Ayudas diagnósticas y diagnóstico diferencial de la enfermedad de Pompe / Diagnostic aids and differential diagnosis of Pompe disease

Introducción: La enfermedad de Pompe (EP) o glucogenosis tipo II es una enfermedad autosómica recesiva causada por mutaciones en el gen GAA que codifica para la proteína alfa-1,4-glucosidasa. Su deficiencia lleva a un almacenamiento anormal de glucógeno en los lisosomas de varias células, a través de los diferentes tejidos, lo que causa un compromiso musculoesquelético predominante. Contenidos: Los fenotipos de la enfermedad dependen de las variantes genéticas y de los niveles de la actividad enzimática residual. La enfermedad se presenta como EP de inicio infantil, EP de inicio tardío y EP intermedio, por lo que es de suma importancia su diagnóstico temprano, por medio de estudios moleculares como la secuenciación de Sanger y la secuenciación de nueva generación. Conclusiones: Se ha demostrado, mediante diferentes estudios, que las variaciones genéticas pueden diferir entre etnias, y es importante su caracterización molecular para determinar el tratamiento más adecuado, de acuerdo con el estado del material inmunológico de reacción cruzada (CRIM).

Introduction: Pompe disease (PD) or Glycogenosis Type II is a rare autosomal recessive disease caused by mutations in the GAA gene that codes for the alpha-1,4-glucosidase protein. Its deficiency leads to abnormal glycogen storage in the lysosomes of various cells throughout the different tissues causing a predominant musculoskeletal compromise. Contents: The phenotypes of the disease depend on the genetic variants and the levels of residual enzyme activity, presenting as infantile-onset PD, late-onset PD, and intermediate PD; Therefore, early diagnosis of the disease through molecular studies such as Sanger sequencing and new generation sequencing is of utmost importance. Conclusions: It has been shown through different studies that genetic variations can vary between ethnic groups and the molecular characterization of the variants is important to determine the most appropriate treatment depending on the state of the cross-reactive immunological material (CRIM)

MTHFR 677C>T (rsRS1801133) variant is associated with hyperhomocysteinemia but not with clinical severity in patients with peripheral arterial disease / A variante MTHFR 677C>T (RS1801133) está associada a hiperhomocisteinemia, mas não a gravidade clínica em pacientes com doença arterial periférica

Abstract Background The MTHFR 677C>T variant's involvement with hyperhomocysteinemia and peripheral arterial disease (PAD) is still unclear. Objectives To evaluate associations between the MTHFR 677C>T (rs1801133) variant and susceptibility to and severity of PAD and homocysteine (Hcy) levels. Methods The study enrolled 157 PAD patients and 113 unrelated controls. PAD severity and anatomoradiological categories were assessed using the Fontaine classification and the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC), respectively. The variant was genotyped using real-time polymerase chain reaction and Hcy levels were determined using chemiluminescence microparticle assay. Results The sample of PAD patients comprised 60 (38.2%) females and 97 (61.8%) males. Patients were older and had higher Hcy than controls (median age of 69 vs. 45 years, p<0.001; and 13.66 µmol/L vs. 9.91 µmol/L, p=0.020, respectively). Hcy levels and the MTHFR 677C>T variant did not differ according to Fontaine or TASC categories. However, Hcy was higher in patients with the CT+TT genotypes than in those with the CC genotype (14.60 µmol/L vs. 12.94 µmol/L, p=0.008). Moreover, patients with the TT genotype had higher Hcy than those with the CC+CT genotypes (16.40 µmol/L vs. 13.22 µmol/L, p=0.019), independently of the major confounding variables. Conclusions The T allele of MTHFR 677C>T variant was associated with higher Hcy levels in PAD patients, but not in controls, suggesting a possible interaction between the MTHFR 677C>T variant and other genetic, epigenetic, or environmental factors associated with PAD, affecting modulation of Hcy metabolism.

