Presymptomatic Testing for Huntington's Disease in Mexico: 28 Years of Experience.

INTRODUCTION: Huntington's disease (HD) is a genetic neurodegenerative disorder with dominant inheritance. Our center in Mexico City has offered presymptomatic testing (PT) since 1995. OBJECTIVE: To describe the main clinical and demographic characteristics of at-risk HD individuals who applied to the PT program, the reasons for seeking it, and the molecular results. METHODS: A cross-sectional study was conducted with sociodemographic and clinical data of all PT applicants from 1995-2023. Reasons for seeking PT were assessed using a modified questionnaire. In addition, anxiety, and depressive symptoms before and after PT were evaluated with Beck's instruments; cognitive impairment (CI) was assessed with the Mini-Mental State Examination (MMSE) and molecular results. RESULTS: 214 people applied for PT (2.1% of the at-risk population identified in our center); 63% were women (mean age of 37.11 years). 204 (95.3%) were accepted and 190 received results. 70% indicated that the main reason for applying for PT was to inform their offspring about the risk of inheriting HD. Significant differences were observed in the reasons for seeking PT by age group. Although some subjects received treatment, Beck's instrument scores did not indicate special attention or pharmacological treatment. The MMSE showed probable CI in 20 subjects. Of those who received results, 37% were carriers of a full penetrance allele. CONCLUSION: Our center has the only formal PT program for HD in Mexico. The reasons for seeking PT are varied and age-related. Although PT is offered to all subjects at risk for HD, uptake remains low.

A Comparative Analysis of Laparoscopic Gastrectomy Versus Laparoscopic-Assisted Gastrectomy: The Overall and Disease-Free Survival.

Gastric cancer remains a significant global health challenge with varied survival rates, emphasizing the need for research into effective surgical treatments. In this retrospective study, we compared the 72-month overall and disease-free survival between laparoscopic gastrectomy (LG) and laparoscopic-assisted gastrectomy (AG) in a cohort of 139 patients treated for gastric cancer. The analysis revealed that patients undergoing LG exhibited a significantly higher overall survival rate at 72 months compared to those undergoing AG. Although disease-free survival rates were comparable between the two groups, LG showed a marginal advantage. Subgroup analyses based on the type of gastrectomy and anastomosis demonstrated varied survival probabilities, with laparoscopic-assisted partial gastrectomy yielding the most favorable outcomes. These results highlight the importance of the choice of surgical technique in influencing survival outcomes in gastric cancer.

Association of variants in the ABCB1, CYP2C19 and CYP2C9 genes for Juvenile Myoclonic Epilepsy.

Juvenile myoclonic epilepsy (JME) is the most common of the generalized genetic epilepsies, with multiple causal and susceptibility genes; however, its etiopathogenesis is mainly unknown. The toxic effects caused by xenobiotics in cells occur during their metabolic transformation, mainly by enzymes belonging to cytochrome P450. The elimination of these compounds by transporters of the ABC type protects the central nervous system, but their accumulation causes neuronal damage, resulting in neurological diseases. The present study has sought the association between single nucleotide genetic variants of the CYP2C9, CYP2C19, and ABCB1 genes and the development of JME in patients compared to healthy controls. The CC1236 and GG2677 genotypes of ABCB1 in women; allele G 2677, genotypes GG 2677 and CC 3435 in men; the CYP2C19*2A allele, and the CYP2C19*3G/A genotype in both sexes were found to be risk factors for JME. Furthermore, carriers of the TTGGCC genotype combination of the ABCB1 gene (1236/2677/3435) have a 10.5 times higher risk of developing JME than non-carriers. Using the STRING database, we found an interaction between the proteins encoded by these genes and other possible proteins. These findings indicate that the CYP450 system and ABC transporters could interact with other genes in the JME.

Longitudinal Changes in Mitochondrial DNA Copy Number and Telomere Length in Patients with Parkinson's Disease.

