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Med. U.P.B ; 38(2): 182-186, 17 de octubre de 2019.
Artigo em Espanhol | LILACS | ID: biblio-1023414


La acroqueratoelastoidosis de Costa es una rara genodermatosis autosómica dominante con expresividad variable, que se caracteriza por la presencia de múltiples pápulas hiperqueratósicas en la zona marginal de las manos, los pies o ambas. Debuta predominantemente en la niñez y vida adulta temprana, es de curso crónico y generalmente asintomática. Su diagnóstico diferencial del resto de las acroqueratodermias es un desafío para el clínico, sin embargo, el hallazgo histológico de elastorrexis nos permite categorizarla. Presentamos un caso esporádico de una paciente joven, con características clínicas e histopatológicas típicas de la enfermedad.

The acrokeratoelastoidosis of Costa is a rare genodermatosis of autosomal dominant inheritance with variable expressivity. It is characterized by the presence of multiple hyperkeratotic papules in the marginal zone of the hands and / or feet, which appears predominantly in childhood and early adulthood. It is generally asymptomatic and chronic. Its differential diagnosis from the rest of acrokeratodermias is a challenge for the physician; however, the histological finding of elastorhexis allows us to categorize it. We present a sporadic case of a young female patient, with clinical and histopathological characteristics typical of the disease.

A acroqueratoelastoidose de Costa é uma rara genodermatose autossômica dominante com expressividade variável, que se caracteriza pela presença de múltiplos pápulas hiperqueratósicas na zona marginal das mãos, dos pés ou ambas. Debuta predominantemente na infância e vida adulta precoce, é de curso crónico e geralmente assintomática. Seu diagnóstico diferencial do resto das acroqueratodermias é um desafio para o clínico, mas, a descoberta histológica de elastorrexis nos permite categorizá-la. Apresentamos um caso esporádico de uma paciente jovem, com características clínicas e histopatológicas típicas da doença.

Doenças Genéticas Inatas , Queratinas
BMC Bioinformatics ; 20(1): 496, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615419


BACKGROUND: When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance. METHODS: We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network. RESULTS: We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20. CONCLUSIONS: We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.

Algoritmos , Doenças Genéticas Inatas/diagnóstico , Genômica/métodos , Mutação , Doenças Raras/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Humanos , Fenótipo , Polimorfismo Genético , Medicina de Precisão/métodos , Doenças Raras/genética , Estudos Retrospectivos , Análise de Sequência de DNA/métodos , Software
Medicine (Baltimore) ; 98(35): e16909, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464924


RATIONALE: Congenital hepatic fibrosis (CHF) is an autosomal recessive disease characterized by periportal fibrosis, portal hypertension, and renal cystic disease. Essentially, CHF is a variant of fibrocystic disorder in which liver and kidney are commonly affected. Other frequently associated conditions include Caroli syndrome and polycystic kidney disease. CHF is also a known accompaniment in an array of inherited disorders with multiorgan involvement. PATIENT CONCERNS: The 20-year-old male patient with declining vision (14 years duration), intermittent gingival bleeding (7 years duration), and abdominal distension (5 years duration), presented with exacerbation of these symptoms during the prior 2 months. The patient had been previously diagnosed with retinal macular degeneration, idiopathic thrombocytopenic purpura, and hepatosplenomegaly. DIAGNOSES: Liver biopsy showed disordered hepatic acini and fibrous parenchymal banding, indicative of CHF. INTERVENTIONS: After the treatment of diuresis and liver protectants, the clinical symptoms of the patients were improved. We subsequently recommend chromosomal analysis, although the family refused. OUTCOMES: Three months after discharge, the patient was followed up by telephone. The patient had obvious abdominal distension and we advised that he should be admitted again. But the family refused. LESSONS: CHF is an AR disease resulting in portal hypertension and often associated with renal malformations. CHF is also linked to a number of other disorders, many of which are ciliopathies. Because the clinical manifestations of CHF are nonspecific or lacking, its diagnosis is problematic, relying largely on liver biopsy. Once CHF is identified, physicians are obligated to investigate other organ systems, particularly a search for neuromuscular, retina or renal involvement. This case underscores the value of radiologic imaging, pathologic examination, and genetic testing in successfully diagnosing a rare disease.

