This section on Cerebellar Abiotrophy provides a basic knowledge base one need to know about this genetic disease. This documents will cover:
a description of the disease and how it is clinically diagnosed
the scientific details concerning the mode of inheritance. Understanding how genetic diseases are inherited is clearly a key factor in learning how to control the disease.
One of the proposed means for controlling the spread of any genetic disease is a technique called Relative Risk Pedigree Analysis, and this approach is described in the third document.
An on-line version of the Relative Risk Analysis Calculator is available to help users perform their own risk calculations. Links to the Risk Calculator are available in the Relative Risk Analysis article.
a list of reference documents
Familiarity with these introductory documents is critical to a full understanding of the value and purpose of the fourth document.
Disclaimer: ScottiePhile provides resources for informational purposes. The materials contained here are not intended to be used for the diagnosis or treatment of health problems or as a substitute for consulting a veterinarian.
Autosomal Recessive Disorders
Autosomal Recessive Inheritance
Many canine health issues can be attributed to a genetic condition or disease that is inherited from the parents. Genes, or unique sequences of DNA material, are the way that these genetic conditions are passed from parent to offspring.
The canine species has a total of 78 chromosomes and all dogs, regardless of the breed, have similar chromosomes. Chromosomes are large enough that they can actually be observed under a microscope. We also know now that every cell in a dog contains a copy of the same 78 chromosomes and that they are organized within a cell as 39 pairs. Figure 1 below is an illustration of these chromosome pairs. Note that the chromosomes are labeled 1 to 38 and the last one is labeled as the X-Y chromosome pair.
Figure 1. Canine Chromosomes (39 pairs)
Genes are specific sequences of DNA material that actually control the characteristics of living beings. These genes are carried at specific locations on each chromosome. Each chromosome contains hundreds (or thousands) of gene sequences that actually control inheritance. In order to work, the DNA material on each chromosome pair must come together and create a complete gene. This means that every gene receives half of the DNA material from the sire and the other half from the dam.
Some inherited traits are simple traits. These traits are controlled by a single gene that is ultimately located on a single chromosome pair. As mentioned above, this means that one gene (with half of its DNA material coming from the sire and the other half from the dam) controls the trait.Other inherited traits can be polygenic. This means that more than one pair of genes control the inherited trait.
Conditions that are controlled by a single gene fall into one of four inheritance patterns. Through scientific observation it can be determined if the inheritance is a) autosomal recessive, b) autosomal dominant, c) X-linked dominant or d) X-linked recessive. Note that the term “X linked trait” (both dominant and recessive modes) is used to refer to a condition that is linked to a gene found on the X chromosome. All other single gene traits are collectively referred to as “autosomal” or non-sex linked.
If scientific observation shows that a genetic condition follows an autosomal recessive inheritance pattern, this determination implies that the manifestation of the condition is controlled by the presence of one recessive gene pair. For a dog to be affected with the trait (e.g. actually express the condition) both chromosomes must carry the same recessive gene. Conversely, if either parent passes on a dominant copy of the gene, then the dog will not display the condition (but the dog may still be a carrier of the condition).
Not all autosomal recessive conditions are necessarily bad. Some may actually be desirable.& Therefore it would be incorrect to label all recessive gene as “defective.”
The following table shows all of the genetic possibilities for inheritance of a simple autosomal recessive condition. The genetic possibilities are 1) BB, 2) Bb or bB and 3) bb. These representations follow a standard format where the large B stands for the dominant gene; while the small b represents the recessive gene. The only dogs that will display the autosomal recessive condition are the third group, because these dogs have a copy of the recessive gene on both chromosomes. The dogs with Bb or bB will actually be normal in phenotype but can produce the recessive trait if they are bred to another dog that carries the recessive gene. Dogs that have a little b gene on either chromosome are called carriers because they don’t actually exhibit the genetic condition, but they are capable of producing it in their offspring.
Table 1. Inheritance of Autosomal Recessive Genes.
Notice that Table 1 does not label either parent as the Sire or the Dam because autosomal characteristics are not dependent upon the sex of either parent. The only factor is whether or not each parent is either an actual affected dog or a non-affected, carrier of the recessive gene.