Resumo Contexto O envolvimento da variante MTHFR 677C>T na hiperhomocisteinemia e na doença arterial periférica (DAP) ainda não está claro. Objetivos Avaliar a associação da variante MTHFR 677C>T (rs1801133) com suscetibilidade e gravidade da DAP e valores séricos de homocisteína (Hcy). Métodos Este estudo caso-controle envolveu 157 pacientes com DAP e 113 controles não relacionados. A gravidade e as categorias anatomorradiológicas da DAP foram avaliadas pela classificação de Fontaine e pelo Inter-Society Consensus for the Management of Peripheral Arterial Disease, respectivamente. A genotipagem foi realizada por meio de reação em cadeia da polimerase em tempo real, e os valores de Hcy foram determinados por ensaio de micropartículas de quimioluminescência. Resultados Entre os pacientes com DAP, 97 (61,8%) eram homens e 60 (38,2%) eram mulheres, com mediana de idade de 69 anos. Os pacientes com DAP eram mais velhos e apresentaram valores mais elevados de Hcy do que os controles (mediana de 69 vs. 45 anos de idade, p < 0,001; 13,66 µmol/L vs. 9,91 µmol/L, p = 0,020, respectivamente). Os valores de Hcy foram mais elevados em pacientes com os genótipos CT+TT do que aqueles com o genótipo CC (14,60 µmol/L vs. 12,94 µmol/L, p = 0,008). Além disso, os pacientes com o genótipo TT apresentaram valores mais elevados de Hcy do que aqueles com os genótipos CC+CT (16,40 µmol/L vs. 13,22 µmol/L, p = 0,019, respectivamente), independentemente das principais variáveis confundidoras. Conclusões O alelo T da variante MTHFR 677C>T foi associado a valores mais elevados de Hcy nos pacientes com DAP, mas não em controles, sugerindo uma possível interação entre a variante genética MTHFR 677C>T e outros fatores genéticos, epigenéticos ou ambientais associados com a DAP na modulação do metabolismo da Hcy.

The Case Report on Dentatorubral-Pallidoluysian Atrophy / 罕见病研究

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenera-tive disease rarely reported in China. Its symptoms include: cerebellar ataxia, epilepsy, dementia, myoclonus and choreoathetosis. We reported one case of adult-onset DRPLA family in the article. The female proband developed ataxia at the age of 45, followed by cognitive impairment and possible seizure. Five people in her family had similar symptoms. In addition, cranial MRI showed atrophy of the brainstem and cerebellar, as well as diffuse white matter lesions. Analysis of the ATN1 gene showed CAG repeat sizes to be 14/54 in the proband. Besides, we reviewed relevant literature published in recent years to improve the understanding of the disease, including its clinical manifestations, genetic characteristics, diagnosis and treatments.

Parental History of Type 2 Diabetes Mellitus: A Lurking Genetic Threat

Type-2 Diabetes Mellitus (T2DM) is presently the fastest growing disease and has been recognized to be caused by a collision between inherited parental genes and the environment. The current prevalence in Pakistan of type-2 diabetes mellitus is 26.3%. Out of them 19.2% had disease two to three decades back while 7.1% are recently diagnosed cases. Worldwide burden of disease was 415 million in 2015 and this number will increase to 642 million by 2040. Parental history of diabetes mellitus is a chief reason for the development of T2DM in children, but whether this association derives from shared genetic or environmental factors is unclear. Persistent high blood glucose levels can result in drastic outcomes like Diabetic Ketoacidosis and Hyperosmolar non ketotic syndrome. Genome-wide association analyses have uncovered multiple genomic regions associated with T2DM, but identification of the causal variants remains a challenge. This review will discuss the approach of diagnosing T2DM by analyzing the association of gene variants and family history.

Biomarcadores y blancos moleculares del complemento en el diagnóstico de las microangiopatías trombóticas / Complement biomarkers and molecular targets in the diagnosis of thrombotic microangiopathies / Biomarcadores e alvos moleculares do complemento no diagnóstico das microangiopatias trombóticas

Resumen El sistema del complemento juega un papel central en la inmunidad innata, es una línea de defensa contra patógenos y participa en la homeostasis. La activación anormal del complemento contribuye al desarrollo de patologías de variable severidad, tanto inmunológicas y hematológicas como renales. Entre ellas, las microangiopatías trombóticas (MAT) representan un grupo de enfermedades raras con manifestaciones clínicas comunes caracterizadas por anemia hemolítica no inmune, trombocitopenia y daño de órgano(s) blanco. Si bien la clasificación de las MAT sigue siendo desafiante y no ha sido internacionalmente estandarizada, la descripción de entidades asociadas a anomalías del complemento fue comprobada con la eficiencia de la terapia anticomplemento en los pacientes. Las herramientas de diagnóstico desarrolladas en las últimas décadas son esenciales actualmente para diferenciar las MAT más características del grupo; esto es, la púrpura trombótica trombocitopénica (PTT) y el síndrome urémico hemolítico (SUH). En el presente trabajo se presenta una revisión del funcionamiento del sistema del complemento en condiciones fisiológicas, para poder explicar luego cuáles son las alteraciones del sistema implicadas en el desarrollo de las MAT y describir las herramientas disponibles para detectarlas en el laboratorio.

