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PURPOSE: Previous studies have reported on the cardiovascular, ocular, and musculoskeletal findings in patients with Marfan syndrome (MFS). This study aims to report the ocular and genotypic findings in patients with the syndrome in Puerto Rico. PATIENTS AND METHODS: A chart review of a cohort of patients with the syndrome from Puerto Rico was done. Patients were examined by at least one of the authors (NJI). Fibrillin-1 (FBN1) full gene sequencing was done to all patients (Laboratory for Molecular Medicine, Center for Genetics and Genomics, Cambridge, MA). This study was approved by the Institutional Review Board of the Universidad Central del Caribe (approval number: 2024-07).  Results: Six patients aged 28-79 years were examined. There were seven female and three male patients. The average visual acuity was 0.49 and 0.52 in the right eye (OD) and left eye (OS), respectively. The average refraction (spherical equivalent) was -1.28 sph OD and -1.07 sph OS. The average intraocular pressure was 14 mmHg in both eyes (OU). A patient had a dislocated lens OD; a patient had lens dislocation OU; and a patient had prosthesis OD and aphakia OS. Upon optical coherence tomography (OCT), the retinal nerve fiber layer (RNFL) average was 75.86 µm OD and 81.85 ​​µm OS; the average cup-to-disc (C/D) ratio was 0.41 and 0.35 in the right and left eye, respectively. Upon visual field testing, the average mean deviation (MD) was -6.27 dB OD and -8.55 dB OS. CONCLUSIONS: Our findings underscore the significant phenotypic and genotypic heterogeneity of patients with MFS in Puerto Rico. The identification of several mutations in the FBN1 gene in the Puerto Rican population demonstrates the need for an up-to-date approach to diagnose and co-manage patients with the syndrome. This study contributes to a deeper understanding of the genetic heritage of patients with the syndrome and highlights the potential for personalized therapeutic interventions.

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BACKGROUND: Prognosis for autosomal dominant polycystic kidney disease (ADPKD), the main inherited cause of kidney failure, relies on estimating cystic growth using linear formulas derived from height-adjusted total kidney volume (Ht-TKV). However, nonlinear renal growth patterns may occur in typical ADPKD. AIMS: To determine kidney outcomes of subjects diagnosed with typical ADPKD exhibiting nonlinear, and unpredictable cystic growth during follow-up. METHODS: Retrospective cohort study. We categorized TKV changes in individuals with typical ADPKD according to observed kidney growth trajectories. Ht-TKV was calculated from consecutive CT or MRI using the ellipsoid method. We compared estimated glomerular filtration rate (eGFR) trajectories with linear mixed models. RESULTS: We included 83 individuals with ADPKD (67% women; age 47 ± 12 years; follow-up 5.2 years [IQR 2.8-9.0]). Three kidney growth patterns were observed: slow progression (24%, <3%/year linear increase), fast progression (39%, ≥3%/year linear increase), and atypical progression (37%, nonlinear growth). Adjusted ht-TKV change in mL/m/year was +1.4 (IQR -4.5 to +10.0), +40.3 (+16.9 to +89.3), and +32.8 (+15.9 to +85.9) for slow, fast, and atypical progressors, respectively (p < 0.001). Atypical progressors exhibited a significantly greater decline in eGFR in mL/min/m²/year (-7.9, 95% CI -6.5, -3.9) compared to slow (-0.5, 95% CI -3.1 to +0.5) and fast progressors (-3.4, 95% CI -7.9, -2.0; between-group p < 0.001). Atypical progressors had a higher proportion of acute complications, including hemorrhages, infections, and urolithiasis (84%), compared to slow (20%) and fast progressors (31%) (p < 0.001). CONCLUSION: In typical ADPKD, nonlinear, abrupt, and unpredictable cyst growth occurs frequently, leading to a higher risk of acute complications and kidney function decline.

