Distinct Lipids Profiles and Associations With Clinical Indicators and Gut Microbiota in Children With Prader-Willi Syndrome.

Lipid metabolism is closely linked to adiposity. Prader-Willi syndrome (PWS) is a typical genetic disorder causing obesity; however, the distinct lipidomic profiles in PWS children have not been thoroughly investigated. Herein, serum lipidomics analyses were simultaneously explored in PWS, simple obesity (SO), and normal children (Normal). Results indicated that the total concentration of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) in the PWS group were significantly deceased compared with both the SO and the Normal group. In contrast, compared with the Normal group, there was an overall significant increase in triacylglycerol (TAG) levels in both the PWS and the SO groups, with the highest found in SO group. Thirty-nine and 50 differential lipid species were screened among 3 groups: between obesity (PWS and SO) and the Normal group. Correlation analysis revealed distinct profiles in PWS that was different from other 2 groups. Notably, PC (P16:0/18:1), PE (P18:0-20:3), PE (P18:0-20:4)) showed significant negative correlation with body mass index (BMI) only in the PWS group. PE (P16:0-18:2) showed a negative association with BMI and weight in the PWS group, but significant positive correlation in the SO group; no statistically significant association was found in the Normal group. We also found a significant negative correlation between Blautia genus abundance and several significantly changed lipids, including LPC (14:0), LPC (16:0), TAG (C50:2/C51:9), TAG (C52:2/C53:9), TAG (C52:3/C53:10), and TAG (C52:4/C53:11), but no significant correlation in the Normal group and the SO group. Similarly, in the PWS group, the Neisseria genus was significantly negatively associated with acylcarnitine (CAR) (14:1), CAR (18:0), PE (P18:0/20:3), and PE (P18:0/20:4), and extremely positively associated with TAG (C52:2/C53:9); no obvious correlations were observed in the Normal group and the SO group.

Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene.

Background: Severe hyperlipidemia is characterized by markedly elevated blood triglyceride levels and severe early-onset cardiovascular diseases, pancreatitis, pancreatic necrosis or persistent multiple organ failure if left untreated. It is a rare autosomal recessive metabolic disorder originated from the variants of lipoprotein lipase gene, and previous studies have demonstrated that most cases with severe hyperlipidemia are closely related to the variants of some key genes for lipolysis, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1. Meanwhile, other unidentified causes also exist and are equally worthy of attention. Methods: The 29-day-old infant was diagnosed with severe hyperlipidemia, registering a plasma triglyceride level as high as 25.46 mmol/L. Whole exome sequencing was conducted to explore the possible pathogenic gene variants for this patient. Results: The infant was put on a low-fat diet combined with pharmacological therapy, which was successful in restraining the level of serum triglyceride and total cholesterol to a low to medium range during the follow-ups. The patient was found to be a rare novel homozygous duplication variant-c.45_48dupGCGG (Pro17Alafs*22) in GPIHBP1 gene-leading to a frameshift which failed to form the canonical termination codon TGA. The mutant messenger RNA should presumably produce a peptide consisting of 16 amino acids at the N-terminus, with 21 novel amino acids on the heels of the wild-type protein. Conclusions: Our study expands on the spectrum of GPIHBP1 variants and contributes to a more comprehensive understanding of the genetic diagnosis, genetic counseling, and multimodality therapy of families with severe hyperlipidemia. Our experience gained in this study is also contributory to a deeper insight into severe hyperlipidemia and highlights the importance of molecular genetic tests.

Severe forms of Johanson-Blizzard syndrome caused by two novel compound heterozygous variants in UBR1: Clinical manifestations, imaging findings and molecular genetics.

