Bardet-Biedl Syndrome

Table of Content

Disease Definition

Bardet-Biedl syndrome (BBS) is a rare disease affecting several organs, including the kidneys. BBS is caused by an abnormally functioning cell component called a cilium (or cilia, plural) which is present on many cell types from different organs. Cilia are long, thin, hair-like projections that enable the cell to receive signals from outside and inside the cell. Bardet-Biedl syndrome is therefore categorized as a ‘ciliopathy’.

Overview of affected organs and symptoms in BBS:

Affected are Brain, Eye, Kidney, Hand&Foot, Reproductive System, Obesity.

What do you need to know about Bardet Biedl Syndrome?

The aim of this booklet is to explain which organs can be affected by Bardet-Biedl syndrome, and how the prognosis and quality of life of BBS patients can be improved. Early diagnosis is important for quality of life and patients with BBS generally require multi-specialised care.

Kidney problems can cause serious complications of the disease and later in this leaflet we will explain how medication and lifestyle changes can delay the onset of kidney failure.

History of the disease

The disease was first described independently in 1920 by a French doctor, Georges Bardet, and in 1922 by Hungarian-Austrian pathologist, Artur Biedl. Since then, more than 200 cases of BBS have been reported in the world’s medical literature. In 2000, researchers discovered a gene mutation causing Bardet Biedl syndrome. New data indicates that at least 24 genes are involved in the development of BBS. These genes are often called BBS genes and they play a critical role in cilia function.

Laurence-Moon Syndrome ≠ Bardet Biedl Syndrome

In the past, Laurence-Moon-Bardet-Biedl syndrome was described as a single disease. Nowadays, both syndromes (Laurence-Moon syndrome and Bardet-Biedl syndrome) are identified and treated separately, however, both syndromes are categorised as ciliopathies.

Ciliopathies

Ciliopathies are a group of diseases caused by genetic mutations, which result in cilia dysfunction, affecting many organs of the human body.

Since cilia are located on many body cells, the diseases usually appear more complex and include multiple organs, which is the reason they are called syndromes.

The role of cilia in most tissues remains unknown and how ciliary dysfunction leads to such severe disease is a subject of current research.

Other known ciliopathies
Alström syndromeJeune syndromeEllis-van Creveld syndrome
Joubert syndromeLeber congenital amaurosisMcKusick-Kaufman syndrome
Meckel-Gruber syndromeNephronophthisisOrofaciodigital syndrome
Polycystic kidney diseasePrimary ciliary dyskinesiaSenior-Loken syndrome
Sensenbrenner syndromeShortrib-polydactyly syndrome

Genetics and Inheritance of the Disease

Bardet-Biedl syndrome is caused by the change (mutation) of only one single gene and is therefore called monogenic.

The syndrome is inherited in an autosomal recessive manner.

What does this mean?

For an autosomal recessive disease to occur, a child has to inherit two mutated/faulty copies of the gene, one from each parent. If only one mutated/faulty gene is inherited, the child will not have BBS, but will be a carrier of the syndrome. The child from each pregnancy has a 25% chance of receiving both mutated/faulty genes and thus having BBS. Both sexes are equally affected.

In the example below, you can see the genetic tree of a family with BBS.

For parents who have a child with BBS, the risk to future pregnancies is:

25% that the child will have BBS

50% that the child will not have BBS but will be a carrier of the defective gene

25% that the child will not have BBS and will not be a carrier of the defective gene

To date (2022), mutations in 24 BBS genes have been identified.

The BBS genes are the blueprints for various BBS proteins that are important in cilia function and some cellular transport mechanisms (see …).

In this sense, if one of the BBS proteins is not functioning (due to a mutation in the respective gene) the whole apparatus will not work as it should, and it leads to the same disease à Bardet Biedl syndrome.

The prevalence of this disease in Europe is estimated at 1 of 150000 – 175000 people. In some isolated populations (e.g. among Israeli Bedouins and Puerto Ricans), it is found to be more common: approximately 1 of 100000 people. The presence of specific clinical signs (see below) may prompt the genetic testing.

Why does my child have BBS?

In most cases, an individual has BBS because they inherited one copy of the faulty gene from each parent and therefore have two copies of the same, faulty gene.

Carriers generally do not have any signs and symptoms of the disease, because in addition to the faulty gene, they also have a second, normal gene.

Can the disease appear in other family members?

Where one family member has a genetically confirmed diagnosis of BBS, siblings and other relatives can be tested to see if they carry the faulty gene for family planning purposes.

Knowledge of the BBS mutation in the family can also form the basis of prenatal screening, should parents wish to find out in early pregnancy, whether the foetus is affected.

