NIH Study Clinical and Molecular Investigations into Ciliopathies: Findings on Alström Syndrome. J. D. Marshall1, J. Han2, 3, J. K. Naggert1, D. Yildirimli2, 4, J. Bryant2, 4, R. Fischer2, 4, W. M. Zein2, 5, K. Daryanani2, 6, B. Turkbey2, 7, E. Turkbey2, 6, C.-Y. Liu2, 6, P. Choyke2, 7, T. Heller2, 8, D. Rosing2, 9, A. Brofferio2, 9, V. Sachdev2, 9, L. Olivieri2, 9, N. Bridges2, 10, J. Graf-Myles2, 6, S. Bernstein2, 6, K. Olivier2, 10, B. Shamburek2, 9, M. Huizing2, 4, W. A. Gahl2, 4, M. Gunay-Aygun2, 4 1) Jackson Laboratory, Bar Harbor, ME; 2) National Institutes of Health; 3) National Institute of Child Health and Human Development; 4) National Human Genome Research Institute; 5) National Eye Institute; 6) NIH Clinical Center; 7) National Cancer Institute; 8) National Institute of Diabetes and Digestive and Kidney Diseases; 9) National Heart, Lung, and Blood Institute; 10) National Institute of Allergy and Infectious Diseases.

   Alström syndrome (AS) is a ciliopathy characterized by childhood retinal dystrophy, obesity, diabetes, hyperlipidemia, cardiomyopathy, hearing loss, and renal and hepatic involvement. The causative gene ALMS1 encodes a large protein that localizes to the centrosome and basal body. The exact function of the ALMS1 protein is not known; it may play a role in centrosome assembly and/or function and endosome recycling. The frequency and nature of kidney, liver, cardiac, hormonal/metabolic, and other organ system involvement in AS is not well defined. Under our ciliopathy study (www.clinicaltrials.gov, trial NCT00068224), ongoing since 2003, we have evaluated a total of 275 patients including AS patients fulfilling the clinical diagnostic criteria. Evaluations included abdominal ultrasonography and magnetic resonance imaging (MRI) to quantitate visceral adiposity, echocardiogram, biochemical and hormone testing, ALMS1 sequencing, dual-energy X-ray absorptiometry to measure total body bone mineral content, lean mass, fat mass, MR-spectroscopy for liver and thigh muscle fat content, breakfast mixed-meal test to assess hormones related to energy homeostasis and resting metabolic rate measurement. Our AS cohort included 25 patients from 20 families; 3 families had 2 affected children and 1 contributed 3 affected siblings. Ages ranged from 1.7 to 38.9 years (15.7 + 10.9); there were 8 adults and 13 females. Early onset retinal degeneration and progressive sensorineural hearing loss were constant features. Even among siblings, there was considerable variability in the frequency and severity of individual components of the syndrome including cardiomyopathy and obesity, suggesting the presence of modifier genes. For example, in the family with 3 affected sons, the oldest had infantile-onset cardiomyopathy while the other 2, monitored from birth, had normal echocardiograms at ages 5 and 1.7 years. Three patients from 2 families including two 12-years-old non-identical twin brothers (with 2 truncating ALMS1 mutations) had no obesity (weight at 25th % since birth); potentially explainable by ALMS1 isoform-specific effects. We continue to enroll new AS patients to define the full phenotypic spectrum of this disorder, and to provide the groundwork for more focused studies and future therapeutic interventions. These data might potentially contribute to development of novel treatments for non-syndromic forms of obesity, diabetes and hyperlipidemia.

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