Genotype FBN1/phenotype relationship in a cohort of patients with Marfan syndrome.

Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene, and cardiovascular involvement is the leading cause of mortality. We sought to examine the genotype/phenotype realtionship in 61 consecutive patients with a phenotype and genotype compatible with MFS. The FBN1 gene was analyzed by massive sequencing using a hybridization capture-based target enrichment custom panel. Forty-three different variants of FBN1 were identified, of which 17 have not been previously reported. The causal variants of MFS were grouped into mutations resulting in haploinsufficiency (HI group; 23 patients) and mutations producing a dominant-negative effect (DN group; 38 patients). Patient information was collected from electronic medical records and clinical evaluation. While no significant differences were found between the two groups, the HI group included more cases with aortic dissection and occurring at a younger age that the DN group (34.7% vs. 15.8%; p = 0.160). Irrespective of the mutation group, males presented with a higher probability of aortic involvement (4-fold higher risk than females) and aortic dissections events occurred at younger ages. Patients with DN variants carrying a cysteine substitution had a higher incidence of ectopia lentis.

Factor XIII deficiency in two Spanish families with a novel variant in gene F13A1 detected by next-generation sequencing; symptoms and clinical management.

Coagulation factor XIII (FXIII) has a major role in coagulation stabilizing the haemostatic clot. FXIII deficiency is associated with an increased risk of bleeding. Severe phenotypes lead to spontaneous, traumatic and surgical bleeding. Umbilical cord bleeding is especially common, and intracranial bleeding may occur in up to one third of patients without prophylaxis. In this work, we used NGS for screening all the coding and intronic boundary regions of F13A1 and F13B genes in two families affected by severe FXIII deficiency. Outcome confirmation analysis and variant studies in related patients was done by Sanger sequencing. Two variants were found: c.34A > G (p.Arg12Gly; NM_00129.3) and c.514C > T (p.Arg172Ter; NM_00129.3), both located in the F13A1 gene. The variant p.Arg172Ter is already described in literature and was found in homozygosis in one family and in compound heterozygosis in the other family. The variant p.Arg12Gly variant has not been described previously. This variant is located in the activation peptide of the FXIII A-subunit which is highly conserved among FXIII homologs. Given the high risk of dangerous bleeding and early manifestation in severe FXIII-deficient patients, a prompt genetic confirmation is imperative. In this sense, NGS technology allows a rapid and simultaneous analysis of all regions of all the genes involved in the pathology.

Familial hyperaldosteronism type III a novel case and review of literature.

Less than 15% of hypertension cases in children are secondary to a primary hyperaldosteronism. This is idiopathic in 60% of the cases, secondary to a unilateral adenoma in 30% and 10% remaining by primary adrenal hyperplasia, familial hyperaldosteronism, ectopic aldosterone production or adrenocortical carcinoma.To date, four types of familial hyperaldosteronism (FH I to FH IV) have been reported. FH III is caused by germline mutations in KCNJ5, encoding the potassium channel Kir3.4. The mutations cause the channel to lose its selectivity for potassium, allowing large quantities of sodium to enter the cell. As a consequence, the membrane depolarizes, voltage-gated calcium channels open, calcium enters the cell, initiating the cascade that leads to aldosterone synthesis. Somatic mutations in KCNJ5 has also been described in aldosterone-producing adenomas. The most frequent presentation of FH III is with severe hyperaldosteronism symptoms and resistance to pharmacological therapy which leads to bilateral adrenalectomy. We will review current literature and describe a child with FH III due to a novel de novo deletion in KCNJ5 with wild phenotype as a sign of clinical variability of this disease.

Next generation sequencing in bleeding disorders: two novel variants in the F5 gene (Valencia-1 and Valencia-2) associated with mild factor V deficiency.

