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1.
J Pediatr ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31477379

RESUMO

OBJECTIVES: To assess the outcome of population-based newborn screening for mucopolysaccharidosis type II (MPS II) during the first year of screening in Illinois. STUDY DESIGN: Tandem mass spectrometry was used to measure iduronate-2-sulfatase (I2S) activity in dried blood spot specimens obtained from 162 000 infant samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. RESULTS: One case of MPS II and 14 infants with pseudodeficiency for I2S were identified. CONCLUSIONS: Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into the statewide newborn screening program in Illinois.

2.
Hum Mutat ; 40(7): 908-925, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30817854

RESUMO

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

3.
Am J Hum Genet ; 102(3): 468-479, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29429572

RESUMO

Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.

4.
J Hum Genet ; 63(3): 349-356, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29279609

RESUMO

Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental syndrome for which mutations in five causative genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex, account for ~70% of cases. Herein we report on four female Subjects who were found to carry novel intragenic deletions in HDAC8. In one case, the deletion was found in mosaic state and it was determined to be present in ~38% of blood lymphocytes and in nearly all cells of a buccal sample. All deletions, for which parental blood samples were available, were shown to have arisen de novo. X-chromosome inactivation studies demonstrated marked skewing, suggesting strong selection against the mutated HDAC8 allele. Based on an investigation of the deletion breakpoints, we hypothesize that microhomology-mediated replicative mechanisms may be implicated in the formation of some of these rearrangements. This study broadens the mutational spectrum of HDAC8, provides the first description of a causative HDAC8 somatic mutation and increases the knowledge on possible mutational mechanisms underlying copy number variations in HDAC8. Moreover our findings highlight the clinical utility of considering copy number analysis in HDAC8 as well as the analysis on DNA from more than one tissue as an indispensable part of the routine molecular diagnosis of individuals with CdLS or CdLS-overlapping features.


Assuntos
Síndrome de Lange/diagnóstico , Síndrome de Lange/genética , Estudos de Associação Genética , Histona Desacetilases/genética , Fenótipo , Proteínas Repressoras/genética , Deleção de Sequência , Sequência de Bases , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Éxons , Facies , Feminino , Duplicação Gênica , Humanos , Análise de Sequência de DNA , Inativação do Cromossomo X
5.
Am J Hum Genet ; 101(5): 768-788, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100089

RESUMO

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Deficiência Intelectual/genética , Mutação/genética , Animais , Encéfalo/patologia , Linhagem Celular , Exoma/genética , Feminino , Ácido Glutâmico/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Fosforilação/genética , Transdução de Sinais/genética
6.
Hum Mol Genet ; 26(24): 4937-4950, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29040572

RESUMO

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.


Assuntos
Ferredoxinas/genética , Atrofia Óptica/genética , Sulfito Redutase (Ferredoxina)/genética , Adolescente , Alelos , Animais , Criança , Pré-Escolar , Transporte de Elétrons , Feminino , Ferredoxinas/metabolismo , Humanos , Lactente , Ferro/metabolismo , Proteínas com Ferro-Enxofre/genética , Masculino , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Mutagênese , Mutação , Oxirredutases/genética , Oxirredutases/metabolismo , Linhagem , Sulfito Redutase (Ferredoxina)/metabolismo , Sequenciamento Completo do Exoma/métodos
7.
J Pediatr ; 190: 130-135, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28728811

RESUMO

OBJECTIVES: To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first cohort of infants tested in the state of Illinois. STUDY DESIGN: Tandem mass spectrometry was used to assay for the 5 LSD-associated enzymes in dried blood spot specimens obtained from 219 973 newborn samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. RESULTS: The total number of cases with a positive diagnosis and the incidence for each disorder were as follows: Fabry disease, n = 26 (1 in 8454, including the p.A143T variant); Pompe disease, n = 10 (1 in 21 979); Gaucher disease, n = 5 (1 in 43 959); mucopolysaccharidosis (MPS) type 1, n = 1 (1 in 219 793); and Niemann-Pick disease type A/B, n = 2 (1 in 109 897). Twenty-two infants had a positive screen for 1 of the 5 disorders but could not be classified as either affected or unaffected after follow-up testing, including genotyping. Pseudodeficiencies for alpha-L-iduronidase and alpha-glucosidase were detected more often than true deficiencies. CONCLUSIONS: The incidences of Fabry disease and Pompe disease were significantly higher than published estimates, although most cases detected were predicted to be late onset. The incidences of Gaucher disease, MPS I, and Niemann-Pick disease were comparable with previously published estimates. A total of 16 infants could not be positively identified as either affected or unaffected. To validate the true risks and benefits of newborn screening for LSD, long term follow-up in these infants and those detected with later-onset disorders will be essential.