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Abstract Introduction: Identifying risk factors for autosomal dominant polycystic kidney disease (ADPKD) progression is important. However, studies that have evaluated this subject using a Brazilian sample is sparce. Therefore, the aim of this study was to identify risk factors for renal outcomes and death in a Brazilian cohort of ADPKD patients. Methods: Patients had the first medical appointment between January 2002 and December 2014, and were followed up until December 2019. Associations between clinical and laboratory variables with the primary outcome (sustained decrease of at least 57% in the eGFR from baseline, need for dialysis or renal transplantation) and the secondary outcome (death from any cause) were analyzed using a multiple Cox regression model. Among 80 ADPKD patients, those under 18 years, with glomerular filtration rate <30 mL/min/1.73 m2, and/or those with missing data were excluded. There were 70 patients followed. Results: The factors independently associated with the renal outcomes were total kidney length - adjusted Hazard Ratio (HR) with a 95% confidence interval (95% CI): 1.137 (1.057-1.224), glomerular filtration rate - HR (95% CI): 0.970 (0.949-0.992), and serum uric acid level - HR (95% CI): 1.643 (1.118-2.415). Diabetes mellitus - HR (95% CI): 8.115 (1.985-33.180) and glomerular filtration rate - HR (95% CI): 0.957 (0.919-0.997) were associated with the secondary outcome. Conclusions: These findings corroborate the hypothesis that total kidney length, glomerular filtration rate and serum uric acid level may be important prognostic predictors of ADPKD in a Brazilian cohort, which could help to select patients who require closer follow up.

Resumo Introdução: É importante identificar fatores de risco para progressão da doença renal policística autossômica dominante (DRPAD). Entretanto, são escassos os estudos que avaliam esse assunto utilizando amostra brasileira. Portanto, o objetivo deste estudo foi identificar fatores de risco para desfechos renais e óbito em coorte brasileira de pacientes com DRPAD. Métodos: Os pacientes tiveram o primeiro atendimento médico entre janeiro/2002 e dezembro/2014, sendo acompanhados até dezembro/2019. Associações entre variáveis clínicas e laboratoriais com desfecho primário (redução sustentada de pelo menos 57% na TFGe em relação ao valor basal, necessidade de diálise ou transplante renal) e desfecho secundário (óbito por qualquer causa) foram analisadas pelo modelo de regressão múltipla de Cox. Entre 80 pacientes com DRPAD, foram excluídos aqueles menores de 18 anos, com TFG <30 mL/min/1,73 m2 e/ou aqueles com dados ausentes. Foram acompanhados 70 pacientes. Resultados: Fatores independentemente associados aos desfechos renais foram: comprimento renal total - Razão de Risco (HR) ajustada com intervalo de confiança de 95% (IC 95%): 1,137 (1,057-1,224), taxa de filtração glomerular - HR (IC 95%): 0,970 (0,949-0,992) e nível sérico de ácido úrico - HR (IC 95%): 1,643 (1,118-2,415). Diabetes mellitus - HR (IC 95%): 8,115 (1,985-33,180) e TFG - HR (IC 95%): 0,957 (0,919-0,997) foram associados ao desfecho secundário. Conclusões: Esses achados corroboram a hipótese de que comprimento renal total, TFG e nível sérico de ácido úrico podem ser importantes preditores prognósticos de DRPAD em uma coorte brasileira, o que pode ajudar a selecionar pacientes que necessitam de acompanhamento mais próximo.

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INTRODUCTION: We aimed to determine the effect of years of schooling (YoS) and age on the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-MX) scores in preclinical carriers group (PCG) and non-carriers group (NCG) of the APP V717I mutation. METHODS: We included 39 first-degree Mexican relatives of APP V717I carriers (PCG = 15; NCG = 24). We report eight CERAD-MX tasks: Mini-Mental State Examination (MMSE), Word List Learning (WLL), Delayed Recall (WLD) and Recognition (WLR), Constructional Praxis Copy (CPC) and Recall (CPR), Semantic Verbal Fluency (SVF), and Verbal Boston Naming (VBN), comparing both groups' performance and simulating new samples' random vectors by inverse transform sampling. RESULTS: PCG and NCG performed similarly on CERAD-MX. In both groups, YoS and age influence all z scores. A positive age effect resulted for PCG on CPC and SVF; for the NCG on MMSE, SVF, and VBN. DISCUSSION: All tasks are influenced by YoS. Higher YoS/younger age or YoS/older age interactions affected different tasks, suggesting that YoS confounds outcomes. Highlights: Years of schooling (YoS) and age affect the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease scores of APP V717I preclinical carriers.Preclinical carriers underperformed non-carriers on Constructional Praxis Recall.Fewer YoS emerges as a confounding variable when detecting cognitive failures.Younger participants in both groups overperformed the older ones in the Memory tasks.Randomized data simulation increases statistical power when analyzing rare diseases.