Inherited bleeding coagulation disorders (IBCDs) have a powerful diagnostic tool in next generation sequencing (NGS) that not only offers confirmation of diagnosis but also aids in genetic counselling, prenatal diagnosis and helps to predict the clinical course and follow-up of a disease. In our group, targeted-NGS using a Custom SureSelect QXT Panel (Agilent Technologies, Inc., Santa Clara, CA, USA) was designed to screen for causal variants in 40 genes related with the coagulation cascade. In this work, we used NGS for screening all the coding and intronic boundary regions of F5 gene in two patients affected by factor V (FV) deficiency (parahemophilia). Two new mutations were found: c.4745A>G (p.Tyr1582Cys, NM_000130.4) and c.1999_2002dupAATT (p.Ser668ter; NM_000130.4), both located in exon 13 of the F5 gene. We designated them Valencia-1 and Valencia-2 respectively. Valencia-1 could provoke loss of the fifth cupredoxin domain of the FV, and would be responsible for its defective activity. Valencia-2 prematurely stops the translation of mRNA, resulting in a truncated FV protein which lacks completely the B domain and the light chain. NGS has permitted to describe an increasing number of FV deficiency-causing mutations and a better understanding of FV's structure and function. The description of deficiency-causing mutations will continue to increase our knowledge of the functional residues of FV, as well as those which are involved in the correct folding of the protein. In this sense, NGS is a useful tool for studying IBCDs, as permits studying the whole coagulation cascade at once and gives a global view of the patient's genetic background.

Hb A1c Determination by Capillary Electrophoresis is an Efficient Method for Detecting ß-Thalassemias and Hemoglobin Variants.

Glycated hemoglobin (Hb A1c) determination by multicapillary zone electrophoresis (MZE) can additionally be used to detect Hb A2, Hb F and most common hemoglobin (Hb) variants. We assessed the effectiveness of this method for detecting ß-thalassemia (ß-thal), δß-thalassemia (δß-thal) and most common Hb variants. Moreover, Hb F/Hb A2 is evaluated as an index for discriminating between ß- and δß-thal traits. The theoretical ß-thalassemia major (ß-TM) birth rate in our healthcare area is calculated and contrasted with real data. A MZE technique was used for Hb A1c measurements in 27,724 patients. Previous criteria for carrier detection were established and subsequently confirmed by molecular biology techniques. Positive predictive value (PPV) was 100.0%. The prevalence of ß-thal trait (including δß-thal) was 0.34%. The most prevalent mutations (estimated per 100,000 population) were HBB: c.118C > T (57.7%), HBB: c.93-21G>A (50.5%), HBB: c.92 + 1G > A (43.3%), HBB: c.92 + 6T > C (32.5%) and HBB: c.20delA (18.0%) for ß-thalassemias, and Hb S (HBB: c.20A > T) (32.5%) and Hb J-Baltimore (HBB:c.3880T>A) (28.9%) for Hb variants. We found a paradoxical result between the theoretical ß-TM birth rate and real data. We calculated an optimal Hb F/Hb A2 index cutoff of 0.71 for discriminating between ß- and δß-thal traits. This method is highly cost-effective for detecting ß-thalassemias and common Hb variants. Prevalence results match previous data for the Spanish population. Heterogeneity of mutations in Spain has markedly increased as a consequence of migration. The Hb F/Hb A2 index cutoff could be used to predict δß-thal trait.

Deletion 1q43-44 in a patient with clinical diagnosis of Warburg-Micro syndrome.

Warburg-Micro syndrome (WARBM) is an autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy and central nervous system malformations. This syndrome is caused by mutations in the RAB3GAP1/2 and RAB18 genes, part of the Rab family, and in the TBC1D20 gene, which contributes to lipid droplet formation/metabolism. Here we present a patient with clinical diagnosis of WARBM syndrome, who did not have mutations in either the RAB3GAP1/2 genes, in the main exons of RAB18, nor in the TBC1D20 gene. However, the analysis with CGH-array detected a 9.6 Mb deletion at 1q43-qter. We performed a genotype-phenotype correlation using 20 previously published patients in whom the coordinates of the deleted regions were defined. The comparative analysis revealed that the current patient and three of the other 20 patients share the loss of six genes, four of which are related with the family of G proteins, and are strongly expressed in the brain, retina, heart and kidney. Consequently, their haploinsufficiency may result in different combinations of clinical alterations, including some of those of WARBM syndrome. In addition, the haploinsufficiency of other genes may contribute to other defects and clinical variability. Additionally, for the genotype-phenotype correlation, one must also consider molecular pathways that can result in the observed alterations. To early confirm a genetic diagnosis is essential for the patient and family. The current patient was considered as having a recessive syndrome, but since he had a "de novo" deletion, there was not an increased recurrence risk.

Genetic and clinical characterization of a novel FH founder mutation in families with hereditary leiomyomatosis and renal cell cancer syndrome.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH(NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype. RESULTS: Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61-0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH_c.1118A > G variant is a Spanish founder mutation that originated 12-26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome. CONCLUSIONS: In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing.

Cognitive Profile and Cardiovascular Risk Factors in Older Adults with Mild Cognitive Impairment.

