NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model.

Two Jack-Russell Terrier × Chihuahua mixed-breed littermates with Leigh syndrome were investigated. The dogs presented with progressive ataxia, dystonia, and increased lactate levels. Brain MRI showed characteristic bilateral symmetrical T2 hyperintense lesions, histologically representing encephalomalacia. Muscle histopathology revealed accumulation of mitochondria. Whole genome sequencing identified a missense variant in a gene associated with human Leigh syndrome, NDUFS7:c.535G > A or p.(Val179Met). The genotypes at the variant co-segregated with the phenotype in the investigated litter as expected for a monogenic autosomal recessive mode of inheritance. We investigated the functional consequences of the missense variant in a Drosophila melanogaster model by expressing recombinant wildtype or mutant canine NDUFS7 in a ubiquitous knockdown model of the fly ortholog ND-20. Neither of the investigated overexpression lines completely rescued the lethality upon knockdown of the endogenous ND-20. However, a partial rescue was found upon overexpression of wildtype NDUFS7, where pupal lethality was moved to later developmental stages, which was not seen upon canine mutant overexpression, thus providing additional evidence for the pathogenicity of the identified variant. Our results show the potential of the fruit fly as a model for canine disease allele validation and establish NDUFS7:p.(Val179Met) as causative variant for the investigated canine Leigh syndrome.

Large felid leucoencephalomyelopathy in a Sumatran tiger (Panthera tigris sumatrae) from an Australian zoo.

CASE REPORT: The clinicopathological features of a case consistent with large felid leucoencephalomyelopathy are described in a 19-year-old, zoo-based Sumatran tiger in which degenerative vertebral disease, renal insufficiency, diaphragmatic hernia and cataracts were comorbid. The principal presenting sign was ataxia, with concurrent deterioration of vertebral stiffness and vision loss. Histological features included marked destruction of the white matter, the formation of large, bizarre astrocytes and accumulation of numerous foamy macrophages (gitter cells). Immunohistochemical investigation of reactive astrocytes revealed several different cytoplasmic proteins. CONCLUSION: This is the first reported case of large felid leucoencephalomyelopathy in Australia.

Severe subacute necrotizing encephalopathy (Leigh-like syndrome) in American Staffordshire bull terrier dogs.

Seventeen American Staffordshire bull terrier puppies, 6-8 weeks of age, from seven closely related litters, presented with rapidly progressive central vestibular neurological signs. Previously reported hereditary ataxias in the breed, including l-2 hydroxyglutaric aciduria and cerebellar cortical degeneration, as well as thiamine deficiency, were excluded. Elevated lactate levels and lactate:pyruvate ratios gave supporting evidence of a defect of the respiratory chain or Leigh-like syndrome. Histopathology in all cases showed a bilaterally symmetrical necrotizing encephalopathy, with malacia of the neuropil centred on the vestibular and olivary nuclei of the brainstem. This is the first documentation of a heritable rapidly progressive lethal necrotizing encephalopathy consistent with Leigh-like syndrome, in American Staffordshire bull terrier dogs.

Leigh-like subacute necrotising encephalopathy in Yorkshire Terriers: neuropathological characterisation, respiratory chain activities and mitochondrial DNA.

Our knowledge of molecular mechanisms underlying mitochondrial disorders in humans has increased considerably during the past two decades. Mitochondrial encephalomyopathies have sporadically been reported in dogs. However, molecular and biochemical data that would lend credence to the suspected mitochondrial origin are largely missing. This study was aimed to characterise a Leigh-like subacute necrotising encephalopathy (SNE) in Yorkshire Terriers and to shed light on its enzymatic and genetic background. The possible resemblance to SNE in Alaskan Huskies and to human Leigh syndrome (LS) was another focus of interest. Eleven terriers with imaging and/or gross evidence of V-shaped, non-contiguous, cyst-like cavitations in the striatum, thalamus and brain stem were included. Neuropathological examinations focussed on muscle, brain pathology and mitochondrial ultrastructure. Further investigations encompassed respiratory-chain activities and the mitochondrial DNA. In contrast to mild non-specific muscle findings, brain pathology featured the stereotypic triad of necrotising grey matter lesions with relative preservation of neurons in the aforementioned regions, multiple cerebral infarcts, and severe patchy Purkinje-cell degeneration in the cerebellar vermis. Two dogs revealed a reduced activity of respiratory-chain-complexes I and IV. Genetic analyses obtained a neutral tRNA-Leu(UUR) A-G-transition only. Neuropathologically, SNE in Yorkshire Terriers is nearly identical to the Alaskan Husky form and very similar to human LS. This study, for the first time, demonstrated that canine SNE can be associated with a combined respiratory chain defect. Mitochondrial tRNA mutations and large genetic rearrangements were excluded as underlying aetiology. Further studies, amongst relevant candidates, should focus on nuclear encoded transcription and translation factors.

