Molecular pathogenesis of subarachnoid haemorrhage

1. Molecular pathogenesis of subarachnoid haemorrhage Baiping Zhang, Kaare Gugleholm, Lorna B. Day, Shu Ye, Roy O. Weller, Ian N.M. Day 5 November 2002

2. Pathogenesis and the stages involved in the formation of saccular aneurysm • Cellular and molecular architecture of the vessel wall • Molecular pathology • PKD1 gene and polycystin • COL3A1 and type III collagen • Fibrillin-1 • Collagen IV and other basement membrane constituents • Alpha1-Antitrypsin (protease inhibitor) • Future focus

3. Subarachnoid haemorrhage (SAH) • Condition caused by the escape of blood from a cerebral artery into the subarachnoid space along the surface of the brain. http://instruct.uwo.ca/anatomy/530/SagSin.gif

4. Mortality of diagnosed cases is about 40% within the first 30 days • Less then 25% have a good functional outcome and the disease has dramatic impact on the lives of carers and relatives. Pritchard, Foulkes, Lang, & Neil-Dwyer. 2001

5. Schematic overview of contributory factors to subarachnoid haemorrhage B. Zhang et al./ The International Journal of Biochemistry & Cell Biology 35 (2003) 1341-1360

6. Commonest sites for Saccular Aneurysms B. Zhang et al./ The International Journal of Biochemistry & Cell Biology 35 (2003) 1341-1360

8. B. Zhang et al./ The International Journal of Biochemistry & Cell Biology 35 (2003) 1341-1360

10. Etiology involved in the formation of saccular aneurysms • Majority of aneurysms occur between the ages of 40 and 70 • Ageing effects on the arteries • Increased incidence of saccular aneurysms in families with • Polycystic kidney disease • Fibromuscular dysplasia • Moyamoya disease • Marfan Syndrome • EDS type IV

12. PKD1 gene and polycystin • Adult polycystic kidney disease is an autosomal dominant disorder in which renal cysts form, leading to progressive loss of glomerular filtration and subsequently to renal failure and end-stage renal disease. • PKD1 gene causing (PKD) • Encodes for a protein named polycystin • Polycystin - participates in protein-protein and protein-carbohydrate interactions in the extracellular matrix adpkd.cimr.cam.ac.uk/ buttons/pkd1_hs_350.gif

13. COL3A1 and type III collagen • Ehlers-Danlos Syndrome Vascular Type • Arterial rupture risk • Thin transparent skin • Early bruising • Joint laxity • Ligament weakness • Bowel rupture • (EDS type IV) • Defective collagen III synthesis • Vascular expression on COL3A1

14. Collagen IV and other basement membrane constituents • Collagen IV defects cause Alport’s syndrome. • Alports syndrome characterized sensorineural hearing loss and haematuria. • Its is therefore plausible new hypothesis that defects in the basement membrane as well as defects in the elastic and medial layer may predispose intracranial aneurysms

15. Protease inhibitor (alpha1-Antitrypsin) • Most abundant and potent natural inhibitor of elastase. • Alpha1-Antitrypsin activity has been claimed to be reduced in both intracranial and abdominal aortic aneurysm.

16. Future focus

17. Fibrillin-1 and FBN1 • Marfan syndrome is an autosomal dominant heritable disorder of connective tissue with prominent manifestations affecting the skeletal, ocular and cardiovascular systems. • Progressive dilation of the aortic root and aortic dissection and rupture are frequent, and mitral and aotic valve insufficiency may also occur early. • Caused by mutations in FBN1 gene encoding fibrilin-1 • Mutations of this gene also cause type I fibrillinopathies