The prevalence of cardiovascular risk factors (CVRFs) in the older adults population and their specific impact on their cognitive profiles still requires further research. For this purpose, a cross-sectional study was carried out to describe the presence of CVRFs and their association with cognitive performance in a sample of older adults (65-85 years old) with Mild Cognitive Impairment (MCI). Participants (n = 185) were divided into three groups concerning their cardiovascular risk level determined by the presence of different CVRFs, including Type 2 Diabetes (T2D), dyslipidemia, hypertension, and obesity. The primary outcome measures were the participant's scores in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Sociodemographic, clinical, and psychosocial data were collected. Non-parametrical statistical analyses and effect sizes were calculated. Findings revealed that a greater presence of CVRFs was not associated with a worse overall cognitive performance. High-risk patients were more likely to have significantly worse performance in the attentional domain compared to medium-risk (p = 0.029, r = 0.42) and compared to low-risk (p = 0.041, r = 0.35), specifically in the digits repetition subtest (p = 0.042). T2D alone was the CVRF associated with cognitive differences (p = 0.037, r = 0.32), possibly mediated by the duration of the condition. Consequently, a higher presence of CVRFs did not lead to a worse overall cognitive performance. However, high-risk individuals were more likely to experience cognitive impairment, particularly in the attentional domain. T2D played a significant role in these cognitive profile differences, possibly influenced by its duration.

The Clinical Spectrum, Diagnosis, and Management of GATA2 Deficiency.

Hereditary myeloid malignancy syndromes (HMMSs) are rare but are becoming increasingly significant in clinical practice. One of the most well-known syndromes within this group is GATA2 deficiency. The GATA2 gene encodes a zinc finger transcription factor essential for normal hematopoiesis. Insufficient expression and function of this gene as a result of germinal mutations underlie distinct clinical presentations, including childhood myelodysplastic syndrome and acute myeloid leukemia, in which the acquisition of additional molecular somatic abnormalities can lead to variable outcomes. The only curative treatment for this syndrome is allogeneic hematopoietic stem cell transplantation, which should be performed before irreversible organ damage happens. In this review, we will examine the structural characteristics of the GATA2 gene, its physiological and pathological functions, how GATA2 genetic mutations contribute to myeloid neoplasms, and other potential clinical manifestations. Finally, we will provide an overview of current therapeutic options, including recent transplantation strategies.

Efficacy of Insulin Titration Driven by SMS in Improving Glycemic Control in People with Type 2 Diabetes.

AIM: To evaluate the efficacy of the self-management of insulin titration based on information received by the Short Message Service (SMS). METHODS: A case-control study including 59 subjects in each arm with 16 weeks of follow-up was performed. The inclusion criteria were: (1) Subjects with type 2 diabetes (T2D) under basal insulin treatment; (2) Suboptimal glycemic control: HbA1c ≥ 7.5% and fasting capillary blood glucose (FCBG) > 140 mg/dL (>3 times per week). Subjects were invited to use an insulin titration service based on SMS feedback aimed at optimizing glycemic control depending on fasting blood glucose levels. Psychological aspects were evaluated in the interventional group by means of validated questionnaires (DDS, HADS and SF-12). RESULTS: The intervention group achieved a lower mean FCBG (126 mg/dL ± 34 vs. 149 mg/dL ± 46, p = 0.001) and lower HbA1c (7.5% ± 1.3 vs. 7.9% ± 0.9, p = 0.021) than the control group. In addition, the intervention group showed a significant improvement in psychological aspects related to Emotional Burden (p = 0.031), Regimen Distress (p < 0.001), Depression (p = 0.049) and Mental Health (p < 0.01). CONCLUSIONS: The SMS-guided titration was effective in terms of improving glucometric parameters in comparison with the standard of care and improved significant psychological aspects-mainly, the stress associated with insulin treatment.

Psychometric validation of the MIND Youth Questionnaire (MY-Q) to assess quality of life in Spanish patients with type 1 diabetes between 12 and 25 years old.

