FDA Patient Listening Session

On May 21, 2025, The Snow Foundation convened a group of patients (3) and caregivers (4) from across the Wolfram syndrome (WS) community for a virtual patient listening session with over 40 representatives from the Food and Drug Administration (FDA). The small, informal virtual meeting was designed to allow community members to share their lived experiences, perspectives, and unmet needs with FDA.

This was the first opportunity for engagement between the community and the Agency and representatives from several areas of FDA, including the Center for Biologics Evaluation and Research, and Center for Drug Evaluation and Research. Specifically, the Office of New Drugs/Office of Neuroscience, and Office of New Drugs/Office of Rare Diseases, Pediatrics, Urology and Reproductive Medicine/Division of Rare Diseases and Medical Genetics, attended. The following WS patients and caregivers generously shared their time and experiences:

Rob. B. (Caregiver)

Father of eight, five of whom died from Wolfram syndrome. One of the earliest advocates and knowledge-sharers in the community. Rob and his wife have spent decades navigating the medical, emotional, and educational complexities of the disease and created an early support website.

Ellie W. (Patient)

23-year-old studying to pursue a career in music therapy. She lives with Wolfram syndrome and openly shares the moment-to-moment challenges of managing type 1 diabetes, vision loss, and progressive neurodegeneration.

Raquel G. (Patient)

20-year-old college student studying International Studies and Spanish. Diagnosed with Wolfram syndrome at age four. Lives with muscle spasms in the throat, vision loss, neurogenic bladder, and trigeminal neuralgia. Passionate about karate, travel, and food.

Elias F. (Patient)

20-year-old psychology student with hopes to further Wolfram syndrome research. Diagnosed with diabetes at 9 and Wolfram syndrome at 11. He manages psychiatric symptoms, chronic fatigue, bladder, and bowel dysfunction, while advocating for treatments that address often-overlooked neurological and autonomic symptoms.

Nancy D. (Caregiver)

Mother to Ford who was diagnosed with Wolfram syndrome in 2021. Committed to early intervention, despite ongoing challenges with communication and progressive sensory loss.

Tracy L. (Caregiver)

Mother to Jennifer, a creative and resilient young woman living with a severe, complex manifestations of Wolfram syndrome. Tracy shares Jennifer’s journey with deep love, highlighting her daughter’s artistic spirit, sense of humor, and unshakable strength. Professionally, Tracy is CEO and Co-Founder of Wolfram syndrome UK.

Pat G. (Caregiver)

Devoted mother to Lauren, who passed away from Wolfram syndrome in 2021. Fierce, compassionate voice for patients and families navigating rare disease care. Patient Liaison Advocate for the Snow Foundation and Global Wolfram syndrome Support Group administrator.

Executive Summary

Quality of life impacts and unmet needs encompass far more than just vision loss and diabetes (brainstem dysfunction, autonomic dysfunction, hearing loss, neurogenic bladder, mental health manifestations, choking, etc.)

• Wolfram syndrome is unpredictable which makes symptom management extremely difficult, and the disease substantially impacts quality of life.
• A meaningful new therapy would stop or slow progression of:
  • Vision loss
  • Hearing loss
  • Diabetes
  • Neurogenic bladder
  • Neuropsychiatric symptoms
  • Choking episodes
• An impactful treatment would result in
  • Increased independence and spontaneity
  • Reduced caregiver burden
  • Reduced anxiety for patients as well as their loved ones
  • Improved sense of health and wellbeing

Meeting Objectives

The main objective of the session was to provide a deeper understanding of Wolfram syndrome—its clinical complexity, emotional and functional burden, and the treatment goals that matter most to the Wolfram community, including both patients and caregivers.

