Are Episodic Neurologic Disorders Genetically Linked?

SANTA CLARA, CA—In recent years, researchers have begun to view a group of episodic neurologic disorders—seemingly disparate on the surface—as clinically related as well as genetically linked. Many patients with these disorders appear to be completely healthy between attacks. Marked by such features as migraine, seizure, cardiac arrhythmia, or an episodic movement disorder, these intermittent attacks are often triggered by environmental stressors or dietary factors such as alcohol or caffeine, and many of the drugs used to treat one of these diseases are applied in the management of others. Findings from recent and ongoing genetic and molecular studies have important diagnostic implications for the practice of clinical neurology and could help lead to novel targets for the treatment of epilepsy, migraine, and other more common episodic disorders.

Louis J. Ptácˇek, MD, PhD, John C. Coleman Distinguished Professor in Neurodegenerative Diseases and Professor of Neurology at the University of California, San Francisco (UCSF), has been studying episodic neurologic disorders for almost 20 years. His views have been substantially altered by his own research, as well as that of other investigators. In time, recognizable patterns emerged among many of his patients with episodic disorders.

“They can be completely normal in between attacks, and yet, under certain environmental stressors, they’re pushed over some threshold into an attack of head pain, seizure, hyperexcitability transitioning to weakness, cardiac arrhythmia, or episodic movement disorder,” Dr. Ptácˇek said at the 37th National Meeting of the Child Neurology Society. “As I saw these patients more and more through the years, I became very impressed with the amount of overlap. Despite being fundamentally different disorders on the surface, there were a lot of similarities that I found really striking.”

One area of overlap involves the cause of onset. “The precipitating factors for one disorder among this diverse group are often the same precipitating factors for other disorders—stress being the most prominent, but also dietary factors,” Dr. Ptácˇek said, citing the role of alcohol and caffeine in one phenotype, paroxysmal nonkinesigenic dyskinesia (PNKD).

In addition, the history can be similar among many patients, as the disease often has a childhood onset that worsens through adolescence and young adult life and then decreases in severity and sometimes completely resolves in middle and later adult life. Hormonal factors can also play an important role, Dr. Ptácˇek emphasized. “Catamenial forms of epilepsy and migraine, periodic paralyses, and other episodic disorders can get better or worse in different patients during a woman’s menses,” he said.

Pharmacotherapy of Episodic Disorders
The drugs used to treat these disorders also overlap. Carbonic anhydrase inhibitors have been found to be effective for many of the diseases, as have anticonvulsants and medications given for cardiac arrhythmias.

Recent advances in understanding episodic disorders have the potential to pay big dividends in the area of pharmacotherapy. Dr. Ptácˇek cited research by John Newsom-Davis, Angela Vincent, and others demonstrating that antibodies against ion channels can cause neurologic phenotypes such as stiff person syndrome—representing, in essence, an acquired channelopathy. Another example is PNKD, which Dr. Ptácˇek referred to as an enzyme and a stress-response pathway.

“It raises the possibility of a completely novel place where mutations in a protein that change the gain on stress-response pathways might contribute to membrane excitability,” he said. “[That] is a very exciting possibility—because all of the anticonvulsants and many of the migraine drugs that we use are targeted for voltage- and ligand-gated channels of various sorts, and many were ‘dirty drugs.’” In other words, they are not specific for one target (channel) but rather affect multiple channels. “To have novel targets to look for new candidate molecules for treating patients with epilepsy, migraine, and other episodic disorders would be a whole new area that might help these patients who don’t respond well or who don’t always respond to some of the drugs that we use in our armamentarium.”

A Highly Variable Disorder
Dr. Ptácˇek highlighted three broad categories of episodic neurologic disease: (1) disorders of the human circadian system such as an autosomal-dominant, highly penetrant phenotype that encompasses familial advanced sleep phase syndrome, asthma, and migraine with aura; (2) sodium, calcium, and potassium channelopathies, with a focus on PNKD and the use of caffeine and ethanol to induce attacks in mouse models; and (3) periodic paralyses such as Andersen-Tawil syndrome.

For the tissues or phenotypes in which researchers can measure electric phenomena in such disorders as periodic paralysis, highly organized but very abnormal regenerative action potentials known as myotonia exist. Although these different tissues are associated with different physiologies, they all share what Dr. Ptácˇek called the “remarkable” similarity of highly synchronous and organized, but abnormal, electric activity.