Family planning for people affected by BBS: genetic counselling

People with BBS who wish to have children, should receive genetic counselling. The partner of the person who has BBS should be tested for carriers’ status, to determine if they carry a disease-causing mutation in the same gene.

If the partner is a carrier of a mutation in the same gene, each child has a 50% chance of having the syndrome. If both parents have BBS, with mutations in the same genes, then all children will have BBS.

The pathology of BBS: what are cilia and how do they work?

The mechanism that leads to BBS is still unclear, however t he main cause of the disorders that occur in BBS is due to abnormally functioning or structured cilia.

Cilia are thin, hair-like structures that are only visible under a microscope. They occur on the surface of almost all cells of our body. There are different types of cilia performing different functions.

The length of a single cilia is 1-10 micrometers and the width is less than 1 micron.

Cilia play a very important role, even before birth, enabling embryo development, cell migration and organ differentiation.

A main function of cilia is sensory and they play an important role in terms of smell, vision, touch, and temperature sensation.

There are different types of cilia:

Cilia which can move are called motile cilia. They are located on the surface of the lung, respiratory cells, or the middle ear, where they help to remove mucus and infectious agents by way of rhythmic, wavy movements.

These cilia also play an important role in the movement of sperm.

Cilia that are not able to move are called non-motile cilia/primary cilia. These structures receive signals from outside of the cell and transmit them to the inside, allowing neighbouring cells to communicate with each other. For example, in the kidney, cells can receive signals about the level of chemicals in the urine.

In BBS, the functioning of primary cilia is impaired

It has been shown that the genes involved in BBS encode proteins, that are responsible for the function or development of cilia.

A primary cilium consists of a basal body (dark blue) and a tube-like structure (green) build of microtubules. The 24 different BBS proteins have different functions within the cilium.

Eight BBS proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBS18) build a stable complex known as the BBSome, which regulates molecule trafficking to the ciliary membrane. Some others constitute a chaperonin complex that is important for the correct construction of the BBSome. Some other BBS proteins help to locate the BBSome to its final position. The partially overlapping functions of BBS proteins explain why different mutations in different BBS genes result in similar disease signs and symptoms.

Symptoms

BBS affects many organs, and the symptoms can vary significantly between patients, even between individuals within the same family. Classically defined by six features (see …), BBS is usually diagnosed in infancy.

Common symptoms include obesity, visual impairment, additional fingers and/or toes, reduced function of the testes in boys, kidney defects and learning disability.

Although BBS may be diagnosed based on genetic tests revealing mutations within specific genes, the presence of primary and secondary symptoms may be used to indicate which patients are suspected of having BBS and need the genetic examination.

Diagnostics, based on the presence of primary and secondary characteristics, was proposed by Forsythe and Beales in 2003. On the basis of this:

BBS could be diagnosed if the person is known to have at least three primary and two secondary characteristics, or if they have at least four primary characteristics.

The usefulness of these clinical criteria may be limited by the fact that many of these clinical characteristics appear gradually as the child develops and thus the sensitivity of the proposed diagnostic criteria is low in young children. Further, some patients who have a genetic diagnosis, do not always meet the clinical diagnostic criteria and there may also be a variability of symptoms, even for those with the same genetic mutation.

Therefore, it is important that: The presence of these clinical criteria is periodically verified in a child considered for a diagnosis of BBS.

The diagnostics criteria for BBS by Beales et all:

diagnostics criteria
Primary criteriaSecondary criteria
Retinal degeneration (Rod-cone dystrophy)Squint (strabismus)
Blurring of lenses (cataracts)
Bending of the cornea (astigmatism)
Additional fingers/toes (polydactyly)Shorter fingers/toes (brachydactyly)
Fused fingers/toes (syndactyly)
Central obesitySpeech disorders
Learning disabilitiesDelayed development/ behavioural disorders
Kidney malformationsabnormally large production or output of urine (polyuria)
Excessive thirst (polydipsia)
Diabetes insipidus
Reduced function of the testes (hypogonadism) (male) / genital abnormalities (female)Dental crowding/hypodontia /small roots/high arched palate
Craniofacial dysmorphism

The major features of the BBS

1. Obesity

Obesity is an excessive accumulation of adipose tissue in the body. The classification of obesity was determined by the WHO (World Health Organization) and is now based on body mass index (BMI), which is calculated from the body weight in kg divided by the height squared (m2).

Body mass index: BMI=kg/m²

In adults, being overweight is defined as having a BMI ≥25 and obesity as having a BMI ≥30. In children and adolescents, being overweight is defined as a BMI ≥85 percentile (pc) for age and gender, and obesity as a BMI ≥95 pc.

