Research Topics

Neuronal Ceroid Lipofuscinosis (NCL or Batten Disease)

The Neuronal Ceroid Lipfuscinoses (NCLs), often referred to as Batten disease, are inherited neurodegenerative disorders characterized by progressive loss of brain function. In the vast majority of cases, the first signs appear during childhood. Among these signs are seizures, progressive vision loss culminating in blindness, and loss cognitive function and muscle control. The childhood-onset forms of NCL are invariably fatal, with death occurring from less than 10 years of age to the 20s, depending on which form of the disease a child suffers from. NCL is almost always an autosomal recessively inherited disease. Neither parent of an affected child shows any signs of the disease, but there is a one-in-four chance that any additional children they have will be affected with NCL. There are many variant forms of NCL. Mutations responsible for different forms of this disease have been found to occur in at least 13 different genes.

With the assistance of our laboratory BioMarin Pharmaceutical has developed the first effective therapy for one of the NCL forms (CLN2 disease). We are conducting research to develop alternative treatments for CLN2 disease as well as effective treatments for other forms of NCL. NCLs occur not only in humans, but also in other species including dogs. NCLs have been reported in numerous dog breeds (see below). The mutations responsible for canine NCL have been identified in Dachshunds (two different forms of NCL), English Setters, American Bulldogs, Border Collies, Tibetan Terriers, Australian Shepherds (two different forms of NCL), Chinese Cresteds, Golden Retrievers, Australian Cattle Dogs, and Chihuahuas. We offer DNA tests for most of these mutations. We are interested in evaluating dogs of any breed that are suspected of suffering from NCL. Please contact us if you have a dog that is exhibiting signs consistent with NCL (tremors, visual impairment, cognitive decline, loss of coordination, changes in personality). We are testing gene and enzyme replacement therapies in dogs to evaluate the potential of these approaches for curing the human NCLs.

If you would like to contribute to our efforts to find cures for the NCLs, you can do so through the University donation portal. At that site you will find a “Please select a fund” drop-down menu. If you would like to donate to developing cures for children with NCL please select the “Batten Disease Research” option. If you would like to donate to our efforts toward finding the genetic causes of NCL in dogs, please select the “Canine Disease Research” option. After selecting the fund, please follow the instructions for making your donation. We will acknowledge any donations that are made for these studies.

Mutation Discovery for Inherited Neurological and Eye Diseases in Dogs

Our laboratory conducts research to identify mutations that are responsible for inherited diseases of the nervous system in dogs. Once we identify the disease-causing mutations, we develop DNA tests that we offer to dog owners so that they can determine whether their dogs harbor these mutations. These tests can be used by breeders to select dogs for mating such that the generation of affected puppies can be avoided. Discovery of the mutations responsible for the canine disorders also enables us to determine which human disease the dog disorder corresponds to. Affected dogs can then be used to help us in gaining a better understanding of the mechanisms involved in the disease processes and to test potential therapies for the disorders.

Below is a list of canine neurological disorders for which we have identified the causative mutations.
Disease Dog Breed Gene Containing Disease-Causing Mutation Reference
Neuronal Ceroid Lipfuscinosis Australian Cattle Dog CLN5 Click here
Neuronal Ceroid Lipfuscinosis Chihuahua CLN7 Click here
Neuronal ceroid lipofuscinosis Dachshund CLN1/PPT1 Click here
Neuronal ceroid lipofuscinosis Dachshund CLN2/TPP1 Click here
Neuronal ceroid lipofuscinosis English Setter CLN8 Click here
Neuronal ceroid lipofuscinosis American Bulldog CTSD Click here
Neuronal ceroid lipofuscinosis Golden Retriever CLN5 Click here
Neuronal ceroid lipofuscinosis Australian Shepherd CLN6 Click here
Neuronal ceroid lipofuscinosis Chinese Crested CLN7 (MFSD8) Click here
Neuronal ceroid lipofuscinosis Tibetan Terrier ATP13A2 Click here
Neuronal ceroid lipofuscinosis Australian Shepherd CLN8 Click here
Degenerative myelopathy Boxers, Pembroke Welsh Corgis, Bernese Mountain Dogs, numerous others SOD1 Click here
Bandera's neonatal ataxia Coton de Tulear GRM1 Click here
Primary lens luxation Miniature Bull Terrier, Jack Russell Terrier, Lancashire Heeler ADAMTS17 Click here
Neonatal encephalopathy Standard Poodle ATF2 Click here
GM2 Gangliosidosis Japanese Chin HEXA Click here
Polyneuropathy Black Russian Terrier RAB3GAP1 Click here

