Louis J. Ptáček, MD

Louis J. Ptáček, M.D. Investigator, Howard Hughes Medical Institute Coleman Distinguished Professor Department of Neurology

Dr. Ptácek’s laboratory focuses on genetic diseases of muscle, heart and brain and hereditary variation of human sleep behavior. His group has cloned genes causing many disease and behavioral phenotypes in humans. In addition, he and his collaborators probe the biology underlying normal function of the encoded proteins in the nervous system and pathophysiology of the mutant proteins in human neurological diseases. To this end, they use cellular electrophysiology, biochemistry, cell biology and animal modeling.

He and Chris Jones identified and characterized the first human families with a Mendelian circadian rhythm variant. These individuals have an extreme "morning lark" phenotype and they called this variant familial advanced sleep phase syndrome (FASPS). His group and the group of Ying-Hui Fu have gone from the clinical and physiologic characterization of this phenotype to the mapping and cloning of the causative genes, biochemical study of the encoded proteins, and generation of animal models. In addition, they have collected a large group of families with FASPS and other circadian sleep disorders, and these are being studied to identify additional human circadian rhythm genes.

This work represents a move from purely ‘disease genetics’ to the genetics of human behavior. Insights into the proteins causing these disorders and traits will ultimately lead to new insights into the normal function of the human nervous system and mechanisms of disease. Ultimately, such insights will lead to new therapies for treating patients with various neurological and other disorders.

His earliest and ongoing work most relevant to the mission of the PPI focused on the familial periodic paralyses. Beginning in 1990 he started to collect families and set out to clone genes causing hyperkalemic periodic paralysis, paramyotonia congenita, potassium activated myotonia, hypokalemic periodic paralysis, and Andersen-Tawil Syndrome (ATS). This was done in collaboration with many outstanding clinical collaborators, but most notably, Berch Griggs and Rabi Tawil at the University of Rochester and Martin Tristani-Firouzi at the University of Utah.

Along with Drs. Griggs, Tawil, and Tristani-Firouzi, Dr. Ptacek’s group has expanded on the initial characterization of a single patient by Andersen and have gone on to expand our data set to over 200 patients and have carefully quantitated the developmental, muscle and cardiac features of the disorder and further described a range of dental and characteristic neurocognitive phenotypes. The Rochester group has led a therapeutic trial involving many centers and stratifying patients based on genetic diagnoses and successfully shown that dichlorphenamide is very beneficial to these patients.

Dr. Ptacek’s group used the precedent established in the familial periodic paralyses to formulate and test a hypothesis regarding the molecular basis of the most common form of periodic paralysis world-wide. Thyrotoxic hypokalemic periodic paralysis (TPP) is a sporadic form of periodic paralysis seen much more often in men than women that only occurs when affected individuals have high thyroid hormone levels. We’ve identified a gene that is mutated in fraction of TPP patients and shown functional consequences of the mutations in the ion channel encoded by this gene in vitro.

Dr. Ptacek’s ongoing studies are focused on identifying genes causing ATS in the ~30% of patients who don’t have mutations in the first ATS gene (KCNJ2) and causing TPP in the ~75% of patients who don’t have mutations in the first TPP gene (KCNJ18).

Dr.  Ptacek has won numerous awards including the Derek Denny-Brown Award from the ANA and is an Investigator of the Howard Hughes Medical Institute and a member of the Institute of Medicine and the American Academy of Arts and Sciences.