Canine Neuronal Ceroid-lipofuscinosis Research Articles

Neuronal ceroid lipofuscinosis in a German Shorthaired Pointer associated with a previously reported CLN8 nonsense variant

Two littermate German Shorthaired Pointers, a male and a female, were adopted as puppies from an animal shelter. Both puppies developed normally until approximately 11 months of age when the male began to exhibit neurological signs including ataxia, vision loss, and behavioral changes indicative of cognitive decline. These signs increased in severity over time. The female remained neurologically normal and healthy. The affected dog was euthanized at approximately 21 months of age. Autofluorescent cytoplasmic storage bodies were detected in neurons in unstained tissue sections from the cerebellum, the cerebrum, and the retina. Electron micrographs of these storage bodies showed that they were membrane bound and that most contained tightly packed aggregates of membranous whorls along with a variety of other ultrastructural features. This ultrastructure, along with the autofluorescence and the clinical signs supported a diagnosis of neuronal ceroid lipofuscinosis (NCL). Unlike earlier investigated forms of canine NCL with causal alleles in ATP13A2, TPP1, MFSD8 and CLN5 that had autofluorescent cytoplasmic storage bodies in cardiac muscle, no autofluorescence was detected in cardiac muscle from the affected German Shorthaired Pointer. A 39-fold average coverage whole genome sequence indicated that the affected German Shorthaired Pointer was homozygous for the A allele of a G > A transversion at position 30,895,648 chromosome 37. This 37:30895648G > A mutation created a CLN8 termination codon that had been previously reported to cause NCL in a mixed breed dog with Australian Shepherd and Australian Cattle Dog ancestry. This nonsense allele was heterozygous in the clinically normal female sibling, while archived DNA samples from 512 other German Shorthaired Pointers were all homozygous for the reference allele. The affected German Shorthaired Pointer and the previously diagnosed mixed breed dog with the same nonsense mutation shaired an identical homozygous haplotype that extended for 4.41 Mb at the telomeric end of chromosome 37, indicating the both dogs inherited the nonsense mutation from a common ancestor.

Neuronal Ceroid-Lipofuscinosis in Longhaired Chihuahuas: Clinical, Pathologic, and MRI Findings

Neuronal ceroid-lipofuscinosis (NCL) is a rare group of inherited neurodegenerative lysosomal storage diseases characterized histopathologically by the abnormal accumulation of ceroid- or lipofuscin-like lipopigments in neurons and other cells throughout the body. The present article describes the clinical, pathologic, and magnetic resonance imaging (MRI) findings of the NCL in three longhaired Chihuahuas between 16 mo and 24 mo of age. Clinical signs, including visual defects and behavioral abnormalities, started between 16 mo and 18 mo of age. Cranial MRI findings in all the dogs were characterized by diffuse severe dilation of the cerebral sulci, dilated fissures of diencephalons, midbrain, and cerebellum, and lateral ventricular enlargement, suggesting atrophy of the forebrain. As the most unusual feature, diffuse meningeal thickening was observed over the entire cerebrum, which was strongly enhanced on contrast T1-weighted images. The dogs' conditions progressed until they each died subsequent to continued neurologic deterioration between 23 mo and 24 mo of age. Histopathologically, there was severe to moderate neuronal cell loss with diffuse astrogliosis throughout the brain. The remaining neuronal cells showed intracytoplasmic accumulation of pale to slightly yellow lipopigments mimicking ceroid or lipofuscin. The thickened meninges consisted of the proliferation of connective tissues with abundant collagen fibers and mild infiltration of inflammatory cells suggesting neuroimmune hyperactivity. Although the etiology of this neuroimmune hyperactivity is not currently known, MRI findings such as meningeal thickening may be a useful diagnostic marker of this variant form of canine NCL.

Magnetic Resonance Imaging of Neuronal Ceroid Lipofuscinosis in a Border Collie

A castrated male border collie 23 months of age weighing 19.4 kg was referred to the Animal Medical Center of Nihon University with complaints of visual disturbance and behavioral abnormality, hyperacusis and morbid fear. The MRI examination revealed the slight dilated cerebral sulci and cerebellar fissures and left ventricular enlargement. This is the first report of MRI findings of canine neuronal ceroid lipofuscinosis.