Obesity in BBS

  • In people with BBS, obesity appears in infancy and progresses with age.
  • The frequency and severity of obesity varies between patients.
  • Obesity in BBS is not the result of an improper diet or parental neglect but is due to an imbalance between hunger and satiety (feeling full).
  • Ciliary defects in the hypothalamus (the hormone producing area of the brain) affects the function of the satiety hormone, leptin, impairing the body’s ability to know when it is full.
  • Those with BBS may also have an excessive appetite, leading to excessive food intake (Hyperphagia)
  • Weight is usually normal at birth, however as many as 90% of people with BBS exhibit rapid weight gain through the first year of life.
  • Obesity in BBS is dominated by a particularly dangerous type, called abdominal obesity, in which adipose tissue accumulates mainly in the abdomen and internal organs and produces hormonally active substances that disrupt the functioning of other organs.
  • Abdominal obesity can lead to the development of type 2 diabetes within a short period of time due to insulin resistance, however, the mechanism is not well understood yet.
  • Diabetes mellitus has been estimated to affect up to 45% of patients with BBS.
  • Poor weight management may further complicate problems with the heart and blood vessels.

Did you know?

Leptin is a hormone produced by fat (adipose) cells that helps to regulate energy balance by inhibiting hunger. The main function of leptin is to send a signal to the brain reporting how much fat is stored in the body’s fat cells. Leptin acts on cell receptors in the hypothalamus, consequently mediating eating.In obesity, a decreased sensitivity to leptin occurs (like insulin resistance in type 2 diabetes), resulting in an inability to detect feeling full, despite high energy stores and high levels of leptin. The condition is known as a leptin resistance. Leptin resistance cause irrepressible hunger and reduced the number of burned calories.

BBS proteins are shown to affect the leptin response and the loss of BBS genes results in leptin resistance. This is a reason why many BBS patients are obese.

2. Retinitis pigmentosa also called Rod-Cone Dystrophy

The eye problems are of central concern in patients with BBS as almost all patients experience progressive vision loss. The first symptom onset is usually that of night-blindness, typically seen around age 8-9 years of age.

What is the reason for this vision loss?

  • The retina is a very thin layer at the back of the eye which receives visual signals. The precise function of the retina is to convert light signals into nerve impulses, which are further transmitted to the brain and thus allow vision.
  • The retina contains two types of visual receptors (photoreceptors) namely rods and cones. There are more rods than cones (about 120 million vs 6 million), and they are more sensitive. Rods are sensitive to light intensity, allow for black and white vision and are found mainly in the peripheral parts of the retina. Cones are concentrated in the central part of the retina and are responsible for colour vision and visual focus.
  • The process of retinal degeneration in BBS patients usually begins in early childhood, initially with the development of night blindness (loss of rods), followed by the development of tunnel vision. The degeneration of rods and cons causes a gradual narrowing of the visual field. Patients may experience a hypersensitivity to light and difficulties with adapting to changing lighting conditions. The order in which symptoms appear will depend on which photoreceptors, the rods or the cones, degenerate first.
  • Further, the degeneration of neural cells occurs, which results the damage of the optic nerve (optic atrophy). Since the optic nerve transmits retinal information to the brain, optic atrophy is associated with vision loss. Also the narrowing of the small retinal vessels are seen and cause ischemic changes.
  • Most people with BBS (over 90%) will be registered as severely sight impaired during puberty or early adulthood.

For more insight into the biology behind the rod-cone degeneration:

Rods and cones are photoceptor cells of the retina and have a special light-absorbing segment. These segments are modified cilia. The BBS mutation leads to an impaired protein transport between the light-absorbing segment and other parts of the cell. This transport deficiency results in the death of rods and cones and in total retinal degeneration and blindness.

Minor common visual symptoms of BBS:

  • Squint (Strabismus) – a condition caused by a weakening of the eye muscles, disrupting the ability of the eyes to line up in the same direction.
  • Involuntary Eye Movement (Nystagmus) – a rhythmic uncontrolled movement of the eyes, from side-to-side, up and down or in circles.
  • Blurring of lenses (Cataract) – a condition that involves the formation of spots or cloudy areas on the usually transparent lens of the eye, which makes it difficult for light rays to enter the retina, impairing visual focus.
  • Bending of the cornea (Astigmatism) – an imperfection in the curvature of the eye that causes vision to be out of focus and distorted.

Visual impairment development in BBS patients:

The first symptom is usually night blindness, which occurs in children as young as 8-9 years old. Field of vision is usually affected from the age of 10. By the age of 17, so-called tunnel vision is usually established. From the second to the third decade of life, visual acuity gradually declines to 10% or less in almost all patients.

3. Polydactyly

Polydactyly is the presence of additional fingers or toes at birth and is a key indication of Bardet-Biedl syndrome. Since these are usually removed in early childhood, their presence may be forgotten, thus impacting on the diagnostic process.

