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3.
J Headache Pain ; 22(1): 89, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380431

RESUMO

BACKGROUND: Considering the involvement of genetics in migraine pathogenesis in diverse ethnic populations, genome-wide association studies (GWAS) are being conducted to identify migraine-susceptibility genes. However, limited surveys have focused on the onset age of migraine (AoM) in Asians. Therefore, in this study, we aimed to identify the susceptibility loci of migraine considering the AoM in an Asian population. METHODS: We conducted a GWAS in 715 patients with migraine of Han Chinese ethnicity, residing in Taiwan, to identify the susceptibility genes associated with AoM. Based on our standard demographic questionnaire, the population was grouped into different subsets. Single-nucleotide polymorphism (SNP) associations were examined using PLINK in different AoM onset groups. RESULTS: We discovered eight novel susceptibility loci correlated with AoM that reached the GWAS significance level in the Han Chinese population. First, rs146094041 in ESRRG was associated with AoM [Formula: see text] 12 years. The other SNPs including rs77630941 in CUX1, rs146778855 in CDH18, rs117608715 in NOL3, rs150592309 in PRAP1, and rs181024055 in NRAP were associated with the later AoM. CONCLUSIONS: To our knowledge, this is the first GWAS to investigate the AoM in an Asian Han Chinese population. Our newly discovered susceptibility genes may have prospective associations with migraine pathogenesis.


Assuntos
Estudo de Associação Genômica Ampla , Transtornos de Enxaqueca , Idade de Início , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Predisposição Genética para Doença , Genótipo , Humanos , Transtornos de Enxaqueca/genética , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Taiwan
5.
Zhonghua Yi Xue Za Zhi ; 101(31): 2433-2437, 2021 Aug 17.
Artigo em Chinês | MEDLINE | ID: mdl-34399555

RESUMO

Objective: To determine the correlation between the titer of anti-muscle-specific tyrosine kinase (anti-MuSK) antibodies (Abs) and the severity and prognosis of Musk-associated myasthenia gravis (Musk-MG). Methods: A total of 33 MuSK-MG patients diagnosed at Department of Neurology, Peking Union Medical College Hospital from May 2018 to June 2020 were prospectively included. Patients were divided into different groups according to immune state, and the immune naive patients were further divided by the Myasthenia Gravis Foundation of America (MGFA) classification. There were 28 Musk-MG patients who completed the follow-up and subdivided into different groups according to post-intervention status (PIS). Twenty-five patients who received immunotherapy were divided into corticosteroid monotherapy group (n=17) and corticosteroid combined with immunosuppressant group (n=8). The comparison of Ab titers between different MGFA groups and PIS groups was determined by Kruskal-Wallis method, and the comparison of Ab titers between different time points was analyzed by Mann-Whitney U method. Results: There were 11 males and 22 females included in the study, with an onset age of 48 (18, 73) years, of which 16 cases were immune naive and 17 cases were treated with corticosteroids or immunosuppressant at least once. In immune naive population, a significant difference of Ab titers among different MGFA phenotypes was detected (P=0.04). Ab titers were reduced by immunosuppression therapy (the median value decreased from 1.20 to 0.87, P=0.01). Twenty-four (85.7%) MuSK-MG patients achieved a good prognosis (PIS-PR/MM), 1 (3.6%) case achieved improvement (PIS-I), and 3 (10.7%) patients' condition worsened (PIS-W), there was no significant difference of Ab titers among the three groups (P=0.21). Meanwhile, there was no significant difference of Ab titers between different treatment groups (P=0.95). Conclusions: In the immune naive state, the concentration of MuSK-Ab is consistent with the severity of the disease, and the Ab titers decrease after immunotherapy. Change of Ab titers is related to the daily dosage of corticosteroid and is not consistent with PIS grades.


Assuntos
Autoanticorpos , Miastenia Gravis , Idade de Início , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
Arterioscler Thromb Vasc Biol ; 41(9): 2494-2508, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34233476

RESUMO

Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population. Approach and Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.


