Stuart F. Eckmann1; Martin L. Katz, PhD2
Several years ago, in a review of the Tibetan Terrier data from the Canine Eye Registration Foundation (CERF), the Tibetan Terrier Club of America (TTCA) Health Committee noticed two separate and distinct ages of diagnosis for the condition called Progressive Retinal Atrophy (PRA). The first incidence occurred between the ages of 3 to 5, and the second incidence was first noted after age 6. Tibetan Terriers in the early-onset CERF group had retinal changes on ophthalmic examination, often followed by observable changes in vision. Tibetan Terriers in the late-onset CERF group also displayed deterioration in vision, but this was only one among a variety of symptoms and pathologic changes. The clinical and pathological evidence we have since accumulated suggests that, regardless of age of onset, the early onset disorder affecting only vision, and the later onset disease with multiple other symptoms besides vision loss are two very different genetic conditions.
Much of the confusion stems from the fact that both of these conditions are usually first diagnosed on ophthalmic examination, and the deterioration in vision had been assumed to be due to similar retinal changes. The deterioration in vision reported by the ophthalmologist, though, could result from a variety of causes. It could be caused by environmental factors, it could be a visible, or phenotypic, change which could be attributed to more than one genetic condition, or it could be due to central (neural) deterioration.
The late-onset condition has now been classified as Canine Ceroid Lipofuscinosis (CCL). It has also been referred to as Neuronal Ceroid Lipofuscinosis (NCL), and it appears to be very similar to the human condition known as Batten Disease. Regardless of what it is called, it is a multi-systemic storage disease thought to be caused by an inborn error of metabolism. This metabolic error results in the accumulation of storage bodies within many types of cells throughout the body, including cells in the retina and brain. These storage bodies can affect the ability of the cells to function and can sometimes result in their destruction, or lysis. CCL in Tibetan Terriers has been characterized by manifestation of at least some of the following symptoms and diagnostic observations:
Changes in dark adaptation;
Decrease in or loss of vision, particularly in dim light;
Ataxia, a loss of normal muscular coordination and movement, often associated with an irregular gait, loss of balance, and a roaching of the back;
Changes in appetite and eating habits;
A progressive Alzheimer's-like dementia, which can include difficulty adapting to changes in environment, confusion, aggressive behavior (often reported during routine grooming), and eventually even failure to recognize the owner;
Seizures in the advanced stages of the disease;
Magnetic Resonance Imaging (MRI) changes, including an overall shrinking of the brain and an increase in the size of the anterior ventricles; and
Accumulation of storage bodies within the brain, retina, and other tissues, observable with fluorescence and electron microscopy.
This is clearly more than just retinal atrophy; it is a multi-systemic condition. Diagnosis of CCL, though, is not so clear cut. Many of these progressive changes develop so slowly that breeders and particularly pet owners often ascribe them to aging rather than any specific condition. Also, not all of the changes will necessarily be present. In fact, dogs with CCL usually do not present with retinal degeneration on ophthalmic examination. One probable explanation for apparent visual deficits is that affected dogs cannot properly process them due to disease-related pathology in the visual cortex. And while changes in the electroretinogram have been observed in a research setting, this abnormality would not be detected with the typical screening ERG that is most commonly used in clinics to assess retinal function. The equipment and staff needed for a technical ERG are usually found at veterinary schools and a small number of practices with state-of-the art equipment.
Even MRI evaluation can be difficult. CCL is not a focal lesion, i.e., a discrete mass like a tumor which the neurologist or radiologist can point out. The shrinkage observed with CCL also occurs with a number of other conditions, including aging, and may not be recognized unless compared to the MRI results obtained on a healthy Tibetan Terrier of the same age. The MRI is just one of many tools used in the differential diagnosis of CCL-an image used, in combination with other tests, to differentiate CCL from other conditions.