AIM: Validate in Spanish the Monitoring Individual Needs in Diabetes Youth Questionnaire (MY-Q), a multi-dimensional self-report HRQoL questionnaire designed for paediatric diabetes care. DESIGN AND METHODS: After translation, 209 patients diagnosed with type 1 diabetes, between 12 and 25 years old were assessed. The patients belonged to 12 hospitals in Spain. RESULTS: Exploratory factor analysis including one-factor up to seven-factor solutions were tested. The three-factor solution (Negative Impact of Diabetes, Empowerment and Control of Diabetes and Worries) was the most parsimonious model with adequate fit: χ2(723)=568.856 (p<0.001), CFI=0.913, RMSEA=0.072 [0.064, 0.080], SRMR=0.075. The three-factor solution and the grouping of the items followed a clear rationale. Cronbach's alpha was 0.816 for Negative Impact, 0.700 for Empowerment and Control and 0.795 for Worries. The study of the relationship between the MY-Q dimensions and socio-demographics variables show a relationship between age and the MY-Q: F(6,410)=10.873 (p<0.001), η2=0.137. Participants younger than 14 years old showed greater scores on Empowerment and Control when compared to participants between 14 and 17 years old (p=0.021); statistically significant differences were found for the participants 18 years old or older, who showed lower levels of Worries than the younger patients. Concurrent validity found that the dimension of Negative Impact of Diabetes was positively related to WHO-5, and the PedsQL Diabetes Module. CONCLUSION: The Spanish version of the MY-Q to measure HRQoL in patients with type 1 diabetes between the ages of 12 and 25, has adequate psychometric properties and conceptual and semantic equivalence with the original version in Dutch.

Switching from treatment with sensor augmented pump to hybrid closed loop system in type 1 diabetes: Impact on glycemic control and neuropsychological tests in the real world.

AIMS: The aim of this study is to assess in the real world the impact of initiating hybrid closed loop (HCL) on glycemic control and quality of life in patients using sensor-augmented pump (SAP). METHODS: In this prospective study, patients using SAP changed to an HCL system in a specialized hospital. HCL devices used were Medtronic 780G®, Tandem Control-IQ® and Diabeloop® system. Glucometric data and hypoglycemia and neuropsychological tests were assessed at baseline and 3 months after initiating HCL. RESULTS: A total of 66 consecutive patients were included (74% women, mean age 44 ± 11 years, diabetes duration 27.2 ± 11 years). Significant improvements were observed in coefficient of variation (from 35.6% to 33.1%), time in range (from 62.2 % to 73.8%), time above 180 mg/dl (from 26.9% to 18%), time below 70 mg/dl (from 3.3% to 2.1%) and time below 55 mg/dl (from 0.7% to 0.3%). In addition, significant improvements were observed in fear of hypoglycemia and grade of distress associated to treatment and to interpersonal sphere. CONCLUSIONS: Switching from SAP to HCL system improves time in range and reduces time in hypoglycemia and glycemic variability at 3 months. These changes are accompanied by significant reduction of neuropsychological burden related to diabetes.

Impact of Diabetic Foot Multidisciplinary Unit on Incidence of Lower-Extremity Amputations by Diabetic Foot.

BACKGROUND: One of the most devastating complications of diabetes is diabetes-related foot disease (DFD), which is a priority for public health systems. The 2016-2020 Catalonia Health Plan aimed to reduce the incidence of total and major lower-extremity amputations (LEAs) due to DFD by 10% in the population aged 45-74 years. The aim of the present study was to compare the incidence of LEA-DFD 5 years before and after the creation of the Diabetic Foot Multidisciplinary Unit at our Hospital. METHODS: We prospectively collected all cases of LEA-DFD performed at Vall d'Hebron University Hospital from 1 January 2016 to 31 December 2020. Cases of LEA-DFD performed from 1 January 2011 to 31 December 2015 were retrospectively reviewed. The incidence of LEA-DFD between these periods was compared. RESULTS: A total of 457 LEAs due to DFD were performed in 316 patients. We observed a reduction of 27.9% [CI: 23.7-32.1%] in the incidence of total LEA in the 2016-2020 period in comparison with the period 2011-2016 (0.8 ± 0.1 vs. 1.1 ± 0.3 per 10.000 inhabitants/year, p < 0.001), as well as a reduction of 49.3% [CI: 44.6-53.9%] in the incidence of major LEA-DFD (0.15 ± 0.1 vs. 0.30 ± 0.1 per 10.000 inhabitants/year, p < 0.001). CONCLUSIONS: The implementation of a Diabetic Foot Multidisciplinary Unit resulted in a significant reduction in the rate of amputations due to DFD in the population with diabetes in North Barcelona.

The Impact of the Length of the Common Intestinal Loop on Metabolic and Nutritional Outcomes of Patients with Severe Obesity Who Undergo of Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy: 5-Year Follow-Up.