Assuntos
Doenças por Armazenamento dos Lisossomos/diagnóstico , Triagem Neonatal/métodos , Teste em Amostras de Sangue Seco , Genótipo , Humanos , Illinois/epidemiologia , Incidência , Lactente , Recém-Nascido , Doenças por Armazenamento dos Lisossomos/epidemiologia , Espectrometria de Massas em Tandem
8.
Neurology ; 86(22): 2085-93, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27164698

RESUMO

OBJECTIVE: To analyze the range of demographic, clinical, MRI, and CSF features of acute disseminated encephalomyelitis (ADEM), a rare, typically monophasic demyelinating disorder, and analyze long-term outcomes including time and risk factors for subsequent clinical events as well as competing diagnoses. METHODS: We performed a retrospective, multicenter study in 4 US academic medical centers of all patients clinically diagnosed with ADEM. Initial presentation of pediatric and adult ADEM and monophasic and multiphasic disease were compared. The Aalen-Johansen estimator was used to produce estimates of the probability of transitioning to a multiphasic diagnosis as a function of time since initial diagnosis, treating death and alternative diagnoses as competing risks. RESULTS: Of 228 patients (122 children, age range 1-72 years, 106 male, median follow-up 24 months [25th-75th percentile 6-67], 7 deaths), approximately one quarter (n = 55, 24%) experienced at least one relapse. Relapsing disease in children was more often diagnosed as multiphasic ADEM than in adults (58% vs 21%, p = 0.007), in whom MS was diagnosed more often. Encephalopathy at initial presentation (hazard ratio [HR] 0.383, p = 0.001), male sex (HR 0.394, p = 0.002), and increasing age at onset (HR 0.984, p = 0.035) were independently associated with a longer time to a demyelinating disease relapse in a multivariable model. In 17 patients, diagnoses other than demyelinating disease were concluded in long-term follow-up. CONCLUSIONS: Relapsing disease after ADEM is fairly common and associated with a few potentially predictive features at initial presentation. Age-specific guidelines for ADEM diagnosis and treatment may be valuable, and vigilance for other, mostly rare, diseases is imperative.


Assuntos
Encefalomielite Aguda Disseminada/epidemiologia , Adolescente , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Encefalomielite Aguda Disseminada/líquido cefalorraquidiano , Encefalomielite Aguda Disseminada/diagnóstico , Encefalomielite Aguda Disseminada/terapia , Feminino , Seguimentos , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto Jovem
9.
Neuropsychology ; 30(2): 135-42, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26237627

RESUMO

OBJECTIVE: To test the hypothesis that late-life depression is associated with dementia-related pathology. METHOD: Older participants (n = 1,965) in 3 longitudinal clinical-pathologic cohort studies who had no cognitive impairment at baseline underwent annual clinical evaluations for a mean of 8.0 years (SD = 5.0). The authors defined depression diagnostically, as major depression during the study period, and psychometrically, as elevated depressive symptoms during the study period, and established their relation to cognitive outcomes (incident dementia, rate of cognitive decline). A total of 657 participants died and underwent a uniform neuropathologic examination. The authors estimated the association of depression with 6 dementia-related markers (tau tangles, beta-amyloid plaques, Lewy bodies, hippocampal sclerosis, gross and microscopic infarcts) in logistic regression models. RESULTS: In the full cohort, 9.4% were diagnosed with major depression and 8.6% had chronically elevated depressive symptoms, both of which were related to adverse cognitive outcomes. In the 657 persons who died and had a neuropathologic examination, higher beta-amyloid plaque burden was associated with higher likelihood of major depression (present in 11.0%; OR = 1.392, 95% CI = 1.088, 1.780) but not with elevated depressive symptoms (present in 11.3%; OR = 0.919, 95% CI = 0.726, 1.165). None of the other pathologic markers was related to either of the depression measures. Neither dementia nor antidepressant medication modified the relation of pathology to depression. CONCLUSION: The results do not support the hypothesis that major depression is associated with dementia-related pathology.


