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 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 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 http://www.caninegeneticdiseases.net/.
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.|
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."|
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.