Bardet-Biedl Syndrome (BBS) is a rare genetic disorder characterized by a multitude of symptoms, including early-onset obesity, hyperphagia (insatiable hunger), vision loss, polydactyly (extra fingers and toes), kidney problems, and developmental delays. Managing the weight of individuals with BBS has been a significant challenge, but recent advancements offer new hope. This article delves into the specifics of BBS, its impact on weight management, and the latest treatment options available.
Understanding Bardet-Biedl Syndrome (BBS)
BBS is a genetically heterogeneous, autosomal recessive disease caused by impaired primary cilium function. This dysfunction affects multiple body systems, leading to a wide range of variable symptoms. The reported prevalence of BBS ranges from 1:100,000 to 1:160,000 in North America and Europe, but may be higher (1:13,500 to 1:18,000) in some isolated populations. BBS is inherited when both parents pass on one BBS gene to their child and evolves slowly throughout the first decade of life, although there is a lot of variability.
Key Characteristics of BBS
- Early-Onset Obesity: Obesity in BBS patients typically begins at an early age, often by age 1, and is progressive. Rapid weight gain is a common component of BBS, occurring during the first year of life in a significant percentage of patients.
- Hyperphagia: Insatiable hunger, or hyperphagia, is a hallmark of BBS, driven by impaired primary ciliary signaling that affects the hypothalamic melanocortin-4 receptor (MC4R) pathway. This pathway is crucial for controlling energy balance, hunger, and satiety.
- Vision Loss: Retinal degeneration and early loss of vision are common in BBS.
- Other Symptoms: Additional symptoms include polydactyly, impairments in renal, hepatic, and cognitive function, and hypogonadism.
Diagnosis of BBS
BBS can be diagnosed based on clinical features (e.g., retinal dystrophy, obesity, postaxial polydactyly) using the Beales diagnostic criteria. The diagnosis may be supported by out-of-country genetic testing. Because it is so rare, BBS may not be recognized early, which may delay the start of treatment and support for at-risk families.
The Challenge of Weight Management in BBS
Patients with BBS experience significant disease-related health burden that both reduces quality of life (QoL) and negatively affects the lives of caregivers, parents, and other family members. Hyperphagia and obesity are among the most distressing manifestations of the disease and constitute a substantial burden for both patients and caregivers.
Impact of Hyperphagia
Primary cilia signaling has an influential role in the hypothalamic melanocortin-4 receptor (MC4R) pathway, which is responsible for controlling energy balance, hunger, and satiety; therefore, impaired primary ciliary signaling results in hyperphagia, an insatiable form of hunger, associated with abnormal food-seeking behaviors. The insatiable hunger children with BBS experience can cause or exacerbate a host of health issues.
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Traditional Weight Management Approaches
Management of obesity in BBS typically follows the same approaches as those used for the general population, such as diet and lifestyle modifications. However, adherence to these practices and sustainability of weight loss are especially low in this population. Lifestyle interventions for obesity management are particularly inefficient and unsustainable in this population because of biologically driven hyperphagia and other potential manifestations of BBS, such as vision loss, behavioural issues, food-seeking behaviours, cognitive impairment, and others.
Limitations of Other Treatments
There are no Health Canada-approved treatments for obesity or control of hunger in patients with BBS. Some pharmacotherapies may be used off-label, such as glucagon-like peptide 1 (GLP1) receptor agonists (e.g., semaglutide injection or liraglutide injection) or gastrointestinal lipase inhibitors (e.g., orlistat). Bariatric surgery with gastric banding or sleeve surgery may be used as a last resort in patients with a body mass index (BMI) greater than 40 kg/m2 or greater than 35 kg/m2 with comorbidities. However, there are significant limitations associated with bariatric surgery. For example, it may be dangerous and lack durability for patients with hyperphagia if the patient’s food environment is not tightly controlled. Additionally, cognitive impairment is common in patients with BBS (affecting approximately 62% of patients).
Imcivree (Setmelanotide): A Breakthrough Treatment
The Food and Drug Administration (FDA) has approved a supplemental indication for Imcivree (setmelanotide) injection for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to Bardet-Biedl Syndrome (BBS). Setmelanotide is the first drug approved specifically for chronic weight management in patients with BBS, a rare genetic disease associated with early-onset childhood obesity.
How Setmelanotide Works
Setmelanotide is an MC4R agonist that restores MC4R pathway signaling. Setmelanotide acts on MC4Rs downstream of the locus for the ciliopathy-related impaired melanocortin signaling seen in BBS. The drug bypasses the leptin signaling disruption and transmits the signal to the brain to stop eating.
