Association of MTHFR (C677T, A1298C) and MTRR A66G polymorphisms with fatty acids profile and risk of neural tube defects.

OBJECTIVE: This study aims to determine if 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms were associated with fatty acid (FA) levels in mothers of fetuses with neural tube defects (NTDs) and whether these associations were modified by environmental factors. METHODS: Plasma FA composition was assessed using capillary gas chromatography. Concentrations of studied FA were compared between 42 mothers of NTDs fetuses and 30 controls as a function of each polymorphism by the Kruskal-Wallis nonparametric test. RESULTS: In MTHFR gene C677T polymorphism, cases with (CT + TT) genotype had lower monounsaturated FAs (MUFA) and omega-3 polyunsaturated FA (n-3 PUFA) levels, but higher omega-6 polyunsaturated FAs (n-6 PUFA) and omega-6 polyunsaturated FAs: omega-3 polyunsaturated FAs (n-6:n-3) ratio levels. In MTRR gene A66G polymorphism, cases with (AG + GG) genotype had lower MUFA levels, but higher PUFA and n-6 PUFA levels. Controls with (AG + GG) genotype had lower n-6 PUFA levels. In MTHFR gene C677T polymorphism, cases with smoking spouses and (CT + TT) genotype had lower MUFA and n-3 PUFA levels, but higher PUFA, n-6 PUFA, and n-6:n-3 ratio levels. Cases with (CT + TT) genotype and who used sauna during pregnancy had lower n-3 PUFA levels. In MTRR gene A66G polymorphism, cases with (AG + GG) genotype and who used sauna during pregnancy had higher PUFA and n-6 PUFA levels. CONCLUSIONS: Further research is required to clarify the association of FA metabolism and (MTHFR, MTRR) polymorphisms with NTDs.

Association of MTHFR C677T, MTHFR A1298C, and MTRR A66G Polymorphisms with Neural Tube Defects in Tunisian Parents.

OBJECTIVE: This study aims to investigate the association of 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms with neural tube defects (NTDs) in a Tunisian population. METHODS: Genotyping was performed by polymerase chain reaction with restriction fragment length polymorphisms (PCR-RFLPs) using the restriction enzymes. Allele and genotype frequencies were compared between mothers and fathers of fetuses with NTDs with matched controls based on an association analysis using SPSS software. RESULTS: MTHFR (C677T, A1298C) and MTRR A66G polymorphisms were found to be protector factors for NTD fetuses in the mother group. In addition, a combination of the three wild-type alleles C677/A1298/A66 has increased four-fold the incidence of NTDs (p = 0.004, OR = 3.96, 95% CI: 1.53-10.23). In the father group, MTHFR C677T was a risk factor for NTDs. However, no association was found between MTHFR A1298C, MTRR A66G, and the occurrence of this anomaly. The analysis of MTHFR C677T and MTRR A66G polymorphisms has demonstrated a significant difference in vitamin B12 levels between recessive and dominant genotypes in case mothers (p < 0.05). CONCLUSION: Additional studies are required to better understand the roles of parental gene polymorphisms related to folate-homocysteine metabolism in the pathogenesis of NTD.

Fetopathological examination for the fetuses with Down syndrome in Tunisia: Epidemiological study and associated malformations.

BACKGROUND: For Down syndrome (DS), traditional epidemiological studies to determine the prevalence, cause, and clinical significance of the syndrome have been conducted over the last 100 years. In Tunisia, the current work is the first in-depth study in epidemiology of DS from fetopathological data. AIM OF THE STUDY: The aim of this epidemiological study was to determine the impact of some feto-maternal characteristics in occurrence of DS and to search the frequency of associated congenital malformations with this syndrome. METHODS: Our retrospective study was realized for 144 fetuses with DS among 9321 autopsied fetuses in embryo-fetopathological service between 1994 and 2011. RESULTS: In our study, the majority of mothers (72.91%) were 35 years and older, with a statistically significant difference (p<10-6, OR=16.7, CI=8.7-32.4). The abnormalities of extremities (31%) were the most common fetal abnormalities followed by facial (23.51%) and digestive abnormalities (19.63%). CONCLUSION: One of the main conclusions of this research is that the most common risk factor for DS is maternal age. On the other hand, the type and the frequency of associated congenital anomalies with DS are still controversial.

