vitamin-b-12 and Marfan-Syndrome

Topics: Administration, Oral; Anticoagulants; Blood Coagulation Tests; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Marfan Syndrome; Multicenter Studies as Topic; Mutation; Polymorphism, Genetic; Randomized Controlled Trials as Topic; Risk Factors; Thrombophilia; Time Factors; Venous Thrombosis; Vitamin B 12; Vitamin B 6

Folic acid metabolism enzyme polymorphisms are believed to be responsible for the elevation of homocysteine (HCY) concentration in the blood plasma, correlating with the pathogenesis of aortic aneurysms and aortic dissection. We studied 71 Marfan patients divided into groups based on the severity of cardiovascular involvement: no intervention required (n=27, Group A); mild involvement requiring intervention (n=17, Group B); severe involvement (n=27, Group C) subdivided into aortic dilatation (n=14, Group C1) and aortic dissection (n=13, Group C2), as well as 117 control subjects. We evaluated HCY, folate, vitamin B12 and the polymorphisms of methylenetetrahydrofolate reductase (MTHFR;c.665C>T and c.1286A>C), methionine synthase (MTR;c.2756A>G) and methionine synthase reductase (MTRR;c.66A>G). Multiple comparisons showed significantly higher levels of HCY in Group C2 compared to Groups A, B, C1 and control group (p<0.0001, p<0.0001, p=0.001 and p=0.003, respectively). Folate was lower in Group C2 than in Groups A, B, C1 and control subjects (p<0.0001, p=0.02, p<0.0001 and p<0.0001, respectively). Group C2 had the highest prevalence of homozygotes for all four gene polymorphisms. Multivariate logistic regression analysis revealed that HCY plasma level was an independent risk factor for severe cardiovascular involvement (Group C; odds ratio [OR] 1.85, 95% confidence interval [CI] 1.28-2.67, p=0.001) as well as for aortic dissection (Group C2; OR 2.49, 95%CI 1.30-4.78, p=0.006). In conclusion, severe cardiovascular involvement in Marfan patients, and especially aortic dissection, is associated with higher HCY plasma levels and prevalence of homozygous genotypes of folic acid metabolism enzymes than mild or no cardiovascular involvement. These results suggest that impaired folic acid metabolism has an important role in the development and remodelling of the extracellular matrix of the aorta.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adolescent; Adult; Aortic Aneurysm; Aortic Dissection; Biomarkers; Case-Control Studies; Chi-Square Distribution; Female; Ferredoxin-NADP Reductase; Folic Acid; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Heterozygote; Homocysteine; Homozygote; Humans; Logistic Models; Male; Marfan Syndrome; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Multivariate Analysis; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Predictive Value of Tests; Risk Factors; Severity of Illness Index; Up-Regulation; Vitamin B 12; Young Adult

Cobalamin is an essential cofactor for two mammalian enzymes: methionine synthase and methylmalonyl-CoA mutase. Patients with the cobalamin C (CblC) defect have combined methylmalonic aciduria and homocystinuria. Recently, the gene responsible for the CblC type, MMACHC, was identified, which enables molecular diagnostics. In this study, we describe two siblings, a 16-year-old girl and her 11-year-old brother, of a consanguineous family who presented with a very distinct clinical manifestation. The girl presented at the age of 13 years with macrocytic anaemia, cognitive regression and Marfanoid features such as increased arm-span, arachnodactyly, joint hyperlaxity and scoliosis. Her brother presented at the age of 10 months with developmental delay and behavioural abnormalities. Biochemical analysis showed severely increased homocysteine and methylmalonic acid levels in plasma of both siblings. In addition, plasma cysteine levels were decreased in the girl but not in her brother. The diagnosis of CblC defect was confirmed by genomic sequencing of the coding exons of the MMACHC gene. Two heterozygous mutations were identified in both siblings; the common c.271dupA p.Arg91LysfsX14 and a novel mutation, c.1A > G p.Met1?. Therapy consisting of folic acid, vitamin B6, l-carnitine and intramuscular vitamin B12 resulted in a clear improvement of biochemical parameters and, importantly, resulted in amelioration of the Marfanoid features in the girl. These data might suggest that low cysteine levels account for the Marfanoid features observed in the girl and indicate that the CblC type of combined methylmalonic aciduria and homocystinuria should be considered in the differential diagnosis of patients with Marfanoid features.

Topics: Adolescent; Carnitine; Carrier Proteins; Child; Cysteine; Diagnosis, Differential; DNA Mutational Analysis; Exons; Female; Folic Acid; Genetic Testing; Heterozygote; Homocysteine; Homocystinuria; Humans; Male; Marfan Syndrome; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Oxidoreductases; Pedigree; Phenotype; Treatment Outcome; Vitamin B 12; Vitamin B 6; Vitamins

Pronounced osteoporosis was discovered in a 44-year-old man presenting with an herniated intervertebral disk. He reported severe myopia, incomplete dislocation of the lenses and retinal detachment. He did not know of any thrombembolic events in the past. On physical examination Marfan-like appearance and a funnel chest were noted. Because of these findings Marfan syndrome was suspected.. Considering the findings of the x-rays, homocystinuria was suspected as a cause of osteoporosis, despite apparently normal cognitive functions. This diagnosis was confirmed by greatly increased values of serum homocysteine and a positive test for urinary homocystine. Since methionine and homocystine were both elevated, the diagnosis of cystathionin-beta-synthase deficiency was established.. After taking folate and vitamin B6, the homocysteine level decreased moderately. Betaine and subsequently vitamin B12 were added. Homocysteine values declined markedly on this therapeutic regimen. Two years later the patient was admitted again because of atypical angina. Coronary heart disease could be excluded by coronary angiography.. Diagnosis of premature osteoporosis should prompt consideration of homocystinuria even in adults. Premature arteriosclerosis, thrombembolic diseases, dislocation of the lens and retinal detachment may give further clues.

Topics: Adult; Age Factors; Angina Pectoris; Betaine; Diagnosis, Differential; Drug Therapy, Combination; Folic Acid; Homocysteine; Homocystine; Homocystinuria; Humans; Intervertebral Disc Displacement; Lens Subluxation; Male; Marfan Syndrome; Myopia; Osteoporosis; Retinal Detachment; Vitamin B 12; Vitamin B 6; Vitamin B Complex