Clinical Trial Results
The safety and effectiveness of Imcivree was evaluated in a 66-week trial that enrolled 44 patients with a clinical diagnosis of BBS and obesity (body mass index [BMI] greater than or equal to 30 kg/m2 or BMI greater than or equal to the 97th percentile for pediatric patients), ages 6 years and older. The trial included an initial 14-week, randomized, double-blind, placebo-controlled treatment period followed by a 52-week, open-label period. After 52 weeks of treatment, patients taking Imcivree lost, on average, 7.9% of their BMI. In clinical trials, IMCIVREE was generally well-tolerated.
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Real-World Patient Experiences
An online survey was conducted to capture the real-world experience of patients with BBS and their caregivers regarding setmelanotide treatment and the use of a specialist nurse support service aimed at educating patients and their caregivers, and enabling them to administer injections independently. The survey was administered between January 2024 and May 2024 to participants who began treatment between June 2023 and December 2023 at a single center in Germany. Of the 35 respondents, 10 were pediatric patients, 13 were adult patients, and 12 were caregivers. Setmelanotide reduced feelings of insatiable hunger and had a positive effect on body weight: ≥ 92% of respondents across survey groups reported feeling less hunger, feeling satiated after meals, and a stable body weight or weight loss (mean BMI z-score ± SD at start: 3.12 ± 0.89, change after 6 months: −0.47 ± 0.37). Improvements in mobility, mood, and behavior were also reported. Overall, pediatric patients frequently mentioned feeling fitter and less hungry, but some also noted pigmentation changes.
Administration and Support
Patients with BBS who are treated with setmelanotide may benefit from targeted supportive measures, including patient education and multidisciplinary support from psychologists, nutritionists, and nurses. In Germany, a specialist nurse service was established to support patients with BBS and their caregivers at the start of treatment with daily subcutaneous injections of setmelanotide.
Important Safety Information and Potential Side Effects
Imcivree comes with warnings and precautions: Imcivree is associated with disturbance in sexual arousal; male patients who have an erection lasting longer than 4 hours are instructed to seek emergency medical attention; Imcivree is associated with suicidal ideation and depression; therefore, individuals should be monitored for mood changes and suicidal thoughts; Imcivree is also associated with increases in skin pigmentation, including changes to pre-existing moles; therefore, individuals should undergo a skin examination before and during setmelanotide treatment.
Common Adverse Reactions
The most common adverse reactions (incidence ≥20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.
Specific Warnings and Precautions
- Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred.
- Depression and Suicidal Ideation: Depression and suicidal ideation have occurred. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors.
- Skin Pigmentation and Darkening of Pre-existing Nevi: Generalized increased skin pigmentation and darkening of pre-existing nevi have occurred. Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmentary lesions.
- Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants: IMCIVREE is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome" can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs.
- Serious Allergic Reactions: Stop taking IMCIVREE and get medical help right away if you have any symptoms of a serious allergic reaction including: swelling of your face, lips, tongue, or throat; problems breathing or swallowing; severe rash or itching; fainting or feeling dizzy; rapid heartbeat
Comprehensive Care and Support for BBS Patients
Because BBS can affect almost any part of the body, different specialists may be needed. Regular, ongoing medical visits are an important part of lifelong care. At each visit, the healthcare professional does a physical exam and checks blood pressure and weight. The medical team does blood tests or other tests to check the liver, kidneys, blood sugar and hormone levels.
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Multidisciplinary Team
A variety of specialists may be responsible for caring for people with BBS, including an ophthalmologist, endocrinologist, and nephrologist. Other specialists - such as genetic counselors, special education specialists, and mental health professionals - can also help people navigate life with BBS.
Lifestyle and Home Remedies
If you have Bardet-Biedl syndrome, these tips can help:
- Learn about Bardet-Biedl syndrome.
- Create healthy eating habits.
- Prevent safety issues.
- Get regular physical activity and exercise.
- Learn what support is available.
- Keep regular follow-up appointments with healthcare professionals.
Coping and Support
Living with Bardet-Biedl syndrome can be a challenge for people with BBS and their families. Sharing your feelings with trusted family and friends or with healthcare professionals can help. If your care team includes social workers, they can help you connect with support and resources.
The Role of Marshfield Clinic Health System
Marshfield Clinic Health System is the only health system in the nation that provides comprehensive care for patients with BBS. The Center of Excellence for Bardet-Biedl Syndrome at Marshfield Clinic has become a renowned resource for BBS care and treatment. Patients from across the world come to Marshfield Clinic to see nephrologists, dieticians, dermatologists, ophthalmologists, cardiologists, psychologists and other specialties with extensive familiarity of BBS for comprehensive care and treatment for this disease. In addition, Marshfield Clinic Research Institute also is the home of the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS), the largest worldwide registry examining the long-term health of individuals with BBS.