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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The CheckRare Brief delivers a concise summary of the week's most important developments in rare diseases. Each episode covers FDA approvals, clinical trial updates, conference highlights, scientific publications, and industry news that matter to healthcare professionals, researchers, advocates, and the rare disease community.

Madaline Spenser; Podcast Editor
James Radke, PhD; Education Director
Peter Ciszewski; Founder and CEO, CheckRare

References for this episode’s topics
FDA Advisory Report on Capricor Therapeutics’ Orphan Drug to Treat Cardiomyopathy in Duchenne Muscular Dystrophy
Link to Advisory Board Report is here https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-july-29-2026-meeting-announcement-updated
Link to Capricor’s response is here https://www.capricor.com/investors/news-events/press-releases/detail/351/capricor-therapeutics-provides-update-on-fda-advisory

Cognitive Decline in Immune Thrombocytopenia
Link to interview with Dr. David Kuter is here https://checkrare.com/going-beyond-lab-values-cognitive-impairment-in-patients-with-immune-thrombocytopenia/

August is SMA Awareness Month
Link to our SMA Awareness Page is here https://checkrare.com/august-is-sma-awareness-month/

The CheckRare Podcast Network is dedicated to delivering news, education, and expert insights across the rare disease community. From physician interviews and conference coverage to weekly news updates and patient stories, our family of podcasts connects healthcare professionals, researchers, advocates, industry leaders, and patients with the information that matters most. Produced by CheckRare, each series is designed to advance awareness, education, and clinical care in rare diseases.

For more information, visit www.CheckRare.com

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Stacey Kallish, MD, Clinical Geneticist at Penn Medicine in Philadelphia, is helping to lead a new wave of innovation at the intersection of artificial intelligence (AI) and rare disease care. With a clinical focus on lysosomal storage diseases (LSDs)—including Fabry disease, Gaucher disease, and Pompe disease—Dr. Kallish is exploring how emerging technologies can improve diagnosis, risk prediction, and long-term management for patients with complex genetic conditions.

AI is increasingly becoming a topic of discussion across healthcare, but in rare diseases, its potential impact may be especially significant. These conditions are often difficult to recognize due to their rarity, variability, and overlap with more common disorders. As a result, patients frequently experience delayed or missed diagnoses. AI offers a powerful opportunity to change that.

By training machine learning models on datasets of patients with confirmed rare diseases, researchers can teach these systems to recognize patterns that distinguish affected individuals from those without disease. These models can then be applied to large-scale datasets, such as electronic health records (EHRs), to flag patients who may otherwise go undiagnosed.
Dr. Kallish explains that one of AI’s greatest strengths lies in its ability to synthesize vast amounts of information. “These models can evaluate countless small data points simultaneously—far more than we can realistically process as clinicians,” she notes. This allows AI to detect subtle signals that may not be immediately apparent, particularly in early or atypical cases.

Beyond diagnosis, AI is also being investigated as a tool for predicting disease progression and guiding treatment decisions. In conditions like Fabry disease, clinicians must often determine when to initiate therapy and how to assess a patient’s risk for complications such as stroke or organ damage. AI-driven models have the potential to analyze longitudinal patient data and generate individualized risk profiles, offering more precise and personalized insights.
However, while these applications are promising, Dr. Kallish emphasizes that the field is still evolving. Diagnostic use cases—such as identifying patients through EHR screening or interpreting genetic variants—are likely to reach clinical utility sooner. More complex applications, like optimizing treatment timing or selecting the most appropriate therapy for an individual patient, will require additional validation and real-world evidence.

Importantly, AI is not intended to replace physicians. Instead, it is best understood as a complementary tool—one that can enhance clinical decision-making and improve access to specialized expertise. This is particularly evident in the field of medical imaging.
Studies have shown that AI models can perform at a level comparable to expert radiologists in interpreting imaging studies such as brain MRIs. In some cases, these models even outperform general radiologists. But rather than viewing this as a threat, Dr. Kallish sees it as an opportunity for collaboration.

“The goal is partnership,” she explains. “AI can help us get to better answers, especially in settings where specialized expertise may not be readily available.” For patients in community hospitals or underserved areas, this could mean more accurate diagnoses and improved care without the need for referral to major academic centers.

Another area where AI may have a transformative impact is biomarker development. Currently, clinicians rely on a combination of enzyme assays, molecular testing, and established biomarkers to diagnose and monitor LSDs. AI has the potential to identify new biomarkers that are more sensitive, more specific, and potentially tailored to individual patients. These insights could help clinicians better determine when to initiate treatment, assess disease progression, and evaluate therapeutic response.

Some AI-driven tools are already making their way into clinical practice. One example is FDrisk, a publicly available platform that uses machine learning to estimate the likelihood of Fabry disease based on a series of clinical inputs. By answering a set of targeted questions, clinicians can generate a dynamic risk score and receive guidance on next steps, including whether to pursue diagnostic testing.

At a broader level, researchers are also leveraging AI to analyze patient journeys within healthcare systems. By studying the clinical trajectories of patients with known rare diseases, machine learning models can identify similar patterns in other patients’ records. This approach has already demonstrated success in detecting conditions such as Rett syndrome and Lowe syndrome, highlighting the potential for earlier identification and intervention.