Assuntos
HDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Hiperlipoproteinemia Tipo II/genética , Proteínas de Transporte de Nucleotídeos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idade de Início , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Fatores de Risco de Doenças Cardíacas , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , Análise da Randomização Mendeliana , México/epidemiologia , Camundongos , Pessoa de Meia-Idade , Proteínas de Transporte de Nucleotídeos/metabolismo , Fenótipo , Medição de Risco
7.
Cancer Epidemiol ; 73: 101973, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34198235

RESUMO

INTRODUCTION: Family history is a risk factor for colorectal cancer (CRC), however whether family history also contributes to non-syndromic early-onset CRC is unknown. METHODS: We estimated risk to first-, second-, and third-degree relatives of early-onset CRC cases in the Utah Pedigree Database. RESULTS: We observed elevated risks beyond RR = 2.0 for early-onset CRC among first- and second-degree relatives of early-onset CRC cases, with RRs of 6.0 and 3.1, respectively. DISCUSSION: Relatives of early-onset CRC cases are at higher risk of both early-onset CRC and CRC at any age, and the location is not necessarily similar to the affected relative.


Assuntos
Neoplasias Colorretais , Família , Predisposição Genética para Doença , Idade de Início , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Humanos , Anamnese , Linhagem , Fatores de Risco
8.
Lancet Diabetes Endocrinol ; 9(9): 575-585, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34303414

RESUMO

BACKGROUND: Cardiovascular disease is the main determinant of premature mortality in patients with type 1 diabetes. However, time trends regarding different types of cardiovascular disease in childhood-onset type 1 diabetes with a long timespan from the diagnosis of diabetes are not well established. This study aimed to investigate the cumulative incidence of cardiovascular disease in individuals with type 1 diabetes in a population-based cohort in Finland, the country with the world's highest incidence of type 1 diabetes. METHODS: In this retrospective, nationwide registry-based, cohort study, all patients who were diagnosed between Jan 1, 1965, and Dec 31, 1999 with type 1 diabetes when they were younger than 15 years old in Finland were followed up and monitored for the occurrence of cardiovascular disease (including coronary artery disease, stroke, peripheral artery disease, and heart failure) until the end of 2016 and for cardiovascular disease mortality until 2017. Cumulative incidences of cardiovascular disease were calculated by the Fine and Gray method according to the year of diabetes diagnosis using six diagnosis cohorts: 1965-69, 1970-74, 1975-1979, 1980-84, 1985-89, 1990-94, and 1990-95. Trends in cardiovascular disease event rates were analysed by Fine and Gray competing risks regression models using year of diabetes diagnosis as continuous variable. In addition, non-linearity in trends was assessed with restricted cubic splines. The excess risk of coronary artery disease and stroke was estimated by comparison with the risk in the Finnish general population by calculating standardised incidence ratios (SIRs) and their time trends. The data for Finnish general population were drawn from the Cardiovascular Disease Register of the National Institute of Health and Welfare. The SIRs were calculated as ratios of observed and expected number of events in individuals with type 1 diabetes during 1991-2014. FINDINGS: 11 766 individuals were included in this study. During 361 033 person-years of follow-up and a median of 29·6 years (IQR 22·3-37·9) follow-up, a total of 1761 individuals had single or multiple types of cardiovascular disease events. 2686 events (864 [32·2%] coronary artery disease events, of which 663 were acute myocardial infarctions; 497 [18·5%] strokes; 854 [31·8%] peripheral artery diseases, of which 498 were lower extremity amputations; and 471 [17·5%] heart failure events) were reported until Dec 31, 2016, and 1467 deaths until Dec 31, 2017. Cardiovascular disease risk decreased linearly by 3·8% (hazard ratio [HR] 0·96 [95% CI 0·96-0·97]; p<0·0001) by later calendar year of diabetes diagnosis (p<0·0001). There was a decrease in the SIRs for both coronary artery disease and stroke within all 10-year age groups under 65 years, except for stroke in the oldest age group. However, the SIR was still 8·9 (95% CI 3·9-17·5) for coronary artery disease and 2·9 (1·3-5·7) for stroke in those diagnosed with type 1 diabetes in the 1990s. Finally, the cardiovascular disease death rate decreased constantly by diagnosis year. INTERPRETATION: The risk of cardiovascular disease has decreased over time in Finland in individuals with childhood-onset type 1 diabetes. However, there is still considerable excess cardiovascular disease risk in individuals with type 1 diabetes compared with the general population. These results highlight the need for studies on the mechanisms of atherosclerosis from the time of diagnosis of type 1 diabetes to facilitate early and effective prevention of cardiovascular disease in these individuals. FUNDING: Folkhälsan Research Foundation, Academy of Finland, Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation, Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation, and Helsinki University Hospital Research Funds.


Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Idade de Início , Feminino , Finlândia/epidemiologia , Humanos , Incidência , Masculino , Estudos Retrospectivos , Fatores de Risco
9.
J Stroke Cerebrovasc Dis ; 30(9): 105997, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34303089

RESUMO

OBJECTIVES: To identify the underlying genetic defect for a consanguineous family with an unusually high number of members affected by cerebral small vessel disease. MATERIALS AND METHODS: A total of 6 individuals, of whom 3 are severely affected, from the family were clinically and radiologically evaluated. SNP genotyping was performed in multiple members to demonstrate genome-wide runs-of-homozygosity. Coding variants in the most likely candidate gene, HTRA1 were explored by Sanger sequencing. Published HTRA1-related phenotypes were extensively reviewed to explore the effect of number of affected alleles on phenotypic expression. RESULTS: Genome-wide homozygosity mapping identified a 3.2 Mbp stretch on chromosome 10q26.3 where HTRA1 gene is located. HTRA1 sequencing revealed an evolutionarily conserved novel homozygous c.824C>T (p.Pro275Leu) mutation, affecting the serine protease domain of HtrA1. Early-onset of cognitive and motor deterioration in homozygotes are in consensus with CARASIL. However, there was a clear phenotypic variability between homozygotes which includes alopecia, a suggested hallmark of CARASIL. All heterozygotes, presenting as CADASIL type 2, had spinal disk degeneration and several neuroimaging findings, including leukoencephalopathy and microhemorrhage despite a lack of severe clinical presentation. CONCLUSION: Here, we clearly demonstrate that CARASIL and CADASIL type 2 are two clinical consequences of the same disorder with different severities thorough the evaluation of the largest collection of homozygotes and heterozygotes segregating in a family. Considering the semi-dominant inheritance of HTRA1-related phenotypes, genetic testing and clinical follow-up must be offered for all members of a family with HTRA1 mutations regardless of symptoms.


Assuntos
Alopecia/genética , CADASIL/genética , Infarto Cerebral/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Mutação , Doenças da Coluna Vertebral/genética , Adulto , Idade de Início , Alopecia/diagnóstico , Alopecia/fisiopatologia , CADASIL/diagnóstico , CADASIL/fisiopatologia , Infarto Cerebral/diagnóstico , Infarto Cerebral/fisiopatologia , Consanguinidade , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Índice de Gravidade de Doença , Doenças da Coluna Vertebral/diagnóstico , Doenças da Coluna Vertebral/fisiopatologia
10.
Eur J Endocrinol ; 185(4): 441-451, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34288885

RESUMO

Objective,: To investigate the genetic characteristics of idiopathic central precocious puberty (ICPP) and validate its polygenic risk for early puberty. Design and methods: A bootstrap subsampling and genome-wide association study were performed on Taiwanese Han Chinese girls comprising 321 ICPP patients and 148 controls. Using previous GWAS data on pubertal timing, a replication study was performed. A validation group was also investigated for the weighted polygenic risk score (wPRS) of the risk of early puberty. Results: A total of 105 SNPs for the risk of ICPP were identified, of which 22 yielded an area under the receiver operating characteristic curve of 0.713 for the risk of early puberty in the validation group. A replication study showed that 33 SNPs from previous GWAS data of pubertal timing were associated with the risk of ICPP (training group: P-value < 0.05). In the validation group, a cumulative effect was observed between the wPRS and the risk of early puberty in a dose-dependent manner (validation group: Cochran-Armitage trend test: P-value < 1.00E-04; wPRS quartile 2 (Q2) (odds ratio (OR) = 5.00, 95% CI: 1.55-16.16), and wPRS Q3 (OR = 11.67, 95% CI: 2.44-55.83)). Conclusions: This study reveals the ICPP genetic characteristics with 22 independent and 33 reported SNPs in the Han Chinese population from Taiwan. This study may contribute to understand the genetic features and underlying biological pathways that control pubertal timing and pathogenesis of ICPP and also to the identification of individuals with a potential genetic risk of early puberty.


