Brian Moseley, MD, Senior Medical Director at UCB, discusses the GEMZ clinical trial of fenfluramine in patients with CDKL5 deficiency disorder (CDD).

CDD is a rare genetic disorder characterized by difficult‑to‑control seizures and severe neuro‑developmental impairment. It’s caused by a mutation of the cyclin-dependent kinase-like 5 (CDKL5) gene, located on the X chromosome.

At the American Association of Neurology 2026 meeting, primary results were presented from the GEMZ (NCT05064878) clinical trial of fenfluramine in patients with CDD. GEMZ is a phase 3 randomized, double-blind, placebo-controlled, fixed-dose, multicenter study evaluating the safety and efficacy of fenfluramine. Fenfluramine is a phenethylamine that is structurally similar to serotonin that has been proven to be effective in treating pharmacoresistant seizures.

Patients were randomized to fenfluramine 0.7 mg/kg/day or placebo over 14 weeks (including a two week titration period [T] and a 12 week maintenance period [M]). The primary endpoint was countable motor seizure frequency (CMSF) percentage change from baseline over T+M versus placebo.

Safety and modified intent-to-treat populations included 87 and 86 patients, respectively. Most patients received 3 or more concomitant anti-seizure medications. Baseline median CMSF was 44 for patients on fenfluramine and 49 for patients on placebo.

Significant differences in efficacy endpoints were observed with fenfluramine versus placebo. Median percentage CMSF change was −47.6% for fenfluramine versus −2.8% for placebo. A total 45.2% of fenfluramine-treated patients achieved 50% or greater CMSF, compared to 4.5% of placebo patients. Additionally, 38.1% on fenfluramine versus 6.8% on placebo demonstrated clinically meaningful improvement on Clinical Global Impression–Improvement scale. Median percentage change in generalized tonic-clonic seizure frequency from baseline was −61.5% for fenfluramine (n=14) and −13.5% for placebo (n=18).

Four patients discontinued due to treatment-emergent adverse events. Of patients on fenfluramine, the most common adverse events were pyrexia, diarrhea, and somnolence. No new safety signals identified and no valvular heart disease or pulmonary arterial hypertension cases observed.

To learn more about CDD and other rare neurological conditions, visit https://checkrare.com/diseases/neurology-nervous-system-diseases/

CHAPTERS
Introduction 00:00
CDKL5 Overview 00:12
GEMZ Clinical Trial Data 1:40
Next Steps 5:16
Targeted Diagnosis and Treatments 5:38
What Physicians Should Know 7:45

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Colin Lake, Head of Digital Business Transformation Neurology at UCB, discusses CareCompass, an online tool for caregivers of patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

DS is the most severe of a group of conditions known as SCN1A-related seizure disorders. Early signs typically include febrile seizures but as the child continues through childhood, other types of seizures may occur and increase in frequency. Other symptoms include loss of motor skills, intellectual disability, speech impairment, and difficulty with movement. Most cases of Dravet syndrome occur due to mutations within the SCN1A gene.

LGS is another form of severe epilepsy that begins in childhood. It is characterized by multiple types of seizures and intellectual disability. This condition can be caused by brain malformations, perinatal asphyxia, severe head injury, central nervous system infection and inherited degenerative or metabolic conditions. In about one-third of cases, no cause can be found.

Caregivers of patients with DS or LGS face significant financial, physical, and emotional burden due to the demanding nature of these diseases. Of note, caregivers report struggling with fragmented care information across multiple sources that make organization difficult.

CareCompass is a website developed to provide caregivers of individuals with DS or LGS with templates, tools, and emotional support to manage everyday challenges and relieve this burden. Unmet needs of caregivers and providers were identified through focus groups and double-blinded interviews. Once the CareCompass website was designed, a 4 week pilot period was conducted to assess usability, acceptability, and preliminary impact.

Over the 4 week pilot, 21 caregivers participated. Satisfaction was high and caregivers valued having access to essential care details, such as medications, emergency contacts, routines, stored securely in one place. The website allowed for the creation and sharing of care guides, tracking wellbeing, and a journaling feature to log seizure-related and general observations. Participants noted that a mobile app version would also be beneficial.

Through the consolidation of information, CareCompass has the ability to simplify communication and care coordination. Future studies should evaluate the long-term impact of the tool on caregiver burden, confidence, and healthcare system engagement.

To learn more about CareCompass, visit https://care-compass.io/

CHAPTERS
Introduction 00:00
Dravet and LGS Overview 00:36
CareCompass Online Tool 2:01
Take Home Message 7:54

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Dena Sherwood, mother to a neuroblastoma survivor and Founder of Arms Wide Open Childhood Cancer Foundation, discusses CureFest.

Ms. Sherwood and her family founded the Arms Wide Open Childhood Cancer Foundation following the struggles their son experiences with neuroblastoma. The organization provides financial and emotional support for families at any stage of the childhood cancer journey. Some of their programs include funding of research and clinical trials, bereavement retreats, survivor retreats, and CureFest.

CureFest is an annual, three-day event that takes place in Washington, DC and is open to families and patients affected by childhood cancer. The goal of CureFest is to raise awareness, build community, and have lawmakers, clinicians, researchers, and families come together in support of the childhood cancer community and amplify their voices.

This year’s CureFest will be held September 18-20, 2026. For more information, visit https://www.curefestusa.org/.

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Tuan Vu, MD, Professor, Department of Neurology at the University of South Florida, discusses positive results of cemdisiran in patients with generalized myasthenia gravis (gMG).

MG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. The condition results from a defect in the transmission of nerve impulses to muscles due to the presence of antibodies against the acetylcholine receptor. The exact reason this occurs is not known.

Cemdisiran is a RNA interference (RNAi) therapy designed to silence the C5 gene, thereby dampening the complement system that appears to be involved in the pathophysiology of gMG.

Positive results from the phase 3 NIMBLE clinical trial (NCT05070858) of cemdisiran in adults with gMG were recently presented at the 2026 American Academy of Neurology (AAN) Annual Meeting and published in The Lancet. Cemdisiran is a novel siRNA therapeutic designed to durably reduce circulating levels of complement factor 5 (C5). The trial enrolled a total of 123 patients, with 59 in the placebo group and 64 patients treated with subcutaneous cemdisiran every 12 weeks.

Compared to placebo, at week 24, a 4.5-point improvement from baseline on the Myasthenia Gravis Activities of Daily Living (MG-ADL) total score was observed. Notably, 76.6% of cemdisiran-treated patients had a 3-point or greater improvement, versus 44.1% for placebo. Clinically meaningful improvements in MG-ADL total score occurred within 2 weeks in cemdisiran-treated patients.

Additionally, a 4.2-point improvement from baseline in Quantitative Myasthenia Gravis (QMG) total score was observed in the cemdisiran group, versus a 1.5-point improvement in the placebo group. Notably, 48.4% of cemdisiran patients had a 5-point or greater improvement, compared to 19% for placebo. Improvements in QMG total scores occurred within 2 weeks in cemdisiran-treated patients.

The most common AEs were: worsening of MG, upper respiratory tract infection, urinary tract infection, nasopharyngitis, headache, rash, and diarrhea. One or more treatment-emergent adverse events occurred in 69.2% of patients receiving cemdisiran and 77.1% receiving placebo. Most AEs were mild-to-moderate in severity.

To learn more about MG and other rare autoimmune conditions, visit https://checkrare.com/diseases/autoimmune-autoinflammatory-disorders/

CHAPTERS
Introduction 00:00
Myasthenia Gravis Treatment Landscape 00:24
Cemdisiran Overview 1:58
NIMBLE Clinical Trial 3:04
Clinically Meaningful Results 4:52
New Dosing and Effect on Patients 5:46
Take Home Message 6:21

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Daniela Carvalho, MD, MMM, pediatric otolaryngologist at the University of California, San Diego, discusses the approval of Otarmeni (lunsotogene parvec) for the treatment of patients with otoferlin (OTOF)-related hearing loss.

The US Food and Drug Administration (FDA) has granted accelerated approval for Otarmeni (lunsotogene parvec) for the treatment of patients with OTOF-related hearing loss. The indication includes pediatric and adult patients with severe-to-profound and profound sensorineural hearing loss associated with molecularly confirmed biallelic variants in the OTOF gene, preserved outer hair cell function, and no prior cochlear implant in the same ear.

OTOF-related hearing loss is a rare genetic auditory synaptopathy that results from defective synaptic transmission from normally functioning cochlear inner hair cells to the auditory nerve. The condition typically results in deafness at birth and current management involves cochlear implants.

Lunsotogene parvec, previously known as DB-OTO, is an adeno-associated virus vector-based gene therapy designed to deliver a working copy of the OTOF gene and restore durable, physiological hearing. It is administered via an infusion into the cochlea, similar to the procedure used for cochlear implantation.

The FDA approval is based on results from the CHORD clinical trial (NCT05788536), in which 20 participants, ages 10 months to 16 years, received a single dose of lunsotogene parvec, either unilaterally (n=10) or bilaterally (n=10). The CHORD study is an ongoing, multicenter, open-label, registrational clinical trial evaluating the safety and efficacy of lunsotogene parvec in patients with OTOF-related hearing loss.

Hearing improvements per pure tone audiometry assessments at a threshold of 70 or less dB HL at 24 weeks was observed in 80% of patients. One additional participant achieved this threshold by week 48. Additionally, 70% of patients demonstrated an auditory brainstem response at 90 or less decibels at 24 weeks. At 48 weeks, all prior responders maintained a response to therapy and 42% of participants achieved normal hearing that included whispers.

The most common adverse events in the safety population (n=24) associated with therapy included otitis media, vomiting, nausea, dizziness, procedural pain, gait disturbance, and nystagmus.

Lunsotogene parvec is the first gene therapy and second new molecular entity approved under the FDA’s National Priority Voucher program. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory portion of the CHORD clinical trial.

CHAPTERS
Introduction 00:00
Otoferlin-Related Hearing Loss Overview 00:45
Limitations to Current Interventions 2:07
Otarmeni Overview 3:04
CHORD Trial Results and Clinical Experience 3:48
Early Diagnosis, Patient Selection, and Referral Pathways 5:33
Take Home Message 7:01

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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.  

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Dareen D. Siri, MD, FAAAAI, FACAAI is a board-certified allergist and immunologist practicing at Midwest Allergy Sinus Asthma, based in central Illinois. She talked with CheckRare about a unique, rare disorder called systemic mastocytosis. 

Systemic mastocytosis involves the proliferation of mast cells, which can accumulate in various areas of the body. The early signs of mastocytosis can be quite variable, said Dr. Siri, and include cutaneous spots or an extensive rash; gastrointestinal symptoms like diarrhea, bloating, or perceived new food intolerance; or even anaphylactic reactions. 

Patients may present with what looks like an allergic reaction, she added, and some patients do not have a very high mast-cell burden. This variability may pose a challenge to accurate diagnosis. Most patients experience some level of fatigue. Patients may also complain of bone pain or “feeling like they have the flu every day.”

Dr. Siri pointed out that these patients may have many symptoms. A convincing allergic reaction that gives a strong gastrointestinal and perhaps an anaphylactic reaction, may suggest to clinicians that mast-cell proliferation is the root of the problem.

Once a clinician suspects systemic mastocytosis as the cause, a key step is obtaining a blood test for increased tryptase levels, which can serve as “a good screener, at least.” However, this is not sufficient alone. A bone marrow biopsy and histology will confirm the diagnosis. An acquired (not inherited) genetic variant (KIT D816V), is present in the stem cells of nearly all patients with systemic mastocytosis.

Systemic mastocytosis comes in two forms—aggressive and indolent. She cautioned that indolent mastocytosis should not necessarily be considered a disorder with a mild course. The rash can be quite extensive and the potential for anaphylactic reactions can result in loss of consciousness and falls. 

Exciting new therapy offers promise to long-suffering patients that this chronic condition can be treated at the source: targeting the genetic mutation responsible. Finally, patients have more than antihistamines and leukotrienes to alleviate their symptoms. 

Dr. Siri concluded that “It’s important for patients to know that this condition is acquired during their lifetime,” and it is not inherited or congenital. Even though the body is now making abnormal mast cells, patients can live a normal, full life.

CHAPTERS
Introduction 00:00
Early Signs and Symptoms 00:36
Indolent SM Variability 1:45
Most Burdensome Symptoms 2:45
Key Steps to Diagnosis 3:38
Approach to Management With Newer Therapies 4:53
What Physicians Should Know 5:20
Take Home Message for Patients 6:41

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Arthur Beisang, MD, Department of Pediatrics at Gillette Children's Specialty Healthcare in Saint Paul, Minnesota, discusses Daybue (trofinetide) Stix, a new formulation of the treatment for Rett syndrome.

Rett syndrome is a neurodevelopmental condition that primarily affects girls. People with the disease appear to have normal psychomotor development during the first 6 to 18 months of life, followed by a developmental "plateau," and then rapid regression in language and motor skills. Additional signs and symptoms may include repetitive, stereotypic hand movements, fits of screaming and inconsolable crying, autistic features, panic-like attacks, teeth grinding, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and slowed head growth. Classic Rett syndrome is most commonly caused by genetic changes in the MECP2 gene.

Trofinetide is a synthetic analog of the N-terminal tripeptide of insulin-like growth factor-1, approved for treatment of Rett syndrome in 2023. Daybue Stix is an oral, dye- and preservative-free powder formulation of the treatment approved in December 2025 and now available in the US for patients 2 years of age and older.

The new formulation has the same efficacy and safety profile of the original formulation, based on results from the phase 3 LAVENDER (NCT04181723) study, while also giving patients flexibility and choice in dose volume and taste of treatment. The approval of this new formulation was informed by the results of a bioequivalence study, which demonstrated that both the original Daybue oral solution and the new Daybue Stix formulation provide comparable exposure.

Daybue Stix comes as a powder that can be mixed with a variety of water-based liquids to customize to a patient's preference of taste. The product comes in individual packets that are easily portable and do not have to be refrigerated unlike the original formulation.

A recent publication of expert recommendations for real-world use of trofinetide in Rett syndrome emphasized the importance of patient-centered approaches. Experts from International Rett Syndrome Foundation-designated centers of excellence agreed that treatment options that allow for individualized decision making help optimize outcomes for patients, families, and caregivers.

CHAPTERS
Introduction 00:00
Rett Syndrome Overview 00:26
Patient Improvements With Daybue Stix 1:13
Impact on Real-World Outcomes 2:36
Choosing Treatment 4:00
Impact on Caregivers 5:13
Unmet Needs in Rett Syndrome 6:53
Take Home Message 9:08

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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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