Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Brain ; 12(1): 92, 2019 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-31707987

RESUMO

We report the identification of a de novo GABRA1 (R214C) variant in a child with epileptic encephalopathy (EE), describe its functional characterization and pathophysiology, and evaluate its potential therapeutic options. The GABRA1 (R214C) variant was identified using whole exome sequencing, and the pathogenic effect of this mutation was investigated by comparing wild-type (WT) α1 and R214C α1 GABAA receptor-expressing HEK cells. GABA-evoked currents in these cells were recorded using whole-cell, outside-out macro-patch and cell-attached single-channel patch-clamp recordings. Changes to surface and total protein expression levels of WT α1 and R214C α1 were quantified using surface biotinylation assay and western blotting, respectively. Finally, potential therapeutic options were explored by determining the effects of modulators, including diazepam, insulin, and verapamil, on channel gating and receptor trafficking of WT and R214C GABAA receptors. We found that the GABRA1 (R214C) variant decreased whole-cell GABA-evoked currents by reducing single channel open time and both surface and total GABAA receptor expression levels. The GABA-evoked currents in R214C GABAA receptors could only be partially restored with benzodiazepine (diazepam) and insulin. However, verapamil treatment for 24 h fully restored the function of R214C mutant receptors, primarily by increasing channel open time. We conclude that the GABRA1 (R214C) variant reduces channel activity and surface expression of mutant receptors, thereby contributing to the pathogenesis of genetic EE. The functional restoration by verapamil suggests that it is a potentially new therapeutic option for patients with the R214C variant and highlights the value of precision medicine in the treatment of genetic EEs.

2.
Front Neurol ; 10: 434, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164858

RESUMO

Targeted whole-exome sequencing (WES) is a powerful diagnostic tool for a broad spectrum of heterogeneous neurological disorders. Here, we aim to examine the impact on diagnosis, treatment and cost with early use of targeted WES in early-onset epilepsy. WES was performed on 180 patients with early-onset epilepsy (≤5 years) of unknown cause. Patients were classified as Retrospective (epilepsy diagnosis >6 months) or Prospective (epilepsy diagnosis <6 months). WES was performed on an Ion Proton™ and variant reporting was restricted to the sequences of 620 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed. A molecular diagnoses (pathogenic/likely pathogenic variants) was achieved in 59/180 patients (33%). Clinical management changed following WES findings in 23 of 59 diagnosed patients (39%) or 13% of all patients. A possible diagnosis was identified in 21 additional patients (12%) for whom supporting evidence is pending. Time from epilepsy onset to a genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 145 days Prospective vs. 2,882 days Retrospective). Costs of prior negative tests averaged $8,344 per patient in the Retrospective group, suggesting savings of $5,110 per patient using WES. These results highlight the diagnostic yield, clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important.

3.
J Child Neurol ; 34(12): 728-734, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31208268

RESUMO

KCNT1 encodes a sodium-activated potassium channel highly expressed in the brain, regulating hyperpolarization following repetitive firing. Mutations in KCNT1 were originally implicated in autosomal-dominant nocturnal frontal lobe epilepsy and epilepsy of infancy with migrating focal seizures. It is now known that there is variability in phenotypic expression and incomplete penetrance. We describe 2 patients with KCNT1-related epilepsy, one with epilepsy of infancy with migrating focal seizures and one with multifocal epilepsy. As most patients with KCNT1 variants have treatment-resistant epilepsy, drugs that specifically target the KCNT1 channel have been of great interest. Quinidine, a broad-spectrum potassium channel blocker, has shown promise; however, clinical trial results have been variable. Our patient with epilepsy of infancy with migrating focal seizures did not respond to a trial of quinidine at 6 weeks of age-one of the earliest reported quinidine trials in the literature for KCNT1-related epilepsy. This indicates that timing of treatment and response may not be related. Both patients responded to high-dose phenobarbital. The patient with epilepsy of infancy with migrating focal seizures also had a significant reduction in seizures with potassium bromide (KBr). Our data suggest that alternative therapies to quinidine should be considered as a therapeutic option for patients with KCNT1-related epilepsy. Although improved seizure control led to parent-reported improvements in neurodevelopment, it is unknown if phenobarbital and KBr impact the overall developmental trajectory of patients with KCNT1-related epilepsy. Further multicenter longitudinal studies are required.