Introduction: Single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) is a recent bariatric surgery technique, highly effective in terms of weight loss. Nevertheless, data regarding the impact of SADI-S at mid-long term (after >5 years of follow-up) are scarce. Objectives: To evaluate the effect of lengths of common intestinal loop on the evolution of patients with morbid obesity (MO), who undergo SADI-S. Materials and Methods: Descriptive study (case series), including patients with MO who underwent SADI-S procedure between January 2012 and December 2015 with at least 5 years of follow-up. Patients were classified as "Old-SADI-S" (OS) when length of the common alimentary loop was <2.5 m and "New-SADI-S" (NS) when length was >2.5 m. Clinical parameters and nutritional parameters were included. Results: Twenty-nine cases were included (17 OS; 12 NS), 86.2% women and mean age 46.7 ± 1 years. After 12 months, OS had significantly lower body mass index (29.7 ± 4.8 kg/m2 versus 32.0 ± 5.1 kg/m2, P = .01), without significant differences in the resolution of comorbidities. Nevertheless, OS group had severe malabsorptive complications requiring surgical conversion of OS to NS in 7 patients after 8 months. At 5 years of follow-up, no significant difference was seen between the two groups and resolution of comorbidities was maintained during this period of time. Conclusions: SADI-S is effective in terms of weight loss and resolution of comorbidities at 5 years of follow-up, regardless of the length of the common intestinal loop. However, a common intestinal loop <2.5 m was associated with severe malabsorptive complications that determined the surgical re-conversion in all cases.

Case Report: Partial Uniparental Disomy Unmasks a Novel Recessive Mutation in the LYST Gene in a Patient With a Severe Phenotype of Chédiak-Higashi Syndrome.

Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive (AR) immune disorder that has usually been associated to missense, nonsense or indels mutations in the LYST gene. In this study, we describe for the first time the case of a CHS patient carrying a homozygous mutation in the LYST gene inherited as a result of a partial uniparental isodisomy (UPiD) of maternal origin. Sanger sequencing of the LYST cDNA and single nucleotide polymorphism (SNP)-arrays were performed to identify the causative mutation and to explain the molecular mechanism of inheritance, respectively. Partial-UPiD leads to a copy neutral loss of heterozygosity (CN-LOH) of the telomeric region of chromosome 1 (1q41q44), unmasking the potential effect of the mutation detected. The mutation (c.8380dupT) is an insertion located in exon 32 of the LYST gene resulting in a premature stop codon and leading to the loss of all the conserved domains at the C-terminal of the LYST protein. This would account for the severe phenotype observed. We also reviewed the only two previously reported cases of CHS as a result of a uniparental disomy. In this study, we show that the combination of different strategies, including the use of SNP-arrays, is pivotal to fine-tune the diagnosis of rare AR disorders, such as CHS. Moreover, this case highlights the relevance of uniparental disomy as a potential mechanism of CHS expression in non-consanguineous families.

Diabetic Retinopathy and Skin Tissue Advanced Glycation End Products Are Biomarkers of Cardiovascular Events in Type 2 Diabetic Patients.

Risk of cardiovascular events is not homogeneous in subjects with type 2 diabetes; therefore, its early identification remains a challenge to be met. The aim of this study is to evaluate whether the presence of diabetic retinopathy and accumulation of advanced glycation end-products in subcutaneous tissue can help identify patients at high risk of cardiovascular events. For this purpose, we conducted a prospective study (mean follow-up: 4.35 years) comprising 200 subjects with type 2 diabetes with no history of clinical cardiovascular disease and 60 non-diabetic controls matched by age and sex. The primary outcome was defined as the composite of myocardial infarction, coronary revascularization, stroke, lower limb amputation or cardiovascular death. The Cox proportional hazard multiple regression analysis was used to determine the independent predictors of cardiovascular events. The patients with type 2 diabetes had significantly more cardiovascular events than the non-diabetic subjects. Apart from the classic factors such as age, sex and coronary artery calcium score, we observed that the diabetic retinopathy and advanced glycation end-products in subcutaneous tissue were independent predictors of cardiovascular events. We conclude that the diabetic retinopathy and advanced glycation end-products in subcutaneous tissue could be useful biomarkers for selecting type 2 diabetic patients in whom the screening for cardiovascular disease should be prioritized, thereby creating more personalized and cost-effective medicine.

The Gaze Fixation Assessed by Microperimetry: A Useful Tool for the Monitoring of the Cognitive Function in Patients with Type 2 Diabetes.

