Objectives of the Presentation
Differentiate secondary from primary causes
Differentiate syndromic from idiopathic seizure disorders
Apply gene discovery strategies to syndromic epilepsy
Overview of the Issue
What is a seizure?
What are the different types of seizures?
Why is it important to recognize the non-genetic causes of seizures?
In genetic diseases, seizures can occur as a part of a more complex syndrome.
It is often easier to find the mutation responsible in syndromic epilepsies than in the idiopathic disease
A seizure is a manifestation of abnormal electrical activity within the cerebral cortex. Normal brain cells (neurons) use electrical and chemical signals to communicate with one another. These communications can be either excitatory, tending to activate the next neuron, or inhibitory, tending to shut the next neuron off. A delicate balance of these excitatory and inhibitory influences on any given neuron determines whether it is going to become activated and pass information on to other neurons (Figure 1). If the balance of these influences in the brain as a whole shifts too far toward excitation, then too many neurons may become excited at once and a seizure could result. A seizure is typically a brief episode and then regulatory mechanisms restore the balance again. The abnormal electrical activity within the brain can be recorded with an electroencephalogram (EEG), but most commonly we only see the physical manifestations of the seizure. These manifestations can be any combination of altered consciousness, abnormal movements, changes in behavior, or autonomic signs such as salivation or urination. Epilepsy is a chronic condition characterized by recurrent seizures.
Figure 1. Seizures are a manifestation of altered balance of excitation and inhibition within the brain.
Seizures can be divided into two broad categories: focal and generalized. In a generalized seizure, the abnormal electrical activity occurs diffusely over the entire brain simultaneously. The classic generalized seizure is the tonic-clonic (grand mal or major motor) seizure. Sometimes the owners can detect a clear warning that their pet is about to have a seizure, the aura or prodrome. During the seizure itself, the dog typically loses consciousness and falls to their side in rigid extension (the tonic phase). This gives way to rhythmic jerking or paddling movements (the clonic phase). Often then animal salivates or voids during the seizure. Most seizures last less than 2 minutes. Following the seizure, the dog often exhibits confusion, blindness, or loss of coordination: the post-ictal behavior. Though the tonic-clonic seizure is the most common type, there are a number of other varieties. These include pure tonic or pure clonic seizures, atonic seizures (drop attacks), and myoclonus.
Focal seizures arise in a limited area on one side of the brain. The manifestation of the focal seizure will depend entirely on where the focus occurs. The classic focal seizure is a focal motor seizure where the activity begins in the motor areas of the cortex. Since dogs and cats utilize their face to interact with their environment, the face occupies the largest area of the cortex in these species. Thus focal seizures are most commonly manifested as twitching of one side of the face and/or chomping of the jaws. During a focal motor seizure, the animal is usually perfectly aware but may be confused or annoyed to the involuntary twitching. Sometimes the electrical storm can spread from the original focus. As it spreads through the motor areas, other parts of one side of the body may join in the twitching, a phenomenon called the Jacksonian march. In some cases, the entire brain will be engulfed by the seizure and the focal seizure will evolve into a generalized seizure. Indeed, the aura seen in some generalized seizures may represent an unseen focal onset. While a person may report and abnormal sensation or hallucination during a focal seizures, in a dog we would only observe altered behavior as the animal responded to that abnormal sensation. Rarely seizures may originate in the areas of the brain involved in emotions and the seizure characterized by bizarre behavior or emotional outbursts (psychomotor seizures).
Many things can alter the excitability of neurons and potentially push the overall excitability past the threshold to produce seizures. Toxins or metabolic imbalances such as hypoglycemia or electrolyte imbalances can alter neuronal excitability. Most commonly these cause a limited episode of seizures following which the animal either recovers or succumbs. Occasionally recurrent seizures can result from chronic poisoning (e.g. lead poisoning) or persistent metabolic problems (e.g. chronic hypocalcemia). Toxic or metabolic insults affect the entire cerebral cortex symmetrically, thus typically produce generalized seizures.
Physical damage to the cerebral cortex can also lead to seizures. This damage can be due to a variety of causes including head trauma, strokes, brain tumors or infections. Once the brain has been damaged, permanent epilepsy can result even if the original cause of the damage such as an infection or tumor has been removed. Such focal damage can result in focal seizures, though we now know that hereditary causes of seizures can result if focal as well as generalized seizures. To further complicate differentiating acquired from hereditary seizures, sometimes the onset of seizures following injury to the brain can be delayed. The longer the delay, the more difficult it is to determine whether the seizures were related to the original injury or not.
In addition to these acquired causes, animals may inherit a propensity to have seizures. If the seizures are the only manifestation of the disease and the animal is normal between seizures, this is referred to as idiopathic epilepsy. A genetic predisposition is suspected but ruling out acquired causes can be challenging. Often recurrent seizures are just one manifestation of a genetic disease. Such diseases where seizures are part of a bigger syndrome are referred to as syndromic epilepsies. These syndromes include structural malformations of the brain and inborn errors of metabolism that affect the brain.
