Malnutrition in early life and its neurodevelopmental and cognitive consequences: a scoping review.

The negative impact of stunting and severe underweight on cognitive neurodevelopment of children is well documented; however, the effect of overweight/obesity is still unclear. The 2018 Global Nutrition Report reported that stunting and overweight concurrently affect 189 million children worldwide. As existing reviews discuss undernutrition and overweight/obesity separately, this scoping review aims to document the impact of mild/moderate and severe underweight, stunting, and overweight/obesity among children aged 0-60 months on their cognitive neurodevelopmental trajectories. Twenty-six articles were analysed to extract significant information from literature retrieved from PubMed and Cochrane databases published from 1 January 2009 to 31 October 2019. Length gain is associated with cognitive neurodevelopment in normo-nourished and stunted children aged under 24 months. Among stunted children, it seems that cognitive and neurodevelopmental deficits can potentially be recovered before 8 years of age, particularly in those whose nutritional status has improved. The impact of overweight/obesity on cognitive neurodevelopment appears to be limited to attention, gross motor skills and executive control. Parental education level, birth weight/length, breastfeeding duration, and sanitation level are some identifiable factors that modify the impact of undernutrition and overweight/obesity on cognitive and neurodevelopment. In conclusion, underweight, stunting and overweight/obesity have a significant impact on cognitive neurodevelopment. Multidimensional approaches with various stakeholders should address all issues simultaneously, such as improving sanitation levels, assuring parental job security and adequate social welfare, and providing access to adequate nutrients for catch-up growth among underweight or stunted children and to affordable healthy foods for those who are overweight/obese and from low socio-economic status.

Genetic dissection of familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is the most common genetic hyperlipidemia in man. FCHL is characterized by familial clustering of hyperlipidemia and clinical manifestations of premature coronary heart disease, i.e., before the age of 60. Although FCHL was delineated about 25 years ago, at present the FCHL phenotype and its complex genetics are not fully understood. Initially, the familial aggregation of high plasma total cholesterol and triglyceride levels, with a bimodal distribution of triglycerides, was taken as evidence of a dominant mode of inheritance. However, it is now clear that the genetics of FCHL is more complex, and it has been suggested that FCHL is heterogeneous. Several approaches can be taken to identify genes contributing to the disease phenotype in complex genetic disorders either by studying the disease in the human situation or by using animal models. Recent reports have shown that a combination of genetic linkage studies, association studies, and differential gene expression studies provides a useful tool for the genetic dissection of complex diseases. Therefore, the genetic strategies that will be used to dissect the genetic background of FCHL are reviewed.

Association between the alpha-adducin Gly460Trp polymorphism and systolic blood pressure in familial combined hyperlipidemia.

BACKGROUND: In a genome scan for familial combined hyperlipidemia (FCHL), a locus contributing to systolic blood pressure (SBP) has been identified on chromosome 4, containing the a-adducin gene (ADD1). In previous studies, an association has been found between the alpha-adducin Gly460Trp polymorphism and salt-sensitive hypertension. In this study, we investigated the association between the a-adducin Gly460Trp polymorphism and blood pressure in FCHL patients. METHODS: A total of 79 unrelated patients with FCHL and 121 unrelated controls (spouses) were recruited for the study. Blood pressure was measured in a standardized fashion, with the subject in sitting position after 10 min of rest. The alpha-adducin Gly460Trp polymorphism was detected by mutagenically separated polymerase chain reaction. RESULTS: The genotype frequencies of both FCHL patients and controls were in Hardy-Weinberg equilibrium. The alpha-adducin Gly460Trp polymorphism showed a significant association with FCHL, the number of subjects carrying a 460Trp allele was significantly higher in patients compared with controls (53% v 33%, chi2 = 8.0, P = .018). In FCHL patients carrying at least one 460Trp allele, SBP was significantly higher compared with patients homozygous for the 460Gly allele (140 mm Hg and 130 mm Hg respectively, P = .015). CONCLUSIONS: This study shows that the 460Trp allele is associated with FCHL. Furthermore, SBP is increased in patients carrying the 460Trp allele.

