Alström syndromeClinical studies and research

R B Paisey on behalf of:National clinical advisory Group

Alström syndrome UKCardiology,endocrinology,vascular medicine, biochemistry, radiology,

dietetics, respiratory medicine, urology,audiology, orthopaedics and

rheumatology.

National Clinical Advisory Team

Major organ transplantationRare disease diagnosis and treatment

“ EU Rules” Alström UK

Alström Syndrome

• Carl Henry Alström 1959• Deaf blind syndrome• Preserved intelligence• Obesity• Insulin resistance• Type 2 diabetes• ? 30 in world-now 600+

Alström friends

ASCO

Autosomal Recessive Inheritance

Two germline mutations (one from each parent) to develop disease

Equally transmitted by men and women

Noncarrier individual

Non-affected carrier

Affected individual

Alström syndrome human chromosomes

Alström syndrome chromosome 2

Alström syndrome location of the gene

The ALMS1 gene is located on the short (p) arm of chromosome 2 at position 13.More precisely, the ALMS1 gene is located from base pair 73,612,885 to base pair 73,837,045 on chromosome 2

Alström syndrome-gene translation

Alström syndrome-ALMS protein function

Alström syndromemicrotubules

Alström syndrome cilia in photoreceptors

The cilium in the eye

Found inside photoreceptors

“Connecting cilium”

Connects inner segment to outer segment

Carries proteins made in the inner segment, to outer segment

Malfunction stops transport of vital proteins, photoreceptors die

Alström syndrome

Alstrom adult clinics 1998 to 2008

Alström families conference UK

Alström Syndrome

• Further features identified:– Congestive heart failure secondary to

cardiomyopathy– Sensorineural hearing loss – Short stature / advanced bone age / scolosis– Progressive, chronic nephropathy– Liver fibrosis

Check list for exclusion of Alström syndrome in visually impaired young people

Alström Syndrome is one of many “ciliopathies”

In most cases there is blindness, kidney disease, obesity

In all cases it is thought that the cilium is not working, in a number of organs

Primary Cilia Dyskinesia (PCD)Polycystic Kidney Disease (PKD)Joubert Syndrome (JS)Orofaciodigital Syndrome type I (OFD1)Meckel-Gruber Syndrome (MKS)Laurence-Moon-Bardet-Biedl Syndrome (LMBBS/BBS)

Alström syndrome

histology

Overview of studies in AS

• But:-• Cardiomyopathy, diabetes, lipid disorders,liver,

kidney, waterworks problems are variable in extent.

• Suggests influence of other genetic and environmental factors:-

• Are these modifiable?

Cause and effect

?

INSULIN EFFECTS ON INTERMEDIARY METABOLISM

PLASMA PLASMAHEPATOCYTE

GLUCOSE

GLUTRECEPTOR

GLYCOGEN

GLUCOKINASE

PHOSPHORYLASE GLYCOGEN SYNTH

FRUCTOSE 6 PHOS GLYCOLYSIS

LACTATE

PYRUVATE

GLUCONEOGENESIS

CHOLESTEROL

MEVALONIC ACID

HMG CoA

PYRUVATE

ACETYL CoA

KETONEBODIES

TCACYCLE

REDUCTASE

MELONYL FATTY ACIDSCoA

CARNITINEACYL TRANSFERASETRIGLYCERIDE

OXIDATIVEPHOSPHORYLATION30ATP

INSULIN SENSITIVELIPOPROTEIN LIPASE

FA +GLYCEROL

TG

ADIPOCYTE

VLDL

MITOCHONDRION

INSULINSENSITIVE

రర

VLDL

LDL

HDL

Could it all be this?

Overview of studies in AS

• Metabolic treatments• Control of diabetes• Control of serum lipids• Testosterone• Thyroxine• Diet and exercise

• Early detection of major organ damage

• Kidneys• Heart• Liver• Musculoskeletal• urological

Alström syndrome

• Tertiary prevention:• Control diabetes low carb,Metformin,incretin• Control lipids-Niaspan• Slow heart and renal failure• Detect liver fibrosis early• Treat hormone deficiencies• Refine audiology intervention

A hopeful sign

• 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.

Proportion of A.S patients with severe cardiomyopathy

75%

25%

Mild /ModerateSevere

Alström syndrome and stem cells

Alström syndrome and stem cells

Procedure for Producing Inducible Pluripotent Stem Cells from a Small Punch Skin Biopsy

Skin biopsy:LA4mm biopsy10 mins

Cultured Dermal Fibroblasts

Pluripotent Stem Cells

Liver Cells

Heart Cells

Muscle Cells

Nerve Cells

Many more...

Freeze and Store

Freeze and Store

Alström syndrome

• ?Hope for the future• Genotype phenotype correlation• Reprogramming of cells in culture to assess

cause of dysfunction• Correction of cell defect and transplantation of

cardiomyocytes.• Insight into more common diabetic, cardiac,

hepatic and renal disease.

Staff involved

Alstrom adult clinics 1998 to 2008

AS UK: Torbay Hospital:

Kay Parkinson Cathy Carey Mary Costelloe

John Parkinson Richard Paisey Claire Rockett

Kevin Goodwin Lee Dobson Kimberley Vogler

Sean Waiting Jamie Smith Chrissie Rowe

Charlotte Parkinson Kathleen Williams Mark Clemence

Kerry Leeson Debbie Hodge Kirsten Mackay

Mike Hales Lynne Bower Sue Bunce

Mark McCarthy Alison White

Sarah Mills Richard Seymour