Assuntos
Herança Multifatorial , Puberdade Precoce/genética , Idade de Início , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene , Heterogeneidade Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Puberdade/genética , Puberdade Precoce/epidemiologia , Fatores de Risco , Taiwan/epidemiologia
11.
Eur J Endocrinol ; 185(4): 463-474, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34291731

RESUMO

Objective: Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management. Methods: A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center. Results: Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4-156)). Conclusion: Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.


Assuntos
Neoplasias das Glândulas Suprarrenais , Ganglioneuroma , Adolescente , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/terapia , Adulto , Idade de Início , Idoso , Bélgica/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Redes Comunitárias , Feminino , Seguimentos , França/epidemiologia , Ganglioneuroma/diagnóstico , Ganglioneuroma/epidemiologia , Ganglioneuroma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
12.
Eur J Endocrinol ; 185(4): 485-496, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34313605

RESUMO

Objective: Pituitary adenomas (PA) are rare in young patients, and additional studies are needed to fully understand their pathogenesis in this population. We describe the clinical and genetic characteristics of apparently sporadic PA in a cohort of young patients. Design: Clinical and molecular analysis of 235 patients (age ≤ 30 years) with PA. Clinicians from several Spanish and Chilean hospitals provided data. Methods: Genetic screening was performed via next-generation sequencing and comparative genomic hybridization array. Clinical variables were compared among paediatric, adolescent (<19 years) and young adults' (≥19-30 years) cohorts and types of adenomas. Phenotype-genotype associations were examined. Results: Among the total cohort, mean age was 17.3 years. Local mass effect symptoms were present in 22.0%, and prolactinomas were the most frequent (44.7%). Disease-causing germline variants were identified in 22 individuals (9.3%), more exactly in 13.1 and 4.7% of the populations aged between 0-19 and 19-30 years, respectively; genetically positive patients were younger at diagnosis and had larger tumour size. Healthy family carriers were also identified. Conclusions: Variants in genes associated with syndromic forms of PAs were detected in a large cohort of apparently sporadic pituitary tumours. We have identified novel variants in well-known genes and set the possibility of incomplete disease penetrance in carriers of MEN1 alterations or a limited clinical expression of the syndrome. Despite the low penetrance observed, screening of AIP and MEN1 variants in young patients and relatives is of clinical value.


Assuntos
Adenoma , Neoplasias Hipofisárias , Adenoma/diagnóstico , Adenoma/epidemiologia , Adenoma/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Chile/epidemiologia , Estudos de Coortes , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Lactente , Recém-Nascido , Perda de Heterozigosidade , Masculino , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/genética , Espanha/epidemiologia , Adulto Jovem
13.
Eur J Endocrinol ; 185(4): 597-606, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34324432