Polydactyly occurs in approximately 70% of BBS patients, with the presence of an extra toe more common than an extra finger.

Fingers and toes may also be fused (syndactyly) and this is especially common between the second and third toes. Fingers and toes may occasionally be abnormally short in length (brachydactyly), feet may be wide, short in length and have a flat arch.

Syndactyly or brachdactyly are categorised as secondary symptoms of BBS.

4. Hypogonadism

In men, a small size and poor function of the testes, is termed “testicular hypogonadism”. This may manifest as a small penis, failure of the testes to descend into the scrotum (“cryptorchidism”) or a delay in the onset of puberty. Undescended testicles are a concern because they are associated with a greater risk for testicular cancer and should not be left unaddressed. Males are almost invariably infertile.

A wide variety of genital malformations have been observed in females, contributing to the low rates of fertility in BBS. This may manifest as an underdeveloped uterus, fallopian tubes, or ovaries. Menstruation cycles are often delayed and may also follow an irregular cycle.

The rate of fertility is low, but individuals from both sexes have been known to have biological children.

5. Delay in intellectual development

  • Patients can present with intellectual disability, speech and language impairment, attention deficit, poor reasoning, and emotional immaturity.
  • The extent of developmental delay in Bardet-Biedl syndrome can be diverse. Severe learning difficulties affect only a minority of BBS patients, and many demonstrate normal mental development.
  • Some BBS children need additional support at school as their problems mainly are related to the memorization processes, especially learning by heart.
  • Developmental delay can be noticeable quite early on, although basic skills are achieved within a normal or slightly delayed timeframe. Speech development is often delayed.
  • BBS is quite often linked to anxiety disorders. Low mood, panic attacks, obsessions and compulsions, anger and poor emotional control also commonly affect adults and young people with BBS. It is unclear whether this is a part of the Syndrome or an indirect result of it. Most likely, it is a combination of both.
  • Children with BBS may show autistic tendencies, compulsive behaviour, aversion to change, emotional immaturity, lack of drive and attention deficit hyperactivity disorder.
  • How the intellectual development of BBS patients is determined remains unclear.

6. Malformation and dysfunction of the kidneys

Cilia are present in kidney cells which explains why BBS patients are affected by kidney dysfunction and malformation. Kidney abnormalities affect at least 50% of BBS patients.

  • In most cases, renal disease is diagnosed by the age of five, however it can be discovered within the first year of life.
  • Kidney disease in BBS can be very different for everyone with different clinical significance.
  • The development of kidney cystsis the most common change and can lead to dangerous complications such as the development of chronic kidney disease (CKD) or kidney failure. The kidney cysts are often detected before childbirth or in early childhood and are caused by impaired cilia function in the kidney cells of the tubule.
    The lack of cilia function within kidney tubuli causes excessive urine output of unconcentrated urine. The fluid pools within the kidney tissue and leads to the formation of cysts (fluid-filled sacs) that destroy and gradually replace kidney tissue. The damaged kidneys cannot perform their function. (picture)
  • Polyuria, excessive urine output and polydipsia, the resulting excessive thirst, are among early symptoms of BBS and results of the destroyed urin concetration
  • A spectrum of kidney disease can be seen in BBS including, urinary tract malformations: vesicoureteral reflux, hydronephrosis, dysplastic cystic disease, absent, duplex, horseshoe or ectopic kidneys, neurogenic bladder; chronic glomerulonephritis and defective tubular concentrating ability. (see…)

Did you know the terms?

Solitary kidney, (one kidney is missing), or kidney dysplasia (the kidney is not fully developed), may occur. If both kidneys are dysplastic, depending on the severity of the abnormalities, kidney function may be impaired and renal replacement therapy (dialysis or kidney transplantation) may be necessary.Vesicoureteral reflux – this is where urine flows from the bladder to the kidneys (instead of from the kidneys to the bladder) and can contribute to the development of urinary tract infections.

Horseshoe kidney is where the two kidneys join (fuse) together at the bottom during pregnancy, to form a ‘U’ shape which gives it the name “horseshoe”. Kidney drainage can be affected, resulting in increased frequency of kidney stones and urinary tract infections. Horseshoe kidney can occur alone or with other disorders.

Crossed fused ectopia occurs when both kidneys develop on the same side of the body. In many cases, the two kidneys could also be fused together retaining their own vessels and ureters.

Renal/ kidney dysplasia also known as multicystic dysplastic kidney this is where the internal structures of one or both kidneys fail to develop normally during pregnancy. Babies with severe kidney dysplasia affecting both kidneys generally do not survive birth. Children with dysplasia in only one kidney will have normal kidney function if the other kidney is unaffected. Those with mild dysplasia of both kidneys may need renal support sooner or later.