“Beginning in the early 1990s, I, and then later my group, began systematically cloning genes for many of these disorders,” he said. “The first and second [genes]—and the subsequent ones as well—all turned out to be ion-channel genes encoding sodium channels, calcium chloride, or potassium channels. Multiple phenotypes that are clinically distinct can be caused by different mutations in the same gene. The same disease—phenotypically indistinguishable—can arise from mutations in different genes as well. And so this knowledge of the genetic and molecular basis of these disorders led us to refine the classification that had been defined so beautifully by clinical leaders in these groups of diseases over the years.”

Among periodic paralyses, the familial forms constitute less than 10% of all patients. Through extensive and careful phenotype/genotype studies conducted in hundreds of patients with these disorders, Dr. Ptácˇek and his colleagues have shown that a large proportion of the cases can be explained by mutations in one of several identified genes.

“There are still some individuals in small families that we can’t explain, but [they are] decidedly a minority,” he said. “The rest is predominantly made up of a sporadic form of disease called thyrotoxic hypokalemic periodic paralysis, and very recently we cloned a gene that has mutated in that disorder in a quarter to a third of the patients…. That is also what we believe is a genetic disease, but it looks sporadic in families, because … the phenotype can only be uncovered in those individuals who happen to be thyrotoxic.”

Although many of the periodic paralyses are isolated muscle diseases, one disorder that stands out among them, in Dr. Ptácˇek’s view, is Andersen-Tawil syndrome, in which patients have cardiac arrhythmia as well as periodic paralysis. “All the other genes causing periodic paralysis are restricted in their expression pattern of skeletal muscle,” he pointed out. “But as one would predict, this gene [for Andersen-Tawil syndrome] is expressed in both skeletal muscle and heart.”

Patients with Andersen-Tawil syndrome have such dysmorphic features as micrognathia, clinodactyly, and hypertelorism, in addition to heart and muscle phenotypes. Most patients have, for example, some degree of syndactyly. Dr. Ptácˇek and his laboratory team at UCSF have brought patients with Andersen-Tawil syndrome to their clinical research center and characterized them in “exquisite detail.” It is an extremely variable disorder with regard to expressivity, he noted.

“It’s highly penetrant with very variable expressivity, with some people being more dramatically affected [than others],” Dr. Ptácˇek said. “We described a new dental phenotype: These patients can have oligodontia or persistent primary dentition, and the highest expression of this gene turns up in the frontal lobe. Through extensive neurocognitive studies with Bruce Miller and Joel Kramer at UCSF, we showed that these patients have similar IQs to their mutation-negative siblings but that they have a very distinctive neurocognitive phenotype with deficits in the abilities of executive function and abstract reasoning. So this disorder is one in which the gene is widely expressed and where two electric phenotypes—cardiac arrhythmia and periodic paralysis—are present in both….

“The gene encodes a protein that is an inwardly rectifying potassium channel, with mutations scattered throughout this protein in hundreds of patients we’ve collected from around the world. All can lead to dominant negative effects and the manifestation of this disease, Andersen-Tawil syndrome.”

SANTA CLARA, CA—In recent years, researchers have begun to view a group of episodic neurologic disorders—seemingly disparate on the surface—as clinically related as well as genetically linked. Many patients with these disorders appear to be completely healthy between attacks. Marked by such features as migraine, seizure, cardiac arrhythmia, or an episodic movement disorder, these intermittent attacks are often triggered by environmental stressors or dietary factors such as alcohol or caffeine, and many of the drugs used to treat one of these diseases are applied in the management of others. Findings from recent and ongoing genetic and molecular studies have important diagnostic implications for the practice of clinical neurology and could help lead to novel targets for the treatment of epilepsy, migraine, and other more common episodic disorders.

Louis J. Ptácˇek, MD, PhD, John C. Coleman Distinguished Professor in Neurodegenerative Diseases and Professor of Neurology at the University of California, San Francisco (UCSF), has been studying episodic neurologic disorders for almost 20 years. His views have been substantially altered by his own research, as well as that of other investigators. In time, recognizable patterns emerged among many of his patients with episodic disorders.

“They can be completely normal in between attacks, and yet, under certain environmental stressors, they’re pushed over some threshold into an attack of head pain, seizure, hyperexcitability transitioning to weakness, cardiac arrhythmia, or episodic movement disorder,” Dr. Ptácˇek said at the 37th National Meeting of the Child Neurology Society. “As I saw these patients more and more through the years, I became very impressed with the amount of overlap. Despite being fundamentally different disorders on the surface, there were a lot of similarities that I found really striking.”

