Bardet-Biedl SyndromeBy: Iyad Jaber

IASHVILI CHILDREN’S CENTRAL HOSPITAL. TBILISI, GEORGIA

Epidemiology and key points

Autosomal recessive ciliopathy.

The estimated incidence is 1:160 000 in northern European populations and 1:13 500 in some Arab populations, more common in the Bedouin population of Kuwait and on the island of Newfoundland

North American population 1:140,000

Characterised by retinal dystrophy, renal dysfunction, post-axial polydactyly, obesity, cognitive deficit and hypogenitalism.

Diagnosis is based on clinical features.

Molecular genetic testing is available and currently 16 genes are known to be associated with Bardet–Biedl syndrome (BBS), accounting for approximately 80% of clinically diagnosed BBS.

Surveillance includes regular ophthalmological evaluation, montoring of renal, liver, glucose, lipid and endocrine profile and regular weight and blood pressure measurements.

LMBBS or BBS ?

BBS is named after Georges Bardet and Arthur Biedl. The first known case was reported by Laurence and Moon in 1866.

Laurence-Moon-Biedl-Bardet syndrome (LMBBS) is no longer considered as a valid term as patients of Laurence and Moon had paraplegia but no polydactyly and obesity, which are the key elements of the BBS.

Hence, Laurence-Moon syndrome is usually considered a separate entity. However, some recent research suggests that the two conditions may not be distinct.

BBS Clinical Features

Eyes: Pigmentary retinopathy, poor visual acuity, low vision, and/or blindness caused by an impaired photoreceptor transport mechanism in the retina.

Nose: Loss of, or reduced sense of, smell. (anosmia). Some patients claim extra-sensitive sense of smell.

Hand and foot: Polydactyly (extra digits) or syndactyly (webbing of fingers and toes).

Cardiovascular system: Hypertrophy of interventricular septum and left ventricle, Hypertension and dilated cardiomyopathy.

Gastrointestinal system: Fibrosis.

Urogenital system: Hypogonadism, renal failure, urogenital sinuses, ectopic urethra, uterus duplex, septate vagina, and hypoplasia of the uterus, ovaries, and fallopian tubes.

Growth and development: Developmental Delay, especially of fine and gross motor skills

Behavior: a wide variety of socialization and social interaction problems have been identified with BBS.

learning difficulties (may or may not be mental retardation)

Diabetes, in some cases.

Dyslipidemia, in some cases.

Defective thermosensation or mechanosensation.

Additional features: Obesity, possibly related to a decreased sensory function that would normally indicate satiation. Hyperphagia in some patients.

Pathophysiology

The detailed biochemical mechanism that leads to BBS is still unclear.

The gene products encoded by these BBS genes, called BBS proteins, are located in the basal body and cilia of the cell.

Using the round worm C. elegans as a model system, biologists found that BBS proteins are involved in a process called Intraflagellar transport (IFT), a bi-directional transportation activity within the cilia along the long axis of the ciliaryshaft that is essential for ciliogenesis and the maintenance of cilia. Recent biochemical analysis of human BBS proteins revealed that BBS proteins are assembled into a multiple protein complex, called "BBSome". BBSome is proposed to be responsible for transporting intracellular vesicles to the base of the cilia and to play an important role in the ciliary function.

Since abnormalities of cilia are known to be related to a wide range of disease symptoms including those commonly seen in BBS patients, it is now widely accepted that mutated BBS genes affect normal cilia functions, which, in turns, causes BBS

A theory that photoreceptor cells are nourished by the IFT of retinal cilia now offers a potential explanation for the retinal dystrophy common in BBS patients after their early years of life

BBsome: BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, TTC8/BBS8, BBS10, TRIM32/BBS11 BBS12, CCDC28B, CEP290, TMEM67, MKS1, MKKS

Autosomal Recessive Ciliopathy.

Other forms of ciliopathies

Other known ciliopathies include

primary ciliary dyskinesia,

polycystic kidney and

nephronophthisis,

Alstrom syndrome,

Meckel–Gruber syndrome

and some forms of retinal degeneration

FrequencyPrimary features

Rod-cone dystrophy 93%

Polydactyly 63–81%

All four limbs: 21%

Upper limbs only: 9%

Lower limbs only:21%

Obesity 72–92%

Genital anomalies 59–98%

Renal anomalies 53%

Learning difficulties 61%

Secondary featuresSpeech delay 54–81%

Developmental delay 50–91%

Diabetes mellitus 6–48%

Dental anomalies 51%

Congenital heart disease 7%

Brachydactyly/ syndactyly 46–100%/8–95%

Ataxia/ poor coordination 40–86%

Anosmia/hyposmia 60%

Gene Frequency Locus FunctionBBS1 23% 11q13 BBSome proteinBBS2 8% 16q21 BBSome protein

BBS3/ARL6 0.4% 3p12-p13 GTPaseBBS4 2% 15q22.3-q23 BBSome proteinBBS5 0.4% 2q31 BBSome protein

BBS6/MKKS 6% 20p12Part of chaperonin complex

BBS7 2% 4q27 BBSome protein

BBS8/TTC8 1% 14q32.1 BBSome protein

BBS9/B1 6% 7p14 BBSome protein

BBS10 20% 12q21.2Part of chaperonin complex

BBS11/TRIM32 0.1% 9q31-q34.1E3 ubiquitin ligase

BBS12 5% 4q27Part of chaperonin complex

BBS13/ MKS1 4.5% 17q23Centriole migration

BBS14/CEP290/NPHP6 1% 12q21.3

Basal body: RPGR interaction

BBS15/ WDPCP 1% 2p15

Basal body: localisation of septins and ciliogenesis

BBS16/SDCCAG8 1% 1q43Basal body: interacts with OFD1

Cilium structure

Postaxial Polydactyly - Ulnar

Preaxial Polydactyly - Radial

PreaxialPostaxial

Genu Valgum Genu Varum

Retinitis Pigmentosa

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