Neurogenic bladder  – this is caused by a malfunction in the nerves that control bladder function and the bladder may not fill or empty in the right way. The muscles of the bladder may become overactive and contract abnormally, even before the bladder is full, or the muscles may become too loose leading to incontinence. In other cases, the muscles become underactive and even if the bladder is full the muscles do not contract, and the person may not feel a sensation or an urge to go to the toilet.

Secondary symptoms in Bardet-Biedl syndrome include

  1. Neurological abnormalities including:
    • Delayed development
    • Speech development disorders have been reported in 60% of patients, mainly consisting of high-pitched nasal speech. Children often do not develop intelligible speech before the age of four.
    • Ataxia (disorders of motor coordination of the body) which can affect balance, walking, speaking and swallowing
    • Epilepsy
    • Low mood, panic attacks, obsessions and compulsions, anger and poor emotional control
    • Hypertonia (abnormal, excessive muscle tone) manifests as the reduced ability of a muscle to stretch causing, for example, arms and legs that are stiff and difficult to move.
    • Anosmia – the loss of smell. BBS patients may have a decreased ability to detect smells, due to a change in a structure located in the brain called the “olfactory bulb”. This is a relatively mild problem but may impact on safety if people are unable to sense, for example, a gas leak from the stove.
    • Neurological impairments may manifest in poor coordination, gross and fine motor skills, and social milestones (e.g.: ability to play complicated games with other children).
    • Many patients report a significant degree of clumsiness and often walk with legs in a wide-based stance.
  2. Brachydactyly (short fingers and toes) and syndactyly (fused fingers or toes)
  3. Polyuria/polydipsia (see above) as symptoms of urinary concentration defects, are prevalent even in patients with near-normal kidney function and no major cysts.
  4. Type 2 diabetes mellitus and metabolic syndrome may develop as a result of obesity.
  5. Dental development disorders, including hypodontia (congenitally missing teethes), teeth crowding, short roots and high-arched palate.
  6. Congenital heart defects (valvular stenosis, patent ductus arteriosus, cardiomyopathies)
  7. Liver changes range from fibrosis to cystic dilatation of the bile duct and all connecting ducts.
  8. Diseases of the gastrointestinal tract, such as Hirschsprung’s disease, coeliac disease, Crohn’s disease (see…)
  9. Dysmorphism (abnormally shaped body part). The most frequent reported features of BBS are:
    • a narrow forehead
    • brachycephaly (shape of the skull is shorter than average) or macrocephaly (a larger than average head)
    • large ears
    • short, narrow, and down-slanted palpebral fissures (opening between the eyelids)
    • deep and widely set eyes
    • depressed nasal bridge (a flatter or lower than average bridge of the nose)
    • long and smooth philtrum/medial cleft (the indented area) between the nose and upper lip.
    • retrognathia – a condition where the lower jaw is set back further compared to the upper jaw

Have you heard of this before?

As recently shown BBS patients have also a higher prevalence of certain autoimmune diseases:

  • inflammatory bowel diseases as Crohn ́s disease
  • diabetes Typ 1
  • rheumatoid arthritis
  • hypothyroidism and Hashimoto’s thyroiditis

Altered red blood cell and platelet compartments, as well as elevated white blood cell levels have been found in BBS patients. Some study reveals a connection between a ciliopathy and dysregulated immune and hematopoietic systems and immunity. Some of these alterations are associated with BBS-induced obesity which leads to elevated concentration of white blood cells in BBS patients. Obesity can induce the state of low-grade metabolic inflammation and one of the major players in obesity-associated inflammation is leptin, an adipocyte-derived hormone which acts as a pro-inflammatory cytokine. It has been shown that leptin signalling in the central nervous system regulates immune responses. Thus, it is possible that defective leptin signalling in the nervous system directly contributes to high prevalence of autoimmunity in BBS patients.

Diagnostics: the tests that should be performed to make a diagnosis of BBS

BBS is such a rare condition that many paediatricians, throughout their careers, have never met a patient with the syndrome. Early diagnosis gives you a better chance of providing your child with the right medical care.

To make a diagnosis, knowledge of the patient’s medical history, symptoms, and physical and intellectual development are needed, as well as the results of laboratory tests. Due to the high variability in the occurrence of clinical manifestations and the different times of their appearance, the patient suspected of BBS requires regular assessment. Ultimately, a genetic test confirms a clear diagnosis, although new mutations responsible for BBS are still to be identified.

Family history: BBS is an autosomal recessive disease, which means that two abnormal copies of a particular gene are required for it to occur. Most often, parents are healthy carriers and show no symptoms, because each of them has only one abnormal copy. However, the gene mutation may also be non-hereticate, i.e., the formation of an abnormal copy of the gene occurred spontaneously during embryo development. This is called “de novo mutation”.

