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The S65C mutation of HFE may contribute to iron overload in C282Y heterozygotes
Genetics, genetic disease, gene therapy P/CLO/13 ] LIPIDS AND GLYCOGEN STORAGE DISEASE R. Garcia l, S. Saksena t, R. Cramb 1, P. Mckiernan 2, C. Garcia 1, J. Johnson l, M. Kaslake 3, C. Packard 3, E. Elias l tLiver Unit and Biochemistry Department, Queen Elizabeth Hospital, Birmingham, UK. 2Children's Hospital, Birmingham, UK. 3Royal Infirmary Hospital, Glasgow, UK.
Background: Glycogen Storage Disease (GSD) are associated w~ a variety of metabolic defects. GSD I present with hypercholesterolemia and hypertriglyceddemia but it is not clear if this wiUcontribute to an increased risk of coronary heart disease (CHD). Aim: To assess lipid profile in GSD patients at Queen Elizabeth Hospital and Children's Hospital in Birmingham- UK Patients and Methods: We studied 20 GSD patients: 9 GSD I, 6 GSD Ill, 5 GSD IX. All patients had their cholesterol (CHOL), triglyceride (TG) and high density lipoprotein (HDLc) measured by conventional methods. Mass of very low-density lipoprotein 1 & 2 (VLDL1, 2) intermediate density lipoprotein (IDL) andLDL were made using density gradient ultracentrifugation..Apoproteins A-I & B (apo/~I, apo B) were measured by immunological methods. Results: The mean age was 22,6 years,(4 F,16M). Raised CHOL (8.17 __2.18 mmol/L), TG (10.32 + 7.11 mmollL) and low HDLc (0.93 ¢ 0.36 retool/L) were found in all GSD I, with increases in apo B (1.26 + 0.30) and decreases in apo A1 (1.78 ¢ 0.44 g/1.). Raised levels of VLDL1, VLDL2 and IDL were also found in this patients (593 + 402.67 C.~%, 229.85 _+266.42 mg% and 114.14 + 64.78 mg%). Patients with D Ill and IX had no gross increases in CHOL (4.98 _ 0.46 mmol/L, 5.21 _+1.17 mmol/L), with no significant abnormalities on apo A1, apo B, VLDL 1 & 2 or LDL mass. Conclusions: Increased CHOL and TG, with high levels of VLDL1 & 2 and IDL were found in all GSD I, and this pattern is similar to patients with CHD. There are no data at the present that confirms ~at these patients have increased incidence of CHD. Patients with omer forms of GSD do not have excess of plasma lipids.
I P/clo/1s I THE $65C MUTATION OF lIFE MAY CONTRIBUTE TO IRON OVERLOAD IN C282Y HETEROZYGOTES D.F. Wallace, A.P. Walker, A. Pietrangelo l, M. Clare 2, A.B. Bomford2, J.S. Dooley Centre for Hepatology, Dept. of Medicine, Royal Free and University College Medical School, London, UK. IDipartimento di Medicina Interna, Universith di Modena, Italy. 21nstitute of Liver Studies, Guy's, King's and St. Thomas' School of Medicine, London, UK.
HFE-related haemoehromatosis is a common disorder of iron metabolism. Most affected individuals are homozygous for the C282Y mutation of HFE. Some are compound heterozygotes for C282Y and another missense substitution H63D. A small proportion of patients have neither of these genotypes. Recently the $65C substitution has been implicated in a mild form of haemoehromatosis. We have investigated this by assessing the phenotypes of five individuals who are compound heterozygous for C282Y and $65C, to determine whether this genotype predisposes to the development of iron overload. Two of the five had evidence of iron overload, one having a hepatic iron index of 9.7 pmol/g/y. This individual also had HCV infection and a history of excess alcohol. Our results suggest that some individuals who are compound heterozygous for C282Y and $65C may have elevated serum iron indices and evidence of iron overload. The penetrance of this genotype appears to be low and other factors may influence iron loading in these individuals.
I PIC10/14 1 MALFORMATION OF DUCTAL PLATE OF THE LIVER: A MAJOR CRITERION FOR THE DIAGNOSIS OF MECKEL SYNDROME C. Sergi, S. Adam, P. Kahl, H.E Otto Institute of Pathology, University Hospital, INF 220, D-69120 Heidelberg, Germany.
Aims: Meckel syndrome (MS, locus: 17q21-q24), is an
autosomal recessive disorder with a variable spectrum of anomalies. In spite of the lapse of over one and 3/4 of century since the first ease report (Meckel, 1822), there are still somewhat unelearly defined diagnostic criteria and the process of defining them continues. Cystic kidney dysplasia, occipital encephalocele or other anomaly of the central nervous system (CNS), and postaxial polydactyly occur in most cases. The arrest of the development of the intrahepatic bile ducts at the stage of the bilaminar plates or ductal plate malformation (DPM) is considered of high diagnostic value in MS, but no complete agreement is found in the literature. Methods: 47 fetuses with MS from four archive pathologic data files (Freiburg, Heidelberg, Mainz, Marburg) were reviewed. Results: Cystic kidney dysplasia, encephalocele, and polydactyly were found in 100%, 91.5%, and 72.3% of the eases, respectively. The DPM of the liver was a constant anomaly in MS, as frequent as the renal lesion. Conclusion: Liver DPM should be considered as a major criterion for the diagnosis of MS. In these fetuses the breakdown of the ductal plate is altered, as also seen in infants with polyeystie kidney disease.
