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Homocystinuria Homocystinuria Sheikha Sheikha Homocystinuria BIOCHEMIST GENETICIST PEDIATRICIAN VASCULAR SURGEON HEALTH CONSCIOUS Sheikha Homocystinuria PROUD MEMBER OF SULY PHYSICIAN’S SYNDICATE BIOCHEMIST FATHER OF 6O HEMATOLOGY/ONCOLOGY POSTGRADUATE BACHAS “BACKBONE OF MM&CC” GENETICIST PEDIATRICIAN VASCULAR SURGEON HEMATOLOGIST “COAGULATION” HEALTH CONSCIOUS Professor Anwar Sheikha MD, FRCP, FRCPath., FCAP, FRCPA, FRCPI, FACP Senior Consultant Clinical & Lab. Hematologist Clinical Professor of Hematology University of Mississippi Medical Center, Jackson, Mississippi Professor of Hematology, University of Salahaddin, Erbil, Kurdistan, IRAQ Owner & C.E.O., Raziana Company for Health Services, Hawler, IRAQ كومبانياى ﺮﺍﺰﯿﺎﻨﻪ پروژﻩى نه خوشخانه و شيرپه نجه خانه ى ميديا دروست دەكات ﭘﺮﻮﮊﻩﻜﻪ ﺑﺮﯾﺘﯾﻪ ﻠﻪ ۲۰۰ﮊﻮﺮﻯ ﻧﻪﺧﻮﺵ ﻮ ﻛﻮﻣﻪﻠﮕﺎﻯ ﻛﻠﯾﻧﯾﻛﻮ ﻣﺎﻠﻰ ﭙﺰﯾﺷﮑﺎﻥ “RAZIANA COMPANY ” MEDYA MEDICAL & CANCER CENTER MEDIA MEDICAL & CANCER CENTER A 200 BED HOSPITAL, MEDICAL OFFICE BUILDINGS & A RESIDENCE VILLAGE AT A COST OF ~ $50 MILLION Sheikha Homocystinuria Homocystinuria Homozygous Homocystinuria and Heterozygous Hyperhomocysteinemia as the cause for Familial Thrombophilia and Atherosclerosis Homocystinuria Sheikha Writing the Abstract: Background Homocysteine has now evolved as an athero-thrombotic risk factor standing in par with Cholesterol & Smoking in causing Coronary, Cerebrovascular, Peripheral & Venous Occlusive Vascular Diseases. Sheikha Homocystinuria Homocysteine has now evolved as an atherothrombotic risk factor standing in par with Cholesterol & Smoking in causing Coronary, Cerebrovascular, Peripheral & Venous Occlusive Vascular Diseases. Homozygous HCNU Heterozygous Hyperhomocysteinemia Aggressive Precocious Arterial & Venous Occlusive Complications ? Major Vaso-occlusive Diseases Homocystinuria Sheikha Patients & Methods: Two Saudi Children from a HCNU family were admitted with an aggressive course of arterial & venous atherothrombosis. Homocystinuria Sheikha Patients & Methods : Two Saudi Children from a HCNU family were admitted with an aggressive course of arterial & venous atherothrombosis. Results: Patients were found to have very high levels of Homocysteine. One also showed other features of HCNU. They both responded well to aggressive management with Anticoagulation, Folate, Pyridoxine & B12 They were discharged with minimal sequale of the thrombotic storm. Homocystinuria Sheikha Conclusion: We conclude that although atherothrombosis is rare in children, one should always keep in mind the possibility of HCNU, especially if other dysmorphic features are also noticed. If the homozygous form of the disease is so athero-thrombogenic, then there should be some grounds for the current homocysteine revolution as a cause for Coronary, Carotid and other atherosclerotic diseases. Sheikha Homocystinuria Conclusion: We conclude that although atherothrombosis is rare in children, One should always keep in mind the possibility of HCN, especially if other dysmorphic features are also noticed. If the homozygous form of the disease is so athero-thrombogenic, then there should some grounds for the current Homocysteine revolution as a cause for Coronary, Carotid and other atherosclerotic diseases. A Folate A Day Will Keep A Heart Attack Away Homocystinuria Sheikha Abstract: Background: Homocysteine has now evolved as an atherothrombotic risk factor standing in par with cholesterol and smoking in causing coronary, cerebrovascular, peripheral and venous occlusive vascular diseases. Homozygous homocystinuria is notorious for causing aggressive precocious arterial and venous occlusive complications. Despite some minor controversies, tens of major studies have recently shown that even mild and moderate hyperhomocysteinemia of the heterozygous variety is also associated with major vaso-occlusive problems. Patients and Methods: We report