Abstract The complement system plays a crucial role in the innate immune response, being the first-line defense against pathogens and regulating homeostasis. Uncontrolled complement activation can cause immunologic, hematologic as well as renal syndromes of variable severity. Among them, thrombotic microangiopathies (TMA) represent a group of rare diseases characterised by similar clinical manifestations such as microangiopathic hemolytic anemia (MAHA), peripheral thrombocytopenia and organ injury. Although TMA classification is still challenging and no international consensus has been reached, complement-associated disorders have been described thanks to the efficiency of anti-complement therapy in patients. Diagnostic tools developed in the last decades are essential to differentiate the two most well characterized TMA: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). This review will describe how the complement system works in physiological conditions in order to explain how complement abnormalities are involved in TMA, and finally how to detect those anomalies using laboratory tests.

Resumo O sistema do complemento desempenha um papel central na imunidade inata, sendo uma linha de defesa contra patógenos e participando da homeostase. A ativação anormal do complemento contribui para o desenvolvimento de patologias de gravidade variável, como imunológicas, hematológicas e renais. Entre elas, as microangiopatias trombóticas (MAT) representam um grupo de doenças raras com manifestações clínicas comuns caracterizadas por anemia hemolítica não imune, trombocitopenia e lesão de órgão(s) alvo. Embora a classificação das MAT continue sendo desafiadora e não tenha sido padronizada internacionalmente, a descrição de entidades associadas a anomalias do complemento foi comprovada com a eficiência da terapia anticomplemento nos pacientes. As ferramentas de diagnóstico desenvolvidas nas últimas décadas são atualmente essenciais para diferenciar as MAT mais características do grupo, que são a púrpura trombocitopênica trombótica (PTT) e a síndrome hemolítica urêmica atípica (SHU). Neste trabalho, é apresentada uma revisão do funcionamento do sistema de complemento em condições fisiológicas, a fim de explicar posteriormente quais são as alterações do sistema compreendidas no desenvolvimento das MAT, e descrever as ferramentas disponíveis para detectá-las em laboratório.

Clinical and genetic analysis of mucolipidosis in 3 pedigrees and literature review / 中华儿科杂志

Objective@#To investigate the clinical and genetic characteristics of 3 patients with mucolipidosis and to perform literature review.@*Methods@#A retrospective analysis was made on the clinical data and genetic test results of 3 pedigrees with mucolipidosis. The patients were followed up at the Genetic and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University from February 2016 to August 2018. A neonatal inherited metabolic diseases gene panel including GNPTAB, GNPTG, MCOLN1, etc. was used for next-generation sequencing (NGS) based testing. Sanger sequencing was subsequently used to confirm the suspected pathological variants in the patients and their family members. Original papers on mucolipidosis published up to December 2018 were retrieved from PubMed, CNKI and WanFang databases by using the key words "mucolipidosis" AND "Chinese" .@*Results@#The onset ages ranged from (9-90) days. The common clinical characteristics of the 3 patients are developmental delay and skeletal abnormalities. Targeted NGS revealed 5 different variations all in GNPTAB including p.Arg364Ter, p.Ser385Leu, p.Try404Ter, p. Arg587Ter, c.1284+1G>T. Two variants p.Ser385Leu and c.1284+1G>T were novel. Twenty-six cases of mucolipidosis have been reported in Chinese from 8 papers, which included 11 type ML Ⅱα/β, 11 type ML Ⅲ α/β and 4 type ML Ⅲ γ. c.2715+1G>A and p.Arg364Ter variants are likely the hot variants in Chinese ML patients.@*Conclusions@#Mucolipidosis is a rare autosomal recessive disorder characterized by developmental delay and skeletal abnormalities. NGS plus Sanger sequencing detection is effective and accurate for making genetic diagnosis. p.Ser385Leu and c.1284+1G>T of GNPTAB gene are identified as novel pathogenic variants. GNPTAB gene is the main disease causing gene among Chinese ML patients, and c.2715+1G>A and p.Arg364Ter are the most common variants.