Johanson-Blizzard Syndrome (JBS) is a rare autosomal recessive genetic disorder characterized by exocrine pancreatic insufficiency, distinct abnormal facial appearance and varying degrees of growth retardation. Variants in UBR1 gene are considered to be responsible for the syndrome. Here, we describe a 3-year old boy, who visited our clinic for severe growth retardation and frequent oily diarrhea. The physical examination revealed nasal alae aplasia, scalp defect, and maldescent of left testicle. Transabdominal ultrasound and computed tomography scan of his abdomen demonstrated complete fatty replacement of the pancreas. The clinical, laboratory, and imaging findings strongly suggest the diagnosis of hereditary pancreatitis. Whole exome sequencing revealed two rare compound heterozygous variants, c.2511T > G (p.H837Q) and c.1188T > G (p.Y396X), in the UBR1 gene of this boy, so, the diagnosis of JBS was established. This is the first report of Chinese patient with JBS, and our study indicates that transabdominal ultrasound and computed tomography are two useful and noninvasive imaging methods for the diagnosis and evaluation of JBS, and identification of these two novel variants expands the database of UBR1 gene variants. Furthermore, with the availability of the identification technology for these variants, prenatal diagnosis could be offered for future pregnancies.

Severe forms of complete androgen insensitivity syndrome caused by a p.Q65X novel mutation in androgen receptor: Clinical manifestations, imaging findings and molecular genetics.

Androgen insensitivity syndrome (AIS), a rare X-linked recessive genetic disorder with a normal 46, XY karyotype, is caused by defect of androgen receptor gene (AR) leading to resistance of the target tissues to androgenic hormones. There is a wide spectrum of clinical presentations of AIS, ranging from male infertility, hypospadias to completely normal female external genitalia. Here, we describe a 15-year old, phenotypically female individual, who visited our clinic for primary amenorrhea. The physical examination revealed normal female external genitalia, normal breast development, as well as sparse pubic hair and absence of axillary hair. A short blind vagina pouch was noticed in gynecological examination apart from the absence of cervix and uterus. Serum testosterone measured a considerable high level, and the karyotype was indicative of a normal male (46, XY). Transabdominal ultrasound (US) and magnetic resonance imaging (MRI) confirmed the absence of uterus, ovaries and fallopian tubes, only with a small blind-ending vagina observed. The clinical, laboratory, imaging, and genetic findings strongly suggest the diagnosis of complete androgen insensitivity syndrome (CAIS). Mutational analysis of the AR gene revealed a novel small insertion mutation c.192_193insTAGCAG(Q65X) in exon 1, which gives rise to a truncated nonfunctional protein, resulting in the loss of the remaining 856 C-terminus amino acid residues. This study indicates that US and MRI are two useful and noninvasive imaging methods for the diagnosis and evaluation of CAIS, and identification of this novel mutation expands the database of AR gene mutations. Furthermore, with the availability of the identification technology for this mutation, prenatal diagnosis could be offered for future pregnancies.

Gray Matter Heterotopia, Mental Retardation, Developmental Delay, Microcephaly, and Facial Dysmorphisms in a Boy with Ring Chromosome 6: A 10-Year Follow-Up and Literature Review.

Ring chromosome 6, r(6), is an extremely rare cytogenetic abnormality with clinical heterogeneity which arises typically de novo. The phenotypes of r(6) can be highly variable, ranging from almost normal to severe malformations and neurological defects. Up to now, only 33 cases have been reported in the literature. In this 10-year follow-up study, we report a case presenting distinctive facial features, severe developmental delay, and gray matter heterotopia with r(6) and terminal deletions of 6p25.3 (115426-384174, 268 kb) and 6q26-27 (168697778-170732033, 2.03 Mb) encompassing 2 and 15 candidate genes, respectively, which were detected using G-banding karyotyping, FISH, and chromosomal microarray analysis. We also analyzed the available information on the clinical features of the reported r(6) cases in order to provide more valuable information on genotype-phenotype correlations. To the best of our knowledge, this is the first report of gray matter heterotopia manifested in a patient with r(6) in China, and the deletions of 6p and 6q in our case are the smallest with the precise size of euchromatic material loss currently known.

Human Gut Microbiota Associated with Obesity in Chinese Children and Adolescents.