here a homocystinuria family whose two children were admitted with an aggressive course of arterial and venous atherothrombosis. One of the children was only three years old when she presented with a violent episode of gangrenous arterial vaso-occlusion. It is unusual for the vascular disease to antedate the other known features of this disease or show up in such a young age and with such a severity. Results: Patients were found to have very high levels of homocysteine. This combined with the other phenotypic features of the disease, made the diagnosis clear. They both responded well to prompt diagnosis and aggressive management with anticoagulation and supplementation with folic acid, pyridoxine and vitamin B12. They were discharged with minimal sequale of the thrombotic storm. Conclusion: We conclude that although atherothrombosis is rare in children, one should always keep in mind the possibility of homocystinuria, especially if the other dysmorphic features are also noticed. If the homozygous form of this disease is so athero-thrombogenic, then there should be some grounds for the current homocysteine revolution as a cause for coronary, carotid and other atherosclerotic diseases. Key Words: Homocystinuria; Hyperhomocysteinemia; Homocysteine; Vascular Occlusive Disease; Atherothrombosis Author’s e-mail: [email protected] Sheikha Homocystinuria THF METHIONINE B1 2 Methylene THF Methyl THF HOMOCYSTEINE MTHFR CH3 CBS CYSTEINE CYSTATHIONINE Abbreviations: CBS: Cystathionine β- Synthase MTHFR: Methylene Tetrahydrofolate Reductase THF: Tetrahydrofolate Sheikha Homocystinuria Introduction: Hyperhomocyteinemia could be associated with both athersclerotic arterial & thrombotic venous occlusive diseases. HOMOZYGOUS HCNU is the rare form of the disease. Incidence is 5 per million live births ~ Precocious atherosclerotic disease & symptomatic VOD at young age Normal at birth, with time, they develop the following features: Scoliosis Ectopia Lentis “High Myopic Eye-glasses” Marfan-Like Skeletal Changes Pectus Excavatum High-Arched Palate Malar Flush Tall & Thin Mental Retardation Long Limbs Arachnodactyly Sheikha Homocystinuria HETEROZYGOUS Hyperhomocysteinemia is quite common. Incidence is 5 to 10 % of the population. ? IHD VOD CVA PVD CAROTID Sheikha Homocystinuria HETEROZYGOUS Hyperhomocysteinemia is quite common. Incidence is 5 to 10 % of the population. HYPERTENSION CHOLESTROL SMOKING DIABETES Could we add High Homocystein level? VOD ? PVD CAROTID IHD CVA Sheikha Homocystinuria Patient 1 10 yr old Saudi girl 12 hours h/o Inability to walk Pain & bluish discoloration of the toes of the left foot Swelling of the left thigh DVT VASCULAR SURGEON DISTAL ARTERIAL OCCLUSION Homocystinuria Sheikha Patient 1 10 yr old Saudi girl 12 hours h/o inability to walk Swelling, pain & bluish discoloration of toes of the left foot DVT VASCULAR SURGEON DISTAL ARTERIAL Swelling of the left thigh OCCLUSION O/E Tall & thin girl Long limbs & arachnodactyly Nocturnal enuresis Smelly urine Mentally subnormal Scoliosis High Arched Palate Pectus Excavatum High myopic glasses Bilateral inferior sublaxation of lenses Mid Left Thigh Mid Calf 45 cm 36 cm 23 20 ABSENT DORSALIS PEDIS VENOGRAM: A LARGE THROMBUS OBSTRUCTING FEMORAL VEIN Homocystinuria Sheikha HOMOCYSTEIN LEVEL IN GERMANY WAS VERY HIGH Dx: HCNU THROMBOPHILIA & ARTERIAL OCCLUSIVE DISEASE R/ Therapeutic heparinazation Warfarin ASPIRIN, FOLATE, B12 & B6 DISCHARGED 16 DAYS LATER THE SWELLING SHRUNK FROM 45 TO 36 cm. FOLLOW UP WAS UNEVENTFUL Homocystinuria Sheikha Patient 2 3 yr old Saudi girl A known sister HCNU Inability to walk Gangrenous Rt. Lower Limb Sick & toxic O/E Tall & thin girl Long limbs & arachnodactyly Mentally subnormal High CPK h/o smelly urine Rt. LL was cold with early evidence of gangrene Rt. Femoral Pulse was absent Angiogram: Embolic obstruction of Rt. Iliac Artery NONE OF THESE HCNU FEATURES Scoliosis High Arched Palate