CADASIL: A Father’s Story

“I am his assistant but he’s still smarter than I am.”

These words are from John Smith* who has witnessed his son deteriorating from a neurological disease called CADASIL, or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Mr. Smith had never heard of CADASIL until his son was diagnosed and, as his son’s primary caretaker, he knows all too well about the many challenges those with the condition can face. “They have problems speaking, they have problems remembering, and they have problems moving. It all depends on what the stroke does to them. My son’s two strokes have done different things to him.”

Mr. Smith says conversations can be frustrating. “Every time you ask a question, the answer part is difficult. He will fumble and stumble for words, not find them, and end up not being able to answer your question, actually forgetting what it was because of the damage to his short-term memory.” His son also cannot use or move his right hand despite physical therapy and other interventions.

The impact of CADASIL varies from patient to patient, but it usually causes premature strokes that can affect movement, speaking ability, and cognitive function. The most serious cases are terminal and progress to vascular dementia. CADASIL is known to be caused from mutations in the NOTCH3 gene, which lead to blood vessel deterioration and abnormal protein build-up in the brain’s arteries, but many more questions remain unanswered.

Michael Wang, M.D., Ph.D., a neurologist at the University of Michigan, is leading the field in CADASIL research. He studies the disease from many angles, like how mutant NOTCH3 leads to cellular injury; identifying NOTCH3’s protein partners; and determining how these related proteins are regulated. His lab’s recent publication describes how NOTCH3 protein is cut and generates fragments that accumulate around vessels affected by CADASIL. Its process is like one found in Alzheimer’s, underscoring how CADASIL research could impact other diseases.

Dr. Wang’s work has placed him on the map nationally, which is why Mr. Smith and his son drove all the way from Massachusetts to meet him and learn about his research. “I was on the internet, finding out all I could about CADASIL,” explained Mr. Smith, “and eventually I ran into information about Dr. Wang.” Dr. Wang invited them to visit U-M and learn about the CADASIL program.

“Dr. Wang picked us up from the hotel saying, ‘We're going to go to lunch and we’re going to stay at lunch until I’ve answered every question you have,’” Mr. Smith recalls.

“Before we left for Michigan, I made my son take a notebook and write down every conceivable question he had. Dr. Wang hadn’t seen the notebook until lunch — which lasted two-and-a-half hours. He’s busy man and he's spending two-and-a-half hours with us. He is one of the nicest people I’ve ever met, and he treated my son like a real human being.”

After lunch, Dr. Wang said, “I want you to talk to my people.” When they asked why, Dr. Wang explained, “They spend their lives in laboratories. I want them to understand all that is behind what they're doing. That there are real people with real problems being affected.”

“My son has never, never forgotten that day, and neither have I. To this day, I still email Dr. Wang. Within two hours, I’ll have a response. He’s the best.”

Dr. Wang collaborates with other Michigan Medicine experts like pathologist Anuska Andjelkovic-Zochowska, M.D., Ph.D., who specializes in human proteins and interactions between the inflammatory system and blood vessels; Richard Keep, Ph.D., Crosby Neurosurgical Lab director who has expertise in the blood-brain barrier; biophysicist Magdalena Ivanova, Ph.D., who works to define the NOTCH3 protein’s structural properties; and Brandon Ruotolo, Ph.D., a professor of chemistry at U-M who uses advanced methods to decipher changes in protein stability.

Because there is little awareness of CADASIL, it is hard to raise money for research into its origins and ways to prevent and cure it. On the horizon Dr. Wang would like to generate a model that capitulates the disease in full to test therapies and advance them for clinical use.

Dr. Wang’s visit with Mr. Smith and his son led to their steadfast support of his research. Asked why he gives, Mr. Smith quickly explains that it is not just for his son but for others with CADASIL. “Obviously seeing your loved one deteriorating and feeling helpless is a huge challenge. But you know, if I can help somebody else by supporting research, even if it doesn’t help my son today, it might help someone else’s tomorrow. Because this disease, it just affects you so dramatically, it breaks your heart.”

CADASIL can be almost as life-changing for caretakers as it is for those diagnosed. “Some days are worse and occasionally you'll find one that’s a little better than others, and you may have a conversation.” While at times his son can speak well, when he can’t, Mr. Smith helps him. “I am proud of my son! I have watched for 16 years as CADASIL has taken away his ability to use his faculties — things most of us take for granted. Through it all, he has never stopped fighting to regain what was taken from him. We know that the disease will win some battles but, with support, hopefully we can win the war.”

*name has been changed