Assuntos
Envelhecimento/psicologia , Peptídeos beta-Amiloides/análise , Química Encefálica , Encéfalo/patologia , Cognição , Demência/diagnóstico , Demência/psicologia , Depressão/diagnóstico , Depressão/psicologia , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Autopsia , Tronco Encefálico/química , Tronco Encefálico/patologia , Córtex Cerebral/química , Córtex Cerebral/patologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/patologia , Transtornos Cognitivos/psicologia , Demência/patologia , Feminino , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos
10.
Chem Asian J ; 10(10): 2221-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26350570

RESUMO

The personal glucose meter (PGM) was recently shown to be a general meter to detect many targets. Most studies, however, focus on transforming either target binding or enzymatic activity that cleaves an artificial substrate into the production of glucose. More importantly, almost all reports exhibit their methods by using artificial samples, such as buffers or serum samples spiked with the targets. To expand the technology to even broader targets and to validate its potential in authentic, more complex clinical samples, we herein report expansion of the PGM method by using alkaline phosphatase (ALP) that links the enzymatic activity of galactose-1-phosphate uridyltransferase to the production of glucose, which allows point-of-care galactosemia diagnosis in authentic human clinical samples. Given the presence of ALP in numerous enzymatic assays for clinical diagnostics, the methods demonstrated herein advance the field closer to point-of-care detection of a wide range of targets in real clinical samples.


Assuntos
Fosfatase Alcalina/sangue , Automonitorização da Glicemia/instrumentação , Galactosemias/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , UTP-Hexose-1-Fosfato Uridililtransferase/metabolismo , Animais , Técnicas Biossensoriais/métodos , Configuração de Carboidratos , Bovinos , Eritrócitos/química , Cavalos/sangue , Humanos
11.
Orphanet J Rare Dis ; 10: 99, 2015 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-26289392

RESUMO

BACKGROUND: This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine ß-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities. PURPOSE OF THE STUDY: The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence. RESULTS AND DISCUSSION: The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 µM or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Heterozigoto , Homozigoto , Metionina Adenosiltransferase/genética , Adolescente , Adulto , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
12.
Mol Genet Genomic Med ; 3(4): 346-53, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26247050

RESUMO

We describe six individuals with microdeletions and microduplications in the distal 22q11.2 region detected by microarray. Five of the abnormalities have breakpoints in the low-copy repeats (LCR) in this region and one patient has an atypical rearrangement. Two of the six patients with abnormalities in the region between LCR22 D-E have hearing loss, which has previously been reported only once in association with these abnormalities. We especially note the behavioral/neuropsychiatric problems, including the severity and early onset, in patients with distal 22q11.2 rearrangements. Our patients add to the genotype-phenotype correlations which are still being generated for these chromosomal anomalies.

13.
Pediatr Neurol ; 52(3): 349-51, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25559937

RESUMO

BACKGROUND: Strokes associated with roller-coaster rides are unusual. PATIENT: A previously healthy 4-year-old boy developed acute onset of left-sided weakness when flying home from a trip to an amusement park. He had frequented two roller coaster rides the day prior. Upon evaluation, he was found to have an acute right middle cerebral artery territory infarction. RESULTS: Cerebral angiography showed dissection of the right cervical internal carotid artery and right middle cerebral artery occlusion involving the M1 segment. He was treated with aspirin. Evaluation for underlying connective tissue diseases was unremarkable. CONCLUSION: We speculate that repetitive forces of acceleration and deceleration may have led to a cervical internal carotid artery intimal tear, followed by thromboembolism. It remains uncertain what the threshold of susceptibility to repetitive rotational changes and tolerability to G forces in an otherwise healthy child truly is.