One area of overlap involves the cause of onset. “The precipitating factors for one disorder among this diverse group are often the same precipitating factors for other disorders—stress being the most prominent, but also dietary factors,” Dr. Ptácˇek said, citing the role of alcohol and caffeine in one phenotype, paroxysmal nonkinesigenic dyskinesia (PNKD).

In addition, the history can be similar among many patients, as the disease often has a childhood onset that worsens through adolescence and young adult life and then decreases in severity and sometimes completely resolves in middle and later adult life. Hormonal factors can also play an important role, Dr. Ptácˇek emphasized. “Catamenial forms of epilepsy and migraine, periodic paralyses, and other episodic disorders can get better or worse in different patients during a woman’s menses,” he said.

Pharmacotherapy of Episodic Disorders
The drugs used to treat these disorders also overlap. Carbonic anhydrase inhibitors have been found to be effective for many of the diseases, as have anticonvulsants and medications given for cardiac arrhythmias.

Recent advances in understanding episodic disorders have the potential to pay big dividends in the area of pharmacotherapy. Dr. Ptácˇek cited research by John Newsom-Davis, Angela Vincent, and others demonstrating that antibodies against ion channels can cause neurologic phenotypes such as stiff person syndrome—representing, in essence, an acquired channelopathy. Another example is PNKD, which Dr. Ptácˇek referred to as an enzyme and a stress-response pathway.

“It raises the possibility of a completely novel place where mutations in a protein that change the gain on stress-response pathways might contribute to membrane excitability,” he said. “[That] is a very exciting possibility—because all of the anticonvulsants and many of the migraine drugs that we use are targeted for voltage- and ligand-gated channels of various sorts, and many were ‘dirty drugs.’” In other words, they are not specific for one target (channel) but rather affect multiple channels. “To have novel targets to look for new candidate molecules for treating patients with epilepsy, migraine, and other episodic disorders would be a whole new area that might help these patients who don’t respond well or who don’t always respond to some of the drugs that we use in our armamentarium.”

A Highly Variable Disorder
Dr. Ptácˇek highlighted three broad categories of episodic neurologic disease: (1) disorders of the human circadian system such as an autosomal-dominant, highly penetrant phenotype that encompasses familial advanced sleep phase syndrome, asthma, and migraine with aura; (2) sodium, calcium, and potassium channelopathies, with a focus on PNKD and the use of caffeine and ethanol to induce attacks in mouse models; and (3) periodic paralyses such as Andersen-Tawil syndrome.

For the tissues or phenotypes in which researchers can measure electric phenomena in such disorders as periodic paralysis, highly organized but very abnormal regenerative action potentials known as myotonia exist. Although these different tissues are associated with different physiologies, they all share what Dr. Ptácˇek called the “remarkable” similarity of highly synchronous and organized, but abnormal, electric activity.

“Beginning in the early 1990s, I, and then later my group, began systematically cloning genes for many of these disorders,” he said. “The first and second [genes]—and the subsequent ones as well—all turned out to be ion-channel genes encoding sodium channels, calcium chloride, or potassium channels. Multiple phenotypes that are clinically distinct can be caused by different mutations in the same gene. The same disease—phenotypically indistinguishable—can arise from mutations in different genes as well. And so this knowledge of the genetic and molecular basis of these disorders led us to refine the classification that had been defined so beautifully by clinical leaders in these groups of diseases over the years.”

Among periodic paralyses, the familial forms constitute less than 10% of all patients. Through extensive and careful phenotype/genotype studies conducted in hundreds of patients with these disorders, Dr. Ptácˇek and his colleagues have shown that a large proportion of the cases can be explained by mutations in one of several identified genes.

“There are still some individuals in small families that we can’t explain, but [they are] decidedly a minority,” he said. “The rest is predominantly made up of a sporadic form of disease called thyrotoxic hypokalemic periodic paralysis, and very recently we cloned a gene that has mutated in that disorder in a quarter to a third of the patients…. That is also what we believe is a genetic disease, but it looks sporadic in families, because … the phenotype can only be uncovered in those individuals who happen to be thyrotoxic.”

Although many of the periodic paralyses are isolated muscle diseases, one disorder that stands out among them, in Dr. Ptácˇek’s view, is Andersen-Tawil syndrome, in which patients have cardiac arrhythmia as well as periodic paralysis. “All the other genes causing periodic paralysis are restricted in their expression pattern of skeletal muscle,” he pointed out. “But as one would predict, this gene [for Andersen-Tawil syndrome] is expressed in both skeletal muscle and heart.”

