Melanie Gander, mother of a son with congenital adrenal hyperplasia (CAH), and Ambassador with Neurocrine Biosciences, discusses her son’s diagnostic journey with congenital adrenal hyperplasia (CAH).

CAH refers to a group of genetic conditions that affect the adrenal glands. Affected people lack an enzyme the adrenal glands need to make one or more of these hormones and often overproduce androgens. For example, females with a severe form of the condition may have ambiguous genitalia at birth and if not properly diagnosed, develop dehydration, poor feeding, diarrhea, vomiting and other health problems soon after. People with milder forms may not be diagnosed with the condition until adolescence or adulthood when they experience early signs of puberty or fertility problems.

Following the birth of her son, Ms. Gander explains that everything was normal. He was eating well and gaining weight as usual. It was not until their newborn follow-up appointment, where his newborn screening results showed slightly elevated markers for CAH, that there were any concerns. The family was then prompted to redo the newborn screening panel, where his levels came back significantly higher for CAH. However, he still showed no signs of disease.

Subsequent metabolic and electrolyte testing, including assessment of 17-hydroxyprogesterone (17-OHP) led to an official diagnosis of CAH, at which point he was started on treatment, even though he showed no signs or symptoms of the disease.

Her son, now 16 years of age, is taking hydrocortisone and following recommendations from the UK that dose 4 times per day following the circadian rhythm. He also takes fludrocortisone to retain sodium levels and started a new treatment a year ago that helps decrease androgen levels and allows for a lower dose of steroids.

Ms. Gander believes her son has a milder form, noting that they have been very lucky in terms of receiving a quick diagnosis and only experiencing a few crises where injection was necessary.

Ms. Gander stresses the importance of advocacy and better knowledge of CAH. There have been many instances where physicians don’t understand the burden of disease on the patient and caregiver, and where paramedics have not understood the disease and what to do in a crisis. She has worked to increase awareness through talks with EMS and implementing protocols for CAH.

CHAPTERS
Introduction 00:00
CAH Overview 00:14
Diagnostic Journey 00:47
Current Treatment 12:43
Importance of Education and Advocacy 15:21

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Kate Stratton, Executive Director of Lipodystrophy United, discusses mental health challenges and care gaps in patients with lipodystrophy.

Lipodystrophies are rare metabolic disorders characterized by the loss of adipose tissue. This leads to complications such as insulin resistance, diabetes mellitus, hypertriglyceridemia, and fatty liver. Lipodystrophies generally begin in childhood and have an underlying autoimmune component associated with its etiology. The disorder can be genetic or acquired. Symptoms that may indicate lipodystrophy include thin arms and legs, prominent muscular veins, cutaneous fat around the abdomen, and difficult to treat diabetes. Current management of patients includes cosmetic surgery, diet, and drug therapy for control of diabetes and dyslipidemia. Leptin replacement therapy is the only lipodystrophy-specific treatment.

Lipodystrophy is also associated with significant mental health burden due to chronic discomfort, altered body habits, chronic disease visibility, and impaired self-image, all of which are under-recognized. At ENDO 2026, a poster presentation characterized the mental health challenges and care gaps faced by patients with lipodystrophies and their caregivers. The study aimed to qualify the mental health burden, identify specific stressors across the care journey, and assess the utilization of support services in the lipodystrophy community to better inform clinical practice.

Of 55 eligible survey-responses, 43 were individuals with lipodystrophy and 12 were caregivers. A total of 75% of participants reported having familial partial lipodystrophy, five having congenital generalized lipodystrophy, and three having acquired generalized lipodystrophy. Multiple mental health difficulties were reported with impact across a wide range of dimensions associated with daily life.

Patients noted that their mental health was at the lowest in the lead up to diagnosis, with the second most affected period being at the time of diagnosis. Mental health experiences in respondents include 85% experiencing chronic stress, 82% low self-esteem, 71% depression, 84% anxiety, 78% embarrassment, and 71% mood swings. These had impacts on 73% od participant’s self-esteem, 65% overall enjoyment of life, 62% sleep/rest, 71% social life, 64% sexual relationships, and 62% romantic relationships.