Soluble receptors for tumor necrosis factor-alpha (TNF-R p55 and TNF-R p75) in familial combined hyperlipidemia.

We investigated the potential role of the 75 kD receptor for tumor necrosis factor-alpha (TNF-alpha) (TNFRSF1B, located on chromosome 1 band p36.2) as a modifier gene in familial combined hyperlipidemia (FCH), based on previous linkage and association data. Age-corrected values for the soluble (s) extracellular domain of TNF-R p75 were lower in 156 well-characterized hyperlipidemic (HL) FCH relatives than in 168 normolipidemic (NL) relatives (P<0.01). Plasma concentrations of the soluble domain of the 55 kD receptor (sTNF-R p55, the other TNF-alpha receptor) did not differ between HL and NL relatives. In conditional logistic regression analysis, plasma sTNF-R p75 concentration was the only non-lipid variable that contributed significantly to prediction of affected FCH status (regression coefficient=-0.413, P=0.01). The present findings have potentially important diagnostic and therapeutic implications in FCH.

Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is the most commonly inherited hyperlipidemia in man, with a frequency of +/-1% in the general population and approximately 10% in myocardial infarction survivors. A genomic scan in 18 Dutch FCHL families resulted in the identification of several loci with evidence for linkage. One of these regions, 1p36.2, contains TNFRSF1B which encodes one of the tumor necrosis factor receptors. An intron 4 polymorphic CA-repeat was used to confirm linkage to FCHL. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function (P = 0.032), and, borderline, with apolipoprotein B levels (P = 0.064). Furthermore, in a case-control study, association was demonstrated since the overall CA-repeat genotype distribution was significantly different among 40 unrelated FCHL patients and 48 unrelated healthy spouse controls (P = 0.029). This difference was due to a significant increase in allele CA271 homozygotes in the FCHL patients (P = 0.019). Mutation analysis of exon 6 in 73 FCHL family members demonstrated the presence of a single nucleotide polymorphism with two alleles, coding for methionine (196M) and arginine (196R). Complete linkage disequilibrium between CA267, CA271 and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype. In conclusion, TNFRSF1B was found to be associated with susceptibility to FCHL. Our data suggest that an as yet unknown disease-associated mutation, linked to alleles 196M and CA271, plays a role in the pathophysiology of FCHL.

Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A.

OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10cM genome-wide scan. DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied. SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n= 198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity. RESULTS: Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximately 9 and 3 cM, respectively. The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3). CONCLUSION: These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome. Novel loci on chromosome 8 and 10 qter need further study.

LHFP, a novel translocation partner gene of HMGIC in a lipoma, is a member of a new family of LHFP-like genes.

A major cytogenetic subgroup among human lipomas is characterized by translocations involving the HMGIC gene at 12q15. In the context of an ongoing research program aiming at the elucidation of the functional consequences of HMGIC translocations in the etiology of lipomas, we have isolated a novel human gene, LHFP (lipoma HMGIC fusion partner), that acts as a translocation partner of HMGIC in a lipoma with t(12;13). The LHFP gene was mapped to the long arm of chromosome 13, a region recurrently targeted by chromosomal aberrations in lipomas. By Northern blot analysis, a transcript of 2. 4 kb was detected in a variety of human tissues. We assembled a cDNA contig containing the entire coding region of LHFP. Nucleotide sequence analysis of the composite LHFP cDNA revealed an open reading frame encoding a protein of 200 amino acids. The predicted human LHFP protein is almost identical to a translated mouse EST that covers almost the entire LHFP coding region. In addition, BLAST searches revealed that the LHFP protein belongs to a new protein family consisting of at least four or five members. In the lipoma studied, the expressed HMGIC/LHFP fusion transcript encodes the three DNA binding domains of HMGIC followed by 69 amino acids encoded by frame-shifted LHFP sequences. LHFP is the second translocation partner of HMGIC identified in lipomas and represents a candidate target gene for lipomas with 13q aberrations.