Parkinson's disease (PD) pathophysiology includes mitochondrial dysfunction, neuroinflammation, and aging as its biggest risk factors. Mitochondrial DNA copy number (mtDNA-CN) and telomere length (TL) are biological aging markers with inconclusive results regarding their association with PD. A case-control study was used to measure TL and mtDNA-CN using qPCR in PBMCs. PD patients were naive at baseline (T0) and followed-up at one (T1) and two (T2) years after the dopaminergic treatment (DRT). Plasmatic cytokines were determined by ELISA in all participants, along with clinical parameters of patients at T0. While TL was shorter in patients vs. controls at all time points evaluated (p < 0.01), mtDNA-CN showed no differences. An increase in mtDNA-CN and TL was observed in treated patients vs. naive ones (p < 0.001). Our statistical model analyzed both aging markers with covariates, showing a strong correlation between them (r = 0.57, p < 0.01), and IL-17A levels positively correlating with mtDNA-CN only in untreated patients (r = 0.45, p < 0.05). TL and mtDNA-CN could be useful markers for monitoring inflammation progression or treatment response in PD. DRT might modulate TL and mtDNA-CN, reflecting a compensatory mechanism to counteract mitochondrial dysfunction in PD, but this needs further investigation.

Low quality of life, increased number of anti-seizure drugs, and the lack of caregiver support are associated with internalized stigma in adult Mexican patients with epilepsy.

BACKGROUND: People with epilepsy (PWE) have been subject to stigma throughout history, a factor that could compromise their performance in daily life. In Mexico, little is known about the factors that may be affecting internalized stigma. OBJECTIVE: To evaluate the internalized stigma in adult PWE, its relationship with the quality of life, cognitive and depressive symptomatology, and clinical-demographic characteristics. MATERIAL AND METHODS: We conducted a cross-sectional study with a consecutive sampling approach in patients with epilepsy treated at the National Institute of Neurology and Neurosurgery Manuel Velasco Suárez (NINNMVS). Sociodemographic and clinical data, depressive symptomatology (Beck's depression inventory, DBI), cognition (MoCA test), quality of life (QOLIE-31 scale), and internalized stigma (King's internalized stigma scale, ISS) were evaluated. Correlations were made between the continuous variables and the ISS to select those with statistical significance and include them in a multiple linear regression model, along with the dummy variables, to explain internalized stigma. RESULTS: Of 128 patients, 74 (58%) were women; 38% of the patients had more than 20 years of epilepsy evolution. In addition, 39% presented depressive symptoms, and around 60% manifested a possible cognitive impairment. The variables that showed statistical significance concerning the ISS were selected along with dummy variables for multiple linear regression analysis. The resultant model considers the QOLIE-31 total score (ß = -0.489), the number of anti-seizure drugs (ASD, ß = 0.253), and those patients without caregiver support (ß = -0.166) with an adjusted R2 value of 0.316. CONCLUSIONS: A diminishing quality of life, an increased number of ASD, and patients without caregiver support influence a slight to moderate variation of internalized stigma in Mexican PWE. Therefore, it is necessary to continue studying other possible factors that influence internalized stigma to generate effective strategies to reduce its negative effects on PWE.

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice.

Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. Exposures: Genetic test results. Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.

Clinical and Molecular Findings of Intermediate Allele Carriers in the HTT Gene from the Mexican Mestizo Population.

INTRODUCTION: There are reports of different clinical statuses in carriers of intermediate alleles (IAs) of CAG trinucleotide repeats in the HTT gene, from individuals affected by a clinical picture indistinguishable from Huntington's disease (HD) to those without manifestations. Therefore, the possible clinical significance of these alleles has been widely debated. OBJECTIVES: The aim of this study was to describe general and clinical features and discard HD phenocopies by molecular assessment in a case series of IA carriers on the HTT gene of a laboratory sample from a neurological center in Mexico. METHODS: We selected individuals who had previously been tested for the HTT gene expansion, which resulted in IAs. Clinical information was obtained from medical records, and molecular analysis of the JPH3, PRNP, and TBP genes was performed only in IA carriers with clinical manifestations. In addition, two patients with IA and acanthocytes were evaluated by whole-exome sequencing. The scientific and ethical committees of the National Institute of Neurology and Neurosurgery Manuel Velasco Suárez (NINNMVS) approved this study. RESULTS: From 1994 to 2019, the Genetics Department of the NINNMVS confirmed 34 individuals with IAs, 15 of whom belonged to 11 families with HD (IA-HD) and 19 of whom had no family history of HD (IA-non-HD). We found a high proportion of manifestations of the HD phenotypic spectrum in the IA-non-HD subgroup. In addition, among the 20 samples of IA carriers with manifestations molecularly evaluated, we identified two unrelated subjects with CAG/CTG repeat expansions on the JPH3 gene, confirming HD-like 2 (HDL2), and one patient with the homozygous pathogenic c.3232G>T variant (p.Glu1078Ter) in the VPS13A gene, demonstrating choreoacanthocytosis. DISCUSSION/CONCLUSION: Our results show the most extensive series of subjects with IAs and clinical manifestations. In addition, we identify three HD phenocopies, two HDL2 cases, and one choreoacanthocytosis case. Therefore, we emphasize evaluating other HD phenocopies in IA carriers with clinical manifestations whose family background is not associated with HD.