General Check of body height, body weight, body mass index (BMI) and blood pressure measurement as part of the routine monitoring for patients with suspected BBS should take place at each consultation.

It is recommended to also monitor and preferably record these measurements regularly at home.

Radiological, ultrasound examinations: To detect the presence of cysts or other abnormalities of the urinary system, testes and liver.

Kidney ultrasound: shows the presence of kidney cysts or other malformations of the urinary or reproductive system.

Cardiac ultrasound: to diagnose heart defects that feature with heart hypertrophy.

Abdomen magnetic resonance imaging (MRI): is more accurate in assessing the number, place and size of cysts andis used primarily to monitor the progression of the disease.

Complete eye examination: to detect the degeneration of the retina e.g. the presence of pigmentary retinopathy.

Pigmentary retinopathy can be detected by an examination of the eyeball, using a special lamp, after the pupil has been dilated.

Electroretinogram (ERG): is an eye test used to diagnose retinopathy and can be done at any age. It involves recording the electrical reaction of the retina to the stimulation of light and may show early changes within the first two years of life, although significant changes are rarely visible before the age of five.

Field of vision measurement: usually carried out after the age of about 7 years, because it requires active cooperation with the patient.

Blood and urine tests: Blood and urine tests are carried out regularly, mainly to monitor kidney function, detect and treat diabetes, as well as common lipid disorders.

Endocrinological assessment must include assessment for any signs and symptoms of diabetes mellitus with subsequent oral glucose tolerance testing if appropriate. Assessment of thyroid function, lipid profile and the development of secondary sexual characteristics is important. If appropriate, further pituitary function testing can be done and hormone replacement therapy instigated. During adolescence, blood tests will detect and prompt
common sex hormone secretion disorders (testosterone or oestrogen).

Genetic testing: Since BBS can be caused by mutations in different genes and symptoms may suggest other syndromes also associated with the malfunction of cilia, molecular methods of genetic testing, including gene oriented research (multigene panel) or comprehensive genomic testing (exon sequencing) are recommended.

Genomic studies may reveal pathogenic variants in known genes that have not yet been included in gene panels ornew pathogenetic variants in genes previously known to be BBS-related.

Currently, genetic mutations in more than 24 genes, that cause this syndrome, have been discovered. All these mutations lead to the abnormal structure and/or impaired action of the primary cilia.

The most common mutations involve the following genes:

BBS 1 – 23.4% of all BBS patients
BBS10 – 14.5% of all BBS patients
BBS 2 – 9.6% of all BBS patients
BBS12 – 6.4% of all BBS patients

Can we confuse BBS with other diseases and how do we tell the difference?

Yes, Bardet-Biedl syndrome can be confused with other syndromes with similar symptoms. It is not always easy to make a diagnosis quickly. Patients often present signs and symptoms common to different syndromes.

Laurence-Moon syndrome, long confused with Bardet-Biedl syndrome, among other symptoms causes neurological disorders (balance disorders or lack of coordination and / or paralysis of the legs) and polydactyly. The genes responsible are different from those that cause Bardet-Biedl syndrome.

Alström syndrome is characterized by abnormalities of the retina, obesity, progressive hearing loss, kidney abnormalities, diabetes and poor sexual organ development (hypogonadism) in boys. Some of these symptoms and manifestations coincide with Bardet-Biedl syndrome, however, there is no polydactyly or learning difficulties. The gene responsible for Alström syndrome has been identified and is different from those involved in Bardet-Biedl syndrome.

Cohen’s syndrome combines retinopathy with myopia (nearsightedness), obesity and specific dental abnormalities. The gene in question is also identified and is different from those involved in Bardet-Biedl syndrome.

McKusick-Kaufman syndrome causes genital abnormalities, supernumerary fingers, and heart defects. However, it does not include retinopathy pigmentosa, which distinguishes it from Bardet-Biedl syndrome

Treatment

A properly made diagnosis in early childhood can support the effective management of Bardet-Biedl syndrome. Research is ongoing to develop a drug for BBS, but so far, no causal treatment has been developed.

The life expectancy of the patient is not reduced by the syndrome, but people with BBS require specialist care and, in many cases, are dependent on the help of other people in their everyday lives.

The medical interventions for BBS patients consist in alleviating the symptoms and side effects of the condition, but most of them are difficult to treat. And although treatment usually focuses on specific symptoms in a person, patients require multidisciplinary care involving a nephrologist, ophthalmologist, endocrinologist, and genetics specialist. Patients and their families also need learning and psychological support.

Likewise, the development of children may be significantly delayed and limited by the syndrome. Anxiety disorders can also occur. Not infrequently, BBS may lead to psychological disorders and depression in relatives or parents of those with BBS.

