Diversity of phenylalanine tolerance in pregnant phenylketonuria patients homozygous for the p.R408W mutation: the need for improved understanding of phenylalanine homeostasis.

Dietetic treatment of phenylketonuria (PKU) includes a low-phenylalanine (phe) diet that provides sufficient phe for maintenance and growth plus special phe-free formulas with amino acids to meet requirements for protein, energy and micronutrients.

Common variants in DLG1 locus are associated with non-syndromic cleft lip with or without cleft palate.

Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common craniofacial anomaly with a complex and heterogeneous aetiology. Knowledge regarding specific genetic factors underlying this birth defect is still not well understood. Therefore, we conducted an independent replication analysis for the top-associated variants located within the DLG1 locus at chromosome 3q29, which was identified as a novel cleft-susceptibility locus in our genome-wide association study (GWAS). Mega-analysis of the pooled individual data from the GWAS and replication study confirmed that common DLG1 variants are associated with the risk of nsCL/P. Two single nucleotide polymorphisms (SNPs), rs338217 and rs7649443, were statistically significant even at the genome-wide level (Ptrend = 9.70E-10 and Ptrend = 8.96E-09, respectively). Three other SNPs, rs9826379, rs6805920 and rs6583202, reached a suggestive genome-wide significance threshold (Ptrend < 1.00E-05). The location of the strongest individual SNP in the intronic sequence of the gene encoding DLG1 antisense RNA suggests that the true causal variant implicated in the risk of nsCL/P may affect the DLG1 gene expression level rather than structure of the encoded protein. In conclusion, we identified a novel cleft-susceptibility locus at chromosome 3q29 with a DLG1 as a novel candidate gene for this common craniofacial anomaly.

Dental arch relationship in 5-year-olds with complete unilateral cleft lip and palate after early alveolar bone grafting.

OBJECTIVE: To evaluate dental arch relationship in preschoolers with unilateral cleft lip and palate after early alveolar bone grafting (ABG). MATERIALS AND METHODS: Three raters blindly assessed the dental arch relationship with the GOSLON Yardstick (using a 5-point scale, from 1--very good to 5--very poor outcome) in Early-grafted group (27 boys and 15 girls; mean age = 5.2 years, SD 0.5) and Non-grafted group (17 boys and 12 girls; mean age = 5.8 years, SD 0.8). The groups differed regarding the age when ABG was performed: between 2 and 4 years (mean = 2.4, SD 0.6) in the Early-grafted group and after 9 years in the Non-grafted group. The strength of agreement of rating was evaluated with kappa statistics. RESULTS: The intra- and inter-rater agreement was high (κ > 0.800). The mean GOSLON score in the Early-grafted group was 2.72 and in the Non-grafted group -2.64. The distribution of the GOSLON grades in the Early-grafted group was: 54.8% had a score 1 or 2, 23.8%--3, and 21.4%--4 or 5; in the Non-grafted group, 38.0% subjects scored 1 or 2, 41.4%--3, and 20.6%--4 or 5 (p = 0.023). CONCLUSIONS: Early alveolar bone grafting carried out between the ages of 2 and 4 years was not found to negatively affect dental arch relationship by the age of 5 years. However, it is possible that such a negative effect could be found if a longer observation period (e.g. at age 10 years or age 15 years) was allowed.

Relation between the concentration of zinc in maternal whole blood and the risk of an infant being born with an orofacial cleft.

We investigated the relation between concentrations of maternal zinc and copper and the risk of an infant being born with an orofacial cleft. We did a case-control study using 116 mothers of children with isolated cleft lip with or without cleft palate (cleft group), and 64 mothers of unaffected children (control group). Mothers with a whole blood zinc concentration of 47.1 micromol/L or less had a risk 2.5 times higher of having a child with an orofacial cleft than those with a higher concentration (or level) (95% CI 1.03-6.23; p<0.05). A low zinc concentration combined with a high copper concentration was seen only in the cleft group. This evidence suggests an association between concentrations of maternal zinc and the risk of orofacial clefts in offspring.

Maternal MTR genotype contributes to the risk of non-syndromic cleft lip and palate in the Polish population.

The aetiology of non-syndromic cleft lip with or without cleft palate (CL/P) is very complex. It has been shown that polymorphic variants of genes encoding key proteins of folate and methionine metabolism might be important maternal risk factors of having a child with this craniofacial anomaly. Therefore, in our study, mothers with CL/P children as well as control mothers were examined for prevalence of polymorphisms of genes that encode methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1) and reduced folate carrier 1 (RFC1). We observed that there were no statistical differences in allele and genotype frequencies of MTHFR c.677C>T, MTHFD1 c.1958G>A and RFC1 c.80G>A between mothers who had children with CL/P and control mothers. However, mothers with MTR c.2756AG or GG genotype displayed a 2.195-fold increased risk of having a child with CL/P (95% CI 1.189-4.050, p = 0.011). The mechanism by which polymorphic transition of MTR gene might increase the maternal risk of having CL/P progeny is unknown. Our observations are consistent with a significant role of the methyl cycle in the development of craniofacial structures in humans.

[Coeliac disease and problems associated with reproduction]. / Choroba trzewna a zaburzenia rozrodu.

Coeliac patients taking a normal diet have a shortened reproductive period with delayed menarche and early menopause. Many studies have shown that coeliac women are susceptible to reproductive difficulties such as infertility and miscarriages. The disease is also associated with low birth weight in babies and short duration of breast feeding. Folic acid deficiency is present in the majority of patients with untreated disease and it might be a maternal risk factor for neural tube defects and orofacial clefts. Coeliac men may have reversible infertility, and as in women, if gastrointestinal symptoms are mild or absent the diagnosis may be missed. It is important to make diagnosis because the giving of gluten free diet may result in conception and favourable outcome of pregnancy.