Doenças Genéticas Inatas/diagnóstico , Cirrose Hepática/diagnóstico , Fígado/patologia , Biópsia , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/patologia , Hemorragia Gengival/etiologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Degeneração Macular , Masculino , Recusa do Paciente ao Tratamento , Adulto Jovem
Rev. Eugenio Espejo ; 13(1): 62-71, Ene-Jul. 2019.
Artigo em Espanhol | LILACS | ID: biblio-1006784


La fibrosis quística constituye una enfermedad autosómica recesiva producida por una alteración del brazo largo del cromosoma 7 (7q31.2). Al respecto se presenta el caso de una paciente de género femenino de 10 años, que acude a una institución de salud del segundo nivel de atención, por presentar dolor abdominal tipo cólico que inicia en epigastrio y se irradia a hipocondrio bilateral; la misma que presenta diagnóstico de fibrosis quística con tres años de evolución; cuyos valores de amilasa y lipasa permitieron establecer diagnóstico presuntivo de pancreatitis, complicación que no resulta frecuente en pacientes pediátricos. El cuadro clínico permitió observar particularidades que le hacen inusual para ese grupo etario, al observarse complicaciones respiratorias y al desarrollo de pancreatitis. Los protocolos de manejo de la enfermedad, seguidos en las instituciones médicas involucradas, estuvieron acorde con los estándares establecidos a nivel nacional e internacional.

Cystic fibrosis is an autosomal recessive disease produced by an alteration of the long arm of chromosome 7 (7q31.2). In this regard, it was presented the case of a female patient of 10 years of age who went to a health institution of the second level of care due to colic abdominal pain that began in the epigastrium and radiated to bilateral hypochondrium. The same one presented a diagnosis of cystic fibrosis with three years of evolution; whose amylase and lipase values allowed to establish a presumptive diagnosis of pancreatitis, a complication that is not frequent in pediatric patients. The clinical picture allowed to observe peculiarities that make it unusual for this age group due to respiratory complications and the development of pancreatitis. The disease management protocols, followed by the medical institutions involved were in accordance with the standards established at the national and international levels.

Humanos , Feminino , Criança , Condições Patológicas, Sinais e Sintomas , Doenças Genéticas Inatas , Doenças e Anormalidades Congênitas, Hereditárias e Neonatais , Sinais e Sintomas , Anormalidades Congênitas
Pesqui. vet. bras ; 39(7): 481-484, July 2019. tab
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1040707


The hereditary autosomal recessive disorders bovine citrullinemia (BC), bovine leukocyte adhesion deficiency (BLAD), factor XI deficiency (FXID), and complex vertebral malformation (CVM) have affected dairy cattle breeding significantly around the world. This study examined the carrier frequency of BC, BLAD, FXID, and CVM autosomal recessive disorders in Bos taurus Holstein cows bred in the Altos Norte region of the state of Jalisco, Mexico. We extracted DNA from 408 random samples of peripheral blood, and then used polymerase chain reaction (PCR) to identify insertion mutations for FXID, and PCR with restriction fragment length polymorphism (PCR-RFLP) for CVM, BC and BLAD. We visualized the PCR products using agarose gel electrophoresis stained with GelRed®. We found that 100% of wild-type (N/N) allele homozygous animals for genes CD18, ASS, and FXI were free of the mutations for BLAD, BC and FXID respectively. For gene SLC35A3 we estimated total carrier frequency of 10.3% and allele frequency of 5%.(AU)

Animais , Feminino , Bovinos , Síndrome da Aderência Leucocítica Deficitária/veterinária , Citrulinemia/veterinária , Transtornos Cromossômicos/epidemiologia , Deficiência do Fator XI/veterinária , Doenças Genéticas Inatas/veterinária , México/epidemiologia
Hum Genet ; 138(10): 1117-1122, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243543


The Israeli population mainly includes Jews, Muslim and Christian Arabs, and Druze. Data on genetic diseases present in the population have been systematically collected and are available online in the Israeli national genetic database. Among the Israeli Arabs in December 31 2018, the database included molecular data on six diseases relatively frequent in the whole population: thalassemia, familial Mediterranean fever (FMF), cystic fibrosis, deafness, phenylketonuria or congenital adrenal hyperplasia as well as data on 632 autosomal recessive diseases among Muslim Israeli Arabs, 52 among the Christian Arabs and 79 among Druze. A single variant was characterized in 590 out of the 771 genes causing disorders in which the molecular basis was known. Many of the variants reported among Arabs in Israel are novels, most being found in one community only. Some variants are ancient and for instance, consistent with the migration history, several variants are found in the Bedouins from the Negev as well as from the Arab peninsula. In the 181 other disorders more than one variant was characterized either in the same gene or in more than one gene. While it is probable that most of these cases represent random events in some cases the reason may be a selective advantage to the heterozygotes.