The rs11191580 variant of the NT5C2 gene is associated with schizophrenia and symptom severity in a South Chinese Han population: evidence from GWAS

Objective: Recent genome-wide association studies have identified a significant relationship between the NT5C2 variant rs11191580 and schizophrenia (SCZ) in European populations. This study aimed to validate the association of rs11191580 polymorphism with SCZ risk in a South Chinese Han population. The relationship of this polymorphism with the severity of SCZ clinical symptoms was also explored. Methods: A case-control study was performed in 462 patients with SCZ and 598 healthy controls. Rs11191580 was genotyped by the Sequenom MassARRAY iPLEX platform. A total of 459 SCZ patients completed the Positive and Negative Syndrome Scale (PANSS) evaluation. Data were analyzed by PLINK software. Results: We confirmed an association of the rs11191580 polymorphism with SCZ risk in South Chinese Han under a dominant genetic model (ORadj = 0.769; 95%CIadj = 0.600-0.984; padj = 0.037). PANSS scores showed a significant association between variant rs11191580 and total score (padj = 0.032), lack of response scale score (padj = 0.022), and negative scale score (additive: padj = 0.004; dominant: padj = 0.016; recessive: padj = 0.021) after data were adjusted for age and sex. Conclusion: NT5C2 variant rs11191580 conferred susceptibility to SCZ and affected the clinical symptoms of SCZ in a South Chinese Han population.

Insights into the genetic determinants of osteoporosis and related traits from genome-wide studies / 中华内分泌代谢杂志

Osteoporosis, which is characterized by reduced bone mineral density (BMD) and an increased risk of fragility fractures, is the result of a complex interaction between environmental factors and genetic variants that confer susceptibility. Fracture and other complications caused by osteoporosis have serious impact on the life quality and life span of patients. Although previous linkage and candidate gene studies have provided few replicated loci for osteoporosis, genome-wide approaches and next generation sequencing have produced clear and reproducible findings. To date, 25 genome-wide studies for osteoporosis and related traits have been conducted, identifying 76 genes and loci. In this review, we will update the genetic study of osteoporosis and provide some perspective views.

Association between PD-1 genetic variants and the risk of epithelial ovarian cancer / 基础医学与临床

Objective To evaluate the effect of PD-1 gene polymorphisms on the risk of developing epithelial ovarian cancer ( EOC) and patients'outcomes.Methods A case-control study was performed in 620 EOC pa-tients and 620 control women.The genotype and allele frequencies of PD-1.1 A/G and PD-1.5 C/T polymor-phisms were determined using the polymerase chain reaction/ligase detection reaction ( PCR-LDR ) method. Results There were significant differences in the genotype and allele distribution frequencies of the PD-1.1 A/G between cases and controls(P=0.028 and P=0.02, respectively).Compared with the AA genotype , AG and GG genotypes may significantly decrease the risk of developing EOC ( OR=0.71, 95%CI=0.54-0.94; OR=0.68, 95%CI=0.50-0.94,respectively).There was no significant difference in the genotype distribution frequency of the PD-1.5 C/T between cases and controls ( P=0.096 ) , but the frequency of T alleles was significantly lower in the EOC cases than that in the controls ( P=0.033) .Compared to the carriers with C alleles , the carriers with T alleles were at a significantly decreased risk of developing EOC ( OR=0.82 , 95%CI=0.69-0.98 ) .Conclusions PD-1.1 A/G and PD-1.5 C/T polymorphisms are potential molecular markers for predicting the risk of epithelial ovarian cancer in Chinese norther women .

Association between the c.910A>G genetic variant of the XRCC1 gene and susceptibility to esophageal cancer in the Chinese Han population

Esophageal cancer (EC) is a common malignancy worldwide. The X-ray repair cross-complementing 1 gene (XRCC1) is one of the most important candidate genes for influencing susceptibility to EC. This study aimed to investigate the effect of XRCC1 genetic variants on susceptibility to EC. A total of 383 EC patients (males: 239, females: 144, mean age: 56.62) and 387 cancer-free controls (males: 251, females: 136, mean age: 58.23) were enrolled in this study. The c.910A>G genetic variant of the XRCC1 gene was determined by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. The allele and genotype frequencies indicated statistical differences between EC patients and cancer-free controls. The c.910A>G genetic variant was statistically associated with increased susceptibility to EC [GG vs AA: odds ratio (OR)=1.79, 95% confidence interval (CI)=1.12-2.86, P=0.014; GG vs AG/AA: OR=1.76, 95%CI=1.13-2.75, P=0.013; G vs A: OR=1.25, 95%CI=1.01-1.55, P=0.041]. The allele G and genotype GG could contribute to the increased susceptibility to EC. Our findings suggest that the c.910A>G genetic variant is associated with susceptibility to EC in the Chinese Han population, and might be used as a molecular marker for detecting susceptibility to EC.