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Background: The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer's disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature. Objective: This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population. Methods: We reviewed and integrated the published research, analyzing studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning. Results: Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized. Conclusions: The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD.

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Localized cystic kidney disease (LCKD) is a distinct renal disorder characterized by the presence of cysts within specific regions of the kidneys. We present a rare case of a 41-year-old African American man, who presented to our medical center with lower urinary tract symptoms and gross hematuria. The initial assessment culminated in the identification of an uncomplicated urinary tract infection, prompting the prescription of appropriate oral antibiotic therapy. On follow-up after 5 months, the patient presented with gross hematuria. Imaging studies revealed a mixed-density cystic lesion of 2.6 cm situated within the interpolar region of the right kidney. This cystic lesion exhibited intricate septations at the superior pole of the kidney. Robotic-assisted right partial nephrectomy was performed, and pathologic examination was diagnostic for LCKD. This report not only underscores the uniqueness of LCKD but also presents a comprehensive review of the existing literature that pertains to this condition. Particular emphasis is placed upon its inherent benign behavior and its marked divergence from the progressive trajectory commonly associated with other renal diseases. We also explored the incidental findings of the disease, its diverse clinical symptomatology, conceivable etiological underpinnings, and the array of diagnostic modalities used. Finally, similarities in histopathologic findings with polycystic kidney disease and other entities are discussed, underscoring the importance of accurate diagnosis and management.

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INTRODUCTION: This study investigates primary lateral sclerosis (PLS) as a rare manifestation of the presenilin 1 (PSEN1) NM_000021 c.851C > T p.Pro284Leu variant in three siblings of a Colombian family, outlining its clinical and neuropathological features and their relationship to Alzheimer's disease (AD). METHODS: Data were gathered using clinical evaluations, next-generation genetic sequencing, magnetic resonance imaging, biomarker analysis, and neuropathological examination. RESULTS: Carriers of the PSEN1 Pro284Leu variant exhibited classic PLS symptoms, including unilateral onset and bulbar syndromes, along with cognitive decline. Neuropathology showed corticospinal tract degeneration without amyloid beta deposition in spinal white matter. DISCUSSION: Our findings suggest an overlap between PLS and AD pathology in PSEN1 variant carriers. Results support considering PLS when diagnosing AD-related motor syndromes and including PSEN1 evaluation when performing genetic testing for PLS. The study highlights the need for further research to clarify the PLS-AD relationship, informing future treatments and clinical trials. HIGHLIGHTS: Pathogenic variants in presenilin 1 (PSEN1) can manifest as hereditary primary lateral sclerosis PSEN1 Pro284Leu carriers present motor, cognitive, and behavioral alterations  Cases had corticospinal tract microgliosis and severe Aß pathology in motor cortex  There was no evidence of amyloid deposition in the spinal cord white matter  All the neuropathology images are available for online visualization  Myelin pallor in the spinal cord is confined to the lateral corticospinal tracts.