Identification of NFIB as recurrent translocation partner gene of HMGIC in pleomorphic adenomas.

Approximately 12% of all pleomorphic adenomas of the salivary glands are characterized by chromosome aberrations involving the chromosome segment 12q13-15. Several chromosomes have been found as translocation partners of chromosome 12, and some of these recurrently. Recently, the HMGIC gene was identified as the target gene affected by the 12q13-15 aberrations. Here, we report the identification and characterization of a new translocation partner gene of HMGIC in pleomorphic adenomas. 3'-RACE analysis of a primary adenoma with an apparently normal karyotype revealed an HMGIC fusion transcript containing ectopic sequences derived from the human NFIB gene, previously mapped to chromosome band 9p24.1. The HMGIC NFIB fusion transcript was also confirmed by RT-PCR. Since the chromosome segment 9p12-24 is repeatedly involved as translocation partner of chromosome 12q13-15 in pleomorphic adenomas, we tested whether NFIB might be a recurrent partner of HMGIC. RT-PCR analysis of a second adenoma with an ins(9;12)(p23;q12q15) as the sole anomaly, revealed that also in this tumor an HMGIC/NFIB hybrid transcript was present. The reciprocal NFIB/HMGIC fusion transcript, however, could not be detected in any of these tumors. Nucleotide sequence analysis of the fusion transcripts indicated that the genetic aberration in both tumors resulted in the replacement of a carboxy-terminal segment of HMGIC by the last five amino acids of NFIB. In conclusion, our results reveal the recurrent involvement of the NFIB gene as translocation partner gene of HMGIC in pleomorphic adenomas.

Molecular characterization of a complex chromosomal rearrangement in a pleomorphic salivary gland adenoma involving the 3'-UTR of HMGIC.

Recently, the high mobility group protein gene, HMGIC, was identified as a common genetic denominator in benign tumors with chromosome 12q13-15 aberrations, such as lipomas, uterine leiomyomas, pleomorphic adenoma of the salivary glands, hamartomas of breast and lung, angiomyxomas, and endometrial polyps. In most cases, the rearrangements resulted in the separation of the three HMGIC DNA-binding motifs from the acidic carboxy-terminal tail. Here, we report about the molecular characterization of a case of pleomorphic adenoma carrying a t(1;12)(p22;q15). Studies were performed on a cell line derived from the primary tumor, i.e., cell line Ad-312/SV40. Although the chromosome 12 breakpoint was initially mapped more than 1 Mb distal to the HMGIC gene by fluorescence in situ hybridization (FISH) analysis, the present molecular studies reveal a more complex chromosomal rearrangement that directly affects the HMGIC gene. Using 3'-RACE analysis, a HMGIC fusion transcript was detected that contained the complete HMGIC, coding region but lacked the putative mRNA destabilizing AUUUA motifs that are normally present in the 3'-UTR of HMGIC. Wild-type HMGIC transcripts were also detected in the tumor cells. The results suggest that alterations in the 3'-noncoding region of HMGIC may have to be considered as pathogenetically relevant.

Expression of reciprocal hybrid transcripts of HMGIC and FHIT in a pleomorphic adenoma of the parotid gland.

The developmentally regulated HMGIC gene, which encodes an architectural transcription factor, has recently been linked to the pathogenesis of benign solid tumors with chromosome aberrations involving 12q13-15. Among these tumors are pleomorphic adenoma of the salivary glands, lipoma, uterine leiomyoma, hamartomas of the breast and lung, fibroadenoma of the breast, angiomyxoma, and endometrial polyps. For most tumor types, however, the translocation partners are variable. At present, no translocation partner genes of HMGIC are known for pleomorphic adenomas. Here, we report that in a primary pleomorphic adenoma of the parotid gland, the FHIT gene, which spans the chromosome 3p14.2 fragile site FRA3B, and is frequently disrupted in tumors, acts as a fusion partner of HMGIC. In addition to normal HMGIC and FHIT transcripts, an HMGIC/FHIT hybrid transcript as well as its reciprocal counterpart, FHIT/HMGIC, were found to be expressed by reverse transcription-PCR. The results establish the concurrent disruption of two tumor-associated genes in a benign tumor.