Decline in glucose metabolism in the brain in neuronal ceroid lipofuscinosis (NCL) in English setter--evidence by positron emission tomography (PET).

Positron emission tomography scans were performed on brains of homozygous and heterozygous English setters with neuronal ceroid-lipofuscinosis (NCL) from 13 months of age to 24-25 months of age for homozygous dogs and to 38 months for heterozygous dogs, respectively. After iv injection of 18F-fluorodeoxyglucose (FDG), 7 coronal brain scans as well as sequential arterial blood samplings were performed for 45 min under pentobarbital anesthesia. From these data, three different functional images (DAR (standardized uptake value), FDG uptake (fractional uptake) and glucose uptake) were reconstructed and quantitatively analysed. In the age range from 13 to 15 months, glucose images were comparable for both homozygous and heterozygous dogs, so that no differentiation was possible between healthy and diseased dogs on the basis of PET findings. Between 18 and 24 months of age, a drastic decline in glucose metabolism was observed in homozygous dogs, while the decline in glucose utilization was very mild in this period for heterozygous dogs. Furthermore, in PET scans, cerebral atrophy and ventricular enlargement were clearly shown in homozygous dogs. Consequently at the age from 20 to 24 months, a clear differential diagnosis between healthy (heterozygous) and diseased (homozygous) dogs became possible even if the clinical symptoms were still not clear in the latter. We conclude that the biochemical alterations in the brain in canine NCL occurs and progresses very rapidly in the last quarter of their lives.

Retina in various animal models of neuronal ceroid-lipofuscinosis.

The childhood forms of human neuronal ceroid-lipofuscinosis (NCL) are invariably associated with a severe progressive retinopathy which commences at the photoreceptor level morphologically and proceeds to a final loss of neuronal cells accompanied by severe gliosis. In respective spontaneous animal conditions of NCL, in English setters, Dalmatian dogs, and New Zealand sheep, retinal involvement is not commensurate although the retina does not seem to be completely unaffected. In canine NCL, there might be functional and electro-physiological impairment of retinal cells, but retinal atrophy is not obvious. In ovine NCL, the retina, apart from accumulating NCL-specific lipopigments within neuronal perikarya, also shows loss of photoreceptors. Conversely, retinal pigment epithelial cells (RPE) in canine and ovine NCL contain peculiar lamellar inclusions, not seen in unaffected animals, possibly an indication of a disturbed phagocytic process of photoreceptor outer segments. Similar such lamellar inclusions have not been observed in RPE cells in human childhood NCL.

An ultrastructural study on retinal neural and pigment epithelial cells in ovine neuronal ceroid-lipofuscinosis

Ovine neuronal ceroid-lipofuscinosis represents another well studied model for human neuronal ceroid-lipofuscinosis (NCL). Accumulation of abnormal lipopigments in various retinal neurons, and loss of photoreceptors are similar to the lesions in human juvenile NCL and indicate that the sheep is a suitable model in which to study the pathogenesis of both NCL lipopigment formation and retinopathia pigmentosa. However, this latter process is not as advanced in NCL-diseased sheep as in human patients but far more obvious than in canine NCL in which retinopathy cannot be unequivocally documented. Ovine NCL shares with canine NCL peculiar lamellar inclusions in retinal pigment epithelial cells which may indicate an impaired catabolism of phagocytosed photoreceptor outer segments. As the peculiar lamellar inclusions seen in RPE cells of both NCL-diseased sheep and dogs do not very much resemble the phagocytosed photoreceptor outer segments, it may be assumed that in NCL the final steps in complete removal of these phagocytosed photoreceptor outer segments are also defective.

Ultrastructure of the Retina in Canine Neuronal Ceroid Lipofuscinosis

Electron microscopic studies on the retinae of 3 English setters, homozygous for the trait of canine neuronal ceroid lipofuscinosis (NCL), revealed preservation of photoreceptors early and late in the