Bardet-Biedl syndrome (BBS) is a rare autosomal-recessive genetic disorder with a wide array of symptoms and complications. It is characterized by abdominal obesity, mental retardation, dysmorphic extremities (syndactyly, brachydactyly or polydactyly), retinal dystrophy or pigmentary retinopathy, hypogonadism or hypogenitalism (limited to male patients), and kidney structural abnormalities or functional impairment. BBS is now considered a significant cause of chronic and end-stage renal disease (ESRD) in children. Its reported prevalence is 1/100,000, with a predicted heterozygote frequency of 1/160.
Understanding Bardet-Biedl Syndrome
BBS is a complex disorder leading to a wide array of symptoms and complications. Among these, eye problems, obesity, polydactyly (extra digits), kidney problems, reproductive issues, and intellectual impairment are the most common. However, every person living with BBS has a different experience. Some will only have a few of these symptoms, while others may have different and less common effects.
BBS is a genetic disorder, and there’s currently no cure. The primary goal of treatment is the management of symptoms to improve quality of life and reduce the likelihood of additional complications. Since so many organ systems are involved, 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.
Genetic Basis and Diagnosis
BBS is a fully penetrant autosomal recessive condition, with variable expressivity. Genetic testing is of utility for diagnosis, genetic counselling, as well as for inclusion in trials or specific prescriptions. Definitive BBS molecular diagnosis requires identification of pathogenic or likely pathogenic bi-allelic variants (class 4/5 of the American College of Medical Genetic and Genomics (ACMG) variant classification) in a given BBS gene. Currently, the total mutational load, taking into account all BBS genes and modifier loci, together with possible epistatic effects and environmental factors, is thought to contribute to the clinical variability of BBS patients but is not considered in routine diagnosis.
At least 26 genes are reported, most well confirmed, but a subset still has limited evidence and needs further replication to date. Four categories of BBS genes are described: BBSome members, chaperonin-like members, Intra Flagellar Transport (IFT) genes and others. The detection rate of pathogenic variants in patients that fulfil the clinical diagnostic criteria for BBS is high (> 90%). About 40-50% of pathogenic variants in Europe are identified in BBS1 and BBS10. Two common founder variants are well recognized: 1) BBS1 exon 12: c.1169 T > G p.(Met390Arg) and 2) BBS10 exon 2c.271dupT p.(Cys91Leufs*5). While the common BBS1 variant is usually absent in non-European descending populations, the BBS10 common variant can be found worldwide. Except for the two mentioned changes and specific population founder variants, most variants are private and many are truncating with straightforward categorization as class 4 or 5 variants. The detection rate also depends on the method used: NGS-based approaches (panel, Whole Exome and Whole Genome Sequencing (WGS)) offer further advantages compared to conventional Sanger sequencing such as the possibility of detecting copy number variants. To date, it is recommended to use panels (with all BBS genes and main differential diagnosis such as Alström syndrome (ALMS, OMIM#203800, ORPHA: 64) and other overlapping ciliopathies) in first intention for diagnostic purposes. Segregation analysis with the parents DNA is always highly recommended especially: 1) for homozygous variants to rule out a masked deletion on one of the parental alleles or a uniparental disomy and; 2) for compound heterozygotes to confirm the bi-allelic status (NB: de novo variants occur in rare cases). Partners of healthy heterozygous carriers (usually siblings) can be tested to evaluate the recurrence risk, especially in the context of BBS1 and BBS10 common variants or if they belong to a population with a founder variation. When the genetic testing confirms bi-allelic pathogenic status, according to the facilities accessible and regulation in a given country, couples can opt for prenatal genetic testing or preimplantation genetic testing. Non-invasive genetic diagnosis via cell free foetal DNA is not common but available in some European centres.
Read also: Diet and Ogilvie Syndrome
Clinical Manifestations and Monitoring
BBS diagnosis can be made at any age, due to clinical variability of pleiotropic symptoms and asynchronous manifestations.
In utero manifestations are often observed during the second trimester prenatal ultrasound (US) examination. However, US is normal in 39% of individuals, with kidney abnormalities or polydactyly detected postnatally. The discovery of bilateral enlarged hyperechogenic kidneys (with or without cystic lesions) should lead to consider BBS as possible diagnosis, especially when concomitant hexadactyly is present. This situation warrants BBS genetic testing. The same stands for hydrometrocolpos.