OBJECTIVE: To investigate the gut microbiota differences of obese children compared with the control healthy cohort to result in further understanding of the mechanism of obesity development. METHODS: We evaluated the 16S rRNA gene, the enterotypes, and quantity of the gut microbiota among obese children and the control cohort and learned the differences of the gut microbiota during the process of weight reduction in obese children. RESULTS: In the present study, we learned that the gut microbiota composition was significantly different between obese children and the healthy cohort. Next we found that functional changes, including the phosphotransferase system, ATP-binding cassette transporters, flagellar assembly, and bacterial chemotaxis were overrepresented, while glycan biosynthesis and metabolism were underrepresented in case samples. Moreover, we learned that the amount of Bifidobacterium and Lactobacillus increased among the obese children during the process of weight reduction. CONCLUSION: Our results might enrich the research between gut microbiota and obesity and further provide a clinical basis for therapy for obesity. We recommend that Bifidobacterium and Lactobacillus might be used as indicators of healthy conditions among obese children, as well as a kind of prebiotic and probiotic supplement in the diet to be an auxiliary treatment for obesity.

Dos mutaciones novedosas en el gen de glicina descarboxilasa en un niño con hiperglicinemia no cetósica clásica: a propósito de un caso / Two novel mutations in the glycine decarboxylase gene in a boy with classic nonketotic hyperglycinemia: case report

La hiperglicinemia no cetósica es una encefalopatía por glicina autosómica recesiva y hereditaria sumamente rara, causada por una deficiencia en el sistema enzimatico de división de la glicina mitocondrial, que provoca síntomas clínicos graves. La hiperglicinemia no cetósica se caracteriza por fenotipos diversos y complejos, por ejemplo, hipotonía, convulsiones, deterioro cognitivo, retrasos del desarrollo y espasmos mioclónicos que podrían causar apnea e incluso la muerte. En este artículo, presentamos el caso de un niño de 1 año con convulsiones mioclónicas, hipotonía y coma, con aumento de la concentración de glicina en el plasma y el líquido cefalorraquídeo y con un índice de glicina en líquido cefalorraquídeo/plasma de 0,24. Existen dos mutaciones heterocigotas novedosas que confirman el diagnóstico de hiperglicinemia no cetósica. Una es una mutación de aminoácido, c.2516A>G (p.Y839C), y la otra es una mutación en los sitios de corte y empalme, c.2457+2T>A, en el gen GLDC.

Nonketotic hyperglycinemia is an extremely rare autosomal recessively inherited glycine encephalopathy caused by a deficiency in the mitochondrial glycine cleavage system, which leads to severe clinical symptoms. Nonketotic hyperglycinemia is characterized by complex and diverse phenotypes, such as hypotonia, seizures, cognitive impairment, developmental delays and myoclonic jerks that may lead to apnea and even death. Here we report a 1-year-old boy with myoclonic seizures, hypotonia and coma; he had elevated plasma and cerebrospinal fluid glycine levels, and cerebrospinal fluid/plasma glycine ratio was 0.24. Two novel heterozygous mutations confirm the diagnosis of nonketotic hyperglycinemia. One is a missense mutation c.2516A>G (p.Y839C) and the other one is a splicing mutation c.2457+2T>A in the GLDC gene.

Two novel mutations in the glycine decarboxylase gene in a boy with classic nonketotic hyperglycinemia: case report. / Dos mutaciones novedosas en el gen de glicina descarboxilasa en un niño con hiperglicinemia no cetósica clásica: a propósito de un caso.

Nonketotic hyperglycinemia is an extremely rare autosomal recessively inherited glycine encephalopathy caused by a deficiency in the mitochondrial glycine cleavage system, which leads to severe clinical symptoms. Nonketotic hyperglycinemia is characterized by complex and diverse phenotypes, such as hypotonia, seizures, cognitive impairment, developmental delays and myoclonic jerks that may lead to apnea and even death. Here we report a 1-year-old boy with myoclonic seizures, hypotonia and coma; he had elevated plasma and cerebrospinal fluid glycine levels, and cerebrospinal fluid/plasma glycine ratio was 0.24. Two novel heterozygous mutations confirm the diagnosis of nonketotic hyperglycinemia. One is a missense mutation c.2516A>G (p.Y839C) and the other one is a splicing mutation c.2457+2T>A in the GLDC gene.