[Neu-Laxova syndrome: Three case reports and a review of the literature]. / Syndrome de Neu-Laxova : rapport de trois cas et revue de la littérature.

INTRODUCTION: The Neu-Laxova syndrome (NLS) is a rare autosomal recessive and early lethal disorder. It is characterized by severe intra-uterine growth retardation, abnormal facial features, ichthyotic skin lesions and severe central nervous system malformations, especially microlissencephaly. Others characteristic features associated with fetal hypokinesia sequence, including arthrogryposis, subcutaneous edema and pulmonary hypoplasia, are frequently reported in NLS. PATIENTS AND METHODS: The clinicopathological characteristics of NLS are described in three cases with striking prenatal diagnostic findings and detailed post-mortem examinations. A review of the literature is undertaken with a focus on molecular basis. RESULTS: We present three new patients with NLS: one stillbirth male and two female newborns, delivered at 29, 35 and 40 weeks of gestational age, respectively. Characteristic ultrasound findings included hydramnios, severe intra-uterine growth restriction, craniofacial and cental nervous system anomalies. The cytogenetic study, performed in one case, was normal. The post-mortem examination revealed characteristic abnormalities in all three cases, that allowed to make a prompt diagnosis of the NLS. Data from these patients suggest that the NLS represents a heterogeneous phenotype. This feature has been highlighted in the literature. CONCLUSION: The SNL is a lethal developmental disorder characterized by phenotypic heterogeneity with striking neurological defects. It is underpinned by genetic heterogeneity. It can be caused by mutations in all three genes involved in de novo L-serine biosynthesis: PHGDH, PSAT1 and PSPH. Hence, the NLS constitutes the most severe end of already known human disease, i.e. serine-deficiency disorder.

Maternal 25-hydroxyvitamin D level and the occurrence of neural tube defects in Tunisia.

OBJECTIVE: To determine whether low vitamin D levels in pregnant women are associated with the occurrence of neural tube defects (NTDs) in Tunisia. METHODS: In a prospective study, pregnant women were recruited at a center in Tunis between January 1, 2012, and December 30, 2013. Women carrying a fetus with a severe NTD were recruited before elective termination. Matched, healthy pregnancy women were enrolled into a control group. Plasma levels of 25-hydroxyvitamin D were measured by a competitive chemiluminescence immunoassay. RESULTS: Overall, 68 women formed the NTD group and 64 the control group. The mean maternal vitamin D level was significantly lower in the NTD group (20.65±10.25nmol/L) than in the control group (28.30±13.82nmol/L; P<0.001). Vitamin D deficiency was recorded for 53 (78%) women in the NTD group and 39 (61%) in the control group. Vitamin D insufficiency was recorded for 15 (22%) women in the NTD group and 20 (31%) in the control group. Vitamin D sufficiency was found only in the control group (n=5 [8%]; P<0.001). CONCLUSION: The findings confirm an association between a decreased vitamin D level in pregnant women and the risk of fetal NTDs.

Association of maternal homocysteine and vitamins status with the risk of neural tube defects in Tunisia: A case-control study.

