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With the benefit of follow-up of up to 10 years in many of these patients, it has been possible to show that all patients have some abnormalities of their heart, but many remain stable , with normal exercise tolerance. 25% have shown progression , of whom six of the seven have died from heart failure.4 of 21 of those with stable heart function have died of chest infection. Add textbox showing key numbers .
Alström syndromeClinical studies and research<br />R B Paisey on behalf of:<br />National clinical advisory Group<br />Alström syndrome UK<br />Cardiology,endocrinology,vascular medicine, biochemistry, radiology, dietetics, respiratory medicine, urology,audiology, orthopaedics and rheumatology.<br />
National Clinical Advisory Team<br />Major organ transplantation<br />Rare disease diagnosis and treatment<br />“ EU Rules” Alström UK<br />
Alström syndrome location of the gene<br />The ALMS1 gene is located on the short (p) arm of chromosome 2 at position 13.<br />More precisely, the ALMS1 gene is located from base pair 73,612,885 to base pair 73,837,045 on chromosome 2<br />
Alström syndrome cilia in photoreceptors<br />
The cilium in the eye<br />Found inside photoreceptors<br />“Connecting cilium”<br />Connects inner segment to <br />outer segment<br />Carries proteins made in the inner segment, to outer segment<br />Malfunction stops transport of vital proteins, photoreceptors die<br />
Alstrom adult clinics 1998 to 2008<br />Alström families conference UK <br />
Alström Syndrome<br />Further features identified:<br />Congestive heart failure secondary to cardiomyopathy<br />Sensorineural hearing loss <br />Short stature / advanced bone age / scolosis<br />Progressive, chronic nephropathy<br />Liver fibrosis<br />
Check list for exclusion of Alström syndrome in visually impaired young people<br />
Alström Syndrome is one <br />of many “ciliopathies”<br />Primary Cilia Dyskinesia (PCD)<br />Polycystic Kidney Disease (PKD)<br />Joubert Syndrome (JS)<br />Orofaciodigital Syndrome type I (OFD1)<br />Meckel-Gruber Syndrome (MKS)<br />Laurence-Moon-Bardet-Biedl Syndrome (LMBBS/BBS)<br />In most cases there is blindness, kidney disease, obesity<br />In all cases it is thought that the cilium is not working, <br />in a number of organs<br />
Overview of studies in AS<br />But:-<br />Cardiomyopathy, diabetes, lipid disorders,liver, kidney, waterworks problems are variable in extent.<br />Suggests influence of other genetic and environmental factors:-<br /> Are these modifiable?<br />
Overview of studies in AS<br />Metabolic treatments<br />Control of diabetes<br />Control of serum lipids<br />Testosterone<br />Thyroxine<br />Diet and exercise<br />Early detection of major organ damage<br />Kidneys<br />Heart<br />Liver<br />Musculoskeletal<br />urological<br />
A hopeful sign<br />Neuropathy-amongst 58 Alström subjects with up to 25 yrs of diabetes none had neuropathy compared with young onset non- genetic type 2 diabetic subjects who had 30% neuropathy and 16% foot ulceration. <br />
Proportion of A.S patients with severe cardiomyopathy<br />
Procedure for Producing Inducible Pluripotent Stem Cells from a Small Punch Skin Biopsy<br />Freeze and Store<br />Freeze and Store<br />Liver Cells<br />Heart Cells<br />Muscle Cells<br />Nerve Cells<br />Many more...<br />Skin biopsy:<br />LA<br />4mm biopsy<br />10 mins<br />Pluripotent Stem Cells<br />Cultured Dermal Fibroblasts<br />
Alström syndrome<br />?Hope for the future<br />Genotype phenotype correlation<br />Reprogramming of cells in culture to assess cause of dysfunction<br />Correction of cell defect and transplantation of cardiomyocytes.<br />Insight into more common diabetic, cardiac, hepatic and renal disease. <br />
Staff involved<br />Alstrom adult clinics 1998 to 2008<br />AS UK: Torbay Hospital:<br /> Kay Parkinson Cathy Carey Mary Costelloe<br /> John Parkinson Richard Paisey Claire Rockett<br /> Kevin Goodwin Lee Dobson Kimberley Vogler<br /> Sean Waiting Jamie Smith Chrissie Rowe<br /> Charlotte Parkinson Kathleen Williams Mark Clemence<br /> Kerry Leeson Debbie Hodge Kirsten Mackay<br /> Mike Hales Lynne Bower Sue Bunce<br /> Mark McCarthy Alison White<br /> Sarah Mills Richard Seymour<br />