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

RESUMO

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.


Assuntos
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
3.
Lancet ; 394(10197): 533-540, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31395441

RESUMO

One of the primary goals of genomic medicine is to improve diagnosis through identification of genomic conditions, which could improve clinical management, prevent complications, and promote health. We explore how genomic medicine is being used to obtain molecular diagnoses for patients with previously undiagnosed diseases in prenatal, paediatric, and adult clinical settings. We focus on the role of clinical genomic sequencing (exome and genome) in aiding patients with conditions that are undiagnosed even after extensive clinical evaluation and testing. In particular, we explore the impact of combining genomic and phenotypic data and integrating multiple data types to improve diagnoses for patients with undiagnosed diseases, and we discuss how these genomic sequencing diagnoses could change clinical management.


Assuntos
Doenças Raras/diagnóstico , Análise de Sequência de DNA/métodos , Adulto , Criança , Diagnóstico Precoce , Genômica , Humanos , Fenótipo , Diagnóstico Pré-Natal/métodos , Doenças Raras/genética , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
4.
Nat Med ; 25(6): 911-919, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160820

RESUMO

It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2-5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6-8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9, and cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.


Assuntos
Doenças Raras/genética , Ceramidase Ácida/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Variação Genética , Humanos , Masculino , Modelos Genéticos , Mutação , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Canais de Potássio/genética , RNA/sangue , RNA/genética , Processamento de RNA/genética , Doenças Raras/sangue , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
5.
Artigo em Inglês | MEDLINE | ID: mdl-31079569

RESUMO

The purpose of this review is to highlight the impact of the alternative splicing process on human disease. Epigenetic regulation determines not only what parts of the genome are expressed but also how they are spliced. The recent progress in the field of epigenetics has important implications for the study of rare diseases. The role of epigenetics in rare diseases is a key issue in molecular physiology and medicine because not only rare diseases can benefit from epigenetic research, but can also provide useful principles for other common and complex disorders such as cancer, cardiovascular, type 2 diabetes, obesity, and neurological diseases. Predominantly, epigenetic modifications include DNA methylation, histone modification, and RNA-associated silencing. These modifications in the genome regulate numerous cellular activities. Disruption of epigenetic regulation process can contribute to the etiology of numerous diseases during both prenatal and postnatal life. Here, I discuss current knowledge about this matter including some current epigenetic therapies and future directions in the field by emphasizing on the RNA-based therapy via antisense oligonucleotides to correct splicing defects.


Assuntos
Epigênese Genética , Doenças Raras/genética , Doenças Raras/terapia , Processamento Alternativo , Animais , Metilação de DNA , Regulação da Expressão Gênica , Inativação Gênica , Código das Histonas , Humanos , Processamento de RNA
6.
Nefrología (Madrid) ; 39(2): 133-140, mar.-abr. 2019. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-181320

RESUMO

Las enfermedades relacionadas con mutaciones del gen MYH9 son un grupo de patologías genéticas raras. Su herencia sigue un patrón autosómico dominante en donde el gen MYH9, codifica la cadena pesada de la miosina IIA no muscular que se expresa en diferentes tejidos pero especialmente en los podocitos y en las células mesangiales. Este trastorno se caracteriza por la presencia de macrotrombocitopenia, inclusiones leucocitarias y un riesgo variable de desarrollar insuficiencia renal, hipoacusia y cataratas en edad juvenil o adulta. Describimos el caso de una mujer de 27 años, de raza caucásica, diagnosticada inicialmente de púrpura trombocitopénica idiopática. Tras una detallada historia familiar y el desarrollo de síntomas clínicos posteriores con afectación renal e hipoacusia, se le realizó un estudio genético que nos permitió el diagnóstico de nefropatía asociada a la mutación en el gen MYH9. Este caso destaca el retraso del diagnóstico y la utilidad del estudio genético en pacientes con enfermedades muy poco frecuentes. Se procede a la revisión de la enfermedad en este artículo


MYH9 related diseases are caused by mutations in the MYH9 gene and constitute a rare group of genetic entities. Its inheritance follows an autosomal dominant pattern. The MYH9 gene, encodes the nonmuscle myosin heavy chain IIA, expressed in different tissues and especially in podocytes and mesangial cells. The disorder is characterized by the presence of macrothrombocytopenia, leukocyte inclusions and a variable risk of developing renal failure, hearing loss and early-onset cataracts. We describe the case of a 27-year-old Caucasian woman, diagnosed initially with idiopathic thrombocytopenic purpura. After a detailed family history and the appearance of renal involvement and hearing loss, genetic testing allowed to make the diagnosis of nephropathy associated with MYH9 mutation. This case is an example of the delayed diagnosis of uncommon diseases and highlights the usefulness genetic testing. A review of the disease is provided