Pectus Excavatum High myopic glasses Bilateral inferior sublaxation of lenses Homocystinuria Sheikha HOMOCYSTEIN LEVEL WAS VERY HIGH Dx: HCNU ARTERIAL OCCLUSIVE DISEASE Rt. Iliac & Femoral artery embolectomy plus faciotomy ASPIRIN, HEPARIN & THEN WARFARIN FOLATE, B12 & B6 SKIN GRAFTING 3 WEEKS LATER DISCHARGED WITH EXCELLENT RESULTS FOLLOW UP WAS UNEVENTFUL WITHOUT THE FIRST PATIENT IN THE FAMILY, ONE COULD HAVE EASLIY MISSED HCNU DIAGNOSIS IN THIS PATIENT EACH MEMBER OF THIS FAMILY DESERVE PROPHYLACTIC MULTIVITAMIN THERAPY Sheikha Homocystinuria RELATIONSHIP BETWEEN HIGH HOMOCYSTEINE LEVEL & VASO-OCCLUSION 38 STUDIES 22% IHD 27% CVD 33% PVD 14% VTE HAVE HOMOCYSTEINE LEVEL > 95% PERCENTILE Sheikha Homocystinuria POTENTIATION OF ATHERO-THROMBO-EMBOLIC EFFECT OF HIGH HOMOCYSTEINE LEVEL CHOLESTROL SMOKING DIABETES HYPERTENSION AT III ↓ PROEIN C ↓ F V LEIDEN + ↑HOMOCYSTEINE DVT IN ↑ HOMOCYSTEINE ALONE DVT IN FACTOR V LEIDEN ALONE 3% 3% DVT IN COMBINED CONDITIONS 22% Sheikha Homocystinuria PATHOPHYSIOLOGY OF VASCULAR DAMAGE BY HIGH HOMOCYSTEINE LEVEL HCN CONSUMES AND DEPLETES NITRIC OXIDE INDUCES SUBENDOTHELIAL SMOOTH MUSCLE & COLLAGEN PROLIFERTAION INHIBITS REPAIR OF DAMAGED ENDOTHELIUM Sheikha Homocystinuria INHIBITS PLATELET ACTIVATION & AGGREGATION POTENT VASODILATOR INHIBITS PROLIFERATON OF SUBENDOTHELIAL SMOOTH MUSCLE CELLS NITRIC OXIDE “EDRF” NEUTRALIZES HOMOCYSTEINE Sheikha Homocystinuria INHIBITS PLATELET ACTIVATION & AGGREGATION POTENT VASODILATOR INHIBITS PROLIFERATON OF SUBENDOTHELIAL SMOOTH MUSCLE CELLS NITRIC OXIDE “EDRF” NEUTRALIZES HOMOCYSTEINE IN HYPERHOMOCYSTEINEMIA “NO” IS DEPLETED & EXCESS UN-NEUTRALIZED HCN INHIBITS GLUTATHIONE PEROXIDASE, RESULTING IN FORMATION OF OXYGEN RADICALS THAT ARE DIRECTLY TOXIC TO ENDOTHELIUM Sheikha Homocystinuria HIGH HCN LEVEL CREATES A HYPERCOAGULABLE STATE THROUGH *ACTIVATION OF CLOTTING FACTORS XII & V AND TISSUE FACTOR ACTIVITY *ALTERING THROMBOMODULIN FUNCTION RESULTING IN ↓PROTEIN C ACTIVATION & ↓AT AVAILABILITY IMPAIRING FIBRINOLYSIS THROUGH BLOCKING OF TISSUE PLASMINOGEN ACTIVITY Sheikha Homocystinuria A FOLATE A DAY MIGHT KEEP A HEART ATTACK AWAY Homocystinuria Sheikha THANK YOU Sheikha Homocystinuria THANK YOU Sheikha Homocystinuria THANK YOU Sheikha Homocystinuria THANK YOU Homocystinuria Sheikha EFFECTS OF PLANTING TREES ON GOEZHA ON REDUCING THE EFFECTS OF RASHABA IN SULY Background: Suly is a densely populated city in the northeastern part of Iraq and a vital city of Kurdistan. Rashaba is a strong summer wind that disturbs life in the city and makes roof top sleep a nightmare. Deforestation was a norm during Saddam’s rule of Iraq and that seems to have compounded the problem. Homocystinuria Sheikha EFFECTS OF PLANTING TREES ON GOEZHA ON REDUCING THE EFFECTS OF RASHABA IN SULY Background: Suly is a densely populated city in the northeastern part of Iraq and a vital city of Kurdistan. Rashaba is a strong summer wind that disturbs life in the city and makes roof top sleep a nightmare. Deforestation was a norm during Saddam’s rule of Iraq and that seems to have compounded the problem. Materials & Methods: The Suly University was funded to plant ten million trees through its college of agriculture. The task took two years to complete and the trees became mature in five years. A sample of a thousand intellectual professionals were interrogated to score the positive effects of this endeavor in regard to the livability in the city, productivity of the citizens, reduction of asthma Attacks, sick leave improvement and immigration desire by displaced Baghdad physicians. Homocystinuria Sheikha EFFECTS OF PLANTING TREES ON GOEZHA ON REDUCING THE EFFECTS OF RASHABA IN SULY Results: The most significant positive effect of re-foresting Goezha was found to be related to the immigration to Kuridstan by the rest of Iraqi physican Homocystinuria Sheikha Homocystinuria Sheikha Homocystinuria Sheikha Homocystinuria Sheikha