Subacute necrotizing encephalopathy in a pig-tailed macaque (Macaca nemestrina) that resembles mitochondrial encephalopathy in humans.

A male pig-tailed macaque (Macaca nemestrina), approximately 5 years old, was found to be vision-impaired and to have profound behavioral abnormalities, including hyperactivity and self-injurious behavior that was not amenable to amelioration by environmental enrichment. Facial and skeletal dysmorphisms also were noted. Magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning revealed areas of possible infarction in the occipital lobes and megaventriculosis. At necropsy, following euthanasia for humane reasons, severe polio- and leukoencephalomalacia accompanied by megaventriculosis were seen in both occipital lobes and in several sulci of the parietal and frontal lobes. Light microscopic findings included loss of neocortical structure, with necrosis, neuronal loss, astrogliosis, vascular proliferation, mild spongiosis, and demyelination. The extent and severity of lesions were most pronounced in the occipital lobes and were greater in the left than in the right hemisphere. Other lesions included mild bilateral atrophy of the optic nerves, thymic involution, necrotizing dermatitis due to trauma, and a spectrum of spermatozoal abnormalities. The imaging and gross and light microscopic changes found in this animal resemble the mitochondrial encephalopathies of humans; this was corroborated by results of immunohistochemical analysis demonstrating decreased expression of enzymes of the mitochondrial oxidative complex ([OC]-I, -III, and -IV) in brain and muscle, and detection of fibrinogen immunoreactivity in neurons and glial cells. The spermatozoal defects may represent yet another aspect of a mitochondrial defect.

A multifocal symmetrical necrotising encephalomyelopathy in Angus calves.

OBJECTIVE: To define a neurological disorder in Angus calves. PROCEDURE: Clinical and pathological examinations were performed on affected Angus calves from a herd experiencing 1% annual mortality from neurological disease. CLINICAL SIGNS: Angus calves developed ataxia, nystagmus, strabismus, muscular tremors, opisthotonus, bruxism, hyperaesthesia, tetanic spasms and episodic convulsions at 2 to 6 weeks of age. Death occurred 4 to 7 days after the onset of clinical signs. GROSS PATHOLOGY: Bilaterally symmetrical, yellow-grey foci were present in the medulla oblongata. HISTOPATHOLOGY: Symmetrical degenerative lesions affected the dorsal vagal motor, lateral cuneate and olivary nuclei in the medulla oblongata and sometimes the spinal cord, substantia nigra and cerebellar peduncles. Malacia was characterised by spongiosis of the neuropile, vascular hyperplasia, infiltration of gitter cells, spheroid formation and delayed degeneration of neurones. CONCLUSION: Angus calves may develop a multifocal symmetrical necrotising encephalomyelopathy.

Multifocal subacute necrotizing encephalomyelopathy in a Simmental calf.

Multifocal subacute necrotizing encephalomyelopathy affects Simmental and Simmental-cross cattle. First clinical signs are ataxia and hind limb paresis. The characteristic gross lesion is bilaterally symmetrical, grey, depressed to cavitated foci involving nuclei in the brainstem. The caudal olivary nucleus is consistently involved. The etiology of the syndrome remains unknown.

Alaskan Husky encephalopathy--a canine neurodegenerative disorder resembling subacute necrotizing encephalomyelopathy (Leigh syndrome).