The most common congenital brain malformation is hydrocephalus which is quite common in some toy breed dogs. The more common manifestations of hydrocephalus are behavioral changes, coordination loss and blindness, but seizures may occur. While mutations causing hydrocephalus have been identified in humans, the contribution of genetics to the disease in dogs remains poorly defined. Nonetheless, the breed predilection suggests a strong genetic component. Hydrocephalus also occurs as part of the Chiari malformation in Cavalier King Charles spaniels and other breeds. Lissencephaly is another brain malformation which is more commonly associated with seizures. In lissencephaly the normal folds of the brain do not develop resulting in a smooth brain surface. This disrupts the normal organization of the cortex making it prone toward seizure activity. Several mutations causing the condition have been identified in humans, but fortunately this condition appears rare in dogs.
The metabolism of all cells involves a series of steps for normal manufacturing and recycling of essential component of the cell and for normal production of the energy needed by the cell. A mutation that interferes with a key enzyme in these processes can lead to hereditary inborn errors of metabolism. The brain is the most demanding organ in the body, so it is not unusual for the brain to be affected and for seizures to be a part of these syndromes. Other brain signs are usually present, and often other organs are affected as well.
Often this sort of enzyme deficiency leads to a roadblock in the process and the metabolite immediately preceding that obstruction accumulates. The lysosome is the recycling center of the cell. Proteins and other large molecules that are worn out or otherwise damaged are transported to the lysosome. The lysosome contains enzymes which break these molecules down to their building blocks which can then be recycled into new proteins. The enzymes need to be walled off in the lysosome to protect the normal proteins in the cell from also being degraded. When an enzyme is deficient, the degradation can only proceed so far and abnormal material accumulates within the lysosome (Figure 2). since the cell was able to manufacture the protein, the animal is normal at first. Eventually enough accumulates to interfere with cell function. The result can be delayed neurologic signs such as weakness, blindness, dementia, and seizures. Identifying the storage material either in a biopsy or at post-mortem confirms the diagnosis.
Figure 2. In storage diseases, seizures and other neurologic signs result from accumulation of abnormal material in neurons. This brain section shows fluorescent yellow material in a dog with ceroid lipofuscinosis.
If the mutation interferes with energy metabolism, the product that accumulates is often an organic acid. Because these are small molecules, they readily diffuse from the cells where they are ultimately excreted in the urine. Hence this group of diseases is called organic acidurias. Specialized assays can detect these abnormal organic acids in the urine and provide an important clue to the underlying cause. Many will show signs as neonates if the road block seriously interferes with the ability of the brain to function while other can show a delayed onset. Since the dietary intake can influence what pathway is being utilized at the time, these conditions may be affected by changes in diet, which provides an avenue for therapy.
There can also be inborn errors of metabolism which do not result in metabolite buildup but simply interfere with function. Because neurons have long processes (axons) to communicate with other cells, they must transport the building blocks of the cell long distances. Mutations that interfere with axonal transport will interfere with the function of the nerves with the longest axons first. The material to be transported will accumulate at the origin of the axon (spheroids) rather than in lysosomes.
Transcription factors are "command and control" proteins. They are responsible for determining which genes are turned on or off either during the complex process of development or in response to the changing needs of a cell in an adult. Mutations in the genes for a major transcription factor results in neonatal encephalopathy with seizures in Standard Poodles. Exactly how this mutation lead to the clinical signs is not yet clear.
It is often easier to identify the gene responsible for syndromic epilepsies. If the disease has a neonatal onset, the entire family (with the possible exception of the sire) is usually available for DNA sampling. While seizures can have a myriad of causes, the constellation of signs within a syndrome such as neuronal ceroid lipofuscinosis or malonic aciduria tends to be more distinctive and stereotyped. Thus the problem of clearly identifying the phenotype of any individual is simplified. If the storage product or the abnormal organic acid can be identified, this may point toward the specific enzyme which is deficient. Then the candidate gene approach can be utilized and the mutation identified without the need for an extensive mapping study.
Seizures are a sign of disease. They can reflect a very wide variety of underlying causes from a clearly acquired disease like a brain tumor to a poorly defined genetic predisposition to seizures. In some genetic diseases, the seizures will be a part of a broader syndrome of neurological signs. The nature of the syndrome can provide important clues to the mutation causing the disease.
1. T. Awano, M. L. Katz, D. P. O'Brien, I. Sohar, P. Lobel, J. R. Coates, S. Khan, G. C. Johnson, U. Giger, and G. S. Johnson. A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Molecular Genetics & Metabolism 89 (3):254-260, 2006.
2. D. P. O'Brien. Pathogenesis of Idiopathic Epilepsy. Proceedings 21st ACVIM Forum, Charlotte NC, 303-305, 2003.
3. D. P. O'Brien. Molecular Approaches to Hereditary Neurodegenerative Diseases. Proceedings 24th Annual ACVIM Forum. Louisville KY:308-310, 2006.
4. D. P. O'Brien. Organic Acidurias. Proceedings of the 23rd ACVIM Forum. Baltimore, MD:346-8, 2005.
5. B. J. Skelly and R. J. Franklin. Recognition and diagnosis of lysosomal storage diseases in the cat and dog. J Vet Int Med 16 (2):133-141, 2002.