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Cynthia Tifft, M.D., Ph.D.

Cynthia Tifft
Deputy Clinical Director
Office of the Clinical Director

B.A. University of California, San Diego, 1973
M.S. Rutgers University, 1975
Ph.D. University of Texas, Houston, 1981
M.D. University of Texas, Houston, 1983

T: (301) 451-8485
F: (301) 496-7157
Building 10-CRC, Room 3-2551
10 CENTER DR, MSC 1205
BETHESDA, MD 20892-1205

Selected Publications

YouTube videoMystery Diagnosis: The NIH Undiagnosed Diseases Program (UDP)

The Glycosphingolipid Disorders Laboratory investigates the pathophysiology of the lysosomal storage disorders (LSDs) Tay-Sachs disease, Sandhoff disease, and GM1 gangliosidosis, all uniformly fatal disorders of impaired glycosphingolipid (GSL) metabolism.

In previous work with the laboratory of Richard Proia, Ph.D., of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Dr. Tifft helped to determine that bone marrow transplantation could double the lifespan of Sandhoff disease mice, not by decreasing the storage of ganglioside, but by inhibiting the inflammatory response of macrophage-derived microglial cells.

Understanding the role of inflammation in the pathogenesis of neurodegeneration in lysosomal storage disorders that affect the central nervous system has been the clinical and laboratory focus of her further work. Her group uses cell culture and biochemical analysis as well as mouse models and induced pluripotent stem cells to study the mechanisms of disease progression.

In the clinic, Dr. Tifft and her colleagues study the natural history of glycosphingolipid storage disorders to understand the process of disease progression and identify biomarkers important for monitoring the disease and as outcome measures in response to therapy. Most recently the collaborative group has constructed iPS cell lines for Sandhoff disease and GM1 gangliosidosis with their isogenic control lines and has differentiated them into cerebral organoids to track the time course of lysosomal storage in neurons and it's remediation by microinjection of AAV9 gene therapy vectors and restoration of enzyme activity demonstrating the efficacy of these vectors in a model system of the human brain.  Further work has demonstrated alterations in RNA transcripts in Sandhoff disease organoids suggesting alterations in early brain development.


Dr. Tifft received her B.A. in biology from Revelle College at the University of California at San Diego and her M.S. in genetic counseling from Rutgers University. She received her Ph.D. in genetics from the University of Texas Graduate School of Biomedical Science at M.D. Anderson Cancer Center and her M.D. from the University of Texas Health Science Center in Houston.  She completed her pediatric residency at Johns Hopkins Hospital and fellowship in Medical Genetics at the National Institutes of Health. Dr. Tifft joined the faculty of the George Washington University School of Medicine at Children's National Medical Center in 1991, becoming chair of the Division of Genetics and Metabolism in 1996.  In 2009, she was recruited to the National Human Genome Research Institute as deputy clinical director, where she also directs the Pediatric Undiagnosed Diseases Program. 

Dr. Tifft's clinical and research interests for many years have been lysosomal disorders affecting the central nervous system. She is the principal investigator of a longitudinal natural history study of children and adults with glycosphingolipid and glycoprotein disorders including Tay-Sachs and Sandhoff disease, GM1 gangliosidosis, and type 1 sialidosis.  Plans for a gene therapy trial for juveniles with GM1 gangliosidosis is in progress.

As director of the Pediatric Undiagnosed Diseases Program, Dr. Tifft coordinates the selection and clinical evaluation of children whose diagnoses have long eluded the medical community.  Using comprehensive phenotyping and next generation sequencing, she and her team have provided diagnoses to nearly one-third of selected patients and have strong candidate genes under study for additional cases.

Scientific Summary

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Last Updated: September 11, 2018