Leigh syndrome)
Subacute necrotising encephalopathy in an Alaskan husky
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UC Davis Multicenter Collaborative Study
In February 2008, we formed a multicenter, collaborative study group of clinical researchers to study a brain disease in Alaskan Huskies called “Alaskan Husky Encephalopathy” (AHE), from the University of Alaska Fairbanks, Sick Children’s Hospital, University of California San Diego and the University of California Davis.
The purpose of this study is to determine if there is a novel genetic mutation in dogs with Alaskan Husky Encephalopathy, by testing the DNA of affected dogs and normal siblings by a procedure called a “whole genome scan”. This may lead to a more complete understanding of the disease, potentially the development of a genetic test to diagnosis AHE, and reduce propagation of the disease.
For this study, dogs suspected of having AHE are transported to the UC Davis Veterinary Medical Teaching Hospital (VMTH) (usually from racing sled dog kennels), where they are examined, have an MRI of their brain, are spayed or neutered, and then placed into new homes. Once settled in their new homes, these dogs are examined on a regular basis, and have follow up MRIs done on their brain.
Alaskan Husky Encephalopathy (AHE) is reported as a fatal disease, reported in 13 Alaskan Huskies from different regions in the northern United States. The disease affects both male and female dogs; multiple dogs from the same litter are often, but not always, affected. Most affected Alaskan Husky dogs are juvenile (range 6 months to 6 years of age), racing sled dogs. A similar disease is reported in 11 European Yorkshire terriers.
Affected dogs may have a sudden onset of signs, but some dogs may have a chronic history. Clinical signs usually reflected disease in multiple parts of the brain, such as seizures, trouble walking, high stepping gait, and trouble eating. No abnormalites were found on extensive blood tests or cerebrospinal fluid analysis. Two affected dogs had either a computed tomography (CT) or magnetic resonance (MR) of the brain. On the MR images of one dog, there were bilateral lesions in the brainstem, (from the thalamus to the medulla, as well as bilateral lesions in the putamen, caudate nucleus and claustrum). All affected dogs died or were euthanized, most within 6 months of onset of clinical signs; one dog lived for 1 year after onset of clinical signs when it died of “natural causes”.
On necropsy, there were bilateral, symmetrical, cavitated lesions in the brainstem. Affected areas included multifocal lesions in the base of sulci of the cerebral cortex, gray matter of the cerebellar folia, the ventral cerebellar vermis, basal nuclei, and brainstem and cervical spinal cord. Pathologically, these lesions were described as “subacute, necrotizing encephalomyelopathy”, and the disease was called AHE.
Leigh Syndrome in People
Alaskan Husky encephalopathy resembles Leigh syndrome (LS) in people. People with LS have characteristic MRI and pathology findings, consisting of focal, bilaterally symmetrical lesions in one or more areas of the brain (thalamus, basal ganglia, cerebellum, brainstem) and spinal cord. (Figure 1) These findings are very similar to the MRI and pathology findings in Alaskan Huskies with AHE.
Clinically, people with LS have heterogenous clinical signs that range from severe neurological abnormalities, to no neurological abnormalities (but have other problems such as renal failure and diabetes). Usually people are affected in early childhood, but adults may also be affected. Leigh syndrome is caused by mitochondrial disease, and is the clinical manifestation of a defect in mitochondrial energy metabolism, caused by a number of biochemical deficiencies, such as pyruvate dehydrogenase complex deficiency and mitochondrial respiratory chain complex deficiency. Genetic mutations causing LS are heterogenous, and are caused by both mitochondrial DNA mutations (e.g.T8993G) and nuclear DNA mutations (e.g. affecting enzymes such as cytochrome c oxidase). However, in 20-50% of people with LS, a molecular diagnosis is not made, likely because many of the nuclear DNA proteins for mitochondrial function have not yet been identified.
Figure 1. Axial T2-weighted magnetic resonance images of 8-month-old girl with Leigh syndrome show hyperintense lesions in substantia nigra and medial thalamic nuclei (A, B). Follow-up images at age 26 months (C) indicate hyperintense putamina and hyperintense left caudate nucleus (Farina et al. MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations. AJNR 2002;23:1095-100.)
Multicenter Collaborative Study Results
Since February 2008, we have examined six dogs with AHE at the UC Davis VMTH. All dogs were juvenile dogs, between 6-12 months of age. All dogs had similar clinical signs to the previously reported Alaskan huskies, such as seizures, unsteady or high stepping gait, trouble walking, central blindness, difficulty eating and altered mentation. The 6 dogs were related, and represented 4 litters (2 brother and sister pairs).
A 1 year old female Alaskan Husky with AHE. She has an unsteady and
high stepping gait. She also has a problems with her vision.