Association of genetic variants of xenobiotic metabolic pathway with systemic lupus erythematosus.

In view of documented evidence that catechol estrogen-DNA adducts serve as epitopes for binding of anti-nuclear antibodies, genetic polymorphisms of the xenobiotic metabolic pathway involved in estrogen metabolism might contribute towards pathophysiology of systemic lupus erythematosus (SLE). To test this hypothesis, a case-control study was conducted. Cytochrome P 450 1A1 (CYP1A1) m4 (OR: 4.93, 95% CI: 1.31-18.49), catecholamine-o-methyl transferase (COMT) H108L (OR: 1.39, 95% CI: 1.03-1.88) and glutathione-S-transferase (GST) T1 null (OR: 1.83, 95% CI: 1.11- 3.01) variants showed association with SLE risk. SHEsis web-based platform analysis showed mild to moderate linkage disequilibrium between the CYP1A1 m1, m2 and m4 variants (D’: 0.19-0.37). Among the different haplotypes of CYP1A1, CAC-haplotype harboring CYP1A1 m1 variant showed association with SLE risk (OR: 1.46, 95% CI: 1.11-1.92). Multifactor dimensionality reduction analysis (MDR) showed potential gene-gene interactions between the phase II variants i.e. COMT H108L × GSTT1 null × GSTM1 null (p<0.0001) and also between the phase II and I variants i.e. COMT H108L × GSTT1 null × CYP1A1 m1 × CYP1A1 m2 in inflating the risk of SLE by 3.33-folds (95% CI: 2.30-4.82) and 4.00-folds (95% CI: 2.77-5.78), respectively. To conclude, hyperinducibility of CYP1A1 due to m1 and m4 variants and defective phase-II detoxification due to COMT H108L and GSTT1 null variants increase the susceptibility to SLE.

Significance of genetic variants in intron 4 of the surfactant protein B gene of preterm infants with neonatal respiratory distress syndrome / 中华实用儿科临床杂志

Objective To explore the association between genetic variants in intron 4 of the surfactant protein B(SP-B) gene and neonatal respiratory distress syndrome(NRDS) in preterm infants.Methods Using 1 ∶ 1 casc-control study method,a cohort of 52 preterm infants with NRDS and 52 preterm infants without NRDS(non-NRDS) were recruited.Within 1 week after the patients hospitalized,2 mL venous blood was collected.Genomic DNA was extracted and polymerase chain reaction(PCR) was performed to amplify the special region with conserved sequence motifs and intermotif dinucleotide repeats(CA) n in intron 4 of SP-B gene.PCR products was demonstrated by agarose gel electrophoresis and variants were identified by product size.Results A 550 bp target band could be seen in all PCR products (including NRDS group and non-NRDS group).Besides,an additional band(about 650 bp) could be seen in 3 cases of NRDS and 1 case of non-NRDS,which represented insertion variation.The variation incidence of intron 4 of SP-B gene in NRDS group and non-NRDS group were 5.77％ and 1.92％,respectively,there was significant differences (x2 =44.18,P ＜ 0.05).Conclusion Genetic variants in intron 4 of SP-B gene may contribute to risk of preterm infants with NRDS.

Genetic variants in the promoter of cyclooxygenase 2 interacting with Hp infection and the risk of esophageal cancer / 中国综合临床

Objective To evaluate the association of COX2 genetic variants with the risk of esophageal cancer and the interaction of COX2 genetic variants with Hp infection. Methods A total of 119 patients with esophageal cancer and 238 frequency-matched controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism method. Odds ratios (OR) and 95% confidence intervals ( CI) were estimated by logistic regression. Results Case-control analysis showed an increased risk of developing esophageal cancer for 1195 GA(OR =2.69,95% CI= 1. 46-5. 14) and 1195AA ( OR = 2. 30,95% CI = 1.23-4. 89) genotype carriers,respectively, compared with non 1195 GG carriers. When stratified by Hp status, the significantly increased risk of esophageal cancer was found among Hp carrier with OR (95%CI) =2.74 (1.35-5.96) ,but not among Hp non-carriers. Conclusion Genetic polymorphism in COX2 promoter region may play an important role in esophageal cancer by Hp infection.