Another way to describe this inheritance pattern is to use several color coded simple inheritance charts as illustrated in Figure 2. This figure uses Green, Yellow and Red Scotties to depict the genetic characteristic of each Scottie.
Green -- Clear These dogs are not affected with the specific recessive condition. Clear dogs have two copies of the dominant gene and they are incapable of producing an offspring that is affected. This type of genetic expression is referred to as Clear -- not carrying the gene and not capable of producing the recessive trait.
Yellow -- Carrier These dogs are not affected with the recessive condition either. They have the same outward health characteristics of a Clear dog. However, if we were able to inspect their chromosomes, we would discover that one chromosome contains a copy of the recessive gene. These dogs are therefore referred to as Carriers, because they carry this one copy of the recessive gene. As a result, these dogs are capable of producing the condition if mated with another Scottie that contributes a second copy of the recessive gene.
Red -- Affected These dogs exhibit the recessive characteristic. Whether by observation, clinical diagnosis, lab test or some other means, these Scottie has been identified as Affected. Both chromosomes in an affected dog carry the recessive gene, so these dogs will always pass on a copy of this gene to their offspring.
Simple autosomal recessive genetic conditions are inherited only from parents that were themselves affected by the condition or were a carrier for the recessive gene. Both affected and carrier parents can pass the recessive gene on to their offspring
Both parents of an affected animal are "obligate" carriers of the recessive gene.
Breeding carriers will not always produce an affected offspring.
Clear bred to Clear will only produce Clear offspring.
The next step:
Understanding options that are available to limit the spread of CA through Relative Risk Pedigree analysis. [Click here]
Cerebellar Abiotrophy Reference Listings
Important Letters of Introduction
Letter 1; STCA President, Karen Hansen, announces new STCA Health Committee
Letter 2; STCA Health Committee announces plans for Grand Central
Letter 3; Dr. Bell speaks to Scottie Owners and Breeders
Letter 4; Dr. Olby speaks to Scottie Owners and Breeders
Ataxia in Scotties: Wobbly Dogs; is an article by Carole Fry Owen that introduces Murphy, a Scottie pup that goes through the lengthy process of trying to determine the origin of his progressive difficulties with movement.
Scottie Cramp or CA; by Debbie Smith, Murphy's owner, picks up his story and describes his diagnosis, Cerebellar Abiotrophy, which explains why he can no longer walk.
Cerebellar Abiotrophy, It ain't cramp!; by Monica Madore and Linda St James who joined together to write this article stressing the need for responsible breeders to take action to help control this new disease.
CA Diagnosis (free of charge) and Pedigree Analysis (for fee), contact:
Freshwater Veterinary Hospital
151 Hazard Ave.
Enfield, CT 06082-4584
STCA CA Counselor
CA Necropsy, for information, contact:
Department of Clinical Sciences, Rm C-312
College of Veterinary Medicine
4700 Hillsborough Street
Raleigh, NC 27606
CA Research DNA Collection Program:
Dr. Bell, Dr. Olby, and Dr. Olby's assistant, Pragna Mehta will contact owners directly. DNA Samples from specific relatives of CA affected Scotties are required for research projects. However specific sample preparation and shipping protocols must be followed. Owners should not send blood samples unless they have been requested to do so and have been given specific instructions. If you own an affected dog, contact your breeder and anyone else with a close relative to see if they would be willing to send blood samples if requested. Typical dogs required for the DNA collection program include: the CA affected dog, their siblings, parents, grandparents and siblings to the parents and grandparents. Dr. Olby may choose to limit the number of samples because of the costs associated with DNA extraction and storage.
Cerebellar Abiotrophy: Its Cause and Diagnosis
by Jerold S Bell DVM, Tufts University School of Veterinary Medicine
This article originally appeared in the Bagpiper, 2004 #3.
To understand the diagnosis of cerebellar abiotrophy (CA) in the Scottish Terrier, you must understand the condition. CA causes a progressive loss of muscular coordination. It is not a painful condition, does not cause muscular weakness, and does not effect the mind of the dog. CA is a simple autosomal recessive genetic disorder. This means that for a dog to be affected, both parents have to be a carrier of the defective gene. Carriers do not show signs of the condition, and do not differ from other normal dogs except for their ability to pass the defective gene to approximately half of their offspring.