Assuntos
Traumatismos em Atletas/complicações , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/diagnóstico , Angiografia Cerebral , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Humanos , Masculino
14.
Neurology ; 83(8): 702-9, 2014 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-25080520

RESUMO

OBJECTIVE: To clarify the relationship between depressive symptoms and the clinical and neuropathologic manifestations of dementia. METHODS: In a clinical-pathologic cohort study, 1,764 older persons without cognitive impairment at enrollment completed annual clinical evaluations for a mean of 7.8 years. The evaluations included assessment of depressive symptoms (10-item Center for Epidemiological Studies Depression Scale) and cognitive function (battery of 17 performance tests). A total of 582 individuals died during follow-up and underwent a uniform neuropathologic examination to quantify ß-amyloid plaques and tau tangle density in multiple brain regions and identify neocortical Lewy bodies, hippocampal sclerosis, and gross and microscopic cerebral infarcts. RESULTS: Level of depressive symptoms slightly increased during follow-up. Incident mild cognitive impairment (52.2%) was associated with higher level of depressive symptoms before the diagnosis but not with change in symptoms after the diagnosis; incident dementia (17.9%) was associated with higher symptom level before dementia onset and with more rapid decline in symptoms after dementia onset. None of the neuropathologic markers was related to level of depressive symptoms or change in symptoms over time. In a mixed-effects model adjusted for the neuropathologic markers, higher level of depressive symptoms averaged over evaluations was associated with more rapid global cognitive decline, accounting for 4.4% of the variability in decline not attributable to the neuropathologic markers. Depressive symptoms did not modify the association of the neuropathologic markers with cognitive decline. CONCLUSION: In old age, depressive symptoms have an association with cognitive decline that is independent of the neuropathologic hallmarks of dementia.


Assuntos
Transtornos Cognitivos/patologia , Demência/patologia , Depressão/patologia , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/complicações , Transtornos Cognitivos/diagnóstico , Estudos de Coortes , Demência/complicações , Demência/diagnóstico , Depressão/diagnóstico , Depressão/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica
15.
Mol Genet Metab Rep ; 1: 114-123, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24749080

RESUMO

OPA3-related 3-methylglutaconic aciduria, or Costeff Optic Atrophy syndrome, is a neuro-ophthalmologic syndrome of early-onset bilateral optic atrophy and later-onset spasticity, and extrapyramidal dysfunction. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is markedly increased. OPA3-related 3-methylglutaconic aciduria is due to mutations in the OPA3 gene located at 19q13.2-13.3. Here we describe two siblings with novel compound heterozygous variants in OPA3: c.1A>G (p.1M>V) in the translation initiation codon in exon 1 and a second variant, c.142+5G>C in intron 1. On cDNA sequencing the c.1A>G appeared homozygous, indicating that the allele without the c.1A>G variant is degraded. This is likely due to an intronic variant; possibly the IVS1+5 splice site variant. The older female sibling initially presented with motor developmental delay and vertical nystagmus during her first year of life and was diagnosed subsequently with optic atrophy. Her brother presented with mildly increased hip muscle tone followed by vertical nystagmus within the first 6 months of life, and was found to have elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid, and optic atrophy by 1.5 years of age. Currently, ages 16 and 7, both children exhibit ataxic gaits and dysarthric speech. Immunofluorescence studies on patient's cells showed fragmented mitochondrial morphology. Thus, though the exact function of OPA3 remains unknown, our experimental results and clinical summary provide evidence for the pathogenicity of the identified OPA3 variants and provide further evidence for a mitochondrial pathology in this disease.

16.
Neuropsychology ; 28(2): 305-11, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24364391

RESUMO

OBJECTIVE: Harm avoidance, a trait indicative of behavioral inhibition, is associated with disability and dementia in old age, but the basis of these associations is uncertain. We test the hypothesis that higher level of harm avoidance is associated with increased likelihood of cerebral infarction. METHOD: Older persons without dementia completed a standard measure of harm avoidance. During a mean of 3.5 years of follow-up, 257 (of 1,082) individuals died of whom 206 (80%) underwent brain autopsy. The number of chronic cerebral infarcts (microscopic plus gross; expressed as 0