For information on requesting DNA tests for these diseases and other canine genetic disorders, please go to

Neurophysiology in Retinal Degenerative Diseases

Figure 1: Fluorescence micrograph of the RPE from an old albino rat showing the substantial accumu-lation of lipofuscin, which emits a golden-yellow light when stimulated with blue light excitation. All of the yellow color is due to lipofuscin fluorescence.
A leading cause of serious visual impairment among the elderly is a disorder known as age-related macular degeneration (ARMD). The NDRL has conducted research to identify the cellular and molecular mechanisms that might underlie ARMD so that we might develop rational approaches to treatment and prevention. The primary risk factor for ARMD is, as the name implies, aging. We have therefore investigated normal age-related changes in retinal tissues that might contribute to the development of ARMD. A single layer of cells at the back the eye called the retinal pigment epithelium (RPE) performs a number of functions that are critical to maintaining the survival and function of retinal photoreceptor cells that convert light input into neurological signals. Age-related changes in the RPE may underlie the degeneration of photoreceptor cells that occurs in ARMD. We have therefore conducted studies to characterize age-related changes in the RPE. One of the most pronounced of these changes is the accumulation of autofluorescent lysosomal storage material (see the fluorescence micrograph below). The accumulation of this material, known as lipofuscin, may interfere with important RPE functions. We have found that lipofuscin is formed by chemical reactions between components of the photoreceptor cells, particularly derivatives of vitamin A. We have also found that impaired protection against nonenzymatic oxidation reactions promotes RPE lipofuscin accumulation. If we can develop methods to prevent these deleterious chemical reactions, we may be able to prevent the development of ARMD.

Understanding Neurodegeneration in Canine Degenerative Myelopathy (DM) and Human Amyotrophic lateral sclerosis (ALS)

In collaboration with Dr. Joan Coates, the NDRL is conducting research on amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease. ALS is an adult-onset disorder that involves degeneration of the portions of the nervous system involved in muscle control. People who suffer from ALS undergo a progressive loss of muscle function because of degenerative changes in the nerves that control the muscles and in the muscles themselves.
In the early stages of DM dogs exhibit severe impairment of hind limb function, but can still move about with the assistance of "wheel chairs."
This loss of muscle function eventually leads to paralysis and is ultimately fatal when the muscles involved in swallowing and breathing no longer function. There are currently no effective treatments for ALS. Some forms of ALS are caused by mutations in a gene known as SOD1, which directs synthesis of the enzyme superoxide dismutase. In people that have SOD1 mutations, large amounts of the superoxide dismutase protein accumulate in nerve cells involved in muscle control. This abnormal protein accumulation is accompanied by impaired ability of the nerves to communicate with muscles. An inherited disease very similar to ALS occurs in many dog breeds. The canine disease is called degenerative myelopathy (DM). Like some forms of ALS, we discovered that DM results from mutations in the SOD1 gene accompanied by accumulation of aggregates of superoxide dismutase protein in nerve cells of the spinal cord. We believe that by studying the mechanisms that underlie the disease pathology in DM, we can gain insight into the reasons people with ALS lose muscle function. This will aide in the development of rational approaches for treating ALS.

Our studies on DM require the analysis of nerve and muscle tissues from dogs that are euthanized as a result of the disease. We also analyze the same tissues from unaffected dogs that have been euthanized for other reasons. Our current focus is on Boxers and Pembroke Welsh Corgis, breeds in which the disease is fairly common. If you own a dog from one of these breeds that is older than 8 years and is going to be euthanized as a result of DM or for some other reason and you are willing to donate tissue samples, please contact Dr. Coates.