Strategies for decreasing the O2 content in the upgraded biogas purified via microalgae-based technology.

Microalgae-bacteria consortium based technology using a High Rate Algal Pond (HRAP) interconnected to an Absorption Bubble Column (ABC) has emerged as an environmentally friendly promising option to upgrade biogas. However, the oxygenic photosynthesis of microalgae induces oxygen contamination in upgraded biogas, which could limit its further applications. Several strategies were proposed to favor the oxygen desorption and oxygen uptake in parts and accessories of the upgrading system. The effect of the volumetric ratio liquid recirculation rate/biogas rate (L/G = 5.0, 1.0 y 0.5) was evaluated in conjunction with the application of a novel accessory called Open Trickling Column (OTC). The O2 content in upgraded biogas was around 2.1%v, attaining CO2 removal efficiencies around 90%, at L/G ratio of 1.0 during diurnal and nocturnal periods. The inclusion of an OTC at the previous L/G, enhanced 54% the removal of O2 by stripping and uptake compared with the basal condition. Mass balances of H2S and methane showed that L/G > 1.0 favored the complete oxidation of H2S but promoted the loss of methane in dissolved form. Additionally the effect of increasing linear velocity of liquid broth in the lab-scale HRAP (from 15 cm s-1 to 20 cm s-1) showed to improve the O2 stripping with a consequential increase of biomass concentration under steady-state (from 0.7 to 1.4 g L-1) besides achieving O2 content in the upgraded biogas around 1.5%v.

Brief Report: Delayed Diagnosis of Treatable Inborn Errors of Metabolism in Children with Autism and Other Neurodevelopmental Disorders.

The objective of our study was to evaluate the frequency of treatable inborn errors of metabolism (IEM) in a clinical sample of Mexican children and adolescents with neurodevelopmental disorders (NDD). Amino acids and acylcarnitines in blood samples of 51 unrelated children and adolescents were analyzed by tandem mass spectrometry to detect treatable IEM of small molecules. One patient with isovaleric acidemia and autism spectrum disorder (ASD) and another with beta-ketothiolase deficiency and ASD/intellectual disability/attention-deficit/hyperactivity disorder (ADHD) were diagnosed, indicating an IEM frequency of 3.9% (1:26 subjects). The high frequency of treatable IEM indicates the need to perform a minimum metabolic screening as part of the diagnostic approach for patient with NDD, particularly when newborn screening programs are limited to a few disorders.

The intellectual developmental disorders Mexico study: situational diagnosis, burden, genomics and intervention proposal / Estudio sobre trastornos del desarrollo intelectual en México: diagnóstico situacional, carga, genómica y propuesta de intervenciones

Abstract: Objective: This study aims to generate evidence on intellectual development disorders (IDD) in Mexico. Materials and methods: IDD disease burden will be estimated with a probabilistic model, using population-based surveys. Direct and indirect costs of catastrophic expenses of families with a member with an IDD will be evaluated. Genomic characterization of IDD will include: sequencing participant exomes and performing bioinformatics analyses to identify de novo or inherited variants through trio analysis; identifying genetic variants associated with IDD, and validating randomly selected variants by polymerase chain reaction (PCR) and sequencing or real-time quantitative PCR (qPCR). Delphi surveys will be done on best practices for IDD diagnosis and management. An external evaluation will employ qualitative case studies of two social and labor inclusion programs for people with IDD. Conclusions: The results will constitute scientific evidence for the design, promotion and evaluation of public policies, which are currently absent on IDD.

