When Louis Ptáček was a neurology resident at the University of Utah, he met a patient who would set the course of the young physician-scientist's life.
The 28-year-old woman had come to the neurology clinic because she often would become paralyzed after exerting herself. With time, she would be able to move again. But the paralysis kept occurring intermittently. She also told Ptáček that other family members suffered like she did with sporadic paralysis.
Ptáček decided to find the cause of his patient's condition, called hyperkalemic periodic paralysis, which appeared to have genetic origins. He always had been interested in genetics and was inspired by Raymond White, a pioneering Utah geneticist who at the time was developing methods to identify genes associated with Mendelian or rare diseases that run in families.
By 1991, Ptáček identified the mutation in the gene causing his patient's disease. The normal gene coded for a muscle cell sodium channel, which allows sodium ions into the cells. The mutation prevents muscle from contracting correctly. "It was the first ion channel shown to cause human disease," Ptáček says. "We coined the term channelopathy to connote disorders of ion channels."
Since then, Ptáček has cloned genes implicated in a wide range of inherited conditions that have episodic symptoms, similar to the periodic paralysis. Many of them are caused by inherited alterations in different ion channels, but others are not. The diseases include familial types of migraines, epilepsy, dyskinesias (or disorders of movement coordination), and other muscle paralyses.
"What characterizes the episodic disorders is that people seem normal in between attacks, but can be pushed to the brink by environmental stresses," Ptáček says. Up until 2004, the episodic disease mutations Ptáček had found had been only in ion channels. But he then identified a mutant gene responsible for a familial dyskinesia, called PNKD, which in healthy people coded for an enzyme, not a channel.
Initially, Ptáček was surprised by the enzyme finding because the genes he had found mutated in episodic diseases before were all ion channels. But now he is busy figuring out how the enzyme acts to cause disease. "We should be able to find something new and different about what causes these conditions," Ptáček says.
The benefit in understanding the genetics of inherited Mendelian diseases, Ptáček explains, is that such knowledge improves diagnosis and treatment for the patients with the conditions. For example, Ptáček is participating in clinical trials that aim to validate the use of a certain drug to reduce the severity and frequency of attacks for periodic paralysis patients who have specific mutations in two different ion channels.
Another value in studying inherited diseases, Ptáček says, is that the genes in the rare familial cases may provide the clues to what causes the more common forms of these diseases, such as migraine and epilepsy, which afflict many more people in the population.
Because of Ptáček's expertise in identifying genes associated with Mendelian traits, Christopher Jones, a colleague at Utah who specializes in sleep disorders, approached him in 1999 with a case of a woman and some of her family members who were very early risers.
Intrigued by the idea of studying an inherited human behavior that affected the human circadian system, an internal clock that allows us to function in a 24-hour cycle of daylight and night, Ptáček collaborated with Jones. The two characterized the family's pedigree, which reveals the inheritance of a trait, and found the gene responsible.
Ptáček and collaborator Ying-Hui Fu have now characterized more than five circadian rhythm genes associated with what is called familial advanced sleep-phase syndrome (FASPS)—or very early risers—and has found almost 90 families who experience either extreme morning bird or night owl behavior, the genetics of which he continues to study. He also is working to develop drugs that could possibly reset the human clock for individuals with these sleep disorders or travelers to different time zones who experience jet lag.
Although scientists had identified circadian rhythm genes in the fruit fly and mouse, the genes Ptáček and his colleagues found were the first circadian rhythm genes described in humans.
Initially, his interest in circadian rhythm genes was unrelated to his episodic disease research. But the two might be connected. Members of one of the families with the FASPS mutation also have migraines with aura and asthma. "Is it a coincidence or could the genetic cause of FASPS also contribute to these other episodic conditions?" Ptáček wonders.
As he reflects on his career, Ptáček recalls that identifying the first genes associated with the episodic conditions was difficult. "It still is hard, but we are much better at it," Ptáček says. "What is now difficult is translating discoveries into better diagnoses and treatments. But the pace of translation is accelerating. Over the next 5 to 10 years, I expect payoffs that will improve the health of people who have both rare and common diseases."