Of the 43 respondents living with lipodystrophy, 47% were not receiving mental health support. The two most common reasons for this were complete lack of assistance or belief that it was not possible to identify someone who understood the condition. However, 75% of patients answered that mental health concerns were just as important as physical health. Participants would prefer to receive mental health support as (1) online support groups, (2) in-person counseling with a mental health provider, (3) videos or websites, and (4) podcasts.

CHAPTERS
Introduction 00:00
Lipodystrophy Overview 00:12
Treatment and Management 1:44
Mental Health Challenges in Lipodystrophy 2:18
Lipodystrophy United 4:40
Take Home Message 5:19

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Spinal muscular atrophy (SMA) has undergone a remarkable transformation over the past decade. Drs. Nancy Kuntz, Alicia Henriquez, and Angela Lek discuss how advances in disease-modifying therapies have fundamentally changed the outlook for children living with SMA, leading clinicians to rethink what constitutes a successful outcome in SMA care.

Over the past decade, the management and treatment of spinal muscular atrophy (SMA) have been transformed, resulting in remarkable effects on young patients’ neuromuscular function status, mobility, and quality of life. These improvements would have been difficult to imagine just a few years ago and challenge clinicians, researchers, patients, and families to rethink what is defined as a successful outcome in SMA care.

According to Nancy Kuntz, MD, a child neuromuscular specialist from Lurie Children’s Hospital, Chicago, when before the use of newborn screening and the latest treatments, the main outcome of interest was prolonged patient survival. Today, achievable patient outcomes include sitting upright, and walking independently. This is a long way from the palliative view of SMA care. The use of standard measurement scales of patient outcomes need to keep up with evolving expectations of caregivers and patients.

This will require objective data, like biomarkers, x-ray changes, and the ability to see significant changes in motor scale scores, focused on types of motor function that is important to patients. Alicia Henriquez, MD, a pediatric neuromuscular specialist from Seattle Children’s Hospital, pointed to one of the standard functional scales used in therapeutic clinical trials, the Hammersmith Functional Motor Scale Expanded (HFMSE). It is based on 33 distinct functional domains, but not all of those domains are of equal importance to patients and caregivers. And a change in HFMSE scale measurement may not be statistically significant for the purposes of clinical trials, but that incremental change in one domain may be highly important for the individual. The scales do a better job of detecting major changes in function but not what those changes mean for patients.

The Muscular Dystrophy Association (MDA) is helping to bring more light to this issue. Angela Lek, PhD, Chief Research Officer at the Association, described how MDA is sponsoring registry studies to collect real-world outcomes of individuals with SMA. This may result in patient-reported measures that may more-directly reflect improvements that patients believe are important.

CHAPTERS
Introduction 00:00
Can Current Outcome Measures Keep Up? 1:10
The Functional Improvements That Matter Most 22:16
The Patient Perspective and Road Ahead 34:19

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Nancy Kuntz, MD, Child Neuromuscular Specialist, based in Lurie Children’s Hospital, Chicago, discusses how the definition of treatment success and normal development is changing amidst revolutionary therapeutic advances in spinal muscular atrophy (SMA).

With the recent advent of disease-modifying treatments, patients with SMA and their parents can hope for real improvements in clinical outcomes. In fact, it is becoming incredibly difficult to restrain one’s expectations in the face of this new reality. Though not a cure, and many questions need to be answered (e.g., differentiating those at higher risk, who might benefit from combination treatment), attitudes within the SMA environment are more positive than ever.

Essentially, this has changed the definition of clinical success and what we expect in terms of "normal development" of young patients with SMA. And are these measures of greatest importance to patients and their caregivers? Motor scale scores, like the Hammersmith Functional Motor Scale Expanded (HFMSE), provide a great deal of information, but much of it is not relevant to every patient at every stage of the disease. For example, infants cannot cooperate on some scale assessments.