La hiperglicinemia no cetósica es una encefalopatía por glicina autosómica recesiva y hereditaria sumamente rara, causada por una deficiencia en el sistema enzimático de división de la glicina mitocondrial, que provoca síntomas clínicos graves. La hiperglicinemia no cetósica se caracteriza por fenotipos diversos y complejos, por ejemplo, hipotonía, convulsiones, deterioro cognitivo, retrasos del desarrollo y espasmos mioclónicos que podrían causar apnea e incluso la muerte. En este artículo, presentamos el caso de un niño de 1 año con convulsiones mioclónicas, hipotonía y coma, con aumento de la concentración de glicina en el plasma y el líquido cefalorraquídeo y con un índice de glicina en líquido cefalorraquídeo/plasma de 0,24. Existen dos mutaciones heterocigotas novedosas que confirman el diagnóstico de hiperglicinemia no cetósica. Una es una mutación de aminoácido, c.2516A>G (p.Y839C), y la otra es una mutación en los sitios de corte y empalme, c.2457+2T>A, en el gen GLDC.

Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children.

Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader-Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation. RESEARCH IN CONTEXT: Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader-Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.

The association between the polymorphism rs2231142 in the ABCG2 gene and gout risk: a meta-analysis.

Gout is a common metabolic disorder with high heritability. We tried to explore the association between rs2231142 and gout. We searched "rs2231142 or Q141K and gout" in four databases and scholar searching website until 1 June, 2013 and included data from 52,010 participants in meta-analysis and subgroup analysis. The T allele of rs2231142 was associated with increased gout susceptibility (odds ratio [OR] [95 % confidence interval (95 % CI)] = 1.73 [1.55-1.91], P < 0.001). It increased gout risk in Caucasians with OR (95 % CI) = 1.68 (1.50-1.87), P < 0.001; Asians with OR (95 % CI) = 1.93 (1.54-2.31), P < 0.001; Africans with OR (95 % CI) = 1.76 (1.15-2.36), P < 0.001; and New Zealand Pacific Islanders with OR (95 % CI) = 2.94 (1.72-4.15), P < 0.001, but not in New Zealand Maoris, with OR (95 % CI) = 1.12 (0.57-1.67), P = 0.061. No publish or other biases were observed. The T allele of rs2231142 was associated with increased risk of gout.

Association between rs10118757(A/G) in methylthioadenosine phosphorylase gene and coronary artery disease in Chinese Hans.

Studies focusing on the association of gene methylthioadenosine phosphorylase (MTAP) with the risk of coronary artery disease (CAD) and myocardial infarction (MI) are limited. In this study, we explored the effects of rs10118757 in MTAP gene on CAD and MI by performing association analysis in a Chinese Han population. rs10118757 was genotyped in 1007 CAD patients (including 338 MI patients) and 885 healthy controls. Allelic analysis showed that allele A of rs10118757 was associated with increased risk of CAD, with OR (95%CI)=1.193 (1.035-1.376), and P=0.015. After adjusted for age, BMI, gender, hypertension and smoking, rs10118757 was still significantly associated with CAD under additive and dominant models, with OR (95%CI)=1.252 (1.070-1.465), P=0.005, and OR (95%CI)=1.698 (1.168-2.467), P=0.006, respectively. Compared to additive model, dominant model may be the best-fitting model (P=6.63E-10 vs P=6.70E-10). As reported previously, rs10118757 was not associated with MI in the current study. Our study firstly reported that SNP rs10118757 was associated with CAD risk in a Chinese Han population, indicating that MTAP gene may play a potential role in the pathophysiological process of CAD.