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Mark LeDoux Identifies Mutations Causing Adult-Onset Cervical Dystonia


A team of researchers led by Mark S. LeDoux, MD, PhD, professor in the Department at Neurology at the UTHSC, has made a discovery that may lead to a cure for primary cervical dystonia.

A team of researchers led by Mark S. LeDoux, MD, PhD, professor in the Department at Neurology at the University of Tennessee Health Science Center (UTHSC), has made a discovery that may lead to a cure for primary cervical dystonia. Also known as spasmodic torticollis and twisted neck syndrome, the disorder affects more than a million patients worldwide. Causes of cervical dystonia are unknown but most patients first experience the symptoms midlife (ages 40 to 60).

Dystonia manifests as sustained muscle contractions and spasms that result in repetitive twisting movements and abnormal postures. A chronic neurological movement disorder, spasmodic torticollis causes the neck to involuntarily turn or tilt to the left, right, upwards and/or downwards. Currently, use of botulinum toxin (Botox) injections is the most common treatment.

Dr. LeDoux and three other UTHSC scientists working in his lab — Satya R. Vemula, PhD, Jianfeng Xiao, MD, PhD, and Yu Zhao, MD, PhD — collaborated with Ryan J. Uitti, MD, Chair, Department of Neurology at the Mayo Clinic in Jacksonville, Fla., and Demetrius M. Maraganore, MD, Chair, Department of Neurology at NorthShore University HealthSystem in Evanston, Ill. Together they identified mutations in CIZ1, a protein expressed in the brain that is involved in DNA synthesis and cell-cycle control. The mutations may cause adult-onset primary cervical dystonia by precipitating neurodevelopmental abnormalities that manifest in adults or cell-cycle dysregulation in terminally differentiated neurons. The Annals of Neurology, the official journal of the American Neurological Association and the Child Neurology Society, recently published the research team’s article: https://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1531-8249

Spasmodic torticollis is one of the most common forms of dystonia seen in neurology clinics in the United States. Worldwide reports show the incidence rate of spasmodic torticollis is at least 1.2 per 100,000 persons, and a prevalence rate of 57 per 1 million. Females are 1.5 times more likely to develop cervical dystonia than males and the rate of development of the syndrome increases with age. Most patients show symptoms from ages 50 to 69, with the average onset age being 41.

“Dystonia remains one of the most mysterious cases seen in terms of general medicine,” observed Stanley Fahn, MD, the H. Houston Merritt Professor of Neurology and Director of the Center for Parkinson’s Disease and Other Movement Disorders at Columbia University Medical Center, New York, NY. “What we need are more genetic studies to give us some clues so the pathophysiology of the disorder can be understood. Any one of the genes could be a breakthrough to understanding the changes that lead to this disorder. This discovery is another step toward conquering dystonia. Every step we take advances science closer to a cure.” One of the founding fathers for the subspecialty of movement disorders, Dr. Fahn is an icon in his field, known to neurologists throughout the world.

“With dystonia, patients assume abnormal postures but we can’t find any other evidence of structural damage in the brain,” Dr. Fahn stated. “In years past, patients with this disorder were thought to have psychological problems. It was only when the genetics of some dystonias were discovered that scientists accepted that this is a biochemical rather than a psychological problem.” Dr. Fahn noted that in addition to the physical discomfort and social embarrassment of dystonia, many patients afflicted with this disorder also often suffer from serious depression.

“Dr. LeDoux’s recent work on CIZ1 mutations in cervical dystonia is a significant piece of research that is the first to identify a gene associated with adult-onset focal dystonia,” stated Mahlon R. DeLong, MD, Professor of Neurology at Emory University, Atlanta, Ga., and Scientific Director of the Dystonia Medical Research Foundation. “The work is also important in providing additional evidence for the role of the cerebellum in the production of this form of dystonia. Dr. LeDoux has already made numerous important contributions to the field and this discovery represents another step forward.” Dr. DeLong is a world-renowned neuroscientist with decades of experience and accolades for his work in movement disorders research.