Prospective evaluation of pregnancy outcome in an Italian woman with late-onset combined homocystinuria and methylmalonic aciduria.

BACKGROUND: Cobalamin metabolism disorders are rare, inherited diseases which cause megaloblastic anaemia and other clinical manifestations. Early diagnosis of these conditions is essential, in order to allow appropriate treatment as early as possible. CASE PRESENTATION: Here we report the case of a patient who was apparently healthy until the age of 20, when she presented with impaired renal function and normocytic anaemia. At the age of 34, when her first pregnancy resulted in an intrauterine death of a morphologically normal growth-restricted foetus, she was diagnosed with homocystinuria and methylmalonic aciduria due to cyanocobalamin C (cblC) defect, which was confirmed by molecular investigation. Consequently, hydroxocobalamin was administered to correct homocysteine plasma levels. This treatment was efficacious in lowering homocysteine plasma levels and restored anaemia and renal function. During a second pregnancy, the patient was also administered a prophylactic dose of low molecular -weight heparin. The pregnancy concluded with a full-term delivery of a healthy male. CONCLUSIONS: This case emphasises the importance of awareness and appropriate management of rare metabolic diseases during pregnancy. We suggest that women with late-onset cblC defect can have a positive pregnancy outcome if this metabolic disease is treated adequately.

Stable-isotope dilution LC-ESI-MS/MS techniques for the quantification of total homocysteine in human plasma.

Homocysteine is an endogenous sulphydryl aminoacid irreversibly catabolized by transsulfuration to cysteine or remethylated to methionine. Increased plasma levels of homocysteine are an independent risk factor for atherosclerosis and cardiovascular disease. Accurate and reliable quantification of this amino acid in plasma samples is essential in clinical practice to explore the presence of a hyperhomocysteinemia, for instance after an ischemic event, or to control a possible adjunctive risk factor in patients at higher risk. In this review, LC-ESI-MS/MS methods are discussed and compared with other analytical methods for plasma homocysteine. LC-ESI-MS/MS is a technique combining the physicochemical separation of liquid chromatography with the analysis of mass spectrometry. It is based on stable-isotope dilution and possesses inherent accuracy and precision. Quantitative analysis is achieved by using commercially available homocystine-d(8) as an internal standard. Taking advantage of the high sensitivity and specificity, approaches involving LC-ESI-MS/MS require less laborious sample preparation, no derivatization and produce reliable results.

Homocysteine metabolism in families from southern Italy with neural tube defects: role of genetic and nutritional determinants.

OBJECTIVE: To evaluate the role of different polymorphic gene variants involved in homocysteine metabolism and plasma levels of homocysteine, folate and vitamin B12 in families from southern Italy with neural tube defects (NTDs). METHODS: Eighteen fathers, 15 NTD children and 60 women who had conceived NTD foetuses were investigated. A group of 100 adults and 43 apparently healthy children was used as control. At the time of blood draw, none were taking vitamin pills or nutritional supplements. RESULTS: Among controls, 79 (55.2%) were heterozygous for C677T MTHFR variant and 26 (18.2%) were TT homozygous. Among the cases, 35 (61.4%) out of 57 mothers and 7 (38.9%) out of 18 fathers carried the T allele; 12 (21.1%) mothers and 2 (11.1%) fathers had the TT genotype. Four (26.7%) out of 15 probands were TT homozygous and 11 (73.3%) were heterozygous (Fisher exact test p = 0.025). No significant difference between groups was observed for the 1298C MTHFR variant and CBS haplotypes. Median homocysteine in NTD children was significantly higher (10.0 micromol/L) than that of controls (median 4.5 micromol/L, Mann-Whitney p < 0.05). Folate and B12 were not different among groups. CONCLUSIONS: The T677 MTHFR allele is significantly associated with the occurrence of NTDs; no significant association has been observed with other genetic determinants analysed. Homocysteine levels in children with NTDs are significantly higher than those of the paediatric population from the same geographical area.

Does endothelial nitric oxide synthase gene variation play a role in the occurrence of hypertension in pregnancy?

OBJECTIVE: Nitric oxide is suggested to play a role in the development of preeclampsia. METHODS: We studied 61 patients with gestational hypertension (GH), 77 with GH and significant proteinuria (urine protein excretion > or = 300 mg/24 h), 82 with essential hypertension (EH) and 188 normotensive women with at least one normal pregnancy. MAIN OUTCOME MEASURE(S): A polymorphism within the constitutive endothelial nitric oxide synthase (ecNOS) gene in various types of hypertension in pregnancy was explored. RESULTS: Allelic and genotypic frequencies did not differ between controls and case groups. A significant difference was observed between the frequency of the rare allele in GH patients and that in EH group (chi2: 4.47, P <.04). This difference approximated the significance when GH subjects with or without proteinuria were grouped (chi2 square: 3.33; P =.068). Cigarette smoking or gravidity did not interact with the ecNOS polymorphism in identifying different types of hypertension in this setting. CONCLUSION: Our findings argue against an association between ecNOS polymorphism and preeclampsia and support the hypothesis for a different pathogenesis of GH in respect to EH.