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 signs in all dogs were of acute onset and included ataxia, seizures, behavioral abnormalities, blindness, facial hypalgesia and difficulties in prehension of food. In animals allowed to survive, the disease was static but with frequent recurrences. Pathological findings were limited to the central nervous system. Grossly visible bilateral and symmetrical cavitated foci were consistently present in the thalamus with variable extension into the caudal brain stem. Microscopic lesions were more widespread and included foci of bilateral and symmetrical degeneration in the basal nuclei, midbrain, pons and medulla, as well as multifocal lesions at the base of sulci in the cerebral cortex and in the gray matter of cerebellar folia in the ventral vermis. Neuronal loss with concomitant neuronal sparing, spongiosis, vascular hypertrophy and hyperplasia, gliosis, cavitation and transient mixed inflammatory infiltration were the main histopathological findings. In addition, a population of reactive gemistocytic astrocytes with prominent cytoplasmic vacuolation was noted in the thalamus. Lesions of this nature in this distribution within the neuroaxis have not been reported in dogs. The neuropathological findings resemble Leigh's disease/subacute necrotizing encephalomyelopathy of man. Neuronal sparing in conjunction with apparently transient astrocytic vacuolation point to the possible pathogenetic role of astrocytes in the evolution of these lesions. An inherited metabolic derangement of unknown nature is postulated as the cause of this breed-specific disorder.

Subacute necrotising encephalopathy in an Alaskan husky.

A 29-month-old female Alaskan husky was presented recumbent, tetraparetic and in a state of dementia, with blindness and cranial nerve deficits. The dog's progress was followed for over two months, as the signs resolved to an non-progressive mild hypermetria with slight proprioceptive ataxia, a diminished menace response and inability to prehend food. Magnetic resonance imaging (MRI) revealed bilateral cavitation extending from the thalamus to the medulla, with less pronounced degenerative lesions in the caudate nucleus, putamen and claustrum. Cerebrospinal fluid lactate and pyruvate concentrations were in their normal ranges. Necropsy and histological examination confirmed the MRI findings as well as neuronal degeneration of the cerebellar cortex in the vermis and degenerative changes in the neocortex at the depths of the cerebral sulci. In view of the similarity of lesions to subacute necrotising encephalomyelopathy, known as Leigh's disease in humans, a tentative diagnosis of a mitochondrial encephalopathy was made.

Hereditary polioencephalomyelopathy of the Australian cattle dog.

A vacuolar degeneration affecting primarily the gray matter in the central nervous system (CNS) of young Australian Cattle Dogs is described. An initial presentation of seizures was followed by a progressive spastic tetraparesis. Grossly evident bilateral and symmetrical foci of malacia were in the nuclei of the cerebellum and brain stem and the gray matter of the spinal cord. Microscopically, vacuolation of glial cells, dilation of the myelin sheaths and reactive astrocytosis characterized mild CNS changes. More advanced lesions displayed progressive dissolution of the neuropil, prominent vacuolation of reactive astrocytes, numerous glial fibrillary acidic protein-positive coiled astrocytic processes, neuronal vacuolation and loss with relative sparing of large neurons. Ultrastructurally marked mitochondrial accumulation and swelling were seen in astrocytes. In the appendicular muscles, changes interpreted as long-term denervation atrophy accompanied by widespread expression of the neonatal isoform of myosin were observed. The character of the neurological sings, the nature and the distribution of the lesions within the neuroaxis have not been reported in domestic animals. An inherited biochemical defect, possibly mitochondrial, is proposed as the cause. Selected conditions with a bilateral and symmetrical distribution affecting the gray matter of domestic animals are summarized.

Multifocal subacute necrotizing encephalomyelopathy in Simmental calves.

In 24 cases of multifocal necrotizing encephalopathy (MNE) in Simmental and Simmental-cross cattle, clinical features varied, consisting of mild rear limb ataxia, caudal paresis, and, less often, sudden death. Bilateral and symmetric malacic lesions were present in the brain stem (olivary nucleus) of all affected calves. Foci of malacia affecting thoracic spinal cord and additional brain stem sites were common. Neuronal cell bodies and hypertrophied capillaries were present within malacic foci. Rarefaction of neuropil, progressing to complete parenchymal loss, characterized advanced lesions. Pathologic features were similar to those of Leigh syndrome in humans, and a similar defect in aerobic metabolism is hypothesized. Occurrence of the syndrome within 1 breed over a wide geographic area suggests that hereditary factors contribute to development of MNE.