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INTRODUCTION: Hereditary angioedema (HAE) is a rare genetic disease characterized by submucosal and subcutaneous edema with high morbidity and possibility of mortality. This study presents the sociodemographic characteristics of a large Brazilian family with HAE. METHODS: Descriptive cross-sectional study with patients from two family branches coming from the same city and HAE diagnosis was carried out. Clinical, laboratory, and treatment data of patients have been collected. Genetic testing was performed on some individuals. Correlation tests and comparisons between variables were applied using IBM SPSS Statistics® 2.0 program. RESULTS: We provide a detailed characterization of two families affected by HAE due to C1-INH deficiency, residing in a small town in southern Brazil. These families harbor an identified mutation in the SERPING1 gene (c.1104del, p.Asp369ThrfsTer2). The mean age at HAE diagnosis was 16.7 (±14.0) years, with the mean onset of symptoms at 6.0 (±6.1) years of age. A correlation was observed between patients' current age and age at HAE diagnosis, with older patients being diagnosed later than younger individuals (p < 0.0001). On average, there were 16.8 emergency visits in the past year (±24.8), and 53.5% of patients reported at least one lifetime hospitalization. Notably, treatment modalities often diverged from consensus recommendations regarding optimal prophylaxis and management of HAE attacks. CONCLUSIONS: This study describes one of the largest known families with HAE in Brazil and highlights the significant impact of unfavorable social conditions on disease control.

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Las enfermedades quísticas renales son condiciones frecuentes cuya etiología puede ser muy heterogénea, por lo que se requiere un adecuado abordaje para su diagnóstico y manejo. El objetivo de este trabajo fue ilustrar parte del espectro de la enfermedad renal quística por medio de casos clínicos manejados en la Fundación Valle del Lili. Se describen 11 casos clínicos que incluyen enfermedades como displasia multiquística renal, enfermedad poliquística renal autosómica dominante y autosómica recesiva, entre otras. Las enfermedades quísticas renales varían en su presentación clínica, historia natural, hallazgos imagenológicos, bases genéticas y fisiopatológicas, por consiguiente, el enfoque diagnóstico y el manejo integral se debe realizar de forma individualizada y con un abordaje multidisciplinario.

Renal cystic diseases are common conditions whose etiology can be highly heterogeneous. They require a correct approach for adequate diagnosis and management. We aimed to illustrate part of the spectrum of renal cystic diseases through some clinical cases managed in our service. We describe 11 clinical cases including clinical entities such as renal multicystic dysplasia, and autosomal dominant and autosomal recessive polycystic renal disease, among other pathologies. Renal cystic diseases are heterogeneous in their clinical presentation, natural history, radiological findings, and genetic and pathophysiological basis. An integral clinical approach is needed to get a clear etiological diagnosis and offer adequate individualized care and follow-up for patients.

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ABSTRACT Localized cystic kidney disease (LCKD) is a distinct renal disorder characterized by the presence of cysts within specific regions of the kidneys. We present a rare case of a 41-year-old African American man, who presented to our medical center with lower urinary tract symptoms and gross hematuria. The initial assessment culminated in the identification of an uncomplicated urinary tract infection, prompting the prescription of appropriate oral antibiotic therapy. On follow-up after 5 months, the patient presented with gross hematuria. Imaging studies revealed a mixed-density cystic lesion of 2.6 cm situated within the interpolar region of the right kidney. This cystic lesion exhibited intricate septations at the superior pole of the kidney. Robotic-assisted right partial nephrectomy was performed, and pathologic examination was diagnostic for LCKD. This report not only underscores the uniqueness of LCKD but also presents a comprehensive review of the existing literature that pertains to this condition. Particular emphasis is placed upon its inherent benign behavior and its marked divergence from the progressive trajectory commonly associated with other renal diseases. We also explored the incidental findings of the disease, its diverse clinical symptomatology, conceivable etiological underpinnings, and the array of diagnostic modalities used. Finally, similarities in histopathologic findings with polycystic kidney disease and other entities are discussed, underscoring the importance of accurate diagnosis and management.