Assuntos
Humanos , Feminino , Adulto , Nefropatias/genética , Mutação/genética , Nefrite Hereditária/genética , Doenças Raras/genética , Perda Auditiva Súbita/complicações , Perda Auditiva Súbita/genética , Trombocitopenia/complicações , Trombocitopenia/genética , Diagnóstico Diferencial
7.
Medicina (Kaunas) ; 55(3)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934652

RESUMO

The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediak⁻Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.


Assuntos
Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/imunologia , Anormalidades Múltiplas/patologia , Adulto , Síndrome de Chediak-Higashi/diagnóstico , Síndrome de Chediak-Higashi/genética , Síndrome de Chediak-Higashi/imunologia , Síndrome de Chediak-Higashi/patologia , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/imunologia , Anormalidades Craniofaciais/patologia , Diagnóstico Diferencial , Feminino , Cabelo/anormalidades , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/patologia , Humanos , Hipertricose/induzido quimicamente , Iris/anormalidades , Masculino , Mutação , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/imunologia , Síndromes Neurocutâneas/patologia , Piebaldismo/diagnóstico , Piebaldismo/genética , Piebaldismo/imunologia , Piebaldismo/patologia , Transtornos da Pigmentação/imunologia , Transtornos da Pigmentação/patologia , Qualidade de Vida , Doenças Raras/imunologia , Doenças Raras/patologia , Anormalidades da Pele , Proteínas rab27 de Ligação ao GTP/genética
9.
Dis Model Mech ; 12(2)2019 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-30819728

RESUMO

Individual rare diseases may affect only a few people, making them difficult to recognize, diagnose or treat by studying humans alone. Instead, model organisms help to validate genetic associations, understand functional pathways and develop therapeutic interventions for rare diseases. In this Editorial, we point to the key parameters in face, construct, predictive and target validity for accurate disease modelling, with special emphasis on rare disease models. Raising the experimental standards for disease models will enhance successful clinical translation and benefit rare disease research.


Assuntos
Modelos Animais de Doenças , Doenças Raras/genética , Doenças Raras/terapia , Pesquisa Médica Translacional , Animais , Humanos , Reprodutibilidade dos Testes
11.
Methods Mol Biol ; 1922: 407-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838594

RESUMO

Rare genetic disorders are often challenging to diagnose. Anomalies of tooth number, shape, size, mineralized tissue structure, eruption, and resorption may exist as isolated symptoms or diseases but are often part of the clinical synopsis of numerous syndromes (Bloch-Zupan A, Sedano H, Scully C. Dento/oro/craniofacial anomalies and genetics, 1st edn. Elsevier, Boston, MA, 2012). Concerning amelogenesis imperfecta (AI), for example, mutations in a number of genes have been reported to cause isolated AI, including AMELX, ENAM, KLK4, MMP20, FAM83H, WDR72, C4orf26, SLC24A4, and LAMB3. In addition, many other genes such as DLX3, CNNM4, ROGDI, FAM20A, STIM1, ORAI1, and LTBP3 have been shown to be involved in developmental syndromes with enamel defects. The clinical presentation of the enamel phenotype (hypoplastic, hypomineralized, hypomature, or a combination of severities) alone does not allow a reliable prediction of possible causative genetic mutations. Understanding the potential genetic cause(s) of rare diseases is critical for overall health management of affected patient. One effective strategy to reach a genetic diagnosis is to sequence a selected gene panel chosen for a determined range of phenotypes. Here we describe a laboratory protocol to set up a specific gene panel for orodental diseases.


Assuntos
Anormalidades Craniofaciais/genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Raras/genética , Anormalidades Dentárias/genética , Amelogênese Imperfeita/diagnóstico , Amelogênese Imperfeita/genética , Anormalidades Craniofaciais/diagnóstico , DNA/genética , Desenho de Equipamento , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Humanos , Doenças Raras/diagnóstico , Anormalidades Dentárias/diagnóstico
12.
Methods Mol Biol ; 1922: 453-492, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838595

RESUMO

This chapter describes methods related to the diagnosis of genetic dental diseases. Based on the present knowledge, clinical phenotyping and next-generation sequencing techniques are discussed. Methods necessary for Sanger sequencing, multiplex ligation-dependent probe amplification, and epigenetic modification methods are detailed. In addition, protocols for cell culture establishment and characterization from patients with inherited dental anomalies are described.