4.
Genet Med ; 21(7): 1621-1628, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30542205

RESUMO

PURPOSE: The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP). METHODS: Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following: severe intellectual disability, progressive neurological deterioration, other abnormalities on neurological examination, multiorgan disease, congenital anomalies outside of the central nervous system, an abnormal neurotransmitter profile, family history, brain imaging findings not typical for cerebral palsy. Previous assessment by a neurologist and/or clinical geneticist, including biochemical testing, neuroimaging, and chromosomal microarray, did not yield an etiologic diagnosis. RESULTS: A precise molecular diagnosis was established in 65% of the 50 patients. We also identified candidate disease genes without a current OMIM disease designation. Targeted intervention was enabled in eight families (~15%). CONCLUSION: NGS enabled a molecular diagnosis in ACP cases, ending the diagnostic odyssey, improving genetic counseling and personalized management, all in all enhancing precision medicine practices.

5.
J Genet Couns ; 2018 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-30033481

RESUMO

Clinical use of genome-wide sequencing (GWS) requires pre-test genetic counseling, but the availability of genetic counseling is limited. We developed an interactive online decision-support tool, DECIDE, to make genetic counseling, patient education, and decision support more readily available. We performed a non-inferiority trial comparing DECIDE to standard genetic counseling to assess the clinical value of DECIDE for pre-GWS counseling. One hundred and six parents considering GWS for their children with epilepsy were randomized to conventional genetic counseling or DECIDE. Following the intervention, we measured parents' knowledge and empowerment and asked their opinions about using DECIDE. Both DECIDE and conventional genetic counseling significantly increased parents' knowledge, with no difference between groups. Empowerment also increased but by less than 2% in each group. Parents liked using DECIDE and found it useful; 81% would recommend it to others; 49% wished to use it along with a genetic counselor; 26% of parents preferred to see a genetic counselor; 7% preferred DECIDE alone; and 18% had no preference. DECIDE appears equivalent to genetic counseling at conveying information. In addition, it was highly acceptable to the majority of study participants, many of whom indicated that it was useful to their decision-making. Use of DECIDE as a pre-test tool may extend genetic counseling resources.

6.
Am J Hum Genet ; 102(1): 175-187, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29276005

RESUMO

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.


Assuntos
Deficiências do Desenvolvimento/enzimologia , Deficiências do Desenvolvimento/genética , Histona Desmetilases/genética , Histona-Lisina N-Metiltransferase/genética , Adolescente , Criança , Pré-Escolar , Feminino , Haploinsuficiência , Humanos , Masculino , Mutação
7.
Am J Hum Genet ; 101(2): 300-310, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777935

RESUMO

Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3γ) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n = 1) and YWHAG (n = 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder's etiology and genotype-phenotype correlations.


Assuntos
Proteínas 14-3-3/genética , Predisposição Genética para Doença , Proteínas de Transporte de Glutamato da Membrana Plasmática/genética , Espasmos Infantis/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Exoma/genética , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Fenótipo , Adulto Jovem
8.
Pediatr Neurol ; 75: 87-90, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28811059

RESUMO

BACKGROUND: Pathogenic heterozygous variants in the ATP1A2 gene have most commonly been associated with familial hemiplegic migraine. However, a wide spectrum of phenotypes that include alternating hemiplegia of childhood and epilepsy have been described. PATIENT DESCRIPTION: We describe a boy who presented at age three months with a complex phenotype that included epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. Magnetic resonance imaging demonstrated unilateral cortical edema during a severe episode of hemiplegia that was followed by a persistent mild hemiparesis. RESULTS: Whole-exome sequencing identified a previously reported ATP1A2 missense variant (p.Arg548Cys) classified as pathogenic and a novel missense variant (p.Arg1008Trp) classified as a variant of uncertain significance. After this genetic diagnosis, treatment with flunarizine was initiated and no further episodes of hemiplegia have occurred. CONCLUSIONS: This is only the second report of compound heterozygosity of the ATP1A2 gene. It demonstrates the spectrum of paroxysmal neurological events that can arise as a result of ATP1A2 variants, with unique features overlapping alternating hemiplegia of childhood, hemiplegic migraine, and epilepsy. This child illustrates the diagnostic challenges that these disorders can present and the importance of genetic diagnosis in guiding management.


Assuntos
Epilepsia/genética , Hemiplegia/genética , Mutação/genética , ATPase Trocadora de Sódio-Potássio/genética , Pré-Escolar , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Hemiplegia/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Fenótipo
9.
Am J Hum Genet ; 101(1): 65-74, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28669405

RESUMO

KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.