Resumen: Objetivo: Esta investigación busca generar evidencia sobre trastornos del desarrollo intelectual (TDI) en México. Material y métodos: La carga de la enfermedad por TDI se estimará con un modelo probabilístico usando encuestas poblacionales. Se estimarán costos directos e indirectos de gastos catastróficos de familias con un integrante conTDI. La caracterización genómica deTDI incluirá secuenciar exomas, realizar análisis bioinformático para identificar variantes de novo o heredadas a través de análisis de tríos, identificar variantes genéticas asociadas con TDI, y validar variantes aleatoriamente seleccionadas con reacción en cadena de polimerasa y secuenciación o qPCR. Se harán encuestas Delphi sobre mejores prácticas de diagnóstico y manejo de TDI. Una evaluación externa empleará estudios cualitativos de caso de dos programas de inclusión social y laboral para personas con TDI. Conclusiones: Los resultados serán evidencia científica que podrá ser la base para el diseño, promoción y evaluación de políticas públicas, actualmente ausentes para TDI.

The intellectual developmental disorders Mexico study: situational diagnosis, burden, genomics and intervention proposal.

OBJECTIVE:: This study aims to generate evidence on intellectual development disorders (IDD) in Mexico. MATERIALS AND METHODS:: IDD disease burden will be estimated with a probabilistic model, using population-based surveys. Direct and indirect costs of catastrophic expenses of families with a member with an IDD will be evaluated. Genomic characterization of IDD will include: sequencing participant exomes and performing bioinformatics analyses to identify de novo or inherited variants through trio analysis; identifying genetic variants associated with IDD, and validating randomly selected variants by polymerase chain reaction (PCR) and sequencing or real-time quantitative PCR (qPCR). Delphi surveys will be done on best practices for IDD diagnosis and management. An external evaluation will employ qualitative case studies of two social and labor inclusion programs for people with IDD. CONCLUSIONS:: The results will constitute scientific evidence for the design, promotion and evaluation of public policies, which are currently absent on IDD.

Consideraciones éticas del diagnóstico prenatal de la enfermedad de Huntington / Ethical considerations in the prenatal diagnosis of Huntington's disease

La enfermedad de Huntington (EH) es una condición neurodegenerativa de origen genético por la expansión de repetidos de trinucleótidos que codifican tractos de poliglutamina. Tiene un modelo de herencia autosómico dominante, de inicio en la vida adulta, que suele presentarse entre los 37 y 55 años, con una esperanza de vida de 15 años después de iniciados los síntomas. Se encuentra asociada a la generación de movimientos involuntarios, desarrollo de alteraciones psiquiátricas y deterioro cognitivo. El diagnóstico es clínico y molecular, una vez iniciados los síntomas. Existen dos maneras de realizar una detección temprana en aquellas parejas con sospecha o con diagnóstico confirmatorio de alguno de sus miembros: mediante el abordaje prenatal y preimplantación. La postura actual sobre la realización del diagnóstico antenatal sólo se realiza en aquellas parejas que desean interrumpir el embarazo. En el presente ensayo, se analiza esta postura mediante el principialismo médico, concluyendo lo siguiente: en cuestión de autonomía, no se respeta la integridad del ser humano portador de la enfermedad. No es justo realizar una prueba para determinar la conducta de interrumpir el embarazo cuando existen otras enfermedades con pronósticos similares que no cuentan con la misma oportunidad de diagnóstico. Se viola la beneficencia y la no maleficencia al promover la muerte. Sugerimos que la participación del médico debe impulsar la mejor situación para ofrecer la noticia de la confirmación diagnóstica, preparando a la familia y al paciente en los aspectos emocional, físico y nutricional para el momento en que se inicien los síntomas.