CA is a simple autosomal recessive disease (e.g. Both parents of an affected dog are carriers for the defective gene)
The cerebellum controls muscular coordination in the body. CA causes a specific cell, called a Purkinje cell to die off in the cerebellum. The Purkinje cell acts as a connector between several other cells in the cerebellum to control a process called proprioception. This process allows the mind to recognize where your limbs and body are “in space.” Because of this process, you can close your eyes and touch your nose, because you “know” where your nose and hand are. This process is progressively lost in CA.
CA manifests itself as an over and under modulation in muscle activity. Affected dogs cannot smoothly control the rate, force, and range of their movements. This can cause an over-reaching and high stepping gait. There can also be abnormal body movements of the trunk, with swaying of the pelvic limbs, and a characteristic bounce of the hind end. There can also be a mild disturbance of balance in CA, where affected dogs can fall over, but then get right up. There is a great range of severity of affected Scottish Terriers. Some can progress in their severity to the point that they fall all the time, while others can remain mildly affected and only show limited signs of incoordination. Some dogs plateau and their clinical signs can remain static for long periods of time, while others can slowly progress over months to years.
CA is a constant condition, as opposed to an episodic condition like Scottie Cramp. Affected dogs always have the disability, though it may not be evident with all motion. Clinical signs of CA are most evident when observing complex movements, such as running and stairwalking. Such complex maneuvers are more than most CA affected dogs can deal with through their ability to concentrate.
Some Scottish Terriers affected with CA can compensate for the lack of proprioceptive control by watching where they place their feet, and consciously “learning” everyday movements that would be automatic for any other dog. Some dogs that have a specific set of stairs that they use every day, can learn to place one foot at a time, and get up and down cleanly. For these dogs, their clinical signs become more evident when they are tired or excited (and can’t concentrate as well). For this reason the classical signs of CA may be most evident when running and chasing a ball, or doing a “new” set of stairs that the dog may not be used to.
Because of the ability for some CA affected dogs to compensate, their clinical signs of incoordination may appear episodic, rather than constant. If an owner only sees the signs when the dog is running, they may think that the running causes the onset of signs, and may confuse what they are seeing with Scottie Cramp. However the specific muscular movements of Scottie Cramp differ from CA (see below).
Together with Dr. Alexander de Lahunta at Cornell University, we have been studying cerebellar abiotrophy in several animal species and several breeds of dogs. Each of the breeds that have CA have the same pathological cause; that being the degeneration of the Purkinje cells of the cerebellum. The dog breeds with the most similar CA presentations as the Scottish Terrier include the Gordon Setter, Old English Sheepdog, American Staffordshire Terrier, and Spinone Italiano. All of these breeds show a later onset, slowly progressive form of CA.
Each breed has its own specific characteristics of the disorder. In the Gordon Setter, the onset of CA is 4 to 12 months of age, with most owners recognizing the incoordination by 1 to 3 years of age. The American Staffordshire Terrier has a much later age of onset – usually recognized between 3 to 5 years of age. There are Scottish Terriers with CA whose owners believe that they first recognized clinical signs at 5 to 10 weeks of age, and some with very mildly affected dogs that did not recognize the clinical signs until 3-5 years of age.
Diagnosis of CA in affected dogs occurs in stages; a pathological examination of the brain after death is the most definitive .
The most definitive diagnosis of CA is through a pathological examination of the brain and cerebellum after death. The degeneration of the Purkinje cells (with the secondary changes that occur due to this degeneration) confirms the pathological diagnosis. Because of the size of the Purkinje cells, their cellular processes (axons and dendrites), and the stimulation of the cells that they connect to, there is a gross reduction in size and weight of the cerebellum compared to the rest of the brain in CA affected dogs.
