Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders

Objective: The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls. Methods: The sample included 75 patients with psychotic disorders on clozapine therapy and 40 paired healthy controls. Plasma clozapine/N-desmethylclozapine, GSH concentrations, and GPx activity were determined, along with genotyping of GCLC and GSTP1 variants and copy number variations of GSTP1, GSTT1, and GSTM1. Clinical, molecular and biochemical data were analyzed with a logistic regression model. Results: GSH levels were significantly reduced and, conversely, GPx activity was higher among patients than controls. GCLC_GAG-7/9 genotype (OR = 4.3, 95%CI = 1.40-14.31, p = 0.019) and hetero-/homozygous genotypes of GCLC_rs761142 (OR = 6.09, 95%CI = 1.93-22.59, p = 0.003) were found to be risk factors for psychosis. The genetic variants were not related to clozapine/N-desmethylclozapine levels or metabolic ratio. Conclusions: GCLC variants were associated with the oxidative stress profile of patients with psychotic disorders, raising opportunities for intervention to improve their antioxidant defenses. Further studies with larger samples should explore this proposal.

Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders.

OBJECTIVE: The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls. METHODS: The sample included 75 patients with psychotic disorders on clozapine therapy and 40 paired healthy controls. Plasma clozapine/N-desmethylclozapine, GSH concentrations, and GPx activity were determined, along with genotyping of GCLC and GSTP1 variants and copy number variations of GSTP1, GSTT1, and GSTM1. Clinical, molecular and biochemical data were analyzed with a logistic regression model. RESULTS: GSH levels were significantly reduced and, conversely, GPx activity was higher in PD patients compared to controls. GCLC_GAG-7/9 genotype (OR=4.3, CI95=1.40-14.31, p=0.019) and hetero-/homozygous genotypes of GCLC_rs761142 (OR=6.09, CI95=1.93-22.59, p=0.003) were found as risk factors for psychosis. The genetic variants were not related to clozapine/N-desmethylclozapine levels or to metabolic ratio. CONCLUSIONS: GCLC variants were associated with the oxidative stress profile of PD patients raising opportunities for intervention to improve their antioxidant defenses. Further studies with larger samples should explore this proposal.

Alcohol intake potentiates clozapine adverse effects associated to CYP1A2*1C in patients with refractory psychosis.

Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation-dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR = 3.55 CI95  = 1.041-12.269, p = .043) and demonstrated that this effect is doubled by concomitant alcohol consumption (OR = 7.9 CI95  = 1.473-42.369, p = .016). Clinicians should be aware of this information before starting CLZ use, when treating patients with refractory psychosis, who are alcohol drinkers and carriers of this genetic variant in order to prevent CLZ-related adverse reactions. Nevertheless, our findings should be replicated in larger samples.

Frecuencia de polimorfismos de nucleótido único y haplotipos de alfa-sinucleína asociados con la enfermedad de Parkinson esporádica en población mexicana / Frequency of single nucleotide polymorphisms and alpha-synuclein haplotypes associated with sporadic Parkinson’s disease in the Mexican population

Introducción. La enfermedad de Parkinson (EP) es una entidad neurodegenerativa común de inicio en la etapa adulta. Su incidencia en México se estima en 40-50 casos por 100.000 habitantes/año y constituye la cuarta causa de atención médica en el Instituto Nacional de Neurología y Neurocirugía. La proteína alfa-sinucleína, SNCA, es clave en la patología de la EP y sus polimorfismos se han asociado a un riesgo aumentado de desarrollarla. Objetivo. Evaluar el riesgo que representan los polimorfismos rs2619364, rs2619363, rs2736990, rs7684318, rs17016074, rs356219, rs356220 y rs356203 de SNCA en una muestra de sujetos mexicanos para la EP. Sujetos y métodos. Se evaluaron 171 pacientes con diagnóstico de EP y 171 controles pareados por sexo y edad mediante reacción en cadena de la polimerasa en tiempo real, y se realizó un análisis estadístico para determinar la asociación de los polimorfismos con la enfermedad. Resultados. Las variantes rs356220, rs356203, rs7684318 y rs2736990 de SNCA están asociadas a la enfermedad y forman dos haplotipos de riesgo elevado para desarrollar EP esporádica en la población mexicana. Conclusiones. Las variaciones en SNCA son un factor de riesgo para desarrollar EP y pueden ser biomarcadores genéticos específicos para pacientes mestizos mexicanos como herramienta de apoyo diagnóstico en la EP esporádica (AU)

Introduction. Parkinson’s disease (PD) is a common neurodegenerative disease which begins in adulthood. Its incidence in Mexico is estimated to be 40-50 cases per 100,000 inhabitants/year and is the fourth reason for medical care in the National Institute of Neurology and Neurosurgery. The protein alpha-synuclein, SNCA, plays a key role in the pathology of PD, and its polymorphisms have been associated with an increased risk of developing the disease. Aim. To evaluate the risk of PD represented by the polymorphisms rs2619364, rs2619363, rs2736990, rs7684318, rs17016074, rs356219, rs356220 and rs356203 of SNCA in a sample of Mexican subjects. Subjects and methods. Altogether 171 patients diagnosed with PD and 171 gender- and age-paired controls were assessed by means of real-time polymerase chain reaction, and a statistical analysis was performed to determine the association between the polymorphisms and the disease. Results. The SNCA variants rs356220, rs356203, rs7684318 and rs2736990 were associated with the disease and form two haplotypes with a high risk of developing sporadic PD in the Mexican population. Conclusions. Variations in SNCA are a risk factor for the development of PD and can act as specific genetic biomarkers as a diagnostic support tool in sporadic PD for Mexican mestizo patients (AU)

Multiple hereditary exostoses and stroke due to vertebral artery dissection.

UNLABELLED: Vascular complications related to multiple hereditary exostoses are uncommon. We present a 39-year-old male patient with multiple exostoses in the upper and lower limbs with an associated positive familial history of such lesions. He experienced a sudden onset of left-side ataxia and hypoesthesia secondary to a left lateral medullary infarction, which was due to a stenotic-pattern vertebral artery dissection (V1-V4). This complication is very rare as a differential diagnosis in the vertebro-basilar dissection spectrum, and a nonspecific relation has been found. ABBREVIATIONS: MHEMultiple hereditary exostosesATangiotomographyVADvertebral artery dissectionCADcervical artery dissectionOIosteogenesis imperfecta.

Cytogenomic and phenotypic analysis in low-level monosomy 7 mosaicism with non-supernumerary ring chromosome 7.

We present the literature review of ring chromosome 7 and clinical, cytogenetic and fine molecular mapping of the first postnatal report of a male child with a non-supernumerary ring chromosome 7, r(7). The patient had dysmorphic features, developmental delay, dermatologic lesions with variable pigmentation, hypogenitalism, lumbar dextroscoliosis, cerebellar and ophthalmological abnormalities, and melanocytic congenital nevi. Cytogenetic analysis of peripheral blood and the nevus sample showed the presence of three different cell lines r(7), monosomy 7, and duplicated r(7) (idic r(7)), while findings on fibroblasts from both light and dark skin showed only mosaicism with r(7) and monosomy 7 cell lines in various proportions. FISH assay of the ring chromosome showed subtelomeric loss in both chromosome arms in all tissues studied. Analysis by genome-wide single-nucleotide polymorphism array showed a 0.8 Mb deletion in 7p22.3 (involving eight genes) and a 7.5 Mb deletion in 7q36 (involving 29 genes including some involved in genital and central nervous system development). The combination of results from our karyotypic and array analyses enabled us to establish an accurate genotype-phenotype relationship.