A 6-Mb yeast artificial chromosome contig and long-range physical map encompassing the region on chromosome 12q15 frequently rearranged in a variety of benign solid tumors.

Cytogenetic analysis of a variety of benign solid tumors, among which uterine leiomyoma, lipoma, pleomorphic salivary gland adenoma, and pulmonary chondroid hamartoma, has indicated that these tumors often display chromosome breakpoints in region q13-q15 of chromosome 12. In previous studies, we have reported that these breakpoints map between locus D12S8 and the CHOP gene, the latter of which has been shown to be consistently rearranged in myxoid liposarcomas with t(12;16)(q13;p11). Here, we report directional chromosome walking studies starting from D12S8 and resulting in the construction of a YAC contig of about 6 Mb. This YAC contig, whose orientation on chromosome 12 was determined by double-color fluorescence in situ hybridization (FISH) analysis, has at least double coverage and consists of 75 overlapping YAC clones, all isolated from CEPH YAC libraries. Their insert sizes were estimated by contour-clamped homogeneous electric field (CHEF) gel electrophoresis. Chromosomal localization and chimerism of the YACs were investigated by FISH analysis. Chimerism of YAC clones was independently determined by restriction mapping. On the basis of YAC end-derived DNA markers and sequence-tagged sites (STSs), with an average spacing of approximately 70 kb, as well as restriction enzyme analysis, a long-range physical map was established for the 6-Mb DNA region of chromosome 12 covered by the YAC contig. Within the YAC contig, the relative positions of various known genes, an expressed sequence-tagged site, and a number of CEPH/Généthon polymorphic markers were determined. The latter data allow full integration of our mapping data with those obtained by CEPH/Généthon as well as those reported at the Second International Workshop on Human Chromosome 12 Mapping. Finally, this YAC contig constitutes the basis for the contstruction of a transcriptional map of this region and is likely to facilitate identification of genes involved in the formation of various benign solid tumor types.

Molecular characterization of MAR, a multiple aberration region on human chromosome segment 12q13-q15 implicated in various solid tumors.

Chromosome arm 12q breakpoints in seven cell lines derived from primary pleomorphic salivary gland adenomas were mapped by FISH analysis relative to nine DNA probes. These probes all reside in a 2.8 Mb genomic DNA region of chromosome segment 12q13-q15 and correspond to previously published sequence-tagged sites (STS). Their relative positions were established on the basis of YAC cloning and long range physical and STS content mapping. The 12q breakpoints of five of the cell lines were found to be mapping within three different subregions of the 445 kb DNA interval that was recently defined as the uterine leiomyoma cluster region of chromosome 12 breakpoints (ULCR12) between STS RM33 and RM98. All seven breakpoints appeared to map within the 1.7 Mb DNA region between STS RM36 and RM103. Furthermore, the chromosome 12 breakpoints of three primary pleomorphic salivary gland adenomas were also found to be mapping between RM36 and RM103. Finally, FISH analysis of two lipoma cell lines with 12q13-q15 aberrations pinpointed the breakpoints of these to relatively small and adjacent DNA segments which, as well as those of two primary lipomas, appeared to be located also between RM36 and RM103. We conclude from the observed clustering of the 12q breakpoints of the three distinct solid tumor types that the 1.7 Mb DNA region of the long arm of chromosome 12 between RM36 and RM103 is a multiple aberration region which we designate MAR.

Identification of the chromosome 12 translocation breakpoint region of a pleomorphic salivary gland adenoma with t(1;12)(p22;q15) as the sole cytogenetic abnormality.