One problem, according to Dr. Nancy Kuntz, is that clinical trials of a new therapy use test subjects who don’t exactly match patients in the real world. How does a treatment work in patients who have some level of leg movement but little or no arm function? The existing scales may be inadequate to show small levels of improvement in different patients. Motor function variables like having more endurance (e.g., holding the head up for hours per day or controlling hand movements) are not captured well on today’s functional scales.

Are current outcome measures adequately capturing what matters most to patients and families today? For a core group of individuals, the ones available today do capture important function, but this applies to a small subgroup of the population.

Many questions remain, including:
- As we gain longer-term follow-up, what have we learned about durability of response, and are we reaching a point where sustained benefit can be considered an expectation?
- As patients live longer and achieve greater independence, how has the outlook for long-term complications and adult life changed?
- Do the new treatment approaches help individuals with SMA who were diagnosed years before it became available?
- Will attempts to treat patients with a prenatal diagnosis of SMA result in benefit?

CHAPTERS
Introduction 00:00
Evolving Definitions of Success 2:03
Current Outcome Measures 7:10
Changing Expectations 8:10
Effects of Newborn Screening and Pre-Symptomatic Treatment 11:18
Unmet Needs 12:57
Awareness Months 17:41

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Alicia Henriquez, MD, Pediatric Neuromuscular Specialist, Seattle Children’s Hospital, offered that seemingly minor improvements in existing SMA motor function scales may actually represent significant improvements in activities that are important to patients and their caregivers.

Today’s targeted treatments and gene therapies for SMA are a world away from our approach in 2015, when palliative care was all that could be offered, focused on the management of pain and quality of life. Today, we can address the things that truly matter to the patient and caregiver. Our ability to address the natural history of SMA and motor function deterioration have been game changing to children and their parents.

Historically, motor function scales used to assess SMA were considered objective methods for researchers to measure the clinical effects of an intervention. The Hammersmith Functional Motor Scale Expanded scale might reveal an incremental improvement in a couple or a few of its many domains. A change of that magnitude may not be statistically significant in terms of a clinical trial, but for patients, it may actually result in very noticeable improvement in a single important function, like sitting up straight for an extended period.

For clinicians, these motor function scores provide clinicians with objective data, but it doesn’t yield useful information about the day-to-day life of the patient, according to Dr. Henriquez. Instead, she advises, listening more to what the patients and caregivers are saying about the improvements that would be most important to them.
Over time, the definition of a successful outcome in SMA will need to evolve, to better reflect the state of the art and to perhaps emphasize changes that mean more to the patients/families.

CHAPTERS:
Introduction 00:00
Evolving Patient Outcomes 00:36
Functional Outcome Measures 2:21
Interpreting Functional Scores 3:20
Considering Additional Outcome Measures 5:00
Advice to Newly Diagnosed Families 5:54
Choosing Treatment 6:46
Unmet Needs 7:53
The Changing Definition of Success 9:11
Take Home Message 9:44
New Scales 11:11

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Angela Lek, PhD, Chief Research Officer, Muscular Dystrophy
Association (MDA), describes how the introduction of disease-
modifying therapies for spinal muscular atrophy (SMA) has pushed
the boundaries of health outcomes and developmental milestones.

The landscape for treating SMA has been completely transformed over the last decade, with multiple disease-modifying therapies that address the underlying cause of SMA. Indeed, it is one of the great success stories in neuromuscular medicine, according to Dr. Lek.

The impact of these targeted and gene therapies on families has been extraordinary. Children with SMA are attaining milestones not dreamed of a decade ago, and even participating in sports. Furthermore, there is still room to improve outcomes for people with SMA.

In 2026, successful treatment of SMA is increasingly measured in broad real-world outcomes, such as independence and even employment. For example, preserved hand function for one patient with SMA may enable expansive use of a computer, making employment a more-attainable goal. For another individual, success may be defined as having enough energy to function outside of the home.

These types of functional improvements are not always captured by measurement tools such as the Hammersmith scale. As a result, patient-reported outcomes are increasingly important, according to Dr. Lek.