Patients with Andersen-Tawil syndrome have such dysmorphic features as micrognathia, clinodactyly, and hypertelorism, in addition to heart and muscle phenotypes. Most patients have, for example, some degree of syndactyly. Dr. Ptácˇek and his laboratory team at UCSF have brought patients with Andersen-Tawil syndrome to their clinical research center and characterized them in “exquisite detail.” It is an extremely variable disorder with regard to expressivity, he noted.

“It’s highly penetrant with very variable expressivity, with some people being more dramatically affected [than others],” Dr. Ptácˇek said. “We described a new dental phenotype: These patients can have oligodontia or persistent primary dentition, and the highest expression of this gene turns up in the frontal lobe. Through extensive neurocognitive studies with Bruce Miller and Joel Kramer at UCSF, we showed that these patients have similar IQs to their mutation-negative siblings but that they have a very distinctive neurocognitive phenotype with deficits in the abilities of executive function and abstract reasoning. So this disorder is one in which the gene is widely expressed and where two electric phenotypes—cardiac arrhythmia and periodic paralysis—are present in both….

“The gene encodes a protein that is an inwardly rectifying potassium channel, with mutations scattered throughout this protein in hundreds of patients we’ve collected from around the world. All can lead to dominant negative effects and the manifestation of this disease, Andersen-Tawil syndrome.”

SANTA CLARA, CA—In recent years, researchers have begun to view a group of episodic neurologic disorders—seemingly disparate on the surface—as clinically related as well as genetically linked. Many patients with these disorders appear to be completely healthy between attacks. Marked by such features as migraine, seizure, cardiac arrhythmia, or an episodic movement disorder, these intermittent attacks are often triggered by environmental stressors or dietary factors such as alcohol or caffeine, and many of the drugs used to treat one of these diseases are applied in the management of others. Findings from recent and ongoing genetic and molecular studies have important diagnostic implications for the practice of clinical neurology and could help lead to novel targets for the treatment of epilepsy, migraine, and other more common episodic disorders.

Louis J. Ptácˇek, MD, PhD, John C. Coleman Distinguished Professor in Neurodegenerative Diseases and Professor of Neurology at the University of California, San Francisco (UCSF), has been studying episodic neurologic disorders for almost 20 years. His views have been substantially altered by his own research, as well as that of other investigators. In time, recognizable patterns emerged among many of his patients with episodic disorders.

“They can be completely normal in between attacks, and yet, under certain environmental stressors, they’re pushed over some threshold into an attack of head pain, seizure, hyperexcitability transitioning to weakness, cardiac arrhythmia, or episodic movement disorder,” Dr. Ptácˇek said at the 37th National Meeting of the Child Neurology Society. “As I saw these patients more and more through the years, I became very impressed with the amount of overlap. Despite being fundamentally different disorders on the surface, there were a lot of similarities that I found really striking.”

One area of overlap involves the cause of onset. “The precipitating factors for one disorder among this diverse group are often the same precipitating factors for other disorders—stress being the most prominent, but also dietary factors,” Dr. Ptácˇek said, citing the role of alcohol and caffeine in one phenotype, paroxysmal nonkinesigenic dyskinesia (PNKD).

In addition, the history can be similar among many patients, as the disease often has a childhood onset that worsens through adolescence and young adult life and then decreases in severity and sometimes completely resolves in middle and later adult life. Hormonal factors can also play an important role, Dr. Ptácˇek emphasized. “Catamenial forms of epilepsy and migraine, periodic paralyses, and other episodic disorders can get better or worse in different patients during a woman’s menses,” he said.

Pharmacotherapy of Episodic Disorders
The drugs used to treat these disorders also overlap. Carbonic anhydrase inhibitors have been found to be effective for many of the diseases, as have anticonvulsants and medications given for cardiac arrhythmias.

Recent advances in understanding episodic disorders have the potential to pay big dividends in the area of pharmacotherapy. Dr. Ptácˇek cited research by John Newsom-Davis, Angela Vincent, and others demonstrating that antibodies against ion channels can cause neurologic phenotypes such as stiff person syndrome—representing, in essence, an acquired channelopathy. Another example is PNKD, which Dr. Ptácˇek referred to as an enzyme and a stress-response pathway.