RESUMO

Objective: Childhood brain tumor survivors (CBTS) are at risk to develop hypothalamic-pituitary (HP) dysfunction (HPD). The risk for HPD may vary between different age groups due to maturation of the brain and differences in oncologic treatment protocols. Specific studies on HPD in infant brain tumor survivors (infant-BTS, 0-1 years at diagnosis) or toddler brain tumor survivors (toddler-BTS, ≥1-3 years) have not been performed. Patients and methods: A retrospective nationwide cohort study in CBTS was performed. Prevalence and risk factors for HPD were compared between infant-, toddler-, and older-BTS. Subgroup analysis was performed for all non-irradiated CBTS (n = 460). Results: In total, 718 CBTS were included, with a median follow-up time of 7.9 years. Overall, despite the less frequent use of radiotherapy (RT) in infants, no differences in the prevalence of HPD were found between the three groups. RT (OR: 16.44; 95% CI: 8.93-30.27), suprasellar tumor location (OR: 44.76; 95% CI: 19.00-105.49), and younger age (OR: 1.11; 95% CI: 1.05-1.18) were associated with HP dysfunction. Infant-BTS and toddler-BTS showed more weight gain (P < 0.0001) and smaller height SDS (P = 0.001) during follow-up. In non-irradiated CBTS, infant-BTS and toddler-BTS were significantly more frequently diagnosed with TSH-, ACTH-, and ADH deficiency, compared to older-BTS. Conclusion: Infant and toddler brain tumor survivors seem to be more vulnerable to develop HP dysfunction than older children. These results emphasize the importance of special infant and toddler brain tumor treatment protocols and the need for endocrine surveillance in children treated for a brain tumor at a young age.


Assuntos
Neoplasias Encefálicas/epidemiologia , Sobreviventes de Câncer/estatística & dados numéricos , Doenças Hipotalâmicas/epidemiologia , Adolescente , Adulto , Idade de Início , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/reabilitação , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Doenças Hipotalâmicas/etiologia , Lactente , Masculino , Países Baixos/epidemiologia , Doenças da Hipófise/epidemiologia , Doenças da Hipófise/etiologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
14.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299126

RESUMO

Friedreich's ataxia (FRDA) is a comparatively rare autosomal recessive neurological disorder primarily caused by the homozygous expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene. The repeat expansion causes gene silencing that results in deficiency of the frataxin protein leading to mitochondrial dysfunction, oxidative stress and cell death. The GAA repeat tract in some cases may be impure with sequence variations called interruptions. It has previously been observed that large interruptions of the GAA repeat tract, determined by abnormal MboII digestion, are very rare. Here we have used triplet repeat primed PCR (TP PCR) assays to identify small interruptions at the 5' and 3' ends of the GAA repeat tract through alterations in the electropherogram trace signal. We found that contrary to large interruptions, small interruptions are more common, with 3' interruptions being most frequent. Based on detection of interruptions by TP PCR assay, the patient cohort (n = 101) was stratified into four groups: 5' interruption, 3' interruption, both 5' and 3' interruptions or lacking interruption. Those patients with 3' interruptions were associated with shorter GAA1 repeat tracts and later ages at disease onset. The age at disease onset was modelled by a group-specific exponential decay model. Based on this modelling, a 3' interruption is predicted to delay disease onset by approximately 9 years relative to those lacking 5' and 3' interruptions. This highlights the key role of interruptions at the 3' end of the GAA repeat tract in modulating the disease phenotype and its impact on prognosis for the patient.


Assuntos
Ataxia de Friedreich/epidemiologia , Ataxia de Friedreich/genética , Fenótipo , Expansão das Repetições de Trinucleotídeos , Adolescente , Adulto , Fatores Etários , Idade de Início , Criança , Estudos de Coortes , Humanos , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Adulto Jovem
15.
Paediatr Drugs ; 23(4): 331-347, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34244988