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Introduction: Inosine monophosphate dehydrogenase 1 (IMPDH1) is a critical enzyme in the retina, essential for the correct functioning of photoreceptor cells. Mutations in IMPDH1 have been linked to autosomal dominant retinitis pigmentosa subtype 10 (adRP-10), a genetic eye disorder. Some of these mutations such as the Asp226Asn (D226N) lead to the assembly of large filamentous structures termed cytoophidia. D226N also gives IMPDH1 resistance to feedback inhibition by GDP/GTP. This study aims to emulate the adRP-10 condition with a long-term expression of IMPDH1-D226N in vitro and explore cytoophidium assembly and cell survival. We also assessed whether the introduction of an additional mutation (Y12C) to disrupt the cytoophidium has an attenuating effect on the toxicity caused by the D226N mutation. Results: Expression of IMPDH1-D226N in HEp-2 cells resulted in cytoophidium assembly in ∼70% of the cells, but the presence of the Y12C mutation disrupted the filaments. Long-term cell survival was significantly affected by the presence of the D226N mutation, with a decrease of ∼40% in the cells expressing IMPDH1-D226N when compared to IMPDH1-WT; however, survival was significantly recovered in IMPDH1-Y12C/D226N, with only a ∼10% decrease when compared to IMPDH1-WT. On the other hand, the IMPDH1 expression level in the D226N-positive cells was <30% of that of the IMPDH1-WT-positive cells and only slightly higher in the Y12C/D226N, suggesting that although cell survival in Y12C/D226N was recovered, higher expression levels of the mutated IMPDH1 were not tolerated by the cells in the long term. Conclusion: The IMPDH1-D226N effect on photoreceptor cell survival may be the result of a sum of problems: nucleotide unbalance plus a toxic long-life cytoophidium, supported by the observation that by introducing Y12C in IMPDH1 the cytoophidium was disrupted and cell survival significantly recovered, but not the sensibility to GDP/GTP regulation since higher expression levels of IMPDH1-D226N were not tolerated.

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INTRODUCTION: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD. METHODS: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.61 years later in non-demented age- and education-matched presenilin-1 E280A carriers (n = 24) and non-carrier (n = 20) family members. RESULTS: Carriers had higher plasma p-tau217 levels than non-carriers. Baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function. DISCUSSION: Our findings suggest that plasma p-tau217 predicts subsequent brain pathological burden and memory performance in presenilin-1 E280A carriers. These results provide support for plasma p-tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials. HIGHLIGHTS: Non-demented presenilin-1 E280A carriers have higher plasma tau phosphorylated at threonine 217 (p-tau217) than do age-matched non-carriers. Higher baseline p-tau217 is associated with greater future amyloid positron emission tomography (PET) pathology burden. Higher baseline p-tau217 is associated with greater future tau PET pathology burden. Higher baseline p-tau217 is associated with worse future memory performance.

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ABSTRACT Polycystic liver disease, a hereditary pathology, usually manifests as autosomal dominant polycystic kidney disease. The many cysts in the liver cause massive hepatomegaly, majorly affecting the patient's quality of life. In cases of refractory symptoms, liver transplantation is the only treatment choice. A 43-year-old woman was followed up as a hepatology outpatient in August 2020, with a progressive increase in abdominal volume, lower limb edema, and cachexia. The patient was diagnosed with polycystic renal and liver disease with massive hepatomegaly in March 2021, a combined kidney-liver transplant. Liver size represented 13% of the patient's corporal composition, weighing 8.6kg. The patient was discharged on the 7th postoperative day with no complications. Only 10-20% of patients with polycystic liver disease have clinical manifestations, most of which result from hepatomegaly. An increase in liver volume deteriorates liver function until the condition becomes end-stage liver disease, as kidney function is already compromised; liver-kidney transplantation remains the only treatment choice. The case described drew significant attention to the massive hepatomegaly presented in the patient, with the liver representing over 10% of the patient's body weight, approximately five to six times larger than a normal-sized liver.