BACKGROUND: This study was conducted to determine whether low folate and vitamin B12 levels, as well as high homocysteine levels in pregnant women are associated with neural tube defects (NTDs) in Tunisia. METHODS: A total of 75 NTDs pregnancies and 75 matched controls were included in the study. Their vitamin B12, folate, and red blood cell folate concentrations were measured using a radio-immunoassay kit and total homocysteine concentrations were determined using a fluorescent polarization immunoassay. RESULTS: Vitamin B12 and folate concentrations were lower in NTD-affected pregnant women than in controls (respectively, p = 0.009 and p < 0.001). Total homocysteine concentration was significantly higher in the NTDs group than in controls (p = 0.008). In the case group, the folate levels were positively related with vitamin B12 levels (r = 0.54; p < 0.001) and negatively correlated with total homocysteine levels (r = -0.19; p = 0.04). Besides, red blood cell folate levels were positively correlated with folate levels (r = 0.24; p = 0.02) and negatively correlated with total homocysteine levels (r = -0.37; p = 0.001). CONCLUSION: Lower concentrations of folate and vitamin B12 are related to the increased risk of NTDs. Both folate and vitamin B12 intake insufficiency could contribute to the increased risk of NTDs. A dietary supplement, combining folate and vitamin B12, might be an effective measure to decrease the NTDs incidence in Tunisia.

An increase in spina bifida cases in Tunisia, 2008-2011.

BACKGROUND: The term spina bifida refers to a group of neural tube defects that result in malformations of the spinal cord and the surrounding vertebrae. Though the etiologies of spina bifida remain largely unknown, several risk factors have been identified, including feto-maternal characteristics. AIM OF THE STUDY: To discover possible underlying reasons for the increase of spina bifida and identify intervention targets, an investigation was undertaken comparing spina bifida-affected pregnancy notifications in 2008-2011 with notifications in the period 1991-1994. METHODS: Characteristics and outcomes of births with spina bifida and pregnancy characteristics of mothers were recorded in the medical chart. Comparisons of pregnancies affected by a spina bifida in 2008-2011 were made with pregnancies affected by a spina bifida in the period 1991-1994. Statistical analysis was undertaken using Poisson regression and Chi-squared tests. RESULTS: From 1991 through 1994, the prevalence of identified spina bifida cases was equal to 0.3/10,000 births compared to 1.6/10,000 births in 2008-2011. This increase was statistically significant (P<0.001). The prevalence of females was equal to 0.45 per 10,000 births over the period 1991-1994 compared to 1.88 per 10,000 births during the period 2008-2011. As for males, the prevalence was equal to 0.16 per 10,000 births in 1991-1994 compared to 1.88 in 2008-2011. The difference was statistically significant (P<0.001) between both genders. A mother's age of over 30 years had significant impact on the emergence of spina bifida (P=0.02, OR=3.93, CI=1.23-12.47). As well as, maternal blood type was a significant risk factor for the appearance of spina bifida (P=0.008). Results also had shown that fetal weight and term, gestity and parity were significant risk factors for the occurrence of spina bifida (P<0.05).In this study, results have been interpreted with caution due to analyses not being adjusted. CONCLUSION: This analysis highlighted areas where prevention efforts should be strengthened and surveillance data improved.

Epidemiology of neural tube defect subtypes in Tunisia, 1991-2011.

BACKGROUND: Neural tube defects are common major congenital anomalies that result from very early disruption in the development of the brain and spinal cord. AIM OF THE STUDY: We conducted an epidemiological study to determine the impact of some feto-maternal characteristics in the occurrence of NTD subtypes. METHODS: Characteristics and outcomes of births with NTD and pregnancy characteristics of mothers over a period of twenty years (1991-2011) were recorded in the medical chart. RESULTS: From 1991 through 2011, 769 stillborns with NTD were delivered, yielding a prevalence of 2.02/10,000. The increase in NTD prevalences over these years was statistically significant (P = 0.000). In addition, differences between prevalences of NTD subtypes over season (P = 0.003) and between genders (P < 0.001) were significant. The highest frequency was noticed in winter with 3, 7 per 10,000 births among females. The difference in fetal term between subtypes was significant (P = 0.017). The probability to have a malformed fetus with a weight less than 1500 g was three times higher in myelomeningocele than in craniorachischisis, two times higher in anencephaly and encephalocele, but two times lower than rachischisis. Mothers with one gestation were two fold higher in anencephaly than in encephalocele. Nulliparous mothers' cases were significantly more likely to have NTD than uni- or multiparous mothers. O+ mother's blood type presented a significant risk factor and was significantly less common in myelomeningocele than in rachischisis, but three times higher than in craniorachischisis. Consanguinity was present in cases with rachischisis and was two times higher than in cases with anencephaly, and three times higher than in cases with encephalocele. In this study, the results have been interpreted with caution due to analyses not being adjusted. CONCLUSION: One of the main findings of the study is that there are many differences between NTD subtypes, which suggests that there may be etiologic differences between subtypes. This suggests that, although epidemiologic studies frequently do not distinguish between NTD subtypes in analyses, they should be analyzed separately when possible.

