At 44, Janet Waterhouse should have been the picture of health; a former Division I soccer player, she taught yoga, enjoyed running, and didn’t drink alcohol. Despite her extremely healthy and active lifestyle, over a span of decades she experienced a number of unexplained symptoms that no amount of healthy habits could help her shake. 

As a teenager, she had “inexplicably bad” menstrual cycles, which led to several surgeries, including the removal of her appendix. She was diagnosed with endometriosis, irritable bowel syndrome, and a number of food allergies, but found no relief in following the treatments prescribed by her physicians.

Her symptoms continued to worsen into her twenties when she began to sporadically lose function of her hands and experience severe bouts of vertigo. Most doctors attributed her symptoms to stress and anxiety, as Waterhouse was a creative director at a competitive advertising agency in New York.

The mother of three sons, Waterhouse had very difficult pregnancies, the third of which culminated in life-threatening blood loss during her C-section. Doctors were able to save her, but she suffered massive blood loss, and was left feeling exhausted for years.

While doctors couldn’t pinpoint a diagnosis, Waterhouse accepted her “new normal,” and dedicated herself to making her healthy lifestyle even healthier in hopes of managing her symptoms. She became a certified yoga instructor and invested her time and energy listening to her body. She developed a strict sleep schedule, going to bed at 8 p.m. sharp every night, and waking up at 3 a.m., the period when her body rested the best. She started researching vitamins and supplements, fine-tuning her doses to her body’s response.

All the while, she continued seeing a neurologist, who suspected she might have multiple sclerosis (MS), but MRIs revealed no damage, called lesions, to her brain or spinal cord— a typical indicator of the disease. Despite the lack of MS lesions, Waterhouse continued to struggle to use her hands and experienced weakness on one side of her body.

Over the course of the next five years, Waterhouse started to experience double vision in addition to her other symptoms. Still searching for a diagnosis, doctors wondered if it wasn’t MS, but another autoimmune disorder, called Myasthenia Gravis (MG), which affects the voluntary muscles of the body, especially those that control the eyes and limbs.

During this time, Waterhouse was seeing a pain management specialist, who was concerned enough about her worsening symptoms to run a blood test, where he found irregularly shaped blood cells, called acanthocytes.

A series of serendipitous referrals led Waterhouse to Ali Hamedani, MD, MHS, an assistant professor of Neurology and Ophthalmology in the Perelman School of Medicine at the University of Pennsylvania. Based on her symptoms and exam, he suspected a genetic condition called chronic progressive external ophthalmoplegia (CPEO) and referred her to Laynie Dratch, a certified genetic counselor in the Penn Neurogenetics Therapy Center, for genetic testing.

In May of 2022, Dratch gave Waterhouse what she had been chasing for decades: a diagnosis.

“When the genetic counselor told me they found the genetic mutation they were looking for, I cried for a solid five minutes out of relief,” Waterhouse said. “It’s like having a popcorn kernel stuck in your teeth — you can feel it and it’s bothering you, and it feels so good to get it out.”

Waterhouse‘s case of CPEO was found to be caused by a variation on her RRM2B gene, which affects the mitochondria in her cells. While the condition is very rare and can sometimes take years to locate and diagnose, Hamedani’s hunch about the gene mutation led them right to it.

Because little is known about CPEO, treatment options are limited. “Most people would be discouraged by the uncertainty,” she said, “but it thrills me to get to be the blueprint. I get to show people how to live with this.”

This summer, Waterhouse was enrolled in a clinic specifically for patients with mitochondrial defects, which provided her more insight into her condition and strategies for managing her symptoms. 

“I was already doing a lot of the recommended things to manage my condition, like exercising, abstaining from alcohol, eating incredibly healthily. I was even already taking twelve of the recommended fourteen supplements to manage CPEO symptoms,” Waterhouse said. “Even so, just having a team who believed me and treated me as an equal and not a problem to solve lifted an enormous weight off my shoulders.”

One notable effect of CPEO is that when under anesthesia, patients can develop hypoventilation, or abnormally slow breathing, resulting in increased carbon dioxide levels in the blood — the likely cause of Waterhouse’s complications while giving birth to her third son.

Further, RRM2B variation is hereditary, and in her case, with a 50 percent chance of being passed to her children. While symptoms don’t typically present until adulthood, Waterhouse is advocating to test her sons for the genetic variant now. “God forbid an accident happens and one of them needs emergency surgery,” she said. “Had I not known they could have this mutation, they could suffer complications like I did. This diagnosis is crucial for keeping me and my family safe and healthy.”