RESUMO

Childhood-onset systemic lupus erythematosus (cSLE) is a prototype of a multisystemic, inflammatory, heterogeneous autoimmune condition. This disease is characterized by simultaneous or sequential organ and system involvement, with unpredictable flare and high levels of morbidity and mortality. Racial/ethnic background, socioeconomic status, cost of medications, difficulty accessing health care, and poor adherence seem to impact lupus outcomes and treatment response. In this article, the management of cSLE patients is updated. Regarding pathogenesis, a number of potential targets for drugs have been studied. However, most treatments in pediatric patients are off-label drugs with recommendations based on inadequately powered studies, therapeutic consensus guidelines, or case series. Management practices for cSLE patients include evaluations of disease activity and cumulative damage scores, routine non-live vaccinations, physical activity, and addressing mental health issues. Antimalarials and glucocorticoids are still the most common drugs used to treat cSLE, and hydroxychloroquine is recommended for nearly all cSLE patients. Disease-modifying antirheumatic drugs (DMARDs) should be standardized for each patient, based on disease flare and cSLE severity. Mycophenolate mofetil or intravenous cyclophosphamide is suggested as induction therapy for lupus nephritis classes III and IV. Calcineurin inhibitors (cyclosporine, tacrolimus, voclosporin) appear to be another good option for cSLE patients with lupus nephritis. Regarding B-cell-targeting biologic agents, rituximab may be used for refractory lupus nephritis patients in combination with another DMARD, and belimumab was recently approved by the US Food and Drug Administration for cSLE treatment in children aged > 5 years. New therapies targeting CD20, such as atacicept and telitacicept, seem to be promising drugs for SLE patients. Anti-interferon therapies (sifalimumab and anifrolumab) have shown beneficial results in phase II randomized control trials in adult SLE patients, as have some Janus kinase inhibitors, and these could be alternative treatments for pediatric patients with severe interferon-mediated inflammatory disease in the future. In addition, strict control of proteinuria and blood pressure is required in cSLE, especially with angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use.


Assuntos
Gerenciamento Clínico , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Idade de Início , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Criança , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Imunoterapia/métodos , Lúpus Eritematoso Sistêmico/imunologia , Ácido Micofenólico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207526

RESUMO

Mutations in the PSEN1 gene are the most common cause of autosomal dominant Alzheimer's disease, and are characterized by a high phenotype variability. This study describes a five-generation family, with a prevalent late-onset of the disease and a high frequency of depression, in which a new missense mutation (c.789T > G, p.Cys263Trp) in exon 8 of the PSEN1 gene was found. Only the proband presented an early onset at the age of 45 with attention deficit, followed by spatial disorientation, psychiatric symptoms and parkinsonian signs. The other two cases had a late onset of the disease and a typical presentation with memory loss. Both were characterized by a high level of anxiety and depression. The disease course was different with signs of Lewy body dementia for the proband's mother, and pyramidal involvement and a shorter disease duration for the proband's maternal aunt. The other eight cases with late-onset dementia and three cases with a long history of depression have been reported in the family pedigree, underlying the high phenotype variability of PSEN1 mutations.


Assuntos
Doença de Alzheimer/genética , Família , Mutação de Sentido Incorreto , Linhagem , Presenilina-1/genética , Idade de Início , Substituição de Aminoácidos , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade
17.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299237

RESUMO

Juvenile systemic lupus erythematosus (JSLE) is characterised by onset before 18 years of age and more severe disease phenotype, increased morbidity and mortality compared to adult-onset SLE. Management strategies in JSLE rely heavily on evidence derived from adult-onset SLE studies; therefore, identifying biomarkers associated with the disease pathogenesis and reflecting particularities of JSLE clinical phenotype holds promise for better patient management and improved outcomes. This narrative review summarises the evidence related to various traditional and novel biomarkers that have shown a promising role in identifying and predicting specific organ involvement in JSLE and appraises the evidence regarding their clinical utility, focusing in particular on renal biomarkers, while also emphasising the research into cardiovascular, haematological, neurological, skin and joint disease-related JSLE biomarkers, as well as genetic biomarkers with potential clinical applications.


Assuntos
Biomarcadores , Lúpus Eritematoso Sistêmico/patologia , Adolescente , Idade de Início , Autoanticorpos/imunologia , Biomarcadores/sangue , Biomarcadores/urina , Ceruloplasmina , Quimiocina CCL2 , Criança , Pré-Escolar , Feminino , Humanos , Oxirredutases Intramoleculares , Rim/patologia , Lipocalina-2 , Lipocalinas , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Orosomucoide , Fenótipo , Índice de Gravidade de Doença , Transferrina
18.
J Clin Neurosci ; 90: 161-164, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275543