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H. Miles Prince, MD, MBBS, Professor at the University of Melbourne, Australia, and Director, Peter MacCallum Cancer Center, and Director of Molecular Oncology and Cancer Immunology, Epworth HealthCare describes the objectives and results of a new investigation which studied the previous results from the MAVORIC trial in patients with cutaneous T-cell lymphoma with those of patients in an Australian cancer registry.

The mogamulizumab versus vorinostat therapy in previously treated cutaneous T-cell lymphoma (MAVORIC) trial sought to compare the efficacy of the monoclonal antibody mogamulizumab against the standard of care (vorinostat) in patients with mycosis fungoides or Sézary syndrome, which together comprise cutaneous T-cell lymphoma (CTCL).

Patients were eligible if they had failed at least one previous systemic therapy. They were randomized to one of two treatment arms: mogamulizumab or vorinostat. Researchers found that the study was superior in terms of the main clinical endpoint of the study—progression-free survival (PFS) (7.7 mo vs. 3.1 mo; hazard ratio = 0.53; P less than .0001).

The study also included a crossover arm for patients who could not tolerate vorinostat or whose disease progressed. Total overall survival (OS) for the intent-to-treat population taking mogamulizumab was just less than 5 years, but the difference from the comparator group was not statistically significant, possibly due to the crossover arm, according to Dr. Prince. Yet, the regulatory authorities of several countries, including those in northern Europe and Australia, require OS as primary clinical endpoint when seeking market authorization.

To determine whether mogamulizumab exhibited a true OS benefit, his team of researchers evaluated an Australian cancer registry, seeking patients who took vorinostat and who fulfilled MAVORIC study inclusion criteria. Matched to those in the study arm of MAVORIC, they were able to confirm a distinct improvement in OS in those taking mogamulizumab.

The results of this research help fulfill the OS data requirements for regulatory approval of mogamulizumab, but it also raises questions as to whether it should be used first line, especially in patients with aggressive forms of CTCL. Furthermore, it might be interesting to consider mogamulizumab as a foundation for drug combinations in managing this difficult-to-treat cancer.

CHAPTERS
Introduction 00:00
Mogamulizumab Clinical Trial 00:35
Role in Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome 3:24
Influencing Treatment Decisions and Research Efforts 4:53
Regulatory Impact 6:43

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Merlin G. Butler, MD, Medical Geneticist and Professor, Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, and one of the pioneers in Prader–Willi syndrome research, discusses the clinical features of this very rare disease and the critical importance of early identification.

Prader–Willi syndrome was first reported in 1956, and deletions in chromosome 15 were first identified in the 1980s. Dr. Butler has been working on the genetics of Prader–Willi syndrome since that decade.

Dr. Butler said that Prader–Willi syndrome was the first example of a disorder caused by “genetic imprinting,” in which it matters whether genes are contributed by the mother or the father. In 70% of the cases of this disorder, the father’s contribution is missing from chromosome 15q13, and 25% of cases are the result of both copies of chromosome 15 being from the mother (referred to as “disomy”).

Babies born with this genetic anomaly have severe hypotonia, and they have no interest in sucking or feeding. They often have decreased muscle mass and energy. “These infants look like they have a major problem at birth,” stated Dr. Butler. They need to be tube-fed. Once a genetic cause is suspected, Prader-Willi syndrome is quickly diagnosed; it is a very rare disease that also has very unique features. Pediatricians may see only one of these patients every 10 years. Therefore, according to Dr. Butler, “it is the parents who oftentimes make the diagnosis, through what they have seen on the Internet, prompting genetic testing.”

Despite their problems with feeding in the neonatal period, infants with Prader–Willi syndrome will begin to gain an interest in feeding by around age 2 to 3 years. By age 6 years, they develop hyperphasia. “Once their appetite is turned on,” he said, “it is never off.” Uncontrolled, this results in obesity and life-threatening conditions, such as type 2 diabetes and stomach rupture.

Early identification is key, and determining the genetic subtype is extremely important to building a multidisciplinary care team. There are seven different genetic subtypes, which can impact outcomes and management. Typically, the care team will include the medical geneticist and genetic counselors, endocrinologists (to manage the use of growth hormone and diabetes-related treatment), dietitians to manage and monitor caloric intake, mental health experts to address behavioral issues and the risk of self-injury, gastroenterologists, and potentially even sleep medicine professionals. The specialists comprising the care team will change over the patient’s lifespan; occupational therapy and speech therapy may well be required as the patient ages.

The treatment of hyperphagia associated with Prader–Willi syndrome, the number 1 issue, is a particularly active area of research. The idea is to avoid the onset of obesity, which can lead to most of the comorbidities and complications.

