https://www.hal.inserm.fr/inserm-00549873/document

Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting

Bardet-Biedl syndrome (BBS) and Laurence-Moon syndrome (LMS) have a similar phenotype, which includes retinal dystrophy, obesity, and hypogenitalism. They are differentiated by the presence of spasticity and the absence of polydactyly in LMS. The aims of this study were to describe the epidemiology of BBS and LMS, further define the phenotype, and examine genotype-phenotype correlation. The study involved 46 patients (26 males, 20 females) from 26 families, with a median age of 44 years (range 1-68 years). Assessments were performed in 1986, 1993, and 2001 and included neurological assessments, anthropometric measurements, and clinical photographs to assess dysmorphic features. The phenotype was highly variable within and between families. Impaired co-ordination and ataxia occurred in 86% (18/21). Thirty percent (14/46) met criteria for psychiatric illness; other medical problems included cholecystectomy in 37% (17/46) and asthma in 28% (13/46). Dysmorphic features included brachycephaly, large ears, and short, narrow palpebral fissures. There was no apparent correlation of clinical or dysmorphic features with genotype. Two patients were diagnosed clinically as LMS but both had mutations in a BBS gene. The features in this population do not support the notion that BBS and LMS are distinct. The lack of a genotype-phenotype correlation implies that BBS proteins interact and are necessary for the development of many organs.

/pdf/clinical-and-genetic-epidemiology-of-bardet-biedl-syndrome-19mbwxsu28.pdf

Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: A 22-year prospective, population-based, cohort study

Autism is a heterogeneous neurodevelopmental disorder with a variety of different etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of autism is still unclear. This review refers to all the genetic syndromes that have been described in children with pervasive developmental disorders (tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Gilles de la Tourette, Williams, etc.). Issues covered include prevalence and main characteristics of each syndrome, as well as the possible base of its association with autism in terms of contribution to the current knowledge on the etiology and genetic base of pervasive developmental disorders.

Childhood autism and associated comorbidities

Primary cilia are nearly ubiquitous cellular appendages that provide important sensory and signaling functions. Ciliary dysfunction underlies numerous human diseases, collectively termed ciliopathies. Primary cilia have distinct functions on different cell types and these functions are defined by the signaling proteins that localize to the ciliary membrane. Neurons throughout the mammalian brain possess primary cilia upon which certain G protein-coupled receptors localize. Yet, the precise signaling proteins present on the vast majority of neuronal cilia are unknown. Here, we report that dopamine receptor 1 (D1) localizes to cilia on mouse central neurons, thereby implicating neuronal cilia in dopamine signaling. Interestingly, ciliary localization of D1 is dynamic, and the receptor rapidly translocates to and from cilia in response to environmental cues. Notably, the translocation of D1 from cilia requires proteins mutated in the ciliopathy Bardet-Biedl syndrome (BBS), and we find that one of the BBS proteins, Bbs5, specifically interacts with D1.

/pdf/dopamine-receptor-1-localizes-to-neuronal-cilia-in-a-dynamic-4kcz70jsb3.pdf

Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet-Biedl syndrome proteins

From a handful of uncloned genetic loci 6 years ago, great strides have been made in understanding the genetic and molecular aetiology of Bardet-Biedl syn- drome (BBS), a rare pleiotropic disorder characterised by a multitude of symptoms, including obesity, retinal degen- eration and cystic kidneys. Presently, 11 BBS genes have been cloned, with the likelihood that yet more BBS genes remain undiscovered. In 2003, a major breakthrough was made when it was shown that BBS is likely caused by defects in basal bodies and/or primary cilia. Since then, studies in numerous animal models of BBS have corrob- orated the initial findings and, in addition, have further refined the specific functions of BBS proteins. These include roles in establishing planar cell polarity (nonca- nonical Wnt signaling) in mice and zebrafish, modulating intraflagellar transport and lipid homeostasis in worms, and regulating intracellular trafficking and centrosomal functions in zebrafish and human tissue culture cells. From these discoveries, a common theme has emerged, namely that the primary function of BBS proteins may be to mediate and regulate microtubule-based intracellular transport processes.

Human Genome & Diseases: Review Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport

Bardet-Biedl syndrome (BBS), also known as Laurence-Moon-Bardet-Biedl syndrome (LMBBS), has long been regarded as an autosomal recessive condition but recent evidence now points to a more complex pattern of inheritance.1–3 Prevalence rates range from 1 in 100 000 to 1 in 160 000,4–6 although there are communities in which BBS appears to be more common as a result of consanguinity.3,7 BBS is a heterogeneous genetic condition with six gene loci mapped to date: 11q13 ( BBS1 ),8 16q21 ( BBS2 ),9 3p12-13 ( BBS3 ),10 15q23 ( BBS4 ),11 2q31 ( BBS5 ),12 and 20p12 ( BBS6 / MKKS ).13,14 Three of these genes have now been identified, BBS2 , BBS4 , and BBS6 .15 The phenotype of BBS varies from one family to another and within families, with only subtle phenotypic difference related to the different genes identified to date.16,17

The accepted major criteria for diagnosis include retinal dystrophy, obesity, polydactyly, male hypogonadism, mental retardation, and renal dysfunction.3 In addition to the primary features, a number of associated secondary features, including neurological, speech, and language deficits, behavioural traits, facial dysmorphism, and dental anomalies have been identified.18 The motor problems identified include delay in acquisition of motor skills, unsteady gait, and ataxia.18 Language development is delayed in many cases, although this may be commensurate with overall intellectual function, and there are also reports of speech problems that include articulation difficulties, consonant omission or distortions, dysarthria and hypernasality.3,4,17–19 Developmental delay has been widely described as a major feature of BBS, with two-thirds to three-quarters of patients performing in the mental retardation range on formal testing4,18,20 (but see Green et al 3 for an exception).

Disturbances in behaviour have been reported in …

https://jmg.bmj.com/content/jmedgenet/39/12/e76.full.pdf

I Ojo

Papers

Behavioural phenotype of Bardet-Biedl syndrome.