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Anterior segment dysgenesis (ASD) and Axenfeld-Rieger spectrum (ARS) are mainly due to PITX2 and FOXC1 defects, but it is difficult in some patients to differentiate among PITX2-, FOXC1-, PAX6- and CYP1B1-related disorders. Here, we set out to characterize the pathogenic variants (PV) in PITX2, FOXC1, CYP1B1 and PAX6 in nine unrelated Mexican ARS/ASD patients and in their available affected/unaffected relatives.Automated Sanger sequencing of PITX2, FOXC1, PAX6 and CYP1B1 was performed; those patients without a PV were subsequently analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA) for PITX2, FOXC1 and PAX6. Missense variants were evaluated with the MutPred, Provean, PMUT, SIFT, PolyPhen-2, CUPSAT and HOPE programs.We identified three novel PV in PITX2 (NM_153427.2:c.217GA, c.233TC and c.279del) and two in FOXC1 [NM_001453.2:c.274CT (novel) and c.454TA] in five ARS patients. The previously reported FOXC1 c.367CT or p.(Gln123*) variant was identified in a patient with ASD. The ocular phenotype related to FOXC1 included aniridia, corneal opacity and early onset glaucoma, while an asymmetric ocular phenotype and aniridia were associated with PITX2. No gene rearrangements were documented by MLPA analysis, nor were any PV identified in PAX6 or CYP1B1.Heterozygous PV in the PITX2 and FOXC1 genes accounted for 66% (6/9) of the ARS/ASD cases. The absence of PAX6 or CYP1B1 abnormalities could reflect our small sample size, although their analysis could be justified in ARS/ASD patients that present with congenital glaucoma or aniridia.

Objective. The aim of this study was to estimate the incidence of delirium and its risk factors among critically ill cancer patients in an intensive care unit (ICU). Materials and Methods. This is a prospective cohort study. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was measured daily at morning to diagnose delirium by a physician. Delirium was diagnosed when the daily was positive during a patient’s ICU stay. All patients were followed until they were discharged from the ICU. Using logistic regression, we estimated potential risk factors for developing delirium. The primary outcome was the development of ICU delirium. Results. There were 109 patients included in the study. Patients had a mean age of 48.6 ± 18.07 years, and the main reason for admission to the ICU was septic shock (40.4%). The incidence of delirium was 22.9%. The mortality among all subjects was 15.6%; the mortality rate in patients who developed delirium was 12%. The only variable that had an association with the development of delirium in the ICU was the days of use of mechanical ventilation (OR: 1.06; CI 95%: 0.99–1.13;p=0.07). Conclusion. Delirium is a frequent condition in critically ill cancer patients admitted to the ICU. The duration in days of mechanical ventilation is potential risk factors for developing delirium during an ICU stay. Delirium was not associated with a higher rate of mortality in this group of patients.

The aim of this study was to improve knowledge of the mutational spectrum causing tuberous sclerosis complex (TSC) in a sample of Mexican patients, given the limited information available regarding this disease in Mexico and Latin America. Four different molecular techniques were implemented to identify from single nucleotide variants to large rearrangements in the TSC1 and TSC2 genes of 66 unrelated Mexican-descent patients that clinically fulfilled the criteria for a definitive TSC diagnosis. The mutation detection rate was 94%, TSC2 pathogenic variants (PV) prevailed over TSC1 PV (77% vs. 23%) and a recurrent mutation site (hotspot) was observed in TSC1 exon 15. Interestingly, 40% of the identified mutations had not been previously reported. The wide range of novels PV made it difficult to establish any genotype-phenotype correlation, but most of the PV conditioned neurological involvement (intellectual disability and epilepsy). Our 3D protein modeling of two variants classified as likely pathogenic demonstrated that they could alter the structure and function of the hamartin (TSC1) or tuberin (TSC2) proteins. Molecular analyses of parents and first-degree affected family members of the index cases enabled us to distinguish familial (18%) from sporadic (82%) cases and to identify one case of apparent gonadal mosaicism.