BBS patients may be significantly limited in their everyday lives and suffer from a greatly reduced visual field. The blindness itself can lead to severe psychological discomfort or even depression.

BBS may also lead to behavioral problems, and children especially may experience bullying or teasing as a result.

Recent studies have demonstrated that the common point for all BBS symptoms and cilia disfunction is the dysregulation of the glycosphingolipid (GSL) metabolism. Research is exploring how this metabolic defect may be targeted, to maintain cilia structure and signalling, and therefore lead to an improvement of pathology in multiple organs. This therapy option is only at experimental stages and is yet to be proven.

Vision problems:

  • There is currently no treatment for progressive vision loss and adapting to vision loss is an ongoing lifestyle
    challenge.
  • The vision loss in BBS causes numerous difficulties for the young patient when attending school, in their free time and regarding their physical safety. The risk of accidents increases significantly, for example in respect of road traffic.
  • The education of children who have BBS should include planning for future sight loss.
  • Instruction in the use of Braille, mobility training, adaptive living skills and computing skills (including voice recognition and transcription software), as well as the use of large-print reading materials, while vision is still present, are crucial.
  • Living spaces should be designed/adapted to remove any sources of danger for the visually impaired person.
  • Early cane-training is essential to support independence and may be commenced in younger children who have night-blindness.
  • Early assessment by a VI specialist can help with providing mobility training and support the development of independent living skills.
  • Visual disturbances should be discussed with the GP or optometrist.
  • Corrective glasses will protect your eyes from the sun. For this purpose, special contact lenses are used with a centrally located red filter.

Obesity:

  • Obesity treatment may include diet management, exercise, and behavioural therapies. Complications resulting from obesity such as high cholesterol and diabetes are treated as they are in the general population. Approximately 60% of BBS patients also have hypertension (high blood pressure) requiring medication.
  • To support the BBS patient, the whole family should change their eating and lifestyle habits.
  • Parents should model healthy behaviours for their children, including eating healthily, being active and
    setting activity goals for the family, of at least 1 hour of physical activity each day.
  • Always look for opportunities to walk; avoid using the lift and if possible, avoid taking the car or bus.
  • Take advantage of the offers of local sports clubs and give you /your child the possibility to meet regularly with other children and be a part of sports group.
  • It is important to decrease the screen-time of children and young people on mobile phones, gadgets, TVs and computers.
  • Don’t provide food as a reward or take it away as a punishment.
  • Encourage children to drink water rather than beverages with added sugar, such as soft drinks, sports drinks, and fruit juice drinks.
  • Take care with portion sizes and try to reduce them.
  • Regularly monitor your child’s body weight, height and blood pressure.

Behavioural disorders:

  • Developmental delay is addressed through early intervention, physiotherapy, special education, and speech therapy.
  • The majority of adults with Bardet-Biedl syndrome are able to develop independent life skills.
  • Active life style started early inhibits the development of obesity, improves the development of motility and also positively affects the development of cognitive skills, including learning.
  • The approach to developmental delay and/or cognitive impairment should be individualised based on age and identified needs.

Impaired renal function

  • Patients with impaired renal function may experience chronic renal failure.
  • There is no cure for CKD, but early detection of impaired renal function and the implementation of appropriate treatment, significantly slows down the progression of the disease and can delay the need for renal replacement therapy (kidney transplantation, dialysis) for many years.
  • The presence of complications of impaired renal function, such as renal anaemia or renal metabolic acidosis, is an indication for pharmacological correction.
  • Some dietary changes may be needed, especially if the disease progresses and kidney function is further impaired. The dietary guidelines would be based on the stage of chronic kidney disease, which ranges from stage 1 for minimal impairment to stage 5 for ESRD (End-Stage Renal Disease).
  • It is usually best, particularly in the early stages, to work with a certified dietitian to tailor a diet appropriate to kidney function. The goals of a CKD diet are to slow the progression of the disease and minimise any harm the accumulation of waste and fluids can do to other organs, most predominately the heart and cardiovascular system.
  • Generally, the reduction of sodium intake is recommended.
  • Based on the stage of disease, limiting the intake of protein could be eventually recommended.
  • As the disease progresses and renal function drops below 70 percent of what it should be, a restriction of phosphorus and potassium may be recommended, two electrolytes that can harm the body if they accumulate excessively.
  • A number of supplements are commonly used to correct nutritional deficits that can occur in later stages of CKD.
  • In some patients in case of development of end-stage renal failure, renal replacement therapy/dialysis or kidney transplantation will be necessary.
  • Patients with renal insufficiency have a good prognosis associated with kidney transplantation.