Postnatally diagnosed agenesis of corpus callosum in fetuses.

OBJECTIVES: To examine and characterize the agenesis of the corpus calosum (ACC) in an epidemiological study of fetal autopsies, as well as, to analyze the associated anomalies and to emphasize the importance of the clinical examination of ACC. METHODS: The subjects of observation are 20 fetuses from a total of 2238 autopsies carried out during a period of three years (2006-2009) in Tunis. RESULTS: The associated abnormalities are hydrocephalus, cerebellar hypoplasia, agenesis of vermis cerebelli, polymicrogyria and lissencephaly. Sixteen of the cases (80%) are syndromic: Trisomy 13,18,21 (5,1,2 fetuses respectively) and Thanatophoric dysplasia, Fetal akinesia syndrome, Dandy-Walker Malformation and the Association VACTERL are represented by two cases each. CONCLUSION: The prenatal diagnosis of ACC must be the result of a multidisciplinary approach. The phenotype of the XLAG syndrome creates an interest to study asymptomatic patients with ACC, especially when the anomaly is detected prenatally.

Gender and associated skeletal abnormalities in fetuses with neural tube defects.

OBJECTIVE: To determine the association between gender and skeletal defects in fetuses with NTDs. METHODS: 150 NTD fetuses have been examined in three years' course (01.2006-01.2009) in the Clinic of Fetopathology at the Center for Maternity and Neonatology, Tunis. RESULTS: The most common gender associated anomalies for males are cleft palate, anomalies in the form and attachment of the outer ear and the agenesis of corpus callosum. For women, they are distortions of the spine and "frog" face. CONCLUSION: The proven associations in the study are important indicators in the purposeful search for NTDs in early prenatal ultrasound diagnosis.

Fetopathological aspects of holoprosencephaly.

UNLABELLED: Holoprosencephaly (HPE) is a congenital central nervous system malformation estimated to occur in 1/250 conceptuses and 1/10,000 live births. While the severe forms, which are incompatible with life, are easier to detect in the prenatal period, the milder forms can remain unrecognised. As this can have serious consequences for the pregnancy and malformation carriers it is of crucial importance to find ways of timely detection of this pathological condition. The present study AIMED at finding an association of holoprosencephaly with facial dysmorphia and anomalies of visceral organs that would alert the physician to be very careful in making the prenatal diagnosis, which may require termination of pregnancy by medical indications. MATERIAL AND METHODS: The study included 15 fetuses diagnosed with holoprosencephaly out of 2095 cases analysed post-mortem in the Fetopathology Clinic at the Centre for Maternity and Neonatology in the town of Tunisia over a period of 3 years (Oct. 2006 - Oct. 2009). The fetuses were analysed macro- and microscopically. RESULTS: All forms of holoprosencephaly include elements of facial dysmorphism with the facial phenotypes of cyclopia, cebocephaly and ethmocephaly. It can be associated with specific internal organs anomalies, the hydrocephaly being the most common anomaly of the central nervous system. Our study suggested that holoprosencephaly can be correlated with craniofacial anomalies affecting the midfacial and medium craniovisceral structures. CONCLUSION: The anatomical variations of HPE and the phenotypic facial correlations require a systematic and targeted study of central nervous system.