CHAPTERS
Introduction 00:00
Prader-Willi Syndrome Overview 00:48
Diagnostic Odyssey 6:30
Multidisciplinary Approach to Management 8:42
Emerging Therapies and Research 10:21
Key Message for Clinicians 11:58
Advice for Newly Diagnosed Families 17:37

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Robert Rapaport, MD, Professor of Pediatric Endocrinology, and Director of the Comprehensive Growth Center at the Icahn School of Medicine, Mount Sinai Medical Center, New York City, discussed the differences between severe, primary IGF-1 deficiency and growth hormone (GH) deficiency in patients with short stature.

In young patients with short stature, GH deficiency is the most common cause. However, in a small subset of patients, the underlying problem is not GH deficiency but an abnormality in insulin-like growth factor-1 (IGF-1) levels. This peptide hormone was first discovered 50 years ago, and IGF-1 deficiency has been found to be caused by mutations in the GH receptor and defects in the IGF-1 gene. In patients with a specific subtype of severe, primary IGF-1 deficiency (SPIGF1D) called Laron syndrome, the specific cause is GH-receptor mutations.

Severe, primary IGF-1 deficiency is generally associated with the following patient characteristics: severe postnatal growth failure, short limb length, typical facial features (e.g., small forehead), and delays in sexual development and skeletal maturation. Crucially, affected children do not respond to a GH stimulation test.

Patients who have abnormally low GH levels can also be considered IGF-1 deficient. On the other hand, if the patient has normal GH levels, IGF-1 concentrations may still be abnormally low. According to Dr. Rapaport, patients with IGF-1 deficiency may be found to have abnormal IGF-1 levels across a spectrum from borderline low to extremely low, the latter of which represents the main feature of SPIGF1D (IGF-1 levels are 5–6 standard deviations below the mean for healthy individuals).

The only effective treatment for SPIGF1D is IGF-1 supplementation, with mecasermin, a human recombinant IGF-1 preparation. Although mecasermin is proven to increase patients’ growth velocity, patients taking the product are expected to attain “near normal” adult height only. It is given twice daily, and it does carry a risk of hypoglycemia, as IGF-1 lowers blood glucose levels. It is thus important that patients and their caregivers are well educated about avoiding this dangerous adverse effect.

CHAPTERS
Introduction 00:00
Primary IGF-1 Deficiency Overview 00:44
Severe IGF-1 Deficiency 3:32
Diagnosis in Children 4:42
Treatment for Severe IGF-1 Deficiency 5:29
Safety Considerations 8:07
Unmet Needs 8:56
Take Home Message 9:36

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Systemic mastocytosis is a rare disease in which excess mast cells are produced and activated, resulting in chronic, severe, and heterogenous symptoms. CheckRare spoke with Patrick C. Foy, MD, a Clinical Hematologist practicing at Froedtert Hospital, Milwaukee, and Associate Professor, Medical College of Wisconsin, about the diagnostic challenges of systemic mastocytosis and optimizing patient care.

Systemic mastocytosis can present as a simple rash, cutaneous lesions, generalized fatigue, or even spontaneous anaphylaxis, said Dr. Foy. That is one of the greatest challenges in diagnosing the disorder. “We have a bias that allergists deal with these types of problems in general,” he noted. A patient with skin lesions and an unexplained elevation of blood tryptase level (greater than 15 ng/mL) should tip off that the cause is systemic, not an external allergen, and systemic mastocytosis may be the cause.

Systemic mastocytosis is classified into two categories, indolent (the most common) and aggressive, which is an advanced form that may threaten damage to organs that have been infiltrated by mast cells. “It’s a paradigm that comes from the oncology world,” explained Dr. Foy. Even though patients with indolent systemic mastocytosis have a longer life expectancy than those with the aggressive form, “It does not mean it is a benign disease,” he said. Patients are still at risk for several chronic symptoms, like fatigue, brain fog, pruritic, rash, diarrhea, and bone pain.
Treatment of patients (commonly with antihistamines) with systemic mastocytosis has been directed at symptom control, but these don’t address the root cause of the problem. In the vast majority of patients, the mast cell proliferation is driven by a gene variant, KIT D816V, “and the more we understand about the biology of mast cells and the regulation, the more we understand about treatment targets,” Dr. Foy stated.

Meaningful clinical benefit would include lower tryptase levels (a surrogate for clinical improvement in mast cell status), lower patient-reported fatigue scores, fewer (or clearance of) cutaneous lesions, and improved quality-of-life ratings. Dr. Foy emphasized that “we have therapies that will impact the patient’s quality of life, they are relatively simple to administer and tend to be effective. We can make a big difference in their lives.”

Our greatest unmet need is to reduce or eliminate diagnostic delays, he said: Patients can remain undiagnosed for years or even decades. That calls for increased awareness by both generalists and specialists.

At Dr. Foy’s institution, he works with allergists and immunologists to optimally treat patients with systemic mastocytosis. “It is a multisystem disease, and it needs a multidisciplinary approach,” he concluded.

CHAPTERS
Introduction 00:00
Challenges in Diagnosing Systemic Mastocytosis 00:41
Signs and Symptoms 1:50
Indolent Systemic Mastocytosis 2:40
Current Management 3:41
Meaningful Clinical Benefit 4:35
Unmet Needs 5:20
Take Home Message for Physicians 6:43

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