Árabes/genética , Genes Recessivos , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Doenças Genéticas Inatas/diagnóstico , Variação Genética , Heterozigoto , Humanos , Israel/epidemiologia , Programas de Rastreamento , Vigilância da População
Mol Cell ; 74(5): 866-876, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31173722


The replisome quickly and accurately copies billions of DNA bases each cell division cycle. However, it can make errors, especially when the template DNA is damaged. In these cases, replication-coupled repair mechanisms remove the mistake or repair the template lesions to ensure high fidelity and complete copying of the genome. Failures in these genome maintenance activities generate mutations, rearrangements, and chromosome segregation problems that cause many human diseases. In this review, I provide a broad overview of replication-coupled repair pathways, explaining how they fix polymerase mistakes, respond to template damage that acts as obstacles to the replisome, deal with broken forks, and impact human health and disease.

Reparo do DNA/genética , Replicação do DNA/genética , Doenças Genéticas Inatas/genética , Genoma Humano/genética , Ciclo Celular/genética , Segregação de Cromossomos/genética , Dano ao DNA/genética , Instabilidade Genômica/genética , Humanos , Mutação/genética
Nat Rev Dis Primers ; 5(1): 43, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249310


Conduct disorder (CD) is a common and highly impairing psychiatric disorder that usually emerges in childhood or adolescence and is characterized by severe antisocial and aggressive behaviour. It frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD) and often leads to antisocial personality disorder in adulthood. CD affects ~3% of school-aged children and is twice as prevalent in males than in females. This disorder can be subtyped according to age at onset (childhood-onset versus adolescent-onset) and the presence or absence of callous-unemotional traits (deficits in empathy and guilt). The aetiology of CD is complex, with contributions of both genetic and environmental risk factors and different forms of interplay among the two (gene-environment interaction and correlation). In addition, CD is associated with neurocognitive impairments; smaller grey matter volume in limbic regions such as the amygdala, insula and orbitofrontal cortex, and functional abnormalities in overlapping brain circuits responsible for emotion processing, emotion regulation and reinforcement-based decision-making have been reported. Lower hypothalamic-pituitary-adrenal axis and autonomic reactivity to stress has also been reported. Management of CD primarily involves parent-based or family-based psychosocial interventions, although stimulants and atypical antipsychotics are sometimes used, especially in individuals with comorbid ADHD.

Transtorno da Conduta/diagnóstico , Transtorno da Conduta/terapia , Adolescente , Adulto , Criança , Comorbidade , Transtorno da Conduta/tratamento farmacológico , Feminino , Neuroimagem Funcional/métodos , Doenças Genéticas Inatas/epidemiologia , Humanos , Masculino , Programas de Rastreamento/métodos , Transtornos Mentais , Prevalência , Fatores de Risco
Cell Mol Life Sci ; 76(19): 3745-3752, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31165201


RNA-binding proteins (RBPs) and microRNAs (miRNAs) are the most important regulators of mRNA stability and translation in eukaryotic cells; however, the complex interplay between these systems is only now coming to light. RBPs and miRNAs regulate a unique set of targets in either a positive or negative manner and their regulation is mainly opposed to each other on overlapping targets. In some cases, the levels of RBPs or miRNAs regulate the cellular levels of one another and decreased levels of either results in changes in translation of their targets. There is growing evidence that these regulatory circuits are crucial in the development and progression of cancer; however, the rules underlying synergism and antagonism between miRNAs and RNA-binding proteins remain unclear. Synthetic biology seeks to develop artificial systems to better understand their natural counterparts and to develop new, useful technologies for manipulation of gene expression at the RNA level. The recent development of artificial RNA-binding proteins promises to enable a much greater understanding of the importance of the functional interactions between RNA-binding proteins and miRNAs, as well as enabling their manipulation for therapeutic purposes.

MicroRNAs/metabolismo , Neoplasias/genética , Proteínas de Ligação a RNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Doenças Genéticas Inatas/terapia , Humanos , Neoplasias/metabolismo , Neoplasias/terapia , Engenharia de Proteínas , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/genética
Nat Med ; 25(6): 890-897, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160821


Monogenic disorders occur at a high frequency in human populations and are commonly inherited through the germline. Unfortunately, once the mutation has been transmitted to a child, only limited treatment options are available in most cases. However, means of correcting disease-causing nuclear and mitochondrial DNA mutations in gametes or preimplantation embryos have now been developed and are commonly referred to as germline gene therapy (GGT). We will discuss these novel strategies and provide a path forward for safe, high-efficiency GGT that may provide a promising new paradigm for preventing the passage of deleterious genes from parent to child.

Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Terapia Genética/métodos , Mutação em Linhagem Germinativa , Criança , Reparo do DNA , DNA Mitocondrial/genética , Feminino , Fertilização In Vitro , Conversão Gênica , Terapia Genética/ética , Terapia Genética/legislação & jurisprudência , Humanos , Masculino , Terapia de Substituição Mitocondrial , Gravidez , Diagnóstico Pré-Implantação , Segurança
J Med Case Rep ; 13(1): 113, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31036085


BACKGROUND: Isolated adrenocorticotropic hormone deficiency is one kind of hypopituitarism and is triggered by various diseases including autoimmune disorder and/or autoimmune hypophysitis. Adrenocorticotropic hormone deficiency brings out various serious symptoms such as severe hypoglycemia, hypotensive shock, and disturbance of consciousness. CASE PRESENTATION: Here we report a case of 65-year-old Japanese man who developed idiopathic and isolated adrenocorticotropic hormone deficiency. He had continued epigastric comfort without any symptom of hypoglycemia or any autoimmune abnormality. Since he continued to complain of mild epigastric discomfort and general malaise, he was misdiagnosed as having functional dyspepsia and a depression state and took medicine for them for several months. Infection markers and several antibodies which we examined were all negative. An abdominal computed tomography scan showed no mass in adrenal tissue; contrast magnetic resonance imaging of his brain showed that pituitary size was within normal range, and pituitary gland deep dyeing delay and/or deeply stained deficit were not observed. However, in a corticotropin-releasing hormone load test, response of adrenocorticotropic hormone and cortisol was poor after corticotropin-releasing hormone loading, and in growth hormone-releasing peptide 2 load test, adrenocorticotropic hormone response was poor, suggesting the presence of adrenocorticotropic hormone deficiency. Therefore, we started treatment with hydrocortisone, and his various symptoms were soon mitigated. CONCLUSIONS: We should bear in mind the possibility of adrenocorticotropic hormone deficiency even when patients complain of epigastric discomfort or general malaise alone.

Dor Abdominal/diagnóstico , Hormônio Adrenocorticotrópico/deficiência , Anti-Inflamatórios/uso terapêutico , Doenças do Sistema Endócrino/diagnóstico , Doenças Genéticas Inatas/diagnóstico , Hidrocortisona/uso terapêutico , Hipoglicemia/diagnóstico , Dor Abdominal/etiologia , Idoso , Diagnóstico Tardio , Doenças do Sistema Endócrino/complicações , Doenças Genéticas Inatas/complicações , Humanos , Hipoglicemia/complicações , Masculino , Testes de Função Hipofisária , Resultado do Tratamento
Int J Lab Hematol ; 41 Suppl 1: 131-141, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069978


Advances in molecular genetic sequencing techniques have contributed to the elucidation of previously unknown germline mutations responsible for inherited thrombocytopenia (IT). Regardless of age of presentation and severity of symptoms related to thrombocytopenia and/or platelet dysfunction, a subset of patients with IT are at increased risk of developing myeloid neoplasms during their life time, particularly those with germline autosomal dominant mutations in RUNX1, ANKRD26, and ETV6. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Bone marrow features may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis. Progression to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) may be accompanied by progressive bi- or pancytopenia, multilineage dysplasia, increased blasts, cytogenetic abnormalities, acquisition of bi-allelic mutations in the underlying gene with germline mutation, or additional somatic mutations in genes associated with myeloid malignancy. A subset of patients may present with MDS/AML at a young age, underscoring the growing concern for evaluating young patients with MDS/AML for germline mutations predisposing to myeloid neoplasm. Early recognition of germline mutation and predisposition to myeloid malignancy permits appropriate treatment, adequate monitoring for disease progression, proper donor selection for hematopoietic stem cell transplantation, as well as genetic counseling of the affected patients and their family members. Herein, we describe the clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6.

Doenças Genéticas Inatas , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteínas de Neoplasias , Trombocitopenia , Aloenxertos , Genes Dominantes , Aconselhamento Genético , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/terapia