The session was structured as follows:

• Wolfram syndrome Disease Overview, presented by Dr. Sarah Gladstone, a trained pediatrician and Chief Scientific and Medical Officer at The Snow Foundation. Most importantly, Dr. Gladstone is also the mother of a son living with Wolfram syndrome.
• Community Testimonials. In this segment, patients and caregivers described the symptoms that have the greatest impact on daily life, and shared how the disease affects them physically, emotionally, socially, and financially, and discussed their preferences to inform the development of future treatments.
• Moderated Discussion. During this time, speakers shared their perspectives on risk tolerance, what a meaningful therapy would mean for them, and the ways in which they would measure success.
• FDA Question & Answer Session

We are especially grateful to the FDA for creating a space where patients and caregivers can speak candidly about the realities of living with this disease. Listening sessions are a critical step toward ensuring that patient perspectives inform every stage of medical product development—from trial design through regulatory evaluation.

Wolfram Syndrome: Disease Overview

Wolfram syndrome is an ultra-rare, progressive neurodegenerative disorder that causes multi-organ dysfunction. Caused by pathogenic mutations in the WFS1 or CISD2 genes. These mutations result in the misfolding or absence of the Wolfram in or CISD2 protein, leading to cellular stress in the endoplasmic reticulum and mitochondria.

The disease has classically been associated with diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. However, it is now well established that Wolfram syndrome affects nearly every major organ system. While some symptoms may temporarily plateau, the underlying neurodegenerative process continues. To date, no FDA-approved therapies exist that address the root cause of the disease.

Treatment is system-focused and multidisciplinary, often requiring coordination among endocrinologists, neurologists, urologists, ophthalmologists, audiologists, and mental health professionals. Supportive therapies such as insulin, hormone replacements, hearing aids, bladder management, assistive vision devices, and psychiatric care help improve quality of life—but do not slow the disease’s progression.

Wolfram syndrome is far more than a rare form of diabetes or isolated vision loss—it is a devastating, whole-body disease with profound consequences. Its complexity and variability demand more targeted research, earlier diagnosis, and therapeutic innovation that addresses the full spectrum of symptoms. Without disease-modifying treatment, individuals with Wolfram syndrome continue to face a relentless decline in function, independence, and quality of life.

Community Testimonials

Wolfram syndrome is a progressive and multisystem disorder that affects nearly every aspect of daily life. While often first identified through early-onset diabetes or vision loss, the condition extends far beyond its hallmark symptoms—impacting hearing, bladder and bowel function, neurological health, mental well-being, and more.

For individuals and families, life with Wolfram syndrome is shaped by complex care routines, frequent medical appointments, and unpredictable symptom progression. The diagnostic journey is often long and fragmented, as symptoms emerge in varying orders and intensities—leading to delayed diagnosis and years of uncertainty.

At the core of the disease is neurodegeneration, a gradual and irreversible loss of nerve cells throughout the brain and nervous system. This process leads to progressive impairments in movement, breathing, swallowing, temperature regulation, coordination, memory, and behavior. In Wolfram syndrome, neurodegeneration underlies many of the most disabling symptoms and contributes to a loss of independence over time. Patients and caregivers consistently describe neurodegeneration as one of the most distressing and defining aspects of the disease. It does not affect just one area, but steadily erodes multiple systems and senses, often leading to increased dependence, invasive interventions, emotional hardship and, quite often, premature death.

As patient Ellie W. shared: “The most worrisome and emotionally challenging symptom of Wolfram syndrome is the progressive neurodegeneration, because I know that I am slowly losing every sense in my body.”

This symptom progression is echoed in the lived experiences of others. Tracy L., the mother of Jennifer, described how her daughter’s condition advanced to include myoclonic seizures, swallowing impairment, and the need for 24-hour ventilation. Pat G., whose daughter Lauren also experienced late-stage neurodegeneration, witnessed a sequence of devastating complications: loss of smell and taste, life-threatening sodium imbalances, multiple lung collapses, ultimately, leading to the decision to transition to end-of-life care.

These experiences make clear that neurodegeneration is not a single event, but a cascade—one that unfolds over time and touches nearly every aspect of life. This is illustrated by the symptoms that follow, which represent the most disruptive and burdensome aspects of daily living for individuals with Wolfram syndrome and their families.