Assuntos
Epilepsia/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Canais de Potássio KCNQ/genética , Mutação/genética , Eletroencefalografia , Humanos , Ativação do Canal Iônico , Canais de Potássio KCNQ/química , Proteínas Mutantes/química , Proteínas Mutantes/genética , Fenótipo , Alinhamento de Sequência
10.
Neurol Genet ; 2(6): e120, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27872899

RESUMO

OBJECTIVE: We describe 2 additional patients with early-onset epilepsy with a de novo FGF12 mutation. METHODS: Whole-exome sequencing was performed in 2 unrelated patients with early-onset epilepsy and their unaffected parents. Genetic variants were assessed by comparative trio analysis. Clinical evolution, EEG, and neuroimaging are described. The phenotype and response to treatment was reviewed and compared to affected siblings in the original report. RESULTS: We identified the same FGF12 de novo mutation reported previously (c.G155A, p.R52H) in 2 additional patients with early-onset epilepsy. Similar to the original brothers described, both presented with tonic seizures in the first month of life. In the first patient, seizures responded to sodium channel blockers and her development was normal at 11 months. Patient 2 is a 15-year-old girl with treatment-resistant focal epilepsy, moderate intellectual disability, and autism. Carbamazepine (sodium channel blocker) was tried later in her course but not continued due to an allergic reaction. CONCLUSIONS: The identification of a recurrent de novo mutation in 2 additional unrelated probands with early-onset epilepsy supports the role of FGF12 p.R52H in disease pathogenesis. Affected carriers presented with similar early clinical phenotypes; however, this report expands the phenotype associated with this mutation which contrasts with the progressive course and early mortality of the siblings in the original report.

11.
N Engl J Med ; 374(23): 2246-55, 2016 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-27276562

RESUMO

BACKGROUND: Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS: To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient's clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS: We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS: Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children's Hospital Foundation and others.).


Assuntos
Exoma , Testes Genéticos/métodos , Erros Inatos do Metabolismo/genética , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Erros Inatos do Metabolismo/diagnóstico , Fenótipo , Adulto Jovem
12.
Mol Genet Metab ; 117(1): 42-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26647175

RESUMO

We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p.Glu717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy and cerebral/cerebellar atrophy. In the cerebrospinal fluid both homovanillic acid and 5-hydroxyindoleacetic acid were significantly decreased; extensive biochemical and genetic investigations ruled out primary neurotransmitter deficiencies and other known inborn errors of metabolism. In an 8-year old female with an early onset intractable epileptic encephalopathy, developmental regression, and progressive cerebellar atrophy, a previously unreported de novo missense mutation was identified in SCN8A (c.5615G>A; p.Arg1872Gln), affecting a highly conserved residue located in the C-terminal of the Nav1.6 protein. Aside from decreased homovanillic acid and 5-hydroxyindoleacetic acid, 5-methyltetrahydrofolate was also found to be low. We hypothesize that these channelopathies cause abnormal synaptic mono-amine metabolite secretion/uptake via impaired vesicular release and imbalance in electrochemical ion gradients, which in turn aggravate the seizures. Treatment with oral 5-hydroxytryptophan, l-Dopa/Carbidopa, and a dopa agonist resulted in mild improvement of seizure control in the male case, most likely via dopamine and serotonin receptor activated signal transduction and modulation of glutamatergic, GABA-ergic and glycinergic neurotransmission. Neurotransmitter analysis in other sodium channelopathy patients will help validate our findings, potentially yielding novel treatment opportunities.


Assuntos
Canalopatias/metabolismo , Epilepsia Resistente a Medicamentos/metabolismo , Epilepsia/metabolismo , Mutação de Sentido Incorreto , Neurotransmissores/deficiência , Convulsões/etiologia , Transtorno Autístico/etiologia , Transtorno Autístico/genética , Canalopatias/tratamento farmacológico , Criança , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia/tratamento farmacológico , Epilepsia/genética , Exoma , Feminino , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Masculino , Hipotonia Muscular/etiologia , Hipotonia Muscular/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Neurotransmissores/metabolismo , Receptores Dopaminérgicos/metabolismo , Convulsões/genética , Análise de Sequência de DNA , Canais de Sódio/deficiência , Canais de Sódio/genética , Tetra-Hidrofolatos/líquido cefalorraquidiano
13.
Epilepsia ; 56(6): 856-63, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25944453

