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Tubers in the brain that cause autism and epilepsy // Holes that pock the lungs // Tumors that disrupt kidney function // The understanding of which could unlock treatments for other, more common afflictions.

TSC: Full-Body Peril

By Anita Slomski // Illustrations by Daniel Chang // Winter 2011
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tsc tree

Daniel Chang

Laurie’s seizures, which caused her arm to jerk and mouth to go crooked, started when she was one. Neurologists couldn’t identify a cause, nor did they understand why, three years later, she had learned only 12 words. Finally, at age seven, Laurie was diagnosed with tuberous sclerosis complex, a rare genetic disease now believed to afflict one in every 6,000 people. By then, Laurie had a large blisterlike bubble on her nose, as well as a red butterfly pattern on her face. When she was 28, tumors on her kidneys started to bleed. The pain was excruciating, and eventually surgeons had to remove all of one kidney and part of the other. Then, in her mid-thirties, she developed a lung disease, also an outgrowth of TSC, that could ultimately collapse her lungs and kill her.

Like half of all people with TSC, Laurie has cognitive limitations. She has trouble reading and understanding what people say to her, and it’s not easy for her to make decisions about what to wear or which groceries to buy. Other TSC sufferers are in much worse shape. Almost all suffer from intractable epilepsy, and many are profoundly retarded or autistic. Yet there are also those who have scant symptoms, usually skin rashes or bumps, and who may not even know they have the disorder. For one sufferer, a physician, the first sign of trouble came when she developed asthmalike shortness of breath at age 40. Only then did a CT scan reveal the abnormal cells invading her lungs.

Yet as bizarre and obscure as TSC has been—a typical rare disease, little known beyond its small circle of sufferers, family members and caregivers—it has recently emerged as something else entirely. The disease’s hallmarks are noncancerous growths that appear in multiple organs and the tuber-shaped abnormalities—masses of abnormal cells and disorganized tissue—that develop in the brain. Eight years ago, when researchers stumbled onto how two proteins cause the uncontrolled cell growth of TSC’s tumors and tubers, oncologists took notice. “Cancer biologists are intrigued by why mutations in the TSC proteins produce tumors that are benign or actually regress,” says neurologist Elizabeth A. Thiele, director of the Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital. “What causes the cells to grow into a tumor and then sometimes go away?”

Other aspects of the odd disease also caught researchers’ attention. Nine out of 10 people with TSC have epileptic seizures, and answers about how defective genes create signaling abnormalities in brain cells might hint at what causes epilepsy in those who don’t have TSC. And the disease also has a link to autism, one of medicine’s most enduring mysteries. “We don’t know what causes autism in most kids,” Thiele says. “But if your kid has TSC and is autistic, you know that the disease is responsible. So we think we can extend what we learn about TSC to other kids with autism.”

Research has been helped by a ready-made treatment, an immunosuppressant already approved for people who have kidney transplants that also acts on the cellular pathway that includes TSC proteins. “We were immediately able to move from understanding the root cause of TSC to clinical trials for treating it,” says Cheryl L. Walker, professor of carcinogenesis at the University of Texas MD Anderson Cancer Center. Though not a cure, the drug rapamycin seems to shrink the benign tumors of TSC, and cancer researchers wonder whether it might do the same for malignancies, perhaps combined with drugs that actually kill the proliferating cells instead of making them dormant. The same treatment might also prevent seizures in the general population, particularly after brain injury, rather than just suppressing them, as antiepileptic drugs do. While TSC itself still baffles clinicians—more than a third of people with the disease are misdiagnosed, sometimes for decades—it has become what Thiele, at least, describes as an intriguing disease.

The distinctive tuber-shaped growths that appear throughout the cerebral cortex (the brain’s outer layer) in people with TSC were first described by the French physician Désiré-Magloire Bourne­ville in 1880. And when sliced open, TSC tubers indeed resemble the firm, white flesh of a potato. They’re made up of abnormally shaped and dysfunctional brain cells that form during fetal development, and nearly everyone who has TSC has brain tubers. Some people may have just one or two, while others have so many they cover large areas of the brain. Yet while these tubers may calcify and become hard, they do not proliferate and grow, and they’re found only in the brain.

Some of the far-flung maladies of TSC are directly related to these brain masses. In the case of epilepsy, for example, it may be the tubers themselves that generate seizures. “But it’s more likely that the abnormal tissue of the tuber somehow irritates or disrupts the normal-seeming brain tissue around them,” says pediatric neurologist Michael Wong, director of Washington University’s Tuberous Sclerosis Clinic in St. Louis. “Neurons within or surrounding the tubers generate abnormal electrical activity that builds up and results in seizures.”

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1. “The Tuberous Sclerosis Complex,” by Peter B. Crino et al., The New England Journal of Medicine, Sept. 28, 2006. This review article details the wide array of clinical features of TSC, along with the hypothesis that TSC takes on the metastatic characteristics of cancer as benign cells with mutations in their TSC genes migrate from the kidneys to the lungs.

2. “Mammalian Target of Rapamycin (mTOR) Inhibition as a Potential Antiepileptogenic Therapy: From Tuberous Sclerosis to Common Acquired Epilepsies,” by Michael Wong, Epilepsia, January 2010. TSC research has opened a window into potential therapies for cancer and epilepsy, and this author makes the case that the cellular pathway disrupted in TSC may also contribute to nongenetic forms of epilepsy—holding promise that inhibiting the pathway may offer a way to prevent seizures.

3. “Living With TSC.” This comprehensive and interactive Website by Massachusetts General Hospital includes interviews with TSC scientists on the latest research and current treatment and diagnosis options, along with the voices and stories of families coping with TSC.

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