Clinical Encounters in Neurogenetics: Taking Cues from Single Patients to Discover Genes, Mechanisms, and Therapeutic Approaches
Carsten G. Bönnemann, M.D.
Senior Investigator
NINDS
Dr. Bonnemann received his MD from Freiburg University, Germany. He completed pediatric training and venia legendi (Habilitation) in Germany. Residency in pediatric neurology at MGH/Harvard was followed by postdoctoral work with Dr. Louis Kunkel at Children's Hospital Boston working on the molecular genetics of muscular dystrophy. In 2002 he joined the Children's Hospital of Philadelphia/University of Pennsylvania as Assistant Professor, Co-Director of the Neuromuscular Program, and Director of the Neurogenetics Clinic. He joined NINDS in 2010 as Senior Investigator and Chief of the Neuromuscular and Neurogenetic Disorders of Childhood Section. Dr. Bonnemann was a Pew Fellow in the Biomedical Sciences. He received the 2009 Derek Denny Brown Neurological Scholar Award. Research in Dr. Bonnemann's laboratory revolves around molecular mechanisms underlying early onset muscle disease (congenital muscular dystrophies, congenital myopathies, and reducing body myopathy). The laboratory's goal is to identify the genetic and cellular mechanisms in these conditions in order to develop strategies for molecular-based treatments.
Summary
Lecture summary:
This lecture will describe three personal journeys of discovery that led my team and me from encountering a single enigmatic patient to uncovering new genes, mechanisms, and treatment approaches, while also providing fundamental insights into human neurobiology. The journey will take place in the space of the "Neurogenetics of Motion and Sensation" and will follow the peripheral nervous system from the motor neuron, via the muscle, to the sensory system.
We will start with describing the discovery of a new gene for childhood-onset ALS (amyotrophic lateral sclerosis) in a young woman with unexplained motor deterioration that led us to recognize dysregulation of sphingolipid metabolism as a new mechanism for ALS as well as to proposing a precision therapy to address it. Next, we will discuss the identification a hitherto completely hidden deep intronic recurrent mutation in the gene COL6A1 in a patient with a severe form of congenital muscular dystrophy that now emerges as one of the most common single cause for this disease. This deep intronic mutation activates a "poisonous" pseudo-exon that acts in a dominant manner and is eminently amendable to pseudo-exon skipping as a therapeutic approach. Finally, we are encountering a patient with complete absence of proprioception (the sense of body position in space), leading to the insight that the mechanosensor PIEZO2 is responsible for this fundamental sense in human as well as many other aspects of mechanosensation and interoception, and to the development of a sensory prosthesis to eventually help overcome the lack of proprioception using "haptic robotics”.
Lecture objectives:
- To understand the importance of deep and careful clinical phenotyping of even single patients for the recognition of new conditions and hidden genetic mechanisms and proper interpretation of next generation genetic and genomic results.
- To realize the potential of precision therapeutics based on the accurate understanding of genetic causative mechanisms and their physiological consequences.
This page was last updated on Friday, November 21, 2025