During childhood and adulthood, diagnosis and management has to be multidisciplinary. Follow-up and care are adapted according to the severity of clinical manifestations and to the general status of the patient.
As a general statement, it is important to provide detailed and close supervision of any general anaesthesia (GA) for a patient with BBS, because the use of advanced procedures (video-laryngoscopy or intubation techniques) is often necessary, particularly in adults, as respiratory distress has been observed. There is no contraindication to GA if the preoperative, intraoperative and postoperative assessments are closely monitored.
The Role of Nutrition in Managing BBS
Obesity and Weight Management
Constant hunger and an urge to eat that's hard to control can be linked with BBS. This can be challenging when trying to manage eating every day. Your care team can help you create a plan for managing weight that works for your child and your family. A dietitian with expertise in BBS can help create a food plan that considers your child's calorie needs and other health conditions such as kidney conditions, diabetes and high blood pressure. The dietitian also can offer suggestions for meal planning, meal portions and meal schedules.
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Obesity is a well-known feature of BBS. Several abnormalities that can lead to kidney injury have been identified in obese subjects, including insulin resistance, inappropriate activation of the renin-angiotensin-aldosterone system, as well as increased oxidative stress, coagulability, and impaired fibrinolysis. It has been demonstrated that a higher BMI is also a strong and potentially modifiable risk factor for ESRD. We therefore recommend aggressive obesity control in patients with BBS as well as in non-BBS obese subjects.
Dietary Recommendations for Kidney Health
In addition to obesity, healthcare teams may provide special dietary recommendations to help prevent complications from kidney disease, which can affect the way your body processes food. Food waste products can build up when kidney function is impaired, which can affect other body systems like the heart and blood vessels. A nephrologist or nutritionist can help provide recommendations for a kidney and heart-friendly diet, which typically involves limiting sodium (salt) and protein intake. In later stages of kidney disease, other nutrients may need to be restricted or supplemented as well. Among people with obesity, dietary and exercise interventions may also be recommended to prevent associated complications, such as diabetes, hypertension, metabolic disease, and heart disease.
Low Protein Diet and Renal Function
Renal structural and/or functional abnormalities not only constitute one of the principal manifestations of BBS; renal impairment is frequent and an important cause of death, which contributes to the substantially reduced survival. The renal structural and functional abnormalities in BBS include: renal parenchymal cysts, calyceal clubbing, fetal lobulation, scarring, dysplastic kidneys, unilateral agenesis, vesicoureteral reflux, hypertension, chronic renal insufficiency, end-stage renal disease, urinary concentration defects, and renal tubular acidosis.
In patients with CKD it is known that low protein diets are associated with slower progression of renal failure, or a delay in the necessity of renal replacement therapy. Low protein diet manifests its effect by ameliorating proteinuria, decreasing workload on the remaining nephrons, reducing oxidant stress, and decreasing insulin resistance. However, there is not sufficient data on the use of low protein diets in patients with BBS.
A study presented two siblings, aged 32 and 27 years, with BBS. On admission both patients were obese, with body mass indexes (BMI) of 40 and 39 kg/m2. Their creatinine clearances (CrCl) were 41 and 24 mL/min. After 2 years of follow-up with a diet consisting of 0.6 g/kg/day protein and 1400 kcal/day energy, their BMI's were decreased to 29 and 27 kg/m2, whereas their CrCl's were increased to 44 and 32 mL/min, respectively. This study reports, for the first time, the improvement of renal functions by low protein diet and obesity control in 2 siblings with BBS.
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Treatment Options and Management Strategies
While there’s currently no cure for BBS, many treatment options are available to help manage the symptoms. Planning ahead for supportive services can also help you maintain your quality of life. BBS is a rare, inherited genetic disorder. Although there’s currently no treatment that targets the underlying cause of the condition, there are many treatment options that can help you manage the symptoms and reduce their impact on your daily living and overall health. Because BBS affects so many organ systems, you will need a multidisciplinary team to effectively care for your condition. A primary care professional can help with coordinating specialist referrals and care plans.