Polydactyly / genital abnormalities:

  • additional fingers or toes are generally removed and joined fingers may be separated. The operation is usually performed in early childhood, aged 1-2 years.
  • Sometimes surgical correction of abnormalities concerning the genital organs is performed.
  • Surgery may also be a point of concern for patients with BBS. General anaesthesia requires a series of highly coordinated steps that rely on the anatomy of the airways. Some patients with BBS may have significant anatomical anomalies in the airways and this might result in increased difficulty holding the airway open during general anaesthesia. Anaesthetic medications may be introduced in the form of direct nerve blocks to a region of the body with while the patient is breathing for themselves.
  • Puberty:
    • As children approach puberty, hormone levels should be monitored to determine whether hormone replacement therapy is needed.
    • In addition, it should not be assumed that people affected by the disease are infertile, so it is advisable to seek advice on contraception.

What will happen to my child in the future? What are their prospects?

  • Once the diagnosis has been made, tests are likely to be carried out to detect other possible changes associated with this syndrome and further treatment will be established.
  • Regular check-ups/tests will monitor general health, kidney function, sex hormone levels, glucose tolerance/prevalence of diabetes and common concomitant lipid disorders are indicated throughout life.
  • The frequency of testing will depend on the abnormalities found as well as their stage of development. These checks will be carried out more frequently during periods of intense growth, i.e., early childhood or adolescence, or in case of identified problems.
  • The frequency of ophthalmic check-ups will depend on the progression of the retinal dystrophy.
  • In adolescence or early adulthood, it may be very beneficial for many patients to find a support group, psychological help, or contact with people affected by the same disease.
  • It is important to perpetuate a habit of an active lifestyle. This can improve cell insulin sensitivity/counteract excessive weight gain and its related disorders including diabetes or fatty liver disease.
  • An active lifestyle, as demonstrated in recent studies, also improves cognitive function, learning and memory in patients with BBS.

Disease documentation and test results

  • For rare and complex diseases like BBS, it is worthwhile collecting all the results of medical examinations and regularly documenting data such as body weight, growth, and blood pressure.
  • Such data collection and monitoring can be very helpful in assessing the course of the disease, making a diagnosis, and planning further research and specialist care.
  • In many countries, BBS patient surveys are maintained. Participation allows for better understanding of the disease and the development of new strategies for the diagnosis and treatment of the disease

Some useful vocabulary to know

Being diagnosed with kidney disease can feel difficult, but understanding your or your child’s condition is the first step to taking control of its symptoms. Some of these common terms might be mentioned by the doctors. Here’s what they mean.

CKD Chronic Kidney Disease – a progressive and irreversible damage to the kidneys which, over the course of months or years can lead to kidney (renal) failure. There is no cure for CKD, but there are treatments that can significantly slow the progression of the disease if started early.
Creatinine A normal body waste product. Sometimes the level of creatinine in your urine is checked and used to determine how well your kidneys are filtering waste from your blood.
Crohn’s disease a type of inflammatory bowel disease (IBD), autoimmunological disorder, occurring not rarely in BBS pts. It causes inflammation of your digestive tract, which can lead to abdominal pain, severe diarrhoea, fatigue, weight loss and malnutrition.
Dialysis The process of artificially removing waste and excess fluid from your blood. There are two main kinds of dialysis-haemodialysis and peritoneal dialysis. With haemodialysis, your blood is filtered by an external machine called a dialyser. Peritoneal dialysis works by passing dialysis solution into your abdomen through a catheter to filter your blood in your body.
ESRD End-Stage Renal Disease the final stage and most severe form of kidney disease. It signifies that your kidneys have failed, and at this point dialysis or a kidney transplant is needed.
GFR Glomerular Filtration Rate the rate at which your kidneys (specifically the glomeruli in them) filter waste from your blood. The test for it is called estimated glomerular filtration rate test eGFR.
Hirschsprung disease – describes an absence of the nerves, normally found in the colon, that control the innate motion of the colon and move food along the tract. This disorders was observed in BBS patients.
Insulin is a hormone produced by the pancreas that regulates the transport of glucose (sugar) to cells and its use for energy production. The secretion is known to be stimulated by the production of glucose.
Insulin resistance Body’s cells do not respond adequately to insulin stimulation, and as a result glucose don`t penetrate into the cells.
Nycturia Purposeful urination at night, after waking from sleep; typically caused by nocturnal urine volumen.
Polydipsia is an excessive thirst. People with this condition tend to drink too much, may never feel sated and end up consuming much more water than they should.
Polyuria is excessive or an abnormally large production or output of urine (>than 3L over 24h in adults).
Renoprotection measures taken to prevent damage to the kidney from any cause, minimise adverse effects–especially due to oxidative stress–on renal vasculature.

References

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