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Background: Glycogen Storage Disease (GSD) are associated w~ a variety of metabolic defects. GSD I present with hypercholesterolemia and hypertriglyceddemia but it is not clear if this wiUcontribute to an increased risk of coronary heart disease (CHD). Aim: To assess lipid profile in GSD patients at Queen Elizabeth Hospital and Children's Hospital in Birmingham- UK Patients and Methods: We studied 20 GSD patients: 9 GSD I, 6 GSD Ill, 5 GSD IX. All patients had their cholesterol (CHOL), triglyceride (TG) and high density lipoprotein (HDLc) measured by conventional methods. Mass of very low-density lipoprotein 1 & 2 (VLDL1, 2) intermediate density lipoprotein (IDL) andLDL were made using density gradient ultracentrifugation..Apoproteins A-I & B (apo/~I, apo B) were measured by immunological methods. Results: The mean age was 22,6 years,(4 F,16M). Raised CHOL (8.17 __2.18 mmol/L), TG (10.32 + 7.11 mmollL) and low HDLc (0.93 ¢ 0.36 retool/L) were found in all GSD I, with increases in apo B (1.26 + 0.30) and decreases in apo A1 (1.78 ¢ 0.44 g/1.). Raised levels of VLDL1, VLDL2 and IDL were also found in this patients (593 + 402.67 C.~%, 229.85 _+266.42 mg% and 114.14 + 64.78 mg%). Patients with D Ill and IX had no gross increases in CHOL (4.98 _ 0.46 mmol/L, 5.21 _+1.17 mmol/L), with no significant abnormalities on apo A1, apo B, VLDL 1 & 2 or LDL mass. Conclusions: Increased CHOL and TG, with high levels of VLDL1 & 2 and IDL were found in all GSD I, and this pattern is similar to patients with CHD. There are no data at the present that confirms ~at these patients have increased incidence of CHD. Patients with omer forms of GSD do not have excess of plasma lipids.
I P/clo/1s I THE $65C MUTATION OF lIFE MAY CONTRIBUTE TO IRON OVERLOAD IN C282Y HETEROZYGOTES D.F. Wallace, A.P. Walker, A. Pietrangelo l, M. Clare 2, A.B. Bomford2, J.S. Dooley Centre for Hepatology, Dept. of Medicine, Royal Free and University College Medical School, London, UK. IDipartimento di Medicina Interna, Universith di Modena, Italy. 21nstitute of Liver Studies, Guy's, King's and St. Thomas' School of Medicine, London, UK.
HFE-related haemoehromatosis is a common disorder of iron metabolism. Most affected individuals are homozygous for the C282Y mutation of HFE. Some are compound heterozygotes for C282Y and another missense substitution H63D. A small proportion of patients have neither of these genotypes. Recently the $65C substitution has been implicated in a mild form of haemoehromatosis. We have investigated this by assessing the phenotypes of five individuals who are compound heterozygous for C282Y and $65C, to determine whether this genotype predisposes to the development of iron overload. Two of the five had evidence of iron overload, one having a hepatic iron index of 9.7 pmol/g/y. This individual also had HCV infection and a history of excess alcohol. Our results suggest that some individuals who are compound heterozygous for C282Y and $65C may have elevated serum iron indices and evidence of iron overload. The penetrance of this genotype appears to be low and other factors may influence iron loading in these individuals.
I PIC10/14 1 MALFORMATION OF DUCTAL PLATE OF THE LIVER: A MAJOR CRITERION FOR THE DIAGNOSIS OF MECKEL SYNDROME C. Sergi, S. Adam, P. Kahl, H.E Otto Institute of Pathology, University Hospital, INF 220, D-69120 Heidelberg, Germany.
Aims: Meckel syndrome (MS, locus: 17q21-q24), is an
autosomal recessive disorder with a variable spectrum of anomalies. In spite of the lapse of over one and 3/4 of century since the first ease report (Meckel, 1822), there are still somewhat unelearly defined diagnostic criteria and the process of defining them continues. Cystic kidney dysplasia, occipital encephalocele or other anomaly of the central nervous system (CNS), and postaxial polydactyly occur in most cases. The arrest of the development of the intrahepatic bile ducts at the stage of the bilaminar plates or ductal plate malformation (DPM) is considered of high diagnostic value in MS, but no complete agreement is found in the literature. Methods: 47 fetuses with MS from four archive pathologic data files (Freiburg, Heidelberg, Mainz, Marburg) were reviewed. Results: Cystic kidney dysplasia, encephalocele, and polydactyly were found in 100%, 91.5%, and 72.3% of the eases, respectively. The DPM of the liver was a constant anomaly in MS, as frequent as the renal lesion. Conclusion: Liver DPM should be considered as a major criterion for the diagnosis of MS. In these fetuses the breakdown of the ductal plate is altered, as also seen in infants with polyeystie kidney disease.
135