Medications
A variety of different symptoms with BBS may be managed with medications. For instance, medication may be needed to help manage kidney or heart disease in people with these complications, which tend to be the most serious complications of BBS. Other medications may be used to help manage:
- Pubertal development (hormone therapy)
- High blood pressure
- Type 2 diabetes
- Thyroid disease
In 2022, the Food and Drug Administration (FDA) approved the first medication specifically for weight management in adults and children 6 years of age or older with BBS-associated obesity. This medication, setmelanotide (Imcivree), is taken as a daily injection and helps to promote weight loss by reducing food intake and increasing the rate at which calories are burned. In a clinical trial involving 38 people with BBS or another rare genetic disorder (Alström syndrome), nearly a third had at least a 10% reduction in weight after 52 weeks of treatment with setmelanotide, with an average weight loss of 2.4% of the original body weight within 14 weeks of starting treatment. Among those with BBS in the trial, nearly two-thirds reported a significant improvement in quality of life after 1 year of setmelanotide treatment. Most side effects with setmelanotide in this trial were mild and short-lived. The most common side effects were skin hyperpigmentation (darkening), injection site reactions, and nausea.
For vision problems associated with BBS, there are no medications available to slow or prevent them from getting worse. Vitamin A deficiency may contribute to additional visual problems, though, so vitamin A supplements may be recommended to help prevent this. Before starting any new medications, vitamins, or supplements, be sure to talk with your healthcare team to identify any potential interactions or safety concerns.
Surgical Interventions
Surgery may be needed or recommended to correct a variety of anatomical anomalies BBS causes, including:
- Polydactyly (extra fingers or toes)
- Abnormalities of the genitals or urinary tract
- Congenital heart defects
- Dental overcrowding
In some cases, surgery may also be used to treat end-stage kidney disease, obesity, or cataracts. People with BBS are more likely to have structural abnormalities that can make it harder to keep the airways open during surgery. This can make the process more complicated. Before surgery is done, your doctor may order imaging to assess whether it’s safe to use general anesthesia, which requires people to be intubated to support breathing. If your surgeon thinks general anesthesia is too risky, they may opt to use local anesthesia instead, which allows you to stay awake and breathe on your own during surgery.
Therapies
Starting therapy early can help with muscle strength, coordination and speech delays. Therapies can include physical therapy, occupational therapy, and speech and language therapy.
Vision Aids
There is currently no treatment for vision loss. Glasses can help with some early vision changes. Low vision aids, such as magnifiers, large print formats and high-resolution images, can help with low vision. Communication devices or assistive technology, such as audio description devices, text-to-speech programs and smart speakers, can help people with blindness.
Lifestyle and Home Remedies
If you have Bardet-Biedl syndrome, these tips can help.
- Learn about Bardet-Biedl syndrome.
- Create healthy eating habits. Healthy eating habits are important for the body to work well and to prevent extra weight gain and related health conditions. Use meal planning to have nutritious meals and snacks at expected times. Try plating food before sitting down to eat. Put extra food away to make taking seconds less automatic. Plan for outings and special events.
- Prevent safety issues. For low vision or blindness, make sure that the home, daily activities and outings are set up to stay safe. Without a sense of smell, odors such as smoke, a natural gas leak or spoiled food can't be identified.
- Get regular physical activity and exercise.
- Learn what support is available. For example, ask about early intervention programs for babies and young children. Ask about special education services at school. Look for behavioral and mental health services, if needed.
- 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. Your child's care might include meeting with a pediatric psychologist, psychiatrist or other mental health professional. These specialists are trained in supporting families coping with illness and treatment demands. If you or your child is depressed, frequently anxious or overwhelmed, or struggles with challenging behaviors, meeting with a mental health professional could help. Developmental and educational assessments can check for delays in development and in speaking, learning, thinking and memory.
Ophthalmic Manifestations and Management
The prevalence of retinal degeneration (RD), due to degeneration of the photoreceptor cells (cones and rods) is estimated to be > 90%. RD is considered a fully penetrant trait but clinical variability can occur. The spectrum of other BBS systemic manifestations is independent from the retinal phenotype. The mean age for RD diagnosis is between 5 and 12 years of age but the visual symptoms may be obvious before. As not all extra ocular signs are present when RD is diagnosed, this may lead to a delayed diagnosis. Visual impairment in a child with either polydactyly, overweight or a history of prenatal kidney anomaly is suggestive of BBS.