RESUMO

Some patients with Parkinson's disease (PD) report hand tremors in their relatives. This study aimed to compare the clinical characteristics of early PD in patients with and without a family history of hand tremor. This study included 337 early and drug-naïve patients with PD. The family history of hand tremor was obtained from the patients and their caregivers. Motor and non-motor symptoms of PD were assessed using the appropriate scales. A family history of hand tremor was present in 27 of 337 patients with PD (8.0%). Patients with a family history of hand tremor had significantly higher scores for rest tremors than those without. No significant differences were found in action tremor, bradykinesia, rigidity, gait, or posture scores between the two groups. The proportion of tremor-dominant subtypes was higher in patients with a family history of hand tremor than in those without (51.8% vs. 28.7%). Patients with PD, with a family history of hand tremor, had significantly lower scores in the urinary and sexual subdomains of the Non-Motor Symptoms Scale for PD than in those without. A family history of hand tremor affects the motor and non-motor symptoms in patients with early PD. It is necessary to investigate the family history of hand tremor in patients with PD.


Assuntos
Doença de Parkinson , Tremor/epidemiologia , Idade de Início , Idoso , Feminino , Mãos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença
19.
Nutrients ; 13(6)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199265

RESUMO

The association between lifetime weight fluctuations and clinical characteristics has been widely studied in populations with eating disorders (ED). However, there is a lack of literature examining the potential role of weight course as a transdiagnostic factor in ED so far. Therefore, the aim of this study is to compare ED severity and treatment outcomes among four specific BMI profiles based on BMI-trajectories across the lifespan: (a) persistent obesity (OB-OB; (n = 74)), (b) obesity in the past but currently in a normal weight range (OB-NW; n = 156), (c) normal weight throughout the lifespan (NW-NW; n = 756), and (d) current obesity but previously at normal weight (NW-OB; n = 314). Lifetime obesity is associated with greater general psychopathology and personality traits such as low persistence and self-directedness, and high reward dependence. Additionally, greater extreme weight changes (NW-OB and OB-NW) were associated with higher psychopathology but not with greater ED severity. Higher dropout rates were found in the OB-OB group. These results shed new light on the BMI trajectory as a transdiagnostic feature playing a pivotal role in the severity and treatment outcome in patients with ED.


Assuntos
Índice de Massa Corporal , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Transtornos da Alimentação e da Ingestão de Alimentos/terapia , Obesidade , Adulto , Idade de Início , Terapia Cognitivo-Comportamental , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Feminino , Humanos , Comportamento Impulsivo , Masculino , Motivação , Fatores de Risco , Fatores Socioeconômicos , Resultado do Tratamento
20.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206432

RESUMO

Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and extrarenal urate excretion. Importantly, disturbances in urate excretion are a common cause of hyperuricemia and gout. The majority of urate is eliminated by glomerular filtration in the kidney followed by an, as yet, not fully elucidated interplay of multiple transporters involved in the reabsorption or excretion of urate in the succeeding segments of the nephron. In this context, genome-wide association studies and subsequent functional analyses have identified the ATP-binding cassette (ABC) transporter ABCG2 as an important urate transporter and have highlighted the role of single nucleotide polymorphisms (SNPs) in the pathogenesis of reduced cellular urate efflux, hyperuricemia, and early-onset gout. Recent publications also suggest that ABCG2 is particularly involved in intestinal urate elimination and thus may represent an interesting new target for pharmacotherapeutic intervention in hyperuricemia and gout. In this review, we specifically address the involvement of ABCG2 in renal and extrarenal urate elimination. In addition, we will shed light on newly identified polymorphisms in ABCG2 associated with early-onset gout.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Suscetibilidade a Doenças , Gota/etiologia , Hiperuricemia/etiologia , Proteínas de Neoplasias/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Idade de Início , Alelos , Animais , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Gota/diagnóstico , Gota/metabolismo , Gota/terapia , Humanos , Hiperuricemia/diagnóstico , Hiperuricemia/metabolismo , Hiperuricemia/terapia , Proteínas de Neoplasias/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único
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