Assuntos
Epigênese Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Raras/genética , Odontopatias/genética , Amelogênese Imperfeita/genética , Técnicas de Cultura de Células/métodos , DNA/genética , DNA/isolamento & purificação , Humanos , Fenótipo , Reação em Cadeia da Polimerase/métodos , Anormalidades Dentárias/genética
13.
G Ital Nefrol ; 36(1)2019 Feb.
Artigo em Italiano | MEDLINE | ID: mdl-30758154

RESUMO

Renal Diseases represent almost 6% of all Rare Diseases but are often misdiagnosed. In a survey made in Sicily in 2016, based on cases reported from all public hospitals according to a list of rare kidney diseases, we were able to collect 337 cases (199 males and 138 females). The highest prevalence was detected in children: 13.9 cases in 100.000 children; the mean age was 10, and the median 5 years, at the time of the diagnosis. Comparing our data with those available in the Sicilian Register of Rare Diseases we found that only 141 cases (54%) were present in the register. Promoting regional registries of rare kidney diseases in Italy may be useful for epidemiologic studies.


Assuntos
Nefropatias/epidemiologia , Doenças Raras/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Nefropatias/genética , Masculino , Pessoa de Meia-Idade , Prevalência , Doenças Raras/genética , Sistema de Registros/estatística & dados numéricos , Distribuição por Sexo , Sicília/epidemiologia , Adulto Jovem
14.
Orphanet J Rare Dis ; 14(1): 34, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736835

RESUMO

We describe 542 cases of symptomatic hereditary transthyretin amyloid polyneuropathy (ATTR-PN) identified through a review of the literature published between 2005 and 2016. Approximately 18% of the cases were from countries where ATTR-PN is traditionally considered to be endemic (i.e., Portugal, Japan, and Sweden). East Asia (Japan, China, Taiwan, and South Korea) contributed a sizeable combined proportion (37.0%, n = 200) with Japan (n = 92) and China (n = 71) being the primary contributors. The most common genotypes among the 65 genotypes represented in the sample were Val30Met (47.6%), Ser77Tyr (10%), Ala97Ser (6.5%), and Phe64Leu (4.4%). Cases with genotypes other than the aforementioned four had the lowest ages at onset (mean 49.2 [standard deviation {SD} 21.0; inter-quartile range {IQR}14.7]) and diagnosis (mean 53.4 [SD 21.0; IQR 14.7]). Conversely, Phe64Leu mean age of onset was 67.5 (SD 8.8; IQR 5.2) and mean age of diagnosis was 71.3 (SD 8.8; IQR 5.4). The prevalence of upper and lower limb involvement at the time of diagnosis (67 and 41%) observed across all cases is consistent with the typical presentation of ATTR-PN. Other notable findings at the time of diagnosis included a high rate of impotence among the Ala97Ser cases versus all others (67% vs. 21%) and a high rate of non-motor visual symptoms (i.e., visual opacities and glaucoma) in the Ser77Tyr cases versus all others (93% vs. 16%). Though comparisons were made descriptively and were hindered by inconsistency of reporting across the cases, these findings support the notion that ATTR-PN is a more phenotypically and geographically variable disease than is typically considered.


Assuntos
Neuropatias Amiloides Familiares/epidemiologia , Polineuropatias/epidemiologia , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Humanos , Mutação/genética , Polineuropatias/genética , Polineuropatias/patologia , Doenças Raras/epidemiologia , Doenças Raras/genética , Doenças Raras/patologia
15.
Gynecol Oncol ; 153(2): 304-311, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30792002