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BACKGROUND: The enrollment into clinical trials of persons at risk for autosomal dominant Alzheimer's disease (ADAD) in whom the onset of disease can be accurately predicted facilitates the interpretation of outcomes (e.g., biomarkers, treatment efficacy). Attitudes toward involvement in such studies are biased by intrinsic cultural and social characteristics. Our objective was to study how demographic factors such as country of residence, age, sex, schooling, parenthood, and urbanization affect attitudes towards participation in hypothetical clinical trials in Mexican families at risk for ADAD living either in Mexico or in the United States. METHODS: Participants were 74 members of different families known to harbor an ADAD mutation living in Mexico (n = 50) or in the United States (n = 24). Participants were asked, in a written questionnaire, their interest in participating in four hypothetical clinical trial scenarios of increasing perceived invasiveness. The questionnaire then asked about their willingness should there be a 50% chance of being assigned to a placebo group. The influences of demographic variables on decisions were performed using Wilcoxon rank-sum for continuous variables and Fisher's exact test for categorical variables. RESULTS: Participants who live in Mexico, who have or plan to have children, who do not attend or do not plan to attend school, and who live in rural areas gave more positive responses regarding their willingness to participate compared to those living in the U.S. The 50% chance of being in a placebo group increased the willingness to participate for family members living in Mexico. The main reason for participation was to help future generations, while the main reasons for refusal were not wanting to undergo genetic testing and consideration of adverse effects. CONCLUSIONS: We found a higher level of willingness to participate in clinical trials among persons living in rural Mexico and our data suggest that altruism towards future generations is a major motivation, though this was balanced against concerns regarding side effects. Our results emphasize the importance of sharing information and assessing its understanding in potential participants with diverse backgrounds in the nature of ADAD and regarding the design of clinical trials prior to their enrollment in such studies.

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Resumen: La poliquistosis renal autosómica dominante es la enfermedad renal hereditaria más frecuente. Se caracteriza por la progresiva aparición de quistes renales que suelen conducir a la enfermedad renal crónica extrema en la edad adulta. La aprobación del uso de tolvaptán (antagonista del receptor V2 de la vasopresina) ha marcado un cambio significativo en el tratamiento de esta enfermedad. En los últimos años apareció evidencia que demuestra el beneficio en iniciar tratamiento con tolvaptán en pacientes que presentan una enfermedad con rápida evolución. Se realiza una revisión descriptiva de los principales estudios clínicos publicados en el periodo 2012-2022 y se sugiere un esquema de utilidad para seleccionar aquellos pacientes que pueden beneficiarse del inicio de tratamiento.

Abstract: Autosomal dominant polycystic kidney disease is the most common hereditary kidney disease. It is characterized by the progressive appearance of renal cysts that usually lead to extreme chronic kidney disease in adulthood. The approval of the use of tolvaptán (V2 vasopressin receptor antagonist) has meant a significant change in the treatment of this disease. In recent years, evidence has proved the benefits of initiating treatment with tolvaptán in patients with a rapidly evolving disease. A descriptive review of the main clinical studies published in 2012-2022 period is carried out and a useful scheme is suggested to select those patients who can benefit from the start of treatment.

Resumo: A doença renal policística autossômica dominante é a doença renal hereditária mais comum. Caracteriza-se pelo aparecimento progressivo de cistos renais que geralmente levam à doença renal crônica extrema na idade adulta. A aprovação do uso do tolvaptano (antagonista do receptor de vasopressina V2) marcou uma mudança significativa no tratamento dessa doença. Nos últimos anos, surgiram evidências que demonstram o benefício de iniciar o tratamento com tolvaptano em pacientes com doença de evolução rápida. Faz-se uma revisão descritiva dos principais estudos clínicos publicados no período 2012-2022 e sugere-se um esquema útil para selecionar aqueles pacientes que podem se beneficiar do início do tratamento.

