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While digital tools, such as the Internet, smartphones, and social media, are an important part of modern society, little is known about the specific role they play in the healthcare management of individuals and caregivers affected by rare disease. Collectively, rare diseases directly affect up to 10% of the global population, suggesting that a significant number of individuals might benefit from the use of digital tools. The purpose of this qualitative interview-based study was to explore: (a) the ways in which digital tools help the rare disease community; (b) the healthcare gaps not addressed by current digital tools; and (c) recommended digital tool features. Individuals and caregivers affected by rare disease who were comfortable using a smartphone and at least 18 years old were eligible to participate. We recruited from rare disease organizations using purposive sampling in order to achieve a diverse and information rich sample. Interviews took place over Zoom and reflexive thematic analysis was utilized to conceptualize themes. Eight semistructured interviews took place with four individuals and four caregivers. Three themes were conceptualized which elucidated key aspects of how digital tools were utilized in disease management: (1) digital tools should lessen the burden of managing a rare disease condition; (2) digital tools should foster community building and promote trust; and (3) digital tools should provide trusted and personalized information to understand the condition and what the future may hold. These results suggest that digital tools play a central role in the lives of individuals with rare disease and their caregivers. Digital tools that centralize trustworthy information, and that bring the relevant community together to interact and promote trust are needed. Genetic counselors can consider these ideal attributes of digital tools when providing resources to individuals and caretakers of rare disease.
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Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.
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Doenças Raras , Humanos , Doenças Raras/diagnóstico , Doenças Raras/terapia , Doenças Raras/epidemiologia , Estudos Longitudinais , Estados Unidos , Estudos ProspectivosRESUMO
BACKGROUND: A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study. METHODS: Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case. RESULTS: Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia. CONCLUSIONS: We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.
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Proteínas de Transporte/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/fisiopatologia , Criança , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Humanos , Judeus/genética , Imageamento por Ressonância Magnética , Sequenciamento Completo do GenomaRESUMO
Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A-related leukodystrophy, Peroxisomal biogenesis disorders, POLR3-related Leukodystrophy, Vanishing White Matter, and Pelizaeus-Merzbacher Disease. Despite the relative frequency of these conditions, carrier-screening laboratories regularly test only 20 of the 55 leukodystrophy-related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.
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Doenças Autoimunes do Sistema Nervoso/genética , Doenças Desmielinizantes/genética , Malformações do Sistema Nervoso/genética , Doença de Pelizaeus-Merzbacher/genética , RNA Polimerase III/genética , Tubulina (Proteína)/genética , Doenças Autoimunes do Sistema Nervoso/patologia , Doenças Desmielinizantes/epidemiologia , Doenças Desmielinizantes/patologia , Exoma/genética , Feminino , Predisposição Genética para Doença , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/genética , Imageamento por Ressonância Magnética , Masculino , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Malformações do Sistema Nervoso/patologia , Doença de Pelizaeus-Merzbacher/epidemiologia , Doença de Pelizaeus-Merzbacher/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.
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Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Sistema de Registros , Sequenciamento Completo do Genoma , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Leucoencefalopatias/patologia , Masculino , LinhagemRESUMO
Counseling after consumer-driven whole exome sequencing (WES) and whole genome sequencing (WGS) presents challenges for genetic counselors as availability of this testing increases. There are no standard practice guidelines and limited resources for genetic counselors in this area, but consumer demand for counseling and data interpretation exists and is likely to grow along with testing opportunities. In this paper, we comment upon our experiences as three independent, private practice genetic counselors who have provided counseling services for clients with WES/WGS reports and data. In our counseling experience, we have encountered three main types of client motivation for seeking testing and counseling: generally healthy individuals who are curious to learn more about their genomic data, individuals with family histories of various conditions, and/or who want to better understand specific disease risks, and individuals who are ill, undiagnosed and searching for an understanding of their ailments. Research is needed to better understand client motivations for undergoing testing and counseling, as well outcomes of counseling sessions. In addition to improvements in variant identification, classification and bioinformatics, there is a need for practice guidelines, counseling resources, service delivery models, and efforts to increase awareness and access to genetic counseling services.