The conundrum is that fluorescence microscopy and EM (electron microscopy) confirmation of inclusions in neural and retinal tissue is currently the most definitive diagnostic tool for CCL in Tibetan Terriers but is typically only available on necropsy. The other dilemma is that by the time we are able to put enough diagnostic pieces together to definitively call this CCL in any specific Tibetan Terrier many of those affected have had several generations of offspring.
Here's what we have been doing to address this problem. We started by challenging truisms or "sacred cows"-first by asking the question "When is PRA not PRA?," and then by recognizing that the PRA label put on a dog by an ophthalmologist can be a morphological or phenotypic diagnosis-a blanket term for more than one genetic condition. Then we went back and reevaluated pedigrees marked with PRA.
Those with an early diagnosis of retinal degeneration which progressed without other non-ophthalmic symptoms were considered to be PRA. Those with later onset visual perception problems, in conjunction with some of the other symptoms, were considered suspect for CCL. With time and greater understanding of the condition, we have also considered dogs with several of the diagnostic criteria for CCL, even without visual changes, to be suspect for CCL.
We have also been trying to get the word out to veterinary ophthalmologists that not all retinal degenerations are genetic PRA. Julie Gionfriddo, DVM, MS, DACVO, in her former capacity as the American College of Veterinary Ophthalmology/CERF Liaison, published an article on the CERF website http://www.vmdb.org/jan00.html#dxspotlight on Neuronal Ceroid Lipofuscinosis.
In Dr. Gionfriddo's article, she says that CCL-or NCL, as she refers to it-"may initially mimic progressive retinal atrophy (PRA)." She says that in this condition changes in the Tibetan Terrier retina "look identical to the changes similar to those noted in dogs with PRA." She concludes that "it is thus easy to mistake this disease for PRA until other neurologic symptoms manifest themselves." However, Dr. Kristina Narfstrom has since found that at least some Tibetan Terriers with CCL have normal appearing fundi, despite visual impairment. This indicates funduscopy is not a reliable means of diagnosing CCL.
Another thing we have done is to promote annual ophthalmology examinations and CERF registration. Both age of onset and the presence or absence of retinal degeneration are helpful in the differential diagnosis between PRA and CCL. Still another thing we have done is to try to accumulate as much clinical, pathological, and behavioral information as possible. We have worked with primary care veterinarians, ophthalmologists, neurologists, and pathologists throughout the United States and Canada to better define CCL in the Tibetan Terrier, with the hope that it will lead to an earlier and more definitive diagnosis. Information provided over time has identified that this is not a line problem but a condition that affects the entire breed.
As breeders and pet owners have shared this information with us, we've not only defined CCL better but have also been able to fill in pedigrees with likely affected and possible suspects and carriers. This information was instrumental in obtaining as many family members as possible, from as many generations as possible, to look for a DNA marker for CCL in Tibetan Terriers.
The Tibetan Terrier DNA Bank and Registry was developed to archive enough families to be able to find markers for the genetic conditions affecting the breed. MLK is now using samples from our DNA Bank to look for a genetic marker for CCL in Tibetan Terriers. As a collaborator on this study, SFE has shared with MLK the progressive behavior changes reported by owners of CCL-affected Tibetan Terriers. Working together, we developed a profile of these changes and a questionnaire for owners to complete.
Besides looking at these behavior changes and for a genetic marker, MLK has also conducted morphologic and biochemical studies of the tissue of a number of Tibetan Terriers who have died from CCL. He recently identified a component of the storage material in the inclusions that appears to be unique for CCL in Tibetan Terriers. Identification of this compound may become the basis for developing a definitive diagnostic test.
Once we do find a DNA marker, we will be able to go back to archived DNA in our DNA Bank-even if the dog is no longer alive-to test for CCL. Tibetan Terriers are a small breed with a multinational breeding program. The breed is working together with the University of Missouri to accelerate the process of finding a genetic marker, earlier diagnosis, and possible treatment for CCL.