About 80% of patients with tuberous sclerosis complex (TSC) present renal involvement, usually as angiomyolipomas followed by cystic disease. An early diagnosis of polycystic kidney disease (PKD) in such patients is frequently related to the TSC2/PKD1 contiguous gene syndrome (PKDTS). Molecular confirmation of PKDTS is important for a prompt diagnosis, which can be complicated by the phenotypic heterogeneity of PKD and the absence of a clear phenotype–genotype correlation. Herein, we report three PKDTS pediatric patients. The case 3 did not present a classic PKDTS phenotype, having only one observable cyst on renal ultrasound at age 4 and multiple small cysts on magnetic resonance imaging at age 15. In this patient, chromosomal microarray analysis showed a gross deletion of 230.8 kb that involved TSC2, PKD1 and 13 other protein-coding genes, plus a heterozygous duplication of a previously undescribed copy number variant of 242.9 kb that involved six protein-coding genes, including SSTR5, in the 16p13.3 region. Given the observations that the case 3 presented the mildest renal phenotype, harbored three copies of SSTR5, and the reported inhibition of cystogenesis (specially in liver) observed with somatostatin analogs in some patients with autosomal dominant PKD, it can be hypothesized that other genetic factors as the gene dosage of SSTR5 may influence the PKD phenotype and the progression of the disease; however, future work is needed to examine this possibility. Resumen: Un 80% de los pacientes con complejo de esclerosis tuberosa (CET) presentan afectación renal, generalmente angiomiolipomas, seguidos de enfermedad quística. Un diagnóstico temprano de la enfermedad renal poliquística (ERP) en estos pacientes se relaciona con frecuencia con el síndrome de genes contiguos TSC2/PKD1 (PKDTS). La confirmación molecular de PKDTS es importante para establecer un diagnóstico oportuno, que puede complicarse por la heterogeneidad fenotípica de PKD y la ausencia de una clara correlación entre fenotipo y genotipo. En este artículo presentamos los casos de 3 pacientes pediátricos con PKDTS. El caso 3 no presentó un fenotipo PKDTS clásico, con solo un quiste observable en la ecografía renal a los 4 años y numerosos quistes pequeños en la resonancia magnética a los 15 años. En este paciente, el análisis de microarreglos para análisis cromosómico global mostró una eliminación total de 230,8 kb que involucró a TSC2, PKD1 y otros 13 genes codificantes de proteínas, más una duplicación heterocigota para una variante de número de copias no descrita previamente de 242,9 kb que involucró a 6 genes codificantes de proteínas, entre ellos SSTR5, en la región 16p13.3. Dado que el caso 3 mostraba el fenotipo renal menos severo, contaba con tres copias del gen SSTR5 y a que se ha observado una inhibición en la cistogénesis (especialmente en el hígado) con los análogos de somatostatina en algunos pacientes con ERP autosómica dominante, podemos hipotetizar que existen otros factores genéticos como la dosis génica de SSTR5 que pudieran influir en el fenotipo y la progresión de la ERP; sin embargo, se necesitan estudios adicionales para investigar esta posibilidad. Keywords: Tuberous sclerosis complex, Polycystic kidney disease, Copy number variant, TSC2/PKD1 contiguous gene syndrome, SSTR5 gene, Palabras clave: Complejo de esclerosis tuberosa, Enfermedad del riñón poliquístico, Variante del número de copias, Síndrome de genes contiguos TSC2/PKD1, Gen SSTR5

Creutzfeldt-Jakob disease (CJD) is the most frequent human Prion-related disorder (PrD). The detection of 14-3-3 protein in the cerebrospinal fluid (CSF) is used as a molecular diagnostic criterion for patients clinically compatible with CJD. However, there is a pressing need for the identification of new reliable disease biomarkers. The pathological mechanisms leading to accumulation of 14-3-3 protein in CSF are not fully understood, however neuronal loss followed by cell lysis is assumed to cause the increase in 14-3-3 levels, which also occurs in conditions such as brain ischemia. Here we investigated the relation between the levels of 14-3-3 protein, Lactate dehydrogenase (LDH) activity and expression of the prion protein (PrP) in CSF of sporadic and familial CJD cases. Unexpectedly, we found normal levels of LDH activity in CJD cases with moderate levels of 14-3-3 protein. Increased LDH activity was only observed in a percentage of the CSF samples that also exhibited high 14-3-3 levels. Analysis of the PrP expression pattern in CSF revealed a reduction in PrP levels in all CJD cases, as well as marked changes in its glycosylation pattern. PrP present in CSF of CJD cases was sensitive to proteases. The alterations in PrP expression observed in CJD cases were not detected in other pathologies affecting the nervous system, including cases of dementia and tropical spastic paraparesis/HTLV-1 associated myelopathy (HAM/TSP). Time course analysis in several CJD patients revealed that 14-3-3 levels in CSF are dynamic and show a high degree of variability during the end stage of the disease. Post-mortem analysis of brain tissue also indicated that 14-3-3 protein is upregulated in neuronal cells, suggesting that its expression is modulated during the course of the disease. These results suggest that a combined analysis of 14-3-3 and PrP expression pattern in CSF is a reliable biomarker to confirm the clinical diagnosis of CJD patients and follow disease progression.

Classical galactosemia is an autosomal recessive inborn error of metabolism caused by a deficiency of the galactose-1-phosphate uridyltransferase (GALT). More than 200 mutations have been described in the GALT gene. A 5.5-kb GALT deletion, first described in patients of Ashkenazi Jewish ancestry, may lead either to an erroneous genotype assignment of classical galactosemia or to discrepancies with parental genotypes and the expected biochemical phenotype. The presence of the 5.5-kb deletion was examined in 27 Mexican nonrelated families with at least one child with reduced GALT activity in erythrocytes and it was detected in the 5.5% (n=3) of the 54 alleles tested. The first molecular studies in three of our families showed that the genotypes of the parents were inconsistent with those of their children, which were considered initially as homozygous p.N314D-Duarte 2, but after analyzing for the presence of the 5.5-kb deletion, were reassigned as compound heterozygotes [5.5-kb deletion]+[p.N314D-Duarte 2]. Identification of the 5.5-kb deletion in Mexican patients suggests that this mutation might not be exclusive to a given ethnic group and should be tested in other populations, especially when there is a discrepancy between the genotypes of patients and parents or by incongruence between biochemical phenotype and GALT genotype. Establishing a genotype–phenotype correlation for the 5.5-kb GALT deletion and determining the appropriate management will require additional studies in patients with a G/G genotype bearing the 5.5-kb GALT deletion.