Cell line Ad-312/SV40, which was derived from a primary pleomorphic salivary gland adenoma with t(1;12)(p22;q15), was used in fluorescence in situ hybridization (FISH) analysis to characterize its translocation breakpoint region on chromosome 12. Results of previous studies have indicated that the chromosome 12 breakpoint in Ad-312/SV40 is located proximally to locus D12S8 and distally to the CHOP gene. We here describe two partially overlapping yeast artificial chromosome (YAC) clones, Y4854 (500 kbp) and Y9091 (460 kbp), which we isolated in the context of a chromosome walking project with D12S8 and CHOP as starting points. We present a composite long-range restriction map encompassing the inserts of these two YAC clones and show by FISH analysis that both YACs span the chromosome 12 breakpoint as present in Ad-312/SV40 cells. Subsequently, we have isolated cosmid clones corresponding to various sequence-tagged sites (STSs) mapping within the inserts of these YAC clones. These included cRM51, cRM69, cRM85, cRM90, cRM91, cRM110, and cRM111. In FISH studies, cosmid clones cRM85, cRM90, and cRM111 appeared to map distally to the chromosome 12 breakpoint, whereas cosmid clones cRM51, cRM69, cRM91, and cRM110 were found to map proximally to it. These results assign the chromosome 12 breakpoint in Ad-312/SV40 to a DNA region of less than 165 kbp. FISH evaluation of the chromosome 12 breakpoints in five other pleomorphic salivary gland adenoma cell lines indicated that these are located proximally to the one in Ad-312/SV40, at a distance of more than 0.9 Mbp from STS RM91. These results, while pinpointing a potentially critical region on chromosome 12, also provide evidence for the possible involvement of 12q13-q15 sequences located elsewhere.

Identification, molecular cloning, and characterization of the chromosome 12 breakpoint cluster region of uterine leiomyomas.

Recent molecular cytogenetic analysis of uterine leiomyoma cell lines with chromosome 12 aberrations has indicated that their chromosome 12 breakpoints map between linkage locus D12S8 and the CHOP gene. Here, we report fluorescence in situ hybridization (FISH) and molecular cloning studies of the chromosome 12 breakpoints in a panel of seven such uterine leiomyoma cell lines; five with the frequently observed t(12;14)(q15;q24), one with t(12;15)(q15;q24), and one with ins(12;11)(q14;q21qter). Directional chromosome walking studies starting from D12S8 and the CHOP gene resulted in the isolation of a relatively large number of overlapping YAC clones, including Y5355 (465 kbp), Y7673 (360 kbp), and Y9899 (275 kbp). In total, the inserts of these three YAC clones span an 800 kbp long and presumably contiguous stretch of human genomic DNA. All chromosome 12 breakpoints of the uterine leiomyoma cell lines studied were found by FISH analysis to be mapping within a 445 kbp subfragment of this region and, furthermore, to be dispersed over a DNA region which is at least 150 kbp in size. The chromosome 12 breakpoint of t(12;14)(q15;q24) in uterine leiomyoma cell line LM-30.1/SV40 was tentatively mapped within the 60 kbp region between YAC clones Y9899 and Y5355. From this 60 kbp region and close to sequence-tagged site RM99, we isolated probe pRM118-A, which showed in Southern blot analysis that it detected a rearrangement in LM-30.1/SV40 DNA, and generated restriction maps of the normal and rearranged genomic DNA regions detected with this probe. Finally, we molecularly cloned part of one of those rearranged DNA fragments using a vectorette-PCR-based technique and demonstrated that it consisted of 12q13-q15 sequences fused to DNA sequences derived from 14q23-24 and most likely represented the translocation junction on der(14) in LM-30.1/SV40 cells. Our studies strongly suggest that we have identified and isolated the uterine leiomyoma cluster region of chromosome 12 breakpoints, which we designate ULCR12, and molecularly cloned and characterized the der(14) translocation junction in cells derived from a uterine leiomyoma carrying the frequently observed t(12;14)(q15;q24).

An echo-free silicone elastomer block for ultrasonography.

The authors use a silicone elastomer block, rather than less-convenient water baths, to reduce echo reverberations during ultrasound examinations of superficial anatomic structures.