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Sequenciamento do Exoma , Aconselhamento Genético , Sequenciamento Completo do Genoma , HumanosRESUMO
Here we report whole exome sequencing (WES) on a cohort of 71 patients with persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. WES analyses were performed on trio, or greater, family groups. Diagnostic pathogenic variants were identified in 35% (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7% (5 of 71) of cases, giving a total yield of clinical diagnoses in 42% of individuals. These findings provide evidence that WES can substantially decrease the number of unresolved white matter cases. Ann Neurol 2016;79:1031-1037.
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Análise Mutacional de DNA , Exoma/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Substância Branca/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Leucoencefalopatias/patologia , Masculino , Mutação , Adulto JovemRESUMO
Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.
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Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças por Armazenamento dos Lisossomos/diagnóstico , Adrenoleucodistrofia/diagnóstico , Anodontia/diagnóstico , Humanos , Imageamento por Ressonância MagnéticaRESUMO
Uniparental disomy is a genetic cause of disease that may result in the inheritance of an autosomal recessive condition. A child with developmental delay and hypotonia was seen and found to have severely abnormal myelination. Lysosomal enzyme testing identified an isolated deficiency of beta-galactosidase. Subsequently, homozygous missense mutations in the galactosidase, beta 1 (GLB1) gene on chromosome 3 were found. Parental testing confirmed inheritance of two copies of the same mutated maternal GLB1 gene, and no paternal copy. SNP analysis was also done to confirm paternity. The patient was ultimately diagnosed with autosomal recessive GM1 gangliosidosis caused by maternal uniparental isodisomy. We provide a review of this patient and others in which uniparental disomy (UPD) of a non-imprinted chromosome unexpectedly caused an autosomal recessive condition. This is the first case of GM1 gangliosidosis reported in the literature to have been caused by UPD. It is important for genetic counselors and other health care providers to be aware of the possibility of autosomal recessive disease caused by UPD. UPD as a cause of autosomal recessive disease drastically changes the recurrence risk for families, and discussions surrounding UPD can be complex. Working with families to understand UPD when it occurs requires a secure and trusting counselor-family relationship.
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Gangliosidose GM1/genética , Dissomia Uniparental , Feminino , Humanos , Lactente , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: More than half of patients with genetic leukoencephalopathies remain without a specific diagnosis; this is particularly true in individuals with a likely primary neuronal etiology, such as those in which abnormal white matter occurs in combination with severe epilepsy. PATIENT: A child with a severe early infantile epileptic encephalopathy and abnormal myelination underwent whole exome sequencing. RESULTS: Whole exome sequencing identified a heterozygous de novo mutation in KCNT1, a sodium-gated potassium channel gene. CONCLUSIONS: Severely delayed myelination was anecdotally reported in previous patients with KCNT1 mutations. This case reinforces that KCNT1 sequencing should be included in an investigation of patients with severely delayed myelination and epilepsy.
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Epilepsia/complicações , Epilepsia/genética , Leucoencefalopatias/complicações , Leucoencefalopatias/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Criança , Eletroencefalografia , Humanos , Imageamento por Ressonância Magnética , Masculino , Modelos Moleculares , Canais de Potássio Ativados por SódioRESUMO
Pol III-related leukodystrophies are caused by mutations in POLR3A and POLR3B genes and all share peculiar imaging and clinical features. The objectives of this study are (1) to define the neuroradiologic pattern in a cohort of POLR3A and POLR3B subjects and (2) to compare the neuroradiologic pattern of Pol III-related leukodystrophies with other hypomyelinating disorders. The magnetic resonance imaging (MRI) examinations of 13 patients with POLR3A and POLR3B mutations and of 14 patients with other hypomyelinating disorders were analyzed. All the subjects with Pol III-related leukodystrophies presented hypomyelination associated with T2 hypointensity of the thalami and/or the pallida. Twelve subjects (92%) presented T2 hypointensity of the optic radiations. Cerebellar atrophy was observed in most patients (92%). The combination of the analyzed criteria identified patients with Pol III-related leukodystrophies with a sensitivity of 84.6% and a specificity of 92.9%.
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Encéfalo/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Imageamento por Ressonância Magnética , Adolescente , Adulto , Atrofia/patologia , Criança , Pré-Escolar , Estudos de Coortes , Doenças Desmielinizantes/patologia , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Humanos , Modelos Logísticos , Masculino , RNA Polimerase III/genética , Sensibilidade e Especificidade , Adulto JovemRESUMO
Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hereditary leukoencephalopathy that was originally identified by MRI pattern analysis, and it has thus far defied all attempts at identifying the causal mutation. Only 22 cases are published in the literature to date. We performed exome sequencing on five family trios, two family quartets, and three single probands, which revealed that all eleven H-ABC-diagnosed individuals carry the same de novo single-nucleotide TUBB4A mutation resulting in nonsynonymous change p.Asp249Asn. Detailed investigation of one of the family quartets with the singular finding of an H-ABC-affected sibling pair revealed maternal mosaicism for the mutation, suggesting that rare de novo mutations that are initially phenotypically neutral in a mosaic individual can be disease causing in the subsequent generation. Modeling of TUBB4A shows that the mutation creates a nonsynonymous change at a highly conserved asparagine that sits at the intradimer interface of α-tubulin and ß-tubulin, and this change might affect tubulin dimerization, microtubule polymerization, or microtubule stability. Consistent with H-ABC's clinical presentation, TUBB4A is highly expressed in neurons, and a recent report has shown that an N-terminal alteration is associated with a heritable dystonia. Together, these data demonstrate that a single de novo mutation in TUBB4A results in H-ABC.
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Gânglios da Base/patologia , Cerebelo/patologia , Leucoencefalopatias/genética , Modelos Moleculares , Conformação Proteica , Tubulina (Proteína)/genética , Sequência de Aminoácidos , Sequência de Bases , Cristalografia por Raios X , Exoma/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética , Masculino , Modelos Genéticos , Dados de Sequência Molecular , Neurônios/metabolismo , Análise de Sequência de DNA , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismoRESUMO
OBJECTIVE: This study explores a large panel of cytokines in plasma and CSF of patients with Aicardi-Goutières syndrome (AGS) at different ages, in order to establish signatures of cytokines most predictive of AGS. METHODS: Plasma from 22 subjects with known mutations were assayed for cytokines using the Milliplex MAP Immunobead system, and compared to results from 8 age-matched normal controls. CSF of 11 additional patients with mutation-proven AGS was tested in an identical manner and compared to results from age-matched controls. Samples were banked and analysis was carried out retrospectively. RESULTS: Significant elevations were seen in FMS-related tyrosine kinase 3 ligand, IP-10, interleukin (IL)-12p40, IL-15, tumor necrosis factor α, and soluble IL 2 receptor α in both AGS patient plasma and CSF relative to controls. Additionally, this cytokine signature was able to correctly cluster 9 of 11 AGS cases based on CSF values. While most cytokines decreased exponentially with age, a subgroup including IP-10 demonstrated persistent elevation beyond early childhood. CONCLUSION: Patients with AGS exhibit plasma and CSF elevations of proinflammatory cytokines. Selected cytokines remain persistently elevated beyond the initial disease phase. This panel of proinflammatory cytokines may be considered for use as diagnostic and therapeutic markers of disease, and may permit improved understanding of disease pathogenesis.
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Doenças Autoimunes do Sistema Nervoso/patologia , Citocinas/biossíntese , Mediadores da Inflamação/metabolismo , Malformações do Sistema Nervoso/patologia , Adolescente , Doenças Autoimunes do Sistema Nervoso/sangue , Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Criança , Pré-Escolar , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Feminino , Humanos , Lactente , Mediadores da Inflamação/sangue , Mediadores da Inflamação/líquido cefalorraquidiano , Masculino , Malformações do Sistema Nervoso/sangue , Malformações do Sistema Nervoso/líquido cefalorraquidiano , Estudos RetrospectivosRESUMO
Monocarboxylate transporter 8 (MCT8) deficiency is an X-linked disorder resulting from an impairment of the transcellular transportation of thyroid hormones. Within the central nervous system thyroid hormone transport is normally mediated by MCT8. Patients are described as affected by a static or slowly progressive clinical picture which consists of variable degrees of mental retardation, hypotonia, spasticity, ataxia and involuntary movements, occasionally paroxysmal. The authors describe the clinical and neuroradiological picture of 3 males patients with marked delayed brain myelination and in which the clinical picture was dominated by early onset nonparoxysmal extrapyramidal symptoms. In one subject a novel mutation is described.
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Doenças dos Gânglios da Base/diagnóstico , Doenças dos Gânglios da Base/genética , Encéfalo/patologia , Cromossomos Humanos X/genética , Análise Mutacional de DNA , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Transportadores de Ácidos Monocarboxílicos/deficiência , Transportadores de Ácidos Monocarboxílicos/genética , Fibras Nervosas Mielinizadas/patologia , Aberrações dos Cromossomos Sexuais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Pré-Escolar , Colina/metabolismo , Códon sem Sentido/genética , Seguimentos , Humanos , Lactente , Inositol/metabolismo , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Mutação de Sentido Incorreto/genética , Exame Neurológico , Simportadores , Testes de Função TireóideaRESUMO
Objective : Reconstructive surgery to improve psychological well-being is commonly offered to children with craniofacial conditions. Few studies have explored the challenges of reconstructive surgery beyond the physical risks: poor treatment outcomes, infection, brain damage, and death. This qualitative study aims to understand the psychological and social implications such interventions can have for individuals with craniofacial conditions. Design : A total of 38 individuals between the ages of 12 and 61 with such craniofacial conditions as Sturge-Weber syndrome, Treacher Collins syndrome, Möbius syndrome, cleft lip and palate, Noonan syndrome, Crouzon syndrome, and amniotic band syndrome participated in semistructured video-recorded interviews. Participants were recruited at conferences, through study flyers, and by word of mouth. Descriptive, thematic analysis was used to identify themes related to reconstructive surgery. Results : Dominant themes included undergoing surgery to reduce stigmatization, the psychological and social implications of the interventions, outcome satisfaction, parental involvement in decision making about surgery, and recommendations for parents considering surgery for their children with craniofacial conditions. Experiences with reconstructive surgery varied, with some participants expressing surgical benefits and others, disillusionment. Conclusions : The range of participant attitudes and experiences reflect the complexity of reconstructive surgery. Pediatric health care teams involved in the care of children with craniofacial conditions play an important role in advising patients (and their parents) about existing treatment options. The psychological and social implications of reconstructive surgery should be relayed to help families weigh the risks and benefits of surgery in an informed and meaningful way.
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Fenda Labial , Pais , Fenda Labial/cirurgia , Fissura Palatina/cirurgia , Disostose Craniofacial , Humanos , Disostose Mandibulofacial , Pais/psicologia , Procedimentos de Cirurgia PlásticaRESUMO
PURPOSE: The purpose of this study was to explore anecdotal evidence for an increase in the prevalence of autoimmune diseases in family members of patients with Aicardi-Goutières syndrome (AGS). METHODS: Pedigrees of patients and controls were analyzed using chi-square and logistic regression to assess differences in reports of autoimmune disease among family members of cases and controls. Data was collected at Children's National Medical Center in Washington, DC, USA and at the International Aicardi-Goutières Syndrome Association Scientific Headquarters, C. Mondino National Institute of Neurology in Pavia, Italy. RESULTS: The number of individuals with reported autoimmune disease is significantly related to having a family member with AGS (χ(2) = 6.25, P = 0.01); 10% (35/320) of relatives of patients with AGS had a reported autoimmune disease diagnosis compared to 5% (18/344) of relatives of controls. There was a greater percent of maternal relatives of patients with AGS reporting autoimmune disease (14.6%), compared to controls (6.8%), with the association being statistically significant. The association was not significant for paternal relatives. CONCLUSION: The prevalence of autoimmune disease in relatives of children with AGS is significantly increased compared to controls. More research is needed to better understand this association.
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Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Estudos de Casos e Controles , Criança , Saúde da Família , Feminino , Humanos , Masculino , PrevalênciaRESUMO
Integration of genetic and genomic information into the clinical practice of child neurologists is revolutionizing how diagnosis, prognosis, and treatment of neurogenetic diseases are approached. Genetic testing technology, informatics, and interpretation are rapidly expanding. High-throughput next-generation sequencing has changed the landscape of many fields of medicine by enabling new diagnoses and gene/disease associations. Now more than ever, a comprehensive understanding of the risks, benefits, limitations, and nuances of testing in the pediatric population is essential for the child neurologist.
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Doenças do Sistema Nervoso Central/genética , Testes Genéticos/normas , Técnicas de Diagnóstico Molecular/métodos , Neurologia/normas , Criança , Testes Genéticos/métodos , Humanos , Medição de RiscoRESUMO
Epidemiologic frequencies of pediatric white matter disorders as a class have not been well defined. This is particularly true of genetic disorders of the white matter of the brain. In this study, ICD-9 codes were used to estimate relative incidence rates and descriptive statistics of leukodystrophies, other genetic leukoencephalopathies and acquired demyelinating disease among children residing in the Washington, D.C. metropolitan area. Children being treated at US children's hospitals between January 1, 2004, and December 31, 2009, for acquired demyelinating disease or genetic white matter disorders were captured using the Pediatric Health Information System and the Physician Practice Management system and validated with local electronic medical records. Comparisons were made between genetic white matter disorders and acquired demyelinating disorders, to determine differences in incidence, age, gender, ethnicity, and mortality. Genetic causes of white matter disease identified with ICD-9 codes had an estimated incidence of 1.2/100,000 children in the Washington, DC area. What was of interest was nearly 5 out of 10 cases of pediatric white matter disease of any etiology were attributable to genetic causes. When only progressive white matter diseases were considered, 7 out of 10 cases were attributable to genetic causes, and only 3 out of 10 to progressive acquired demyelinating disease such as multiple sclerosis. These findings signify the important contribution of heritable white matter disorders to pediatric neurologic disease in the Washington, DC, metro area as well as throughout the United States. Continued research of these understudied disorders should compare disease incidence and determinants to validate these findings in different populations.
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Doenças Desmielinizantes/epidemiologia , Doenças Desmielinizantes/etiologia , Hospitais Pediátricos/estatística & dados numéricos , Fibras Nervosas Mielinizadas/patologia , Adolescente , Criança , Pré-Escolar , Doenças Desmielinizantes/genética , District of Columbia/epidemiologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Sistemas de Informação em Saúde/estatística & dados numéricos , Humanos , Incidência , Lactente , Recém-Nascido , Classificação Internacional de Doenças , Masculino , Estudos RetrospectivosRESUMO
Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.
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Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/genética , Interferon Tipo I , Malformações do Sistema Nervoso/genética , RNA de Cadeia Dupla/metabolismo , Elementos Alu/genética , Animais , Exoma , Expressão Gênica , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Camundongos , Mutação , Conformação Proteica , RNA de Cadeia Dupla/genética , Proteínas de Ligação a RNA , Análise de Sequência de DNA , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: To report the detection of secondary neurotransmitter abnormalities in a group of SPG11 patients and describe treatment with l-dopa/carbidopa and sapropterin. DESIGN: Case reports. SETTING: National Institutes of Health in the Undiagnosed Disease Program; Children's National Medical Center in the Myelin Disorders Bioregistry Program. PATIENTS: Four SPG11 patients with a clinical picture of progressive spastic paraparesis complicated by extrapyramidal symptoms and maculopathy. INTERVENTIONS: L-Dopa/carbidopa and sapropterin. RESULTS: 3/4 patients presented secondary neurotransmitter abnormalities; 4/4 partially responded to L-dopa as well as sapropterin. CONCLUSIONS: In the SPG11 patient with extrapyramidal symptoms, a trial of L-dopa/carbidopa and sapropterin and/or evaluation of cerebrospinal fluid neurotransmitters should be considered.