Symptoms of Greatest Impact

Vision and Hearing Loss

Vision and hearing loss in Wolfram Syndrome are early, progressive, and profoundly isolating—impacting education, independence, communication, and emotional well-being.

“My vision is not explainable one bit… It’s extremely frustrating and extremely challenging for me and for my family.”

– Ellie W. (patient)

“My children and our entire family really became experts in vision loss… They had to wear glasses that looked like opera glasses… One teacher forbade my son from wearing them in class.”

– Rob B. (caregiver)

“(he) is non-verbal, completely deaf, and still not communicating much.”

– Nancy D. (caregiver)

The dual sensory loss strips away not only functional abilities, but also social interaction, independence, and dignity.

Neurogenic Bladder

Neurogenic bladder, a common symptom in patients with Wolfram syndrome, often results in the complete loss of normal bladder control. During the listening session, several patients and caregivers described the need to catheterize multiple times per day, leading to infections, pain, sepsis, and profound disruption to daily life and independence.

“Eventually that didn’t work anymore, so I had to catheterize eight to 15 times a day, which shows how severe the problem is.”

– Raquel G. (patient)

“Six different neurologists told us that her frequent need to urinate was just an attention-seeking behavior, not understanding that she was experiencing neurogenic bladder.”

– Pat G. (caregiver)

“Every time I got a urinary tract infection, I would get intense head pains—sharp, stabbing pain that would last just a few seconds, but was enough to completely derail my day.”

– Raquel (patient)

Choking and Muscle Spasms

Throat and esophageal spasms can cause sudden loss of airway control, often without warning. These episodes can be frightening, physically exhausting, and sometimes life-threatening.

“When I was about 12 years old, this is when my muscle spasms in my throat started. We call those choking episodes… A lot of times I’ll just have to put my finger up, like ‘Give me a minute,’ because I can’t breathe.”

– Raquel G. (patient)

“In 2011 and 2012, Jennifer experienced severe choking attacks, resulting in being ventilated. Following the 2012 attack, a temporary tracheostomy was inserted as the only safe way to get her off the ventilator after three failed attempts.”

– Tracy L. (caregiver)

Mental Health

Wolfram syndrome presents a number of symptoms impacting emotional well-being including depression, ADHD, anxiety, obsessive-compulsive behaviors, executive dysfunction, paranoia, and social withdrawal; mental health symptoms are common with the disease and often appear relatively early. These symptoms are frequently misdiagnosed or misunderstood, delaying access to appropriate care and intensifying the emotional toll on patients and caregivers.

“At first it was ADHD. Then depression. Then OCD-like behaviors. Eventually we realized—it was all connected to Wolfram.”

– Elias F. (patient)

“I’ve been on antidepressants since my junior year of high school. While they’ve helped somewhat, the improvements have been limited. I still have to cope with a lot of these challenges on my own.”

– Elias F. (patient)

“(she) developed obsessive-compulsive disorder… Her constant concern was that someone was going to break into our house and kill the whole family.”

– Pat G. (caregiver)

Fatigue

Fatigue is another debilitating and often overlooked symptom in patients with Wolfram syndrome. It is not simply tiredness, but a persistent, overwhelming exhaustion that interferes with basic functioning.

“I experience chronic fatigue on a daily basis, which is often mistaken for laziness by those around me. Even mild physical activity or movement causes my body to overheat.”

– Elias F. (patient)

Bowel and Gastrointestinal Dysfunction

Gastrointestinal symptoms in Wolfram syndrome include esophageal spasms, painful reflux, bowel urgency, and incontinence. These symptoms are often embarrassing, socially limiting, and under-recognized in both research and care. They affect eating, travel, school, emotional well-being, independence, and overall confidence—creating a need for constant planning and vigilance.

Despite being some of the most disruptive and unpredictable symptoms, GI and bowel dysfunction are frequently overlooked in treatment plans and clinical priorities.

“Oftentimes, we’ll have to abandon eating mid-meal because it can tend to really hurt.”

– Elias F. (patient)

“I experience a lot of sudden bowel accidents… I’ve nearly had to call security at my school a few times to transport me when it becomes painful and I can’t walk.”

– Elias F. (patient)

Burden of Disease and Impact on Quality of Life

Living within the limits of a progressive disease creates a complex and unpredictable reality for those living with Wolfram syndrome.

Impact of Diagnostic Delays and Uncertainty on Disease Management

For many families, the path to a Wolfram syndrome diagnosis is long, fragmented, and emotionally exhausting. Because symptoms appear at different ages and in varying combinations, most patients do not receive a timely, clear diagnosis. Instead, families often spend years navigating misdiagnoses, unanswered questions, and trial-and-error care, all while watching their loved one’s condition progress.

Loss of Independence and Impact on Childhood

Wolfram syndrome often strips children and teens of the simple joys that define growing up.

“Vision loss and hearing loss are isolating, anxiety-inducing, and can really do a number on a teenager… When Lauren started using a white cane, her friends decided they wanted nothing to do with her.”

– Pat G. (caregiver)

“I have to plan everything around restroom access in case of sudden bowel accident.”

—Elias F. (patient)

“Jennifer remains at home with nurse carers and family working hard to keep her occupied… The medical textbooks are thrown out of the window. She has her own set of rules.”

—Tracy L. (caregiver)

“Travel and many other aspects of life require advanced planning… It’s daily anxiety to do anything with him.”

—Nancy D. (caregiver)

“There’s always been an underlying level of alienation from my friends that I feel because there are just certain social events that I can’t partake in…”

—Elias F. (patient)

Emotional Toll on Caregivers

Caregivers are deeply impacted—not just by the physical needs of their loved ones but by the emotional demands of watching them lose function and autonomy. Many describe living in a state of anticipatory grief, fear, and mental exhaustion.

“I told my husband that if this continued, I would need to be hospitalized—and I wasn’t kidding. I was at my wit’s end.”

—Pat G. (caregiver)

“It was the equivalent of watching a family member fall from a very high cliff in horror of the rocks below… There is simply nothing you can do to stop the inevitable result from occurring. But the length of the fall is very, very far.”

—Rob B. (caregiver)

“The hearing and communication is one thing but adding blindness—I can’t imagine what his life will be like, and the daily worry I have for his future is unbearable.”

– Nancy D. (caregiver)

Financial and Logistical Burden

Daily life often depends on a patchwork of solutions to adequately address unmet needs: creative scheduling, split caregiving, nannies, frequent medical appointments, and an assortment of means to address educational and household needs. This is especially hard for working families with multiple children and complex care demands.

“My husband and I both work full time and can’t be in two places at once… Ford has a nanny for his appointments, and the girls have another nanny for their activities.”

—Nancy D. (caregiver)

Moderated Discussion

Perspectives on Risk Tolerance and the Value of Symptom Relief

The following questions explore how patients with Wolfram syndrome and caregivers weigh the risks of treatment and what meaningful symptom relief would mean for their daily lives. Their responses reflect both personal urgency and broader hopes for future therapies.

Question 1: Considering a potentially effective treatment for any of the symptoms discussed, what level of risk or burden would you or your family be willing to tolerate?

Participants expressed a high willingness to accept risk, burden, or uncertainty in exchange for a meaningful treatment, often motivated by both personal need and a desire to help future generations.

“For me, I think it probably depends how large the risk is versus how much benefit results from it. So nothing like super risking to my livelihood, I don’t think, but I would be willing to go through like inconvenience for a medical trial.”

— Elias F. (patient)

“She’s willing to endure anything for an effective treatment… she’s dealt with horrible manifestations very early on. She does not want to see the younger generation go through what she went through.”

— Stephanie G. (caregiver)

“I know in my future I could lose everything… So, I am willing to endure anything. Even if it’s not for me, I want to benefit the people behind me.”

—Ellie W. (patient)

“With where we are currently, we’d be willing to risk pretty much anything.”

—Tracy L. (caregiver)

“Travel to a trial site would be our biggest issue due to the lack of mobility and the 24-hour ventilation and sleepiness with her.”

—Tracy L. (caregiver)

“We would do pretty much anything to ensure Ford’s deterioration stops—especially if we could reverse any of it.”

—Nancy D. (caregiver)

“Lauren fervently wanted a cure for those below her. She would take any risk—even if there was a possibility of death.”

—Pat G. (caregiver)

Community Testimonials

Patients and caregivers emphasized that better symptom control would bring not only physical relief, but life-changing improvements in safety, communication, mental health, and family well-being.

“And if there were a way to halt, even slow down, the progression (of neurodegeneration), it would be extremely meaningful for all of us, and it will help bring all of us confidence knowing that the extension, or the life expectancy of mine, has been extended to some degree.”

—Ellie W. (patient)

“I just want him to be safe. If Ford could communicate or hear danger, or see what’s around him, it would change everything—not just for him, but for our whole family.”

—Nancy D. (caregiver)

“It would be incredible to have more freedom to be spontaneous and not have this anxiety looming over my head.”

—Elias F. (patient)

“Fewer infections would mean fewer stabbing head pains, and fewer canceled plans with my family. That would change everything.”

—Raquel G. (patient)

“Having a treatment specifically targeting the bowel and bladder would decrease the level of anxiety I currently live with.”

– Elias F. (patient)

“If Jennifer were able to see about one foot in front of her, it would dramatically improve her mental health and overall quality of life… She’d be able to see her artwork, our pets, her baby nephew, and the faces of those who care for her.”

– Tracy L. (caregiver)

FDA Question & Answer Session

Although diabetes is often the first symptom of Wolfram syndrome, it received relatively little attention during the session. One listener from FDA raised this directly, asking:

“We didn’t hear much about diabetes—could you share more about how it impacts your daily life?”

Dr. Gladstone explained that diabetes in Wolfram is fundamentally different from other forms of diabetes. Patients often continue producing insulin long after diagnosis, but the insulin release is delayed and unpredictable, leading to dangerous and difficult-to-manage blood sugar swings.

“They make insulin… but it won’t release for three or four hours, and then it dumps—so your blood sugar drops to 20 or 30.”

This delayed insulin response makes standard insulin dosing calculations unreliable.

“It is different every day, and it is not calculable… It’s dangerous for me, it’s a burden for me and for my family—even for my friends if we’re just having dinner.”

– Ellie W. (patient)

Another patient emphasized the unpredictable nature of his condition despite years of experience and experimentation, “Some days I dose very minimal insulin, and my pancreas seems to be working wonderfully. Other days, my blood sugar just won’t go down.”

The consensus: Wolfram-related diabetes is highly unstable, emotionally draining, and contributes significantly to the overall burden of the disease—yet remains under-discussed because of how overwhelming it is to live with.

Another FDA representative asked whether there is a reliable source of information on how genetic mutations in Wolfram syndrome relate to symptoms.

The response made clear that such resources are currently lacking: “There’s not a great source for that information—it’s very limited right now.”

While researchers are tracking genotype-phenotype relationships extensively, much of the data remains unpublished. One speaker noted: “I have a spreadsheet with about 500 known genotypes and their manifestations, but the combinations vary widely and are not well documented. We need someone to take this on.”

Key Takeaways

During the patient listening session, community members voiced the urgency, struggles, and hopes of those living with Wolfram syndrome. Their insights highlight not only the complex, day-to-day challenges of this rare condition, but also the profound impact that a meaningful therapy could make.

Continued collaboration among patients, families, clinicians, and researchers is essential to drive meaningful progress—toward well-tailored treatment options, and ultimately, a future where quality of life is no longer defined by the limits of this disease.

Attendees

Office of the Commissioner (OC) – 1 office

• OC/OEA/PES – Office of External Affairs/Public Engagement Staff (organizer)

Center for Biologics Evaluation and Research (CBER) – 1 office

• CBER/OCD – Office of the Center Director

Center for Drug Evaluation and Research (CDER) – 12 offices

• CDER/OND/OCHEN/DDLO – Office of New Drugs/Office of Cardiology, Hematology, Endocrinology and
  Nephrology/Division of Diabetes, Lipid Disorders and Obesity
• CDER/OND/ODES/DCOA – Office of New Drugs/Office of Drug Evaluation Science/Division of Clinical Outcome
  Assessment
• CDER/OND/ON – Office of New Drugs/Office of Neuroscience
• CDER/OND/ON/DNI – Office of New Drugs/Office of Neuroscience/Division of Neuroscience I
• CDER/OND/OOD/DOII – Office of New Drugs/Office of Oncologic Diseases/Division of Oncology II
• CDER/OND/ORDPURM/DPMH – Office of New Drugs/Office of Rare Diseases, Pediatrics, Urology and Reproductive
  Medicine/Division of Pediatrics and Maternal Health
• CDER/OND/ORDPURM/ DPTRDPURM – Office of New Drugs/Office of Rare Diseases, Pediatrics, Urology and Reproductive
  Medicine/Division of Pharm Toxicology for Rare Diseases, Pediatrics, Urology and Reproductive Medicine
• CDER/OND/ORDPURM/DRDMG – Office of New Drugs/Office of Rare Diseases, Pediatrics, Urology and Reproductive
  Medicine/Division of Rare Diseases and Medical Genetics
• CDER/OND/OSM/DO – Office of New Drugs/Office of Specialty Medicine/Division of Ophthalmology
• CDER/OTS/OB/DBII – Office of Translational Science/Office of Biostatistics/Division of Biostatistics II
• CDER/OTS/DBIV – Office of Translational Science/Office of Biostatistics/Division of Biostatics IV
• CDER/OTS/OCP/DTPM – Office of Translational Science/Office of Clinical Pharmacology/Division of Translational and
  Precision Medicine

Center for Devices and Radiological Health (CDRH) – 3 offices

• CDRH/OM/DAS/CONT – Office of Management/Division of Acquisition Services/Das Contractors
• CDRH/OPEQ/OHTI/DHTIA – Office of Product Evaluation and Quality/Office of Health Technology I/Division of Health
  Technology IA
• CDRH/OPEQ/OHTIII – Office of Product Evaluation and Quality/Office of Health Technology III

Human Foods Program (HFP) – 1 office

• HFP/OPIE/OIE/PHTS – Office of Policy and International Engagement/Office of International Engagement/Public Health and
  Trade Staff

Non-FDA Attendees

Reagan Udall Foundation

National Institutes of Health (NIH)

• NIH/NCATS – National Center for Advancing Translational Sciences

Disclaimer: Discussions in FDA Patient Listening Sessions are informal. All opinions, recommendations, and proposals are unofficial and nonbinding on FDA and all other participants. This report reflects the perspectives of patients and caregivers who participated in the Patient Listening Session with the FDA. To the extent possible, the terms used in this summary to describe specific manifestations of Wolfram syndrome, health effects and impacts, and treatment experiences, reflect those of the participants. This report is not meant to be representative of the views and experiences of the entire Wolfram syndrome patient population or any specific group of individuals or entities. There may be experiences that are not mentioned in this report.

Financial Disclosure: The Snow Foundation wants to inform the FDA that our foundation has no financial interests disclose for the Patient Listening Session on May 21, 2025. Dr. Gladstone flew to Amylyx company offices in September 2024, as a respresentative of The Snow Foundation, to review WS patient preferences for a potential clinical trial. She received a $600 stipend from Amylyx to help defray the cost of her airfare. Stephanie and Raquel Gebel received a small stipend, airfare and hotel cost coverage from Amylyx in September 2024 to be interviewed regarding the WS lived experience and share that experience with the company. Stephanie also attended sessions to advise Amylyx about the needs and priorities of WS patients in a potential clinical trial.
No other participants in the Patient Listening Session have any financial disclosures.

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