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JAMA Neurol ; 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34459874


Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551


Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.

Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
J Child Neurol ; 29(4): 487-92, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23576414


Using vignettes of real cases and the SimulConsult diagnostic decision support software, neurologists listed a differential diagnosis and workup before and after using the decision support. Using the software, there was a significant reduction in error, up to 75% for diagnosis and 56% for workup. This error reduction occurred despite the baseline being one in which testers were allowed to use narrative resources and Web searching. A key factor that improved performance was taking enough time (>2 minutes) to enter clinical findings into the software accurately. Under these conditions and for instances in which the diagnoses changed based on using the software, diagnostic accuracy improved in 96% of instances. There was a 6% decrease in the number of workup items accompanied by a 34% increase in relevance. The authors conclude that decision support for a neurological diagnosis can reduce errors and save on unnecessary testing.

Tomada de Decisões Assistida por Computador , Erros de Diagnóstico/prevenção & controle , Medicina Baseada em Evidências , Doenças do Sistema Nervoso/diagnóstico , Diagnóstico Diferencial , Erros de Diagnóstico/estatística & dados numéricos , Feminino , Humanos , Internet , Masculino , Software
Am J Med Genet A ; 161A(4): 711-6, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23494996


A variety of candidate genes have been proposed to cause corpus callosum abnormalities (CCAs) in patients with terminal chromosome 1q deletions. Recent data excluded AKT3 and implicated ZNF238 and/or CEP170 as genes causative of corpus callosum anomalies in patients with 1q43-1q44 deletions. We report on a girl with dysmorphic features, seizures beginning in infancy, hypotonia, marked developmental delay, and dysgenesis of the corpus callosum. Chromosomal microarray analysis detected a de novo 1.47 Mb deletion at 1q44. The deleted interval encompasses the ZNF238 gene but not the CEP170 or AKT3 genes, thus providing additional evidence for the former and against the latter as being causative of corpus callosum anomalies in patients with such deletions.

Agenesia do Corpo Caloso/genética , Deleção Cromossômica , Cromossomos Humanos Par 1 , Haploinsuficiência , Proteínas Repressoras/genética , Agenesia do Corpo Caloso/diagnóstico , Encéfalo/patologia , Pré-Escolar , Hibridização Genômica Comparativa , Facies , Feminino , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente , Lactente , Imageamento por Ressonância Magnética , Fenótipo
J Child Neurol ; 28(10): 1309-11, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22952313


We report a child presenting with intermittent ophthalmoplegia and fluctuating ptosis and facial weakness whose evaluation revealed no evidence of myasthenia gravis but did reveal hyperthyroidism secondary to Graves disease. Successful treatment of the child's endocrinopathy resulted in complete resolution of his presenting symptoms. Children presenting with ophthalmoplegia and ptosis without proptosis should be evaluated for hyperthyroidism if no evidence of a myopathy or disorder of neuromuscular junction transmission is found.

Doença de Graves/diagnóstico , Miastenia Gravis/diagnóstico , Pré-Escolar , Diagnóstico Diferencial , Humanos , Masculino
Adv Exp Med Biol ; 724: 154-71, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22411242


Leukodystrophies comprise a broad group of progressive, inherited disorders affecting mainly myelin. They often present after a variable period of normalcy with a variety of neurologic problems. Though the ultimate diagnosis is not found in many patients with leukodystrophies, distinctive features unique to them aid in diagnosis, treatment and prognostication. The clinical characteristics, etiologies, diagnostic testing and treatment options are reviewed in detail for some of the major leukodystrophies: X-linked adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, Alexander disease, Canavan disease, megalencephalic leukoencephalopathy with subcortical cysts and vanishing white matter disease.

Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Doenças Neurodegenerativas , Encéfalo/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/classificação , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/terapia , Humanos , Imageamento por Ressonância Magnética , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/terapia