MRI of the brain was abnormal and remarkably similar in 6 dogs, with symmetrical, multifocal lesions in the subcortical gray matter, thalamus, caudate nucleus, claustrum, putamen, midbrain, cerebellar vermis and brainstem (Figure 2).
Figure 2a. MR images (T2 weighted, transverse) from the brain of an Alaskan Husky with neuropathologically confirmed AHE. There are multifocal regions of abnormal hyperintensity in the brain, which are bilateral and symmetrical (arrows).
Figure 2 b and c. MRI images in a movie format (FLAIR image) from b a normal Alaskan Husky and c an Alaskan Husky with AHE. Note the bilateral and symmetrical hyperintense (white) lesions throughout the brain in c.In two dogs, there were changes in the muscle and liver on electron microscopy, compared to a clinically normal, aged matched control Alaskan Husky. The muscle from these affected dogs had very large mitochondria, called “megamitochondria” (Figure 3).
Figure 3: Electron micrograph of the vastus lateralis muscle from a dog
with AHE. Note the large mitochondria, delineated by the white bar.
Three dogs were placed into homes for long-term follow up. Two dogs are alive with static neurological deficits 1.5 and 2.5 years after diagnosis. One dog had static neurological deficits for 4 months, but then developed progressive clinical signs over 2 months and was euthanized.
To date, 4/6 dogs were humanely euthanized and submitted for a full necropsy. On gross pathology, bilaterally symmetrical areas of cavitation were noted within the thalamus (Figure 4). Microscopically, lesions were widespread, and included foci of bilaterally symmetrical degeneration and encephalomalacia in the basal nuclei, thalamus, and brainstem (pons and medulla). In addition, there were extensive multifocal lesions noted within the subcortical gray matter of the cerebral cortex confined to the base of sulci and symmetrical lesions within the gray matter of cerebellar folia in the ventral vermis. The clinical, neuroradiological and neuropathological findings were almost identical to those of previous reports of AHE in dogs.
Figure 4. Transverse section of the brain of an Alaskan Husky with AHE.
Note the bilaterally symmetrical areas of cavitation in the thalamus (arrow).
Summary and Conclusions
Despite extensive testing enzymatic assays and candidate gene sequencing, we have no evidence to support a systemic defect within the TCA cycle, pyruvate dehydrogenase complex, or respiratory chain enzymes as the cause of AHE, suggesting the disease is unlike any known cause of LS. However, mitochondrial involvement is still suspected in AHE, given the abnormal morphology of the mitochondria on electron microscopy, and the similarity of the neuroimaging and neuropathology to that in people with Leigh syndrome.
Significance to Companion Animal Health
The Alaskan Husky represents a population of dogs of Northern breed ancestry originally developed as a working dog providing the primary means of human transportation in Arctic climates. The late 1930’s saw the establishment of the sport of sled dog racing when modern modes of transportation made the necessity of sled dog transport obsolete. While sled dog racing is commonly associated with Alaska due to the climate and culture, Alaskan Huskies are widely spread across the United States, Canada, Europe, Asia and even in Australia. They are used in competitive racing on both snow and dry ground, by outdoor enthusiasts in touring, and also by hobbyist sled dog mushers.
The Alaskan Husky has gained popularity and territory over the years with the expansion of the sporting events recognized by international sanctioning groups such as the International Sled Dog Racing Association and the International Federation of Sled Dog Sports. They are no longer restricted to northern climates, and there are an increasing number of these dogs placed in pet homes and shelters. A new breed or breeds may someday originate from founder animals.
All of the previously reported dogs with AHE were euthanized or died. Both mushers and pet owners of affected Alaskan Huskies risk suffering emotional and financial loss of dogs with AHE. Mushers, whether sporting or touring, run the added threat of the loss of integral canine members of their teams that would impact their performance and cause a loss of kennel reputation and possible further financial repercussions.
A similar disorder is described in Yorkshire Terriers3 (subacute necrotizing encephalopathy), and it is possible that if there is a genetic mutation associated with AHE, it may be identical in Yorkshire Terriers and Alaskan Huskies. In addition, the similarity of AHE to LS in humans suggests that further investigation of AHE may lead to the development of a canine biomedical animal model for elucidating LS in people. LS affects 1:5000-1:10,000 people in the United States, and 20-50% of people never have a underlying genetic defect identified. It is hoped that further characterization of AHE will lead to determination of the specific defect, and ultimately, testing that will facilitate diagnosis and eradication of this devastating disease in Alaskan Huskies.
HOW CAN YOU HELP?
Please contact Karen Vernau at firstname.lastname@example.org or 530-304-9450 if you have an Alaskan husky that may be affected with AHE.
Link to Sled Dog Central www.sleddogcentral.com