Current guidelines recommend annual screening for cognitive impairment in patients > 65 years with type 2 diabetes (T2D). The most used tool is the mini-mental state evaluation (MMSE). Retinal microperimetry is useful for detecting cognitive impairment in these patients, but there is no information regarding its usefulness as a monitoring tool. We aimed to explore the role of retinal microperimetry in the annual follow-up of the cognitive function of patients with T2D older than 65 years. MATERIALS AND METHODS: Prospective observational study, comprising patients > 65 years with T2D, attended at our center between March-October 2019. A complete neuropsychological evaluation assessed the baseline cognitive status (mild cognitive impairment, MCI, or normal, NC). Retinal microperimetry (sensitivity, gaze fixation) and MMSE were performed at baseline and after 12 months. RESULTS: Fifty-nine patients with MCI and 22 NC were identified. A significant decline in the MMSE score was observed after 12 months in the MCI group (25.74 ± 0.9 vs. 24.71 ± 1.4; p = 0.001). While no significant changes in retinal sensitivity were seen, all gaze-fixation parameters worsened at 12 months and significantly correlated with a decrease in the MMSE scores. CONCLUSION: Retinal microperimetry is useful for the monitoring of cognitive decline in patients > 65 years with T2D. Gaze fixation seems a more sensitive parameter for follow-up after 12 months than retinal sensitivity.

Clinical Applicability of the Specific Risk Score of Dementia in Type 2 Diabetes in the Identification of Patients with Early Cognitive Impairment: Results of the MOPEAD Study in Spain.

INTRODUCTION: Although the Diabetes Specific Dementia Risk Score (DSDRS) was proposed for predicting risk of dementia at 10 years, its usefulness as a screening tool is unknown. For this purpose, the European consortium MOPEAD included the DSDRS within the specific strategy for screening of cognitive impairment in type 2 diabetes (T2D) patients attended in a third-level hospital. MATERIAL AND METHODS: T2D patients > 65 years, without known cognitive impairment, attended in a third-level hospital, were evaluated. As per MOPEAD protocol, patients with MMSE ≤ 27 or DSDRS ≥ 7 were referred to the memory clinic for complete neuropsychological assessment. RESULTS: 112 T2D patients were recruited. A total of 82 fulfilled the criteria for referral to the memory unit (43 of them declined referral: 48.8% for associated comorbidities, 37.2% lack of interest, 13.95% lack of social support). At the Fundació ACE's Memory Clinic, 34 cases (87.2%) of mild cognitive impairment (MCI) and 3 cases (7.7%) of dementia were diagnosed. The predictive value of DSDRS ≥ 7 as a screening tool of cognitive impairment was AUROC = 0.739, p 0.024, CI 95% (0.609-0.825). CONCLUSIONS: We found a high prevalence of unknown cognitive impairment in TD2 patients who attended a third-level hospital. The DSDRS was found to be a useful screening tool. The presence of associated comorbidities was the main factor of declining referral.

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.

Usefulness of Eye Fixation Assessment for Identifying Type 2 Diabetic Subjects at Risk of Dementia.

Type 2 diabetic (T2D) subjects have a significantly higher risk of developing mild cognitive impairment (MCI) and dementia than age-matched non-diabetic individuals. However, the accurate evaluation of cognitive status is based on complex neuropsychological tests, which makes their incorporation into the current standard of care for the T2D population infeasible. Given that the ability to maintain visual gaze on a single location (fixation) is hampered in Alzheimer's disease (AD), the aim of the present study was: (1) To assess whether the evaluation of gaze fixation during fundus-driven microperimetry correlated with cognitive status in T2D subjects; (2) to examine whether the addition of fixational parameters to the assessment of retinal sensitivity increased the predictive value of retinal microperimetry in identifying T2D subjects with MCI. For this purpose, fixation parameters and retinal sensitivity were compared in three age-matched groups of T2D subjects: normocognitive (n = 34), MCI (n = 33), and AD (n = 33). Our results showed that fixation is significantly more unstable in MCI subjects than normocognitive subjects, and even more altered in those affected by AD (ANOVA; p < 0.01). Moreover, adding fixation parameters to retinal sensitivity significantly increases the predictive value in identifying those subjects with MCI: ROC (Receiver Operating Characteristic) Area 0.68 with retinal sensitivity alone vs. ROC Area 0.86 when parameters of fixation are added to retinal sensitivity (p < 0.01). In conclusion, our results suggest that fixational eye movement parameters assessed by fundus-microperimetry represent a new tool for identifying T2D subjects at risk of dementia.