Although Bardet-Biedl syndrome (BBS: severe obesity, polydactyly, learning disabilities, retinopathy, renal disease and cardiac malformations) was described more than 80 years ago, it is only over the past few years that extensive data on the natural history and molecular pathogenesis of this complex disorder have been reported. We now know that BBS can be caused by mutations in at least 12, genes and, although its is typically inherited in an autosomal recessive pattern, BBS may occasionally exhibit more complex inheritance. In this study, we are defining the physical (body mass, percent and distribution of body fat) and metabolic (hyperglycemia, hperinsulinemia, serum levels of lipids and adipokines) characteristics of glucose and fat metabolism in a cohort of adult and pediatric patients with BBS. We are also characterizing the hypogenitalism in BBS, and attempting to determine its relationship, if any, to the incidence of obesity in BBS. In addition, we are studying the retinal dystrophy, the renal dysfunction, and the nature of the reported mental retardation/learning disability that is found in many patients. We plan to correlate the phenotypic manisfestations in our subjects with the results of our mutation analysis studies. Our objective is to learn more about the genetic alterations that may underlie the obesity and associated organ dysfunction that characterizes BBS.

• INCLUSION/EXCLUSION CRITERIA:

We are using previously published clinical diagnostic criteria for BBS to determine study eligibility of probands. As outlined in that report, we will include patients who present with four of the five primary features and two secondary features. Parents are also enrolled for genetic studies. We are not enrolling unaffected siblings or recruiting control subjects, instead, results of testing are being compared to previously published data obtained from appropriate non-BBS control subjects.

The initial determination of eligibility is made by review of prior clinical records. Some patients are not characterized in sufficient detail to know if the person meets the clinical criteria, yet we may suspect the diagnosis. In those cases, the subjects are brought to NIH and undergo clinically appropriate testing to make the diagnosis. If that clinical testing does not confirm the diagnosis, the patients or parents are given appropriate clinical counseling and returned to the care of their personal physician. If features later develop that allow the diagnosis to be made, they may re-enroll and undergo further evaluation.

Our study population includes patients of all ages and ethnic groups, and both genders. The inclusion of children is essential to a research study that is correlating genotype with phenotype, and is attempting an early identification of metabolic abnormalities that may be best treated at an early age. Many of the age-dependent manifestations of BBS develop during childhood and the average age of diagnosis is 9.2 years. Pregnant women and children under the age of 5 yrs do not undergo invasive research procedures or procedures involving ionizing radiation unless that procedure would be performed as part of standard medical care.

Because cognitive dysfunction is known to be a component of BBS, some patients with impaired cognition and understanding may be evaluated under this protocol. If the investigators believe that an adult patient may not be competent to give informed consent to participate, or does not understand the consent document and the procedures of the study, that patient may be excluded from participation. We may request that the patient and accompanying caregiver also be interviewed by an independent ethics panel to confirm that he or she is competent to give consent and to participate if the team feels this would be useful.

Neither healthy volunteers unrelated to an affected patient nor lab personnel will be enrolled.

We might allow the inclusion of cognitively impaired adults by obtaining a durable power of attorney (DPA) under the guidelines of NIH Policy 'Consent Process in Research Involving Impaired Human Subjects.'

Under these guidelines (vide supra) we may also include any child (less than 18 yrs) whose parent or legal guardian is unable to understand the informed consent process or to give consent for his/her child, and children older than 7 yr who are unable to assent to the study.