RESUMO

OBJECTIVES: Conducting clinical trials in rare malignancies is challenging due to the limited number of patients and differences in biologic behavior. We investigated the feasibility and clinical utility of using genomic profiling for rare gynecologic malignancies. METHODS: Rare epithelial gynecologic cancer patients were analyzed for somatic variants through an institutional molecular profiling program using the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel on the MiSeq platform. Clinical trial outcomes by RECIST 1.1, and time on treatment were evaluated. RESULTS: From March 2012 to November 2015, 767 gynecologic patients were enrolled and 194 (27%) were classified as rare epithelial malignancies. At least one somatic mutation was identified in 72% of patients, most commonly in TP53 (39%), KRAS (28%) and PIK3CA (27%). A total of 14% of patients were treated on genotype-matched trials. There were no significant differences in overall response rate between genotype-matched versus unmatched trials, nor in median time on treatment between genotype trials and the immediate prior systemic standard treatment. Among 13 evaluable Low Grade Serous ovarian cancer patients treated on genotype-matched trials with MEK inhibitor-based targeted combinations, there were four partial responses. CONCLUSIONS: Somatic molecular profiling is feasible and enables the identification of patients with rare gynecologic cancers who are candidates for genotype-matched clinical trials. Genotype-matched trials, predominantly MEK-based combinations in KRAS and/or NRAS mutant Low Grade Serous ovarian cancer patients, and genotype-unmatched trials, have shown potential clinical activity. Prospective trials with integrated genotyping are warranted to assess the clinical utility of next generation sequencing tests as a standard clinical application in rare malignancies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Técnicas de Genotipagem/estatística & dados numéricos , Doenças Raras/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Estudos de Viabilidade , Feminino , Neoplasias dos Genitais Femininos/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Estudos Prospectivos , Doenças Raras/genética , Critérios de Avaliação de Resposta em Tumores Sólidos , Adulto Jovem
16.
Mol Diagn Ther ; 23(2): 155-171, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30610665

RESUMO

Since the discovery and classification of non-coding RNAs, their roles have gained great attention. In this respect, microRNAs and long non-coding RNAs have been firmly demonstrated to be linked to regulation of gene expression and onset of human diseases, including rare genetic diseases; therefore they are suitable targets for therapeutic intervention. This issue, in the context of rare genetic diseases, is being considered by an increasing number of research groups and is of key interest to the health community. In the case of rare genetic diseases, the possibility of developing personalized therapy in precision medicine has attracted the attention of researchers and clinicians involved in developing "orphan medicinal products" and proposing these to the European Medicines Agency (EMA) and to the Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) in the United States. The major focuses of these activities are the evaluation and development of products (drugs, biologics, devices, or medical foods) considered to be promising for diagnosis and/or treatment of rare diseases or conditions, including rare genetic diseases. In an increasing number of rare genetic diseases, analysis of microRNAs and long non-coding RNAs has been proven a promising strategy. These diseases include, but are not limited to, Duchenne muscular dystrophy, cystic fibrosis, Rett syndrome, and ß-thalassemia. In conclusion, a large number of approaches based on targeting microRNAs and long non-coding RNAs are expected in the field of molecular diagnosis and therapy, with a facilitated technological transfer in the case of rare genetic diseases, in virtue of the existing regulation concerning these diseases.


Assuntos
Doenças Genéticas Inatas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Redes Reguladoras de Genes , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/terapia , Humanos , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Doenças Raras/genética
17.
Medicina (Kaunas) ; 55(1)2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650640

RESUMO

Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. The aim of this study was to identify novel variations associated with infantile DCM. Materials and Methods: Targeted next generation sequencing (NGS) of 181 cardiomyopathy-related genes was performed in three unrelated consanguineous families from Saudi Arabia. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls. Results: The three index cases presented between 7 and 10 months of age with severe DCM. In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in LAMA4 (c.3925G > A, p.Asp1309Asn) and a known DCM mutation in MYH7 (c.2770G > A; p.Glu924Lys). The LAMA4 p.Asp1309Asn variant was predicted to be likely pathogenic according to international guidelines. The other two families had no identifiable potentially deleterious variants. Conclusions: Inheritance of two genetic variants may have a synergistic or dose effect to cause severe DCM. We report of a novel p.Asp1309Asn variation associated with DCM. Targeted NGS is useful in the molecular diagnosis of DCM and to guide whole-family management and counselling.


Assuntos
Miosinas Cardíacas/genética , Cardiomiopatia Dilatada/genética , Laminina/genética , Mutação de Sentido Incorreto , Cadeias Pesadas de Miosina/genética , Doenças Raras/genética , Estudos de Coortes , Ecocardiografia , Feminino , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Saúde do Lactente , Masculino , Linhagem , Arábia Saudita
18.
Pediatrics ; 143(2)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30606745

RESUMO

In 2016, the EveryLife Foundation for Rare Diseases, in partnership with Dr Pan, who is a pediatrician and state senator in California, launched legislation to advance and expand newborn screening. Researchers have shown that newborn screening can be cost-effective and can greatly improve health outcomes for patients with rare diseases. However, adding additional diseases in newborn screening is a long process, requiring legislative approval in addition to new state funding. Such process delays can lead to protracted diagnostic odysseys for patients, especially those with rare diseases. These delays can result in irreversible morbidity and, in some cases, early mortality for patients. To improve this process, legislation known as Senate Bill 1095 was introduced to require California to adhere to the latest federal recommendations for newborn screening within 2 years. We provide insight and describe the process of advancing state legislation, coalition building, and managing opposition. Senate Bill 1095 would become law in 2016, requiring California to screen for 2 new rare diseases by August 2018: mucopolysaccharidosis type I and Pompe disease. This case study can serve as a model for advocates looking to expand state newborn-screening programs.