The reduction in size of the cerebellum can be measured by magnetic resonance imaging (MRI) in a live dog, and has been used as another diagnostic parameter in CA affected dogs. This was documented in South African CA affected Scottish Terriers in a veterinary journal article. However, at this time, the extent of degeneration that is necessary to cause a measurable gross reduction in the size of the cerebellum has not been established. Because of this, an MRI may not be able to diagnose CA in dogs who are young, whose disease process is not longstanding, or whose clinical signs (and therefore the amount of Purkinje cell degeneration) are mild. The criteria for MRI diagnosis in CA affected dogs with different degrees of severity are one aspect of the ongoing CA research.
As most Scottish Terriers with CA are expected to live a normal lifespan, the majority of CA affected Scottish Terriers will receive a clinical diagnosis of the disorder. It would be unfair and wrong to euthanize these special dogs simply to establish a pathological diagnosis. A clinical diagnosis of CA requires documentation of the specific clinical history, progression, and neurological signs that are consistent with the condition, and that rule out other causes. This can be a confusing process to an owner that does not understand the differences in movement between a dog affected with CA, and other dogs whose movement disorders can be due to other causes.
Clinical diagnosis of CA in a living dog requires documentation; and has been shown to be reliable when performed by an expert in the field
Ruling out other factors
Other disorders that can cause clinical signs of an abnormal gait include brain infections (encephalitis), toxins, injury, spinal cord disorders, Scottie Cramp, luxating patellas, and other musculoskeletal abnormalities. CA affects all four limbs. The signs are always symmetrical between the left and right sides of the body, although either the forelimbs or the hindlimbs may be more severely affected in each dog. This differentiation eliminates most musculoskeletal abnormalities. Spinal cord abnormalities (including intervertebral disc disease) cause pain and weakness, as well as either a sinking or stilted gait (depending on the location of the lesion in the spinal cord).
Encephalitis and toxins will cause more injury in the brain than just the Purkinje cells, and this will be evident in the clinical examination. There are no toxins found to selectively affect just the cerebellar Purkinje cells. Infections and toxins will also present with an acute onset, and more rapid progression than seen with CA. These same differences will be evident with a brain injury. The cerebellum is in a very protected area of the skull. If this area of the brain were injured, the clinical signs would be representative of more than a pure Purkinje cell degeneration. In addition, all of these conditions are likely to present with asymmetrical clinical signs.
Scottie Cramp is an episodic disorder that causes a shortening of the stride and what is called a dystonic component where the limb is held in flexion for a variable period of time. This does not occur in CA. While CA causes over-reaching and incoordination, the movements are fluid, and not spastic. Dogs with cramp also do not exhibit a problem with balance, as is often seen with CA.
A clinical diagnosis of cerebellar abiotrophy is best obtained through a neurological examination by an ACVIM board-certified neurologist, in consultation with Dr. de Lahunta. Dr. de Lahunta has also offered a videotape review of dogs suspected of being affected with CA, which I have coordinated for the owners. In order to make a clinical diagnosis based on videotape, the classical movements that would separate CA from other disorders during a neurological examination need to be present. The clinical history and progression of the clinical signs must also be compatible with CA.
The specific neurological movements of CA that must be present on a videotape for a clinical diagnosis are best shown when stairwalking, and running or chasing a toy off lead. There are several owners who have submitted videotapes of their Scottish Terriers that probably have CA. However, a clinical diagnosis has not been offered in these dogs, because the confirming and ruling out movements are not present in the video. In these cases, we recommend that the dog be examined by a neurologist.
CA is not the most prevalent or most important hereditary condition affecting Scottish Terriers. However, it is a condition that is being diagnosed worldwide in the Scottish Terrier, has a simple autosomal recessive mode of inheritance, and has a wide pedigree base that does not preclude any Scottish Terrier from being affected. With the cooperative efforts of the breeders, owners, and researchers, we should be able to deal with CA, and thus improve this particular health aspect for the Scottish Terrier breed.
CA is an inherited, neurological disease.
The mode of inheritance is an autosomal recessive gene carried by both parents.
CA affected Scotties can be clinically diagnosed with a high degree of reliability.
The next step:
Dr. Bell's most recent article, Perspectives on Cerebellar Abiotrophy, appeared in the April 2006 issue of the Bagpiper. [Click here] for a PDF version of this article.