Homocysteine and methylmalonic acid in Phenylketonuria patients.

Hyperhomocysteinemia and vitamin B12 deficiency have been reported in patients with phenylketonuria. In this study, total homocysteine (tHcy) and methylmalonic acid (MMA) levels were analyzed in samples from 25 phenylketonuria (PKU) patients. Comparisons were made between pre- and post-treatment values (n= 3); on treatment values, between periods with high and normal/low phenylalanine (Phe) levels (n= 20); and in women before, during and after pregnancy (n= 3). THcy levels decreased after treating PKU with metabolic formula (p=0.014). Except for a pregnant woman before pregnancy, none of the patients had tHcy values above the normal range. In fact, tHcy was < 5 µmol/L in 34% of the samples. We observed a decrease in Phe, tHcy, and tyrosine levels during pregnancy. MMA levels did not differ significantly, with values remaining in the normal range. These data indicate that there was no B12 deficiency in patients who adhere to the diet. In conclusion, in PKU patients treated with metabolic formula, tHcy is frequently not elevated, remaining even in the lower normal range in some patients. Thus, clinical follow-up and adherence to dietary treatment are crucial to prevent B12 deficiency.

Three Main Causes of Homocystinuria: CBS, cblC and MTHFR Deficiency. What do they Have in Common?

Abstract Genetic homocystinurias are a group of inborn errors of metabolism that result in the massive excretion of homocysteine (Hcy) in the urine due to Hcy accumulation in the body, usually causing neurological and cardiovascular complications. The three most frequent causes are classical homocystinuria [deficiency of cystathionine beta-synthase (CBS)], methylmalonic aciduria with homocystinuria, cblC type (cblC deficiency) and severe methylenetetrahydrofolate reductase (MTHFR) deficiency. In this review, we highlight the similarities and differences among these disorders. Briefly, their joint manifestation is the accumulation of tHcy, however, the other sulfur amino acids show various and even invers profiles. Vascular disease, developmental delay and seizures are found in all homocystinurias, nevertheless, the complications of CNS differ in a wide variety of presentations and severities and are apparently less pronounced in CBS deficiency. Moreover, patients with remethylation defects typically do not present ectopia lentis and bone disturbances, tall stature and osteoporosis. Whereas hematological alterations, such as megaloblastic anemia, thrombocytopenia neutropenia and life-threatening microangiopathy, are specific findings of cblC deficiency.

Environmental risk factors associated with biliary atresia in Rio Grande do Sul, Brazil

Biliary atresia (BA) seems to be a multifactorial disorder in which environmental factors interact with the patient's genetic constitution. This study aimed to analyze information concerning environmental risk factors associated with BA in southern Brazil. A case-control study with mothers of patients with BA and mothers of patients with cystic fibrosis (CF) was conducted. Inquiry included questions related to exposition to environmental risk factors during the periconceptional and gestational (second and third trimesters) periods. Mothers of BA patients had smoked during pregnancy more frequently in comparison with the mothers of CF patients, but no significant difference was found in a multivariate analysis. There was no between group difference in terms of seasonality, but the multivariate analysis showed a significant difference within the BA group between date of conception in winter compared to other seasons. In conclusion, smoking during pregnancy seemed to increase the risk of BA while date of conception in winter decreased it (AU)

Hypoxic-ischemic gene expression profile in the isolated variant of biliary atresia.

BACKGROUND: Biliary atresia (BA) includes a sclerosing cholangiopathy whose nature is not fully deciphered. Aiming to evaluate the role of an arteriopathy as an etiologic factor in BA, we investigated hypoxia and the correlated angiogenic response in livers from affected patients. METHODS: Gene expression of the molecular axis: hypoxia-inducible factor (HIF)1a, HIF2a and vascular endothelial growth factor A (VEGFA)/VEGFR1, VEGFR2. Liver biopsy specimens collected at exploratory laparotomy of age-matched patients with isolated, cytomegalovirus IgM-negative BA (n = 32) and intrahepatic cholestasis (IHC, n = 9) were evaluated. RESULTS: We observed higher HIF1a and HIF2a expression in BA than in IHC. Paradoxically, VEGFR2, the main target of VEGFA-induced angiogenesis, was underexpressed in BA, and VEGFA was decreased in most BA patients. Patients with the highest expression of HIFs and the lowest VEGFA and VEGFR2 were essentially the same, indicating hypoxia without the necessary angiogenesis. This group included most BA patients and, except for HIF2a, they were older and presented increased bilirubin serum levels. In the highest HIF2a/lowest VEGFR2 subsets, gene expression of the cytokeratin 19, marker of cholangiocyte phenotype, was decreased. CONCLUSION: This study suggests that hypoxia-ischemia is present in the livers of patients with BA, progresses over time and leads to a decreased cholangiocyte mass.