“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.”
—Fred Balzac