Huntington disease is a neurodegenerative disorder caused by expanded trinucleotides which encode polyglutamine tracts. The disease is inherited as an autosomal dominant trait with onset in adult life, normally between 37 to 55 years. Once the symptoms have started, life expectancy will be 15 years. The diagnosis is clinical and molecular after the establishment of the symptomatology. It is characterized by involuntary movements, psychiatric illness and cognitive impairment. There are two ways to approach the antenatal diagnosis in couples with familial background: prenatal and preimplantation. The current posture related to antenatal diagnosis is only for couples that desire termination of the pregnancy. This essay discusses this situation through medical principlism, and arrives to the following conclusions: regarding the principles of autonomy and integrity of the human being, the carrier of the disease is not respected. It does not seem fair to perform a test to determine the behavior of ending a life during pregnancy, while there are other diseases with similar prognosis that do not have the same diagnostic possibilities. This violates the principles of beneficence and non-maleficence, promoting death. We suggest that medical participation must promote the best conditions to confirm the diagnosis, and prepare both family and patient concerning the emotional, physical and nutritional aspects for the moment of the onset of the symptomatology.

[Hyperglycemia as a risk factor for mortality in critically ill neonates]. / La hiperglucemia como factor predictor de mortalidad en neonatos críticamente enfermos.

BACKGROUND: The sick neonate is susceptible to uncontrolled hyperglycemia by several factors. Our objective was to determine the mortality-predictive role of hyperglycemia in critically ill neonates. METHODS: A cohort study was conducted in neonates admitted during the first hour of life in the intensive care unit. Prenatal and perinatal variables were recorded including ventilatory management, comorbidities, arterial blood gas, blood chemistry and blood count. Serum glucose greater than or equal to 126 mg/dL and greater than or equal to 180 mg/dL was considered consistent with hyperglycemia in neonates born at term and preterm infants, respectively. The children were followed until discharge from the unit. Measures of central tendency and dispersion for quantitative variables and frequencies for qualitative variables were obtained, as well as Kaplan-Meier curves. Association test using the chi-square test for exposed and non-exposed groups and Cox regression analysis was performed and risk calculation was made using the hazard ratio. RESULTS: Out of 146 patients, 16 died (10.7 %). Most common causes were respiratory distress syndrome, perinatal asphyxia, meconium aspiration and sepsis. Association was found between hyperglycemia and chest compression, metabolic acidemia, hyperlactatemia, mechanical ventilatory support, intraventricular hemorrhage and death. CONCLUSIONS: Hyperglycemia was an independent risk factor for the prediction of death, with a likelihood of death of 56.8 % when it was present.

INTRODUCCIÓN: el neonato enfermo es susceptible al descontrol de la glucosa por varios factores. Nuestro objetivo fue determinar el papel predictor de mortalidad de la hiperglucemia en neonatos críticamente enfermos. MÉTODOS: se realizó un estudio de cohorte en neonatos que durante la primera hora de vida ingresaron a cuidados intensivos. Se registraron variables prenatales, perinatales, manejo ventilatorio, comorbilidades, gasometría arterial, química sanguínea y biometría hemática. Se consideró que la glucosa sérica mayor o igual a 126 y mayor o igual a 180 mg/dL indicaba hiperglucemia en los neonatos a término y en los pretérmino, respectivamente. Se realizó seguimiento hasta el egreso de la unidad. Se obtuvieron medidas de dispersión y de tendencia central para las variables cuantitativas y frecuencias para las cualitativas, así como curvas de Kaplan-Meier. Se realizó prueba de asociación por chi cuadrada para los grupos expuestos y no expuestos, análisis de regresión de Cox y cálculo de riesgo por hazard ratio. RESULTADOS: de 146 pacientes, fallecieron 16 (10.7 %). Las principales causas fueron síndrome de dificultad respiratoria, asfixia perinatal, aspiración de meconio y sepsis. Se encontró asociación entre hiperglucemia y compresión torácica, acidemia metabólica, hiperlactatemia, asistencia mecánica ventilatoria, hemorragia intraventricular y muerte. CONCLUSIONES: la hiperglucemia fue un factor de riesgo independiente para predecir muerte, con probabilidad de muerte de 56.8 % cuando se encontró presente.