Assuntos
Medicina Baseada em Evidências/métodos , Triagem Neonatal/métodos , Política Pública , Doenças Raras/diagnóstico , California/epidemiologia , Assistência à Saúde/métodos , Assistência à Saúde/tendências , Medicina Baseada em Evidências/tendências , Humanos , Recém-Nascido , Triagem Neonatal/tendências , Política Pública/tendências , Doenças Raras/epidemiologia , Doenças Raras/genética
19.
J Dermatol Sci ; 93(2): 75-81, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30692041

RESUMO

Dyschromatosis symmetrica hereditaria (DSH) and reticulate acropigmentation of Kitamura (RAK) are rare, inherited pigmentary diseases. DSH shows a mixture of pigmented and depigmented macules on the extremities. RAK shows reticulated, slightly depressed pigmented macules on the extremities. The causative gene of DSH was clarified as ADAR1 by positional cloning including linkage analysis and haplotype analysis in 2003. Ten years later, the causative gene of RAK was identified as ADAM10 by whole-exome sequencing, in 2013. ADAR1 is an RNA-editing enzyme which catalyzes the deamination of adenosine to inosine (A-to-I) in double-stranded RNA substrates during post-transcription processing. Inosine acts as guanine during translation, resulting in codon alterations or alternative splice sites that lead to functional changes in proteins when they occur in coding regions. In 2012, it was clarified that ADAR1 mutations cause Aicardi-Goutières syndrome 6, which is a severe genetic inflammatory disease that affects the brain and the skin. A zinc metalloprotease, a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), is involved in the ectodomain shedding of various membrane proteins and shows various functions in vivo. ADAM10 is known to be involved in the ectodomain shedding of Notch proteins as substrates in the skin. We speculate that the pathogenesis of RAK and Dowling-Degos disease (DDD, a pigmentary disease similar to RAK) is associated with the Notch signaling pathway. In addition, ADAM10 mutations proved to be associated with late-onset Alzheimer disease. This review comprehensively discusses the updated pathophysiology of those genetic pigmentary disorders.


Assuntos
Proteína ADAM10/genética , Adenosina Desaminase/genética , Secretases da Proteína Precursora do Amiloide/genética , Hiperpigmentação/genética , Proteínas de Membrana/genética , Transtornos da Pigmentação/congênito , Proteínas de Ligação a RNA/genética , Receptores Notch/metabolismo , Dermatopatias Genéticas/genética , Dermatopatias Papuloescamosas/genética , Humanos , Hiperpigmentação/patologia , Mutação , Transtornos da Pigmentação/genética , Transtornos da Pigmentação/patologia , Doenças Raras/genética , Pele/patologia , Dermatopatias Genéticas/patologia , Dermatopatias Papuloescamosas/patologia , Pigmentação da Pele/genética
20.
Stroke ; 50(3): 750-753, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30651041

RESUMO

Background and Purpose- Providing ongoing care for rare neurological conditions is challenging. Telemedicine can reduce patient travel. We set up and evaluated a telemedicine service for patients with a genetic form of stroke and dementia cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Methods- One hundred fourteen patients with mutation-positive cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (64 telemedicine and 50 face-to-face) were recruited. Patient and clinician satisfaction questionnaires rated the service to create a mean satisfaction score for both face-to-face and telemedicine follow-up appointments. Results- There was no difference in mean (SD) patient or clinician satisfaction scores between telemedicine and face-to-face appointments (patient: 4.57 [0.56] and 4.69 [0.42]; P=0.99; clinician: 4.55 [0.49] and 4.60 [0.43]; P=0.44). Conclusions- Telemedicine follow-up was suited to patients with stroke and dementia and offered satisfaction levels similar to that for face-to-face consultations.


Assuntos
CADASIL/terapia , Doenças do Sistema Nervoso/terapia , Doenças Raras/terapia , Telemedicina , Atitude do Pessoal de Saúde , CADASIL/genética , Seguimentos , Humanos , Doenças do Sistema Nervoso/genética , Satisfação do Paciente , Doenças Raras/genética , Software , Inquéritos e Questionários
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