“It raises the possibility of a completely novel place where mutations in a protein that change the gain on stress-response pathways might contribute to membrane excitability,” he said. “[That] is a very exciting possibility—because all of the anticonvulsants and many of the migraine drugs that we use are targeted for voltage- and ligand-gated channels of various sorts, and many were ‘dirty drugs.’” In other words, they are not specific for one target (channel) but rather affect multiple channels. “To have novel targets to look for new candidate molecules for treating patients with epilepsy, migraine, and other episodic disorders would be a whole new area that might help these patients who don’t respond well or who don’t always respond to some of the drugs that we use in our armamentarium.”

A Highly Variable Disorder
Dr. Ptácˇek highlighted three broad categories of episodic neurologic disease: (1) disorders of the human circadian system such as an autosomal-dominant, highly penetrant phenotype that encompasses familial advanced sleep phase syndrome, asthma, and migraine with aura; (2) sodium, calcium, and potassium channelopathies, with a focus on PNKD and the use of caffeine and ethanol to induce attacks in mouse models; and (3) periodic paralyses such as Andersen-Tawil syndrome.

For the tissues or phenotypes in which researchers can measure electric phenomena in such disorders as periodic paralysis, highly organized but very abnormal regenerative action potentials known as myotonia exist. Although these different tissues are associated with different physiologies, they all share what Dr. Ptácˇek called the “remarkable” similarity of highly synchronous and organized, but abnormal, electric activity.

“Beginning in the early 1990s, I, and then later my group, began systematically cloning genes for many of these disorders,” he said. “The first and second [genes]—and the subsequent ones as well—all turned out to be ion-channel genes encoding sodium channels, calcium chloride, or potassium channels. Multiple phenotypes that are clinically distinct can be caused by different mutations in the same gene. The same disease—phenotypically indistinguishable—can arise from mutations in different genes as well. And so this knowledge of the genetic and molecular basis of these disorders led us to refine the classification that had been defined so beautifully by clinical leaders in these groups of diseases over the years.”

Among periodic paralyses, the familial forms constitute less than 10% of all patients. Through extensive and careful phenotype/genotype studies conducted in hundreds of patients with these disorders, Dr. Ptácˇek and his colleagues have shown that a large proportion of the cases can be explained by mutations in one of several identified genes.

“There are still some individuals in small families that we can’t explain, but [they are] decidedly a minority,” he said. “The rest is predominantly made up of a sporadic form of disease called thyrotoxic hypokalemic periodic paralysis, and very recently we cloned a gene that has mutated in that disorder in a quarter to a third of the patients…. That is also what we believe is a genetic disease, but it looks sporadic in families, because … the phenotype can only be uncovered in those individuals who happen to be thyrotoxic.”

Although many of the periodic paralyses are isolated muscle diseases, one disorder that stands out among them, in Dr. Ptácˇek’s view, is Andersen-Tawil syndrome, in which patients have cardiac arrhythmia as well as periodic paralysis. “All the other genes causing periodic paralysis are restricted in their expression pattern of skeletal muscle,” he pointed out. “But as one would predict, this gene [for Andersen-Tawil syndrome] is expressed in both skeletal muscle and heart.”

Patients with Andersen-Tawil syndrome have such dysmorphic features as micrognathia, clinodactyly, and hypertelorism, in addition to heart and muscle phenotypes. Most patients have, for example, some degree of syndactyly. Dr. Ptácˇek and his laboratory team at UCSF have brought patients with Andersen-Tawil syndrome to their clinical research center and characterized them in “exquisite detail.” It is an extremely variable disorder with regard to expressivity, he noted.

“It’s highly penetrant with very variable expressivity, with some people being more dramatically affected [than others],” Dr. Ptácˇek said. “We described a new dental phenotype: These patients can have oligodontia or persistent primary dentition, and the highest expression of this gene turns up in the frontal lobe. Through extensive neurocognitive studies with Bruce Miller and Joel Kramer at UCSF, we showed that these patients have similar IQs to their mutation-negative siblings but that they have a very distinctive neurocognitive phenotype with deficits in the abilities of executive function and abstract reasoning. So this disorder is one in which the gene is widely expressed and where two electric phenotypes—cardiac arrhythmia and periodic paralysis—are present in both….

“The gene encodes a protein that is an inwardly rectifying potassium channel, with mutations scattered throughout this protein in hundreds of patients we’ve collected from around the world. All can lead to dominant negative effects and the manifestation of this disease, Andersen-Tawil syndrome.”