Contributing to this effort, the MDA is developing a robust patient registry that collects real-world outcomes. Through this patient-centered platform (called MOVR, for neuroMuscular ObserVational Research), individuals with one of several disorders (including SMA) input information from their individual care journey. The Association hopes that the registry will produce high-quality, longitudinal data that can shape long-term research priorities and care.

CHAPTERS
Introduction 00:00
Evolving SMA Landscape 00:49
Choosing Treatment 4:33
Importance on Newborn Screening, Early Diagnosis, and Specialized Care 6:18
Functional Outcome Tools 8:22
SMA Patient Registry 10:15
Unmet Needs 12:41
Ongoing Research 14:46

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Spinal muscular atrophy (SMA) has undergone a remarkable transformation over the past decade. Drs. Nancy Kuntz, Alicia Henriquez, and Angela Lek discuss how advances in disease-modifying therapies have fundamentally changed the outlook for children living with SMA, leading clinicians to rethink what constitutes a successful outcome in SMA care.

Over the past decade, the management and treatment of spinal muscular atrophy (SMA) have been transformed, resulting in remarkable effects on young patients’ neuromuscular function status, mobility, and quality of life. These improvements would have been difficult to imagine just a few years ago and challenge clinicians, researchers, patients, and families to rethink what is defined as a successful outcome in SMA care. 

According to Nancy Kuntz, MD, a child neuromuscular specialist from Lurie Children’s Hospital, Chicago, when before the use of newborn screening and the latest treatments, the main outcome of interest was prolonged patient survival. Today, achievable patient outcomes include sitting upright, and walking independently. This is a long way from the palliative view of SMA care. The use of standard measurement scales of patient outcomes need to keep up with evolving expectations of caregivers and patients.This will require objective data, like biomarkers, x-ray changes, and the ability to see significant changes in motor scale scores, focused on types of motor function that is important to patients.

Alicia Henriquez, MD, a pediatric neuromuscular specialist from Seattle Children’s Hospital, pointed to one of the standard functional scales used in therapeutic clinical trials, the Hammersmith Functional Motor Scale Expanded (HFMSE). It is based on 33 distinct functional domains, but not all of those domains are of equal importance to patients and caregivers. And a change in HFMSE scale measurement may not be statistically significant for the purposes of clinical trials, but that incremental change in one domain may be highly important for the individual. 

The scales do a better job of detecting major changes in function but not what those changes mean for patients.The Muscular Dystrophy Association (MDA) is helping to bring more light to this issue. Angela Lek, PhD, Chief Research Officer at the Association, described how MDA is sponsoring registry studies to collect real-world outcomes of individuals with SMA. This may result in patient-reported measures that may more-directly reflect improvements that patients believe are important.For more information on SMA visit https://checkrare.com/spinal-muscular-atrophy-a-decade-of-progress/

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Chadi Nabhan, MD, Hematologist and Oncologist, Chief Medical Officer at Ryght AI, and Vivek Subbiah, MD, Professor of Medicine at Stanford University and Executive Medical Director of Novel Therapies & Clinical Trial Network at Stanford Health Care, discuss the need for better classification systems in precision oncology.

The 1983 Orphan Drug Act (ODA) defined rare diseases as those affecting fewer than 200,000 Americans, resulting in regulatory incentives that transformed drug development. Since then, oncology has accounted for 38% of all orphan designations and approvals sanctioned by the US Food and Drug Administration (FDA).

An editorial published in the Journal of Clinical Oncology seeks to address the implications this framework and definition have on modern precision oncology and its original intention to enable and advance progress. Drs. Nabhan and Subbiah propose in their thesis that every cancer is effectively a rare disease and should be recognized as such, fundamentally challenging how malignancies are classified, studied, regulated, and treated.

In oncology today, cancers are grouped by subtype, often depending on the specific gene mutations involved. Each of these subtypes have their own unique natural history, treatment responses, and outcomes. When defined at this level, nearly all cancers could be defined as a rare disease, thus requiring new systems of treating cancer.