RESUMO

OBJECTIVE: Infantile spasms (IS) are a severe form of childhood epilepsy associated with autism spectrum disorders (ASD) in up to 35% of cases. The objective of this post hoc analysis of our randomized control trial was to determine whether rapid diagnosis and treatment of IS could limit the incidence of ASD while identifying risk factors related to ASD outcome. METHODS: Patients with IS were randomized in a standardized diagnostic and treatment protocol. Clinical and electroencephalogram (EEG) evaluations were completed at all eight visits over 5 years, while cognitive evaluations were administered at 0, 6, 24 and 60 months, respectively. Autism was initially screened by means of the Checklist for Autism in Toddlers (CHAT) at 24 months, and formally assessed at the 30-and 60-month follow-ups using the Autism Diagnostic Observation Schedule-Generic (ADOS-G). RESULTS: Of the 69 patients included in the study, 25 could not be assessed due to severe delay or death. Eleven of the 42 patients screened with CHAT, were found to be at risk of an ASD outcome. ADOS was performed in 44 and 10 were diagnosed with ASD. The CHAT proved to correlate highly with the ADOS (80% ppv). Only patients with symptomatic IS developed ASD (p = 0.003). Earlier diagnosis or successful treatment did not correlate with a reduced rate of ASD. Other risk factors were identified such as having chronic epileptic discharges in the frontotemporal areas after disappearance of hypsarrhythmia (p = 0.005 and p = 0.007) and being of nonwhite origin (p = 0.009). SIGNIFICANCE: ASD was only observed in children with sympyomatic IS. Other clinical risk factors include chronic frontotemporal epileptic activity and being of non-white origin. Early diagnosis and treatment did not prevent ASD as an outcome of IS. However, patients at risk for ASD could be identified early on and should in the future benefit from early intervention to potentially improve their long-term outcome.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Espasmos Infantis/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/complicações , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Estudos de Coortes , Método Duplo-Cego , Eletroencefalografia , Feminino , Humanos , Incidência , Lactente , Masculino , Fatores de Risco , Espasmos Infantis/complicações , Espasmos Infantis/epidemiologia , Fatores de Tempo
14.
Neurology ; 83(21): 1898-905, 2014 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-25339210

RESUMO

OBJECTIVE: To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. METHODS: We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. RESULTS: The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T>A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis. CONCLUSIONS: 4H is a well-recognizable clinical entity if all features are present. Mutations in POLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features.


Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação/genética , RNA Polimerase III/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Adulto Jovem
15.
Orphanet J Rare Dis ; 9: 94, 2014 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-24961299

RESUMO

Desmosterolosis is an autosomal recessive disorder of cholesterol biosynthesis caused by biallelic mutations of DHCR24 (homozygous or compound heterozygous), which encodes 3-ß-hydroxysterol Δ-24-reductase. We report two sisters homozygous for the 571G>A (E191K) DHCR24 mutation. Comparison of the propositae to other reported individuals shows that psychomotor developmental delay, failure to thrive, dysgenesis of the corpus callosum, cerebral white matter atrophy and spasticity likely constitute the minimal desmosterolosis phenotype. The nonspecific features of desmosterolosis make it difficult to suspect clinically and therefore screening for it should be entertained early in the diagnostic evaluation.


Assuntos
Anormalidades Múltiplas/diagnóstico , Colesterol/biossíntese , Erros Inatos do Metabolismo Lipídico/diagnóstico , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Diagnóstico Diferencial , Feminino , Humanos , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/patologia
16.
Orphanet J Rare Dis ; 9: 15, 2014 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-24468074

RESUMO

BACKGROUND: We undertook genetic analysis of three affected families to identify the cause of dominantly-inherited CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) syndrome. METHODS: We used whole-exome sequencing to analyze two families affected with CAPOS syndrome, including the original family reported in 1996, and Sanger sequencing to assess familial segregation of rare variants identified in the probands and in a third, apparently unrelated family with CAPOS syndrome. RESULTS: We found an identical heterozygous missense mutation, c.2452G > A (p.(Glu818Lys)), in the Na⁺/K⁺ ATPase α3(ATP1A3) gene in the proband and his affected sister and mother, but not in either unaffected maternal grandparent, in the first family. The same mutation was also identified in the proband and three other affected members of the second family and in all three affected members of the third family. This mutation was not found in more than 3600 chromosomes from unaffected individuals. CONCLUSION: Other mutations in ATP1A3 have previously been demonstrated to cause rapid-onset dystonia-parkinsonism (also called dystonia-12) or alternating hemiplegia of childhood. This study shows that an allelic mutation in ATP1A3 produces CAPOS syndrome.