Night blindness is the most common initial symptom in children, followed by or together with impaired central vision. Night blindness may be unnoticed by parents. Photophobia may occur with central retinal involvement. Slow adjustment from dark to light environments and vice versa can be observed. Progressive peripheral visual loss, inducing clumsiness, mobility difficulties (bumping into objects, difficulties walking stairs) and ultimately tunnel vision, is common. Often, poor central vision impairs reading or execution of any fine vision tasks. A wide range of refractive errors (myopia, hyperopia, astigmatism) require refractive correction (spectacles). With age, RD will progress with reduction of visual acuity and visual field worsening.
Most patients are registered as visually impaired (“partially sighted”) or severely visually impaired (“legal blindness”, defined legally as 20 degrees or less of remaining visual field in the best seeing eye, or a visual acuity of 20/200 or worse) by the mid-teens. Strabismus occurs due to the poor vision as well as nystagmus that can be observed early.
Reduced visual function may be present even if the fundus examination is still normal at the early stages. Therefore, recording the function of photoreceptors with an electroretinogram (ERG) is an important exam to confirm RD, especially in young children with limited attention. ERG shows reduced function of rod photoreceptors (scotopic responses) and/or reduced function of cone photoreceptors (photopic conditions) and evolves to usually non-recordable ERG responses (flat ERG).
The RD is usually described as a rod-cone dystrophy (classical Retinitis Pigmentosa) starting with peripheral disease. However a generalised early-onset retinal dystrophy with both central and peripheral features at the time of diagnosis is common due to rapidly evolving RD (rod and cones are affected more or less simultaneously). Early “salt and pepper” appearance can precede to advanced stages with extensive pigment migration.
In rare cases, central disease occur with macular features as a starting point (with altered photopic ERGs) with extension towards the periphery (cone-rod dystrophy) or without extension (cone dystrophy).
Ophthalmic Monitoring and Follow-Up
Ophthalmic follow-up should be adapted to the age of the patient and cooperation. For visual acuity (VA) evaluation, preferential looking and Teller acuity tests are used for preverbal children, and decimal or Snellen chart in school-age children who disclose often low levels of measurable vision. The VA usually declines over years, leading to severe visual impairment. Rarely, even in the late teens or adulthood, patients can maintain a measurable visual acuity or inversely present preserved visual fields (if central involvement only).
Refraction (under cycloplegia, according to age and recommended guidelines) helps to evaluate the Best Corrected Visual Acuity (BCVA). Regular follow-up of refraction is advocated and full correction should be prescribed unless the visual function is undetectable. Visual field are evaluated with Goldmann kinetic perimetry and performed according to age and remaining vision. Slit lamp evaluation is systematic in adults, as cataract is a frequent complication. Fundus imaging is useful, as it can be captured quite easily and evaluates the various sectors of the retina and the optic disc.
Optical Coherence Tomography (OCT) (if the patient can still fixate) evaluates the degree of outer retinal layers (photoreceptors) alteration and retinal lamination and thickness abnormalities. Autofluorescence imaging assesses the distribution of the RD activity usually with a granular pattern, perimacular ring of hyperautofluorescence.
Full-field ERG is performed mainly if needed for diagnosis. Performing an ERG at young age (or when intellectual disability) may require a GA in case of diagnostic uncertainty.
Clinical follow-up should be performed by a senior ophthalmologist, a low vision specialized orthoptist and/or an optometrist, at least on a yearly basis if the RD is evolving, and every two years if the situation is stable in adults.
Ophthalmic Management
No specific therapy for RD in BBS patients is available to date. A few patients have benefited from retinal implants at the late stage of RD for trial purposes. Gene therapies, optogenetics, and cell replacement may be future avenues. Currently, patients benefit from low visions aids, electronic apps, orientation and mobility training, Braille, white canes and guide-dogs. Specific training for poor vision is adapted to the age. Technological/electronic assistance is commonly used, except if hampered by intellectual disability. Refractive errors are observed in 90% of cases and should be corrected. Tinted glasses with photoselective filters may be useful in case of photophobia.
Cataract is a common complication of RD usually in early adulthood. Surgery with intraocular lenses implantation is advocated when the dense opacities are central and aggravate the visual function. Cystoid macular oedema, a classical complication of RD, is rare and should follow the classical therapy.