While drug development often focuses on these rare populations, there is a disconnect in how these diseases are framed in clinical practice, health care delivery, and public discourse. This results in misaligned expectations in clinical trials, inadequate molecule biomarker testing, and misaligned investment incentives for pharmaceutical development.

One concern in labeling most or all cancers are rare is that could weaken the current framework that was designed to advance orphan drug development. Defining all diseases as rare because of their molecular subdivisions may render the term “rare” meaningless. Treating every cancer as rare could also overwhelm regulatory systems and orphan designation reviews could take years. Additionally, this classification would exacerbate already struggling health care delivery to stay current with genomic testing and targeted therapies. Finally, taking this mindset to its logical conclusion every patient can be labeled as having a rare disease based on their unique molecular profile, ultimately defeating the purpose of disease classification entirely.

To overcome these concerns, Drs. Nabhan and Subbiah propose a new way to define and classify rare cancers. They propose a Tiered Rarity Classification System (TRCS) which defines diseases as: Common (prevalence threshold of less than 50 per 100,000), Uncommon (10-50 per 100,000), Rare (less than 6 per 100,000 (US/EU), Ultra-Rare (less than 1 per 100,000), Exceptionally Rare (less than 0.1 per 100,000; Case reports/series level; molecular subsets), and Compounded Rarity (less than 0.1 per 100,000; Ultra-rare cancer plus ultra-rare biomarker).

However, it is stressed that the real solution is not formally reclassifying all cancers as rare diseases, but in building systems that effectively respond to molecular rarity, clinical trial design, regulation of therapies, and delivery of care.

CHAPTERS
Introduction 00:00
Should Every Cancer Be Considered Rare? 00:27
Clinical Trial and Regulatory Implications 6:22
Proposed Incentive Structure 9:42
Next Steps 17:50

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Andrew Kuykendall, MD, Clinical Researcher at Moffitt Cancer Center, discusses the role of rusfertide in decreasing phlebotomies in patients with polycythemia vera (PV).

PV is a condition characterized by an increased number of red blood cells. Affected people may also have excess white blood cells and platelets. The excess cell levels lead to thicker blood and increased risk for blood clots. PV occurs more frequently in men than it does in women. The condition has been associated with genetic changes in the JAK2 and TET2 genes.

Rusfertide is a first-in-class hepcidin mimetic peptide observed to reduce the need for phlebotomy and control hematocrit levels by regulating iron distribution and restricting iron availability for red blood cell production in patients with PV.

Dr. Kuykendall explains how phlebotomies have become so ingrained in the treatment of PV, that the burden it places on patients has not been adequately addressed. However, a recent focus on patient burden is bringing the impact of this treatment strategy to light. Frequent doctor’s office and hospital visits to get labs checked and then get phlebotomies every two to three weeks greatly limit patient’s freedom and autonomy.

While these phlebotomies may help the overproduction of red blood cells in these patients, they do not address the iron deficiency and consequent fatigue, brain fog, and other disabling symptoms that affect patient’s daily lives. Dr. Kuykendall explains how the development of rusfertide was based on mimicking a high-hepcidin state to increase iron levels, control hematocrit, and decrease the need for phlebotomy by reestablishing balance of iron regulation, thus improving fatigue and disease-related symptoms. Additionally, rusfertide may be added to patients on cytoreductive therapy doses that are higher than are comfortably tolerated, to help more optimally dose patients.

Unmet needs still exist for patients with PV, including the development of therapies that address the underlying JAK2 mutation that causes disease, as well as those that prevent progression.

Finally, Dr. Kuykendall highlights that rusfertide was developed by listening to patients and that it should be used in practice the same way, stressing the importance of focusing on how the disease affects them and how this treatment could fit into patients’ lives.

To learn more about PV and other rare hematologic conditions, visit https://checkrare.com/diseases/hematologic-disorders/

CHAPTERS
Introduction 00:00
Burden of Phlebotomies in PV 00:37
Patients’ Input in Developing Rusfertide 2:14
Unmet Needs in PV 4:49
Impact of Potential Rusfertide Approval 7:19
Take Home Message 9:39

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