Assuntos
Ataxia Cerebelar/genética , Deformidades Congênitas do Pé/genética , Perda Auditiva Neurossensorial/genética , Mutação de Sentido Incorreto , Atrofia Óptica/genética , Reflexo Anormal/genética , ATPase Trocadora de Sódio-Potássio/genética , Adulto , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
17.
Eur J Hum Genet ; 21(11): 1232-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23443029

RESUMO

Inflammation is an important contributor to pediatric and adult neurodegeneration. Understanding the genetic determinants of neuroinflammation provides valuable insight into disease mechanism. We characterize a disorder of recurrent immune-mediated neurodegeneration. We report two sisters who presented with neurodegeneration triggered by infections. The proband, a previously healthy girl, presented at 22.5 months with ataxia and dysarthria following mild gastroenteritis. MRI at onset showed a symmetric signal abnormality of the cerebellar and peritrigonal white matter. Following a progressive course of partial remissions and relapses, she died at 5 years of age. Her older sister had a similar course following varicella infection, she died within 13 months. Both sisters had unremarkable routine laboratory testing, with exception of a transient mild cytopenia in the proband 19 months after presentation. Exome sequencing identified a biallelic perforin1 mutation (PRF1; p.R225W) previously associated with familial hemophagocytic lymphohistiocytosis (FHL). In contrast to FHL, these girls did not have hematopathology or cytokine overproduction. However, 3 years after disease onset, the proband had markedly deficient interleukin-1 beta (IL-1ß) production. These observations extend the spectrum of disease associated with perforin mutations to immune-mediated neurodegeneration triggered by infection and possibly due to primary immunodeficiency.


Assuntos
Ataxia/genética , Ataxia/virologia , Proteínas de Homeodomínio/genética , Mutação/genética , Criança , Pré-Escolar , Exoma/genética , Evolução Fatal , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Inflamassomos/metabolismo , Interleucina-1beta/biossíntese , Imagem por Ressonância Magnética , Masculino , Linhagem , Recidiva , Análise de Sequência de DNA
18.
Am J Hum Genet ; 87(6): 905-14, 2010 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-21129721

RESUMO

CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development.


Assuntos
3-Hidroxiesteroide Desidrogenases/genética , Anormalidades Múltiplas/genética , Alelos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Temperatura Ambiente , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Éxons , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Homologia de Sequência de Aminoácidos , Adulto Jovem
19.
Am J Med Genet A ; 149A(11): 2469-78, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19842190

RESUMO

X-linked mental retardation (XLMR) affects 1-2/1,000 males and accounts for approximately 10% of all mental retardation (MR). We have ascertained a syndromic form of XLMR segregating within a five-generation family with seven affected males. Prominent characteristics include mild to severe MR, cortical malformation, microcephaly, seizures, thin build with distinct facial features including a long and thin face, epicanthic folds, almond-shaped eyes, upslanting palpebral fissures and micrognathia and behavioral problems. Carrier females have normal physical appearance and intelligence. This combination of features is unreported and distinct from Lujan-Fryns syndrome, Snyder-Robinson syndrome, and zinc finger DHHC domain-containing 9-associated MR. We propose the name of this new syndrome to be CK syndrome.


Assuntos
Constituição Corporal , Córtex Cerebral/anormalidades , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/genética , Microcefalia/complicações , Microcefalia/genética , Adolescente , Adulto , Criança , Pré-Escolar , Facies , Evolução Fatal , Feminino , Mãos/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Gravidez , Radiografia
20.
Am J Med Genet A ; 149A(7): 1482-6, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19507262

RESUMO

Pathogenic variations of the ARX (aristaless-related homeobox) gene are associated with marked phenotypic pleiotropy. These phenotypes are X-linked neurological disorders that include brain and genital malformation and non-malformation syndromes. Typically, malformation phenotypes result from pathogenic variations that are predicted to truncate the ARX protein, or alter residues in the highly conserved homeodomain. While non-malformation phenotypes tend to be caused by pathogenic variations that are predicted to expand the first two polyalanine tracts of ARX, or alter residues outside of the homeodomain. The most common pathogenic variation of the ARX gene is a duplication of 24 bp, c.429_452 dup, which leads to an expansion of the second polyalanine tract of the ARX protein from 12 to 20 alanine residues. This pathogenic variation is associated with both sporadic and familial nonsyndromic mental retardation. Syndromic manifestations include mental retardation with hand dystonia (Partington syndrome), infantile spasms (West syndrome) and/or other epileptic seizures. Here, we report on a novel pathogenic variant of a tandem 33 bp duplication that is predicted to result in an expansion of polyalanine tract 2 in two brothers with mental retardation, epilepsy, dystonia, and the novel feature of intermittent hyperventilation. This pathogenic variation is predicted to result in a "non-homogeneous" polyalanine tract expansion that is longer than predicted expansion caused by the common 24 bp duplication. The location of the novel 33 bp duplication in the same region as the common 24 bp duplication supports this region as the ARX variation "hot spot."


Assuntos
Duplicação Gênica , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Irmãos , Fatores de Transcrição/genética , Adolescente , Sequência de Bases , Criança , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Síndrome
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA