Kristen Rohli, PhD, Associate Director of Research at Congenital Hyperinsulinism International, discusses congenital hyperinsulinism (HI) diagnosis and management.

Congenital HI is a condition caused by abnormally high levels of insulin, a hormone that helps control blood sugar levels. People with this condition have frequent episodes of low blood sugar (hypoglycemia). In infants and young children, these episodes are characterized by lethargy, irritability, or difficulty feeding. Repeated episodes of low blood sugar increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and coma.

Early symptoms of congenital HI can be challenging to recognize because they often mimic normal behaviors in babies such as excessive crying and eating or generally feeling displeased or uncomfortable. Other, more severe symptoms such as seizures and blue skin, may prompt more tests to be run. These babies often present with high insulin and low glucose in lab tests. Ms. Rohli highlights that about 60% of patients are diagnosed within the first year of life.

The only FDA approved medication for congenital HI is diazoxide, a nondiuretic benzothiadiazine that primarily acts as an ATP-sensitive potassium channel opener. However, Ms. Rohli explains that around 50% of patients do not respond to this medication. Other medications, such as somatostatin analogs octreotide and lanreotide, are used off-label. There are also currently many investigational treatments going through the clinical trial pipeline.

Congenital Hyperinsulinism International provides support, research, and awareness for patients, caregivers, and families. Clinicians can access international guidelines for diagnosis and treatment and families can view a translation of those guidelines into lay terms and images. Additionally, the organization works to connect families with each other and with a global patient registry. Family conferences are held twice a year where patients and families can meet each other and connect with top researchers. The next conference will be held in Marseille, France in September 2026.

CHAPTERS
Introduction 00:00
Congenital HI Overview 00:12
Symptoms and Diagnosis 00:38
Current Management 2:48
Congenital Hyperinsulinism International 3:29

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Rachel Gafni, MD, Senior Research Physician at the National Institutes of Health, discusses results from the CALIBRATE clinical trial in patients with autosomal dominant hypocalcemia type 1 (ADH1).

ADH1 is a rare form of hypoparathyroidism caused by variants of the calcium‐sensing receptor gene (CASR). Inherited variants of CASR alter the set point for extracellular calcium, resulting in inadequate parathyroid hormone (PTH) secretion and inappropriate renal calcium excretion leading to hypocalcemia and hypercalciuria. The most common symptoms of ADH1 include muscle spasms in the hands and feet, muscle cramping, prickling or tingling sensations, and twitching of muscles.

CALIBRATE (NCT05680818) is a global, phase 3, randomized, controlled, open-label trial testing encaleret to treat patients with ADH1. Encaleret is an investigational, oral, negative allosteric modulator of the CASR.


All participants entered period 1, a 4-week standard of care maintenance period. Participants were then randomized to receive encaleret or continue standard of care in period 2, a 20 week dose titration period. Both treatment groups then entered period 3, a 4 week dose maintenance period, with the final follow-up at week 24. Standard of care treatment includes calcium and active vitamin D, which has been shown to worsen hypercalciuria, which may result in renal calcifications and/or chronic kidney disease.

A total of 67 patients with ADH1 due to 46 distinct CASR variants were randomized and 66 completed period 3. The composite primary endpoint assessed the proportion of those randomized to encaleret achieving target mean albumin-corrected blood calciumn (cCa) and 24-hour urine calcium excretion (UCa) at week 24 of period 3 compared to themselves when on standard of care at week 4 of period 1.

The endpoint was met in 75.6% of encaleret-treated participants at week 24 of period 3, compared to only 4.4% at period 1 week 4 of period 1. Encaleret increased mean cCa by day 3 and decreased mean UCa by week 3 during the dose escalation stage (period 2). These improvements were maintained throughout the study. Within the encaleret group, 91.1% had PTH greater than or equal to 15 pg/mL at week 24 of period 3 compared with only 6.7% at week 4 of period 1. Additionally, 91.1% achieved normal serum phosphate at week 24 compared with 55.6% at week 4.

Additional analyses showed that more participants randomized to encaleret (75.6%) had cCa and UCa within the target ranges by the end of the study compared to those randomized to standard of care (19%).

Encaleret was well-tolerated with no discontinuations in the encaleret arm. Few serious adverse events were reported with frequency similar between treatment arms.

CHAPTERS
Introduction 00:00
ADH1 Overview 00:27
Symptoms and Diagnosis 2:05
CALIBRATE Clinical Trial 8:49

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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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