Putting the ‘Counseling’ in ‘Genetic Counseling’

Solving medical mysteries for patients as they did for Waterhouse is one part of what the Penn Neurogenetics Therapy Centerdoes. In addition to the work of genetic counselors, they also focus on establishing clinical trials of molecular and gene therapies for patients with particular genetic disorders. 

When Jim Byelich, an avid runner, suddenly developed a foot drop that neither his primary care provider nor orthopedic specialist could diagnose, a neurologist immediately suspected amyotrophic lateral sclerosis (ALS) based on family history. Seventeen years ago, his brother, one of Jim’s twelve siblings, died of the disease that causes motor nerve cells to break down and reduce functionality in the muscles they supply. He went to see Lauren Elman, MD, a professor of Neurology and director of Penn’s Comprehensive ALS Center, on the recommendation of a family member, who had also undergone genetic testing for ALS.

After clinically diagnosing Byelich with ALS, Elman referred Byelich to Dratch for genetic counseling, and she was able to identify that he carried a variation in the ATXN2 gene that is known to confer increased risk for developing ALS. Dratch highlights the importance of communication during genetic counseling. “We translate complex and uncertain information about health and risk into plain language on a daily basis,” she said. “While it might not be the most satisfying conversation, our priority is to discuss what is known and be transparent about what is not known and why. We want to manage expectations, but also to establish open communication and build trust with patients and their families.”

Fortunately for Byelich, the Penn Neurogenetics Therapy Center had recently helped to launch a clinical trial of an antisense oligonucleotide (ASO) therapy targeting ATXN2. ASO therapies are designed to “turn down” the expression of a specific gene, in this case ATXN2, with the goal of slowing the progression of the disease. With his specific genetic diagnosis in hand, Byelich was able to enroll in a highly targeted clinical trial, and he believes that this experimental therapy has helped his symptoms immensely.

“When you’re diagnosed with something like ALS, you can go down the rabbit hole of joining different groups on Facebook and such, where patients are grasping for solutions,” Byelich said. “For anyone in my shoes, I can’t recommend genetic counseling enough — it told us exactly what kind of treatment to look for, and offered me so much hope. I truly believe I received the benefits I did from treatment because we caught it early, and were able to get specific with treatments.”

There is a high probability that many of Byelich’s other family members carry the same gene variation, and Dratch, the genetic counselor, offered to host a virtual meeting with Byelich and his many siblings, nieces and nephews.

“I could never explain the condition or answer questions as clearly as Laynie,” said Byelich. “She was so helpful in walking them through, and offering guidance on testing, and other steps. She even offered to set up one on one calls with anyone who had further questions.”

Translating Clinical Care to Future Therapies

Launched in March 2020, the Penn Neurogenetics Therapy Center has a team of clinicians, nurses, genetic counselors and clinical research staff who are devoted to the care of patients with inherited neurological disorders and to participating in clinical trials of novel gene and molecular therapies.

The program’s mission is two-fold: first, they utilize the expertise of clinicians and researchers throughout the department of Neurology and across Penn Medicine to achieve a genetic diagnosis for as many patients like Waterhouse and Byelich as possible, creating a database of eligible patients for new treatments and clinical trials. Second, they work to establish clinical trials using novel gene and molecular therapies for patients with genetically-based neurological disorders.

“Our genetics counselors are some of the best in the country, and are incredibly effective at diagnosing patients and matching them with effective treatments and clinical trials,” said Steven Scherer, MD, PhD, a professor of Neurology and director of the Neurogenetics Therapy Center. “Now we can utilize this expertise to design tomorrow’s therapies.”

While the program attracts patients with a number of more “common” genetic neurological diseases — such as ALS, Parkinson’s disease, Huntington’s disease, and frontotemportal dementia — there is no limit to the conditions that it can handle.

“Very few organizations have the operational capacity to run a program like this,” said Sara-Claude Michon, PhD, director of Operations for the Penn Neurogenetics Therapy Center. “But Penn Medicine has made the investment to allow us to realize our potential to be a cutting-edge, future-focused center.”

“Right now, many patients who come to us have to come to terms with living with uncertainty around their diagnosis,” Michon added. “But our mission is to offer the very treatments that give patients and their families a little more certainty, and a lot more hope.”