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Introduction: Although the diurnal fluctuation of motor dysfunction, reversible with small doses of dopamine, is a cornerstone for the phenotype of the autosomal dominant Segawa syndrome, the non-motor symptoms of this neurotransmitter deficiency have still received limited attention. Objective: This study aims to evaluate non-motor symptoms of this dopa-responsive dystonia through an intrafamilial comparative cross-sectional study. Methods: Seventeen individuals with a c.IVS5 + 3insT (c.626 + 3insT) variation in the GTP cyclohydrolase-1 gene (GCH1, HGNC: 4193) and 34 intrafamilial controls were studied using the Beck Depression Inventory-II, the Wiener Matrizen Test 2, the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the MINI/MINI PLUS Questionnaires, the World Health Organization Quality of Life - BREF Instrument and a drug use assessment questionnaire. Results: No significant difference was found between the groups in the prevalence of sleep disorders and in cognitive function. Nevertheless, generalized anxiety disorder (p = 0.050) and attention-deficit/hyperactivity disorder in childhood (p = 0.011) were observed only in individuals without the molecular variation. The group with the GCH1 variation presented a worse perception about how safe they feel in their daily lives (p = 0.034), less satisfaction with themselves (p = 0.049) and with their relationships (p = 0.029), and a higher prevalence of past major depressive episodes before use of L-Dopa (p = 0.046). Conclusion: Low dopamine could have been protective against generalized anxiety disorder and attention-deficit/hyperactivity disorder in childhood in Segawa group individuals. The prevalence of depression was higher in individuals with the molecular variant prior to the L-Dopa treatment. Considering it, the penetrance estimates for the variant carriers increased from 58.8% to up to 88% in this large studied family. Additionally, neuropsychiatric tests of all individuals with a molecular diagnosis in an affected family are a valuable instrument for its clinical management.

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Abstract Introduction: Endothelial nitric oxide synthase (eNOS) genes have been implicated in renal hemodynamics as potent regulators of vascular tone and blood pressure. It has been linked to a reduction in plasma nitric oxide levels. Several studies have recently been conducted to investigate the role of NOS3 gene polymorphisms and end-stage renal disease (ESRD). However, the results are still unclear and the mechanisms are not fully defined. As a result, we conducted a meta-analysis to examine the relationship between NOS3 gene polymorphism and ESRD in autosomal polycystic kidney disease (ADPKD) patients. Methods: To assess the relationship between NOS3 gene polymorphism and ESRD, relevant studies published between September 2002 and December 2020 were retrieved from the PubMed (Medline), EMBASE, Google Scholar, and Web of Science databases. The pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated using a fixed-effect model. To assess the heterogeneity of studies, we used Cochrane's Q test and the Higgins and Thompson I2 statistics. Results: Our meta-analysis of 13 studies showed that the presence of the two NOS3 gene polymorphisms significantly increased ESRD risk in ADPKD patients with 4a/b gene polymorphism (aa+ab vs. bb: OR=1.95, 95% CI=1.24-3.09, p=0.004). In addition, no significant association was found between the NOS3 894G>T (Glu298Asp) polymorphism and the risk of ESRD in ADPKD patients (GT+TT vs. GG: OR=1.21, 95% CI=0.93-1.58, p=0.157). There was no evidence of publication bias. Conclusions: The findings of the current meta-analysis suggest that NOS3 intron 4a/b polymorphism plays a vital role in the increasing risk of ESRD in ADPKD patients.

Resumo Introdução: Genes da óxido nítrico sintase endotelial (eNOS) têm sido implicados na hemodinâmica renal como potentes reguladores do tônus vascular e pressão arterial. Tem sido vinculado a uma redução nos níveis plasmáticos de óxido nítrico. Realizou-se recentemente vários estudos para investigar o papel de polimorfismos do gene NOS3 e doença renal em estágio terminal (DRET). Entretanto, os resultados ainda não são claros e os mecanismos não estão totalmente definidos. Como resultado, realizamos meta-análise para examinar a relação entre polimorfismo do gene NOS3 e DRET em pacientes com doença renal policística autossômica dominante (DRPAD). Métodos: Para avaliar a relação entre polimorfismo do gene NOS3 e DRET, recuperou-se estudos relevantes publicados entre Setembro-2002 e Dezembro-2020 dos bancos de dados PubMed (Medline), EMBASE, Google Scholar, Web of Science. Calculamos odds ratio (OR) e intervalo de confiança (IC) de 95% utilizando modelo de efeitos fixos. Para avaliar a heterogeneidade dos estudos, utilizamos teste Q de Cochrane e estatísticas I2 de Higgins e Thompson. Resultados: Nossa meta-análise de 13 estudos mostrou que a presença dos dois polimorfismos do gene NOS3 aumentou significativamente o risco de DRET em pacientes com DRPAD com polimorfismo do gene 4a/b (aa+ab vs. bb: OR=1,95; IC 95%=1,24-3,09; p=0,004). Ademais, não encontramos associação significativa entre polimorfismo 894G>T NOS3 (Glu298Asp) e risco de DRET em pacientes com DRPAD (GT+TT vs. GG: OR=1,21; IC 95%=0,93-1,58; p=0,157). Não houve evidência de viés de publicação. Conclusões: Achados da meta-análise atual sugerem que o polimorfismo intron 4a/b do NOS3 desempenha papel vital no aumento do risco de DRET em pacientes com DRPAD.

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Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant disorder with febrile or afebrile seizures that exhibits phenotypic variability. Only a few variants in SCN1A have been previously characterized for GEFS+, in Latin American populations where studies on the genetic and phenotypic spectrum of GEFS+ are scarce. We evaluated members in two multi-generational Colombian Paisa families whose affected members present with classic GEFS+. Exome and Sanger sequencing were used to detect the causal variants in these families. In each of these families, we identified variants in SCN1A causing GEFS+ with incomplete penetrance. In Family 047, we identified a heterozygous variant (c.3530C > G; p.(Pro1177Arg)) that segregates with GEFS+ in 15 affected individuals. In Family 167, we identified a previously unreported variant (c.725A > G; p.(Gln242Arg)) that segregates with the disease in a family with four affected members. Both variants are located in a cytoplasmic loop region in SCN1A and based on our findings the variants are classified as pathogenic and likely pathogenic, respectively. Our results expand the genotypic and phenotypic spectrum associated with SCN1A variants and will aid in improving molecular diagnostics and counseling in Latin American and other populations.

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INTRODUCTION: Females may have greater susceptibility to Alzheimer's disease (AD)-pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively-unimpaired Presenilin-1 (PSEN1) E280A mutation carriers and non-carriers. METHODS: We analyzed baseline data from 167 mutation carriers and 75 non-carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir- and fludeoxyglucose-PET, MRI based hippocampal volume and cognitive testing. RESULTS: Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory. DISCUSSION: Our findings suggest that, among cognitively-unimpaired individuals at genetic risk for autosomal-dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex-specific differences in autosomal-dominant AD is key to elucidating mechanisms of AD risk and resilience.

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Cardiovascular manifestations account for marked morbi-mortality in autosomal dominant polycystic kidney disease (ADPKD). Pkd1- and Pkd2-deficient mice develop cardiac dysfunction, however the underlying mechanisms remain largely unclear. It is unknown whether impairment of polycystin-1 cleavage at the G-protein-coupled receptor proteolysis site, a significant ADPKD mutational mechanism, is involved in this process. We analyzed the impact of polycystin-1 cleavage on heart metabolism using Pkd1V/V mice, a model unable to cleave this protein and with early cardiac dysfunction. Pkd1V/V hearts showed lower levels of glucose and amino acids and higher lipid levels than wild-types, as well as downregulation of p-AMPK, p-ACCß, CPT1B-Cpt1b, Ppara, Nppa and Acta1. These findings suggested decreased fatty acid ß-oxidation, which was confirmed by lower oxygen consumption by Pkd1V/V isolated mitochondria using palmitoyl-CoA. Pkd1V/V hearts also presented increased oxygen consumption in response to glucose, suggesting that alternative substrates may be used to generate energy. Pkd1V/V hearts displayed a higher density of decreased-size mitochondria, a finding associated with lower MFN1, Parkin and BNIP3 expression. These derangements were correlated with increased apoptosis and inflammation but not hypertrophy. Notably, Pkd1V/V neonate cardiomyocytes also displayed shifts in oxygen consumption and p-AMPK downregulation, suggesting that, at least partially, the metabolic alterations are not induced by kidney dysfunction. Our findings reveal that disruption of polycystin-1 cleavage leads to cardiac metabolic rewiring in mice, expanding the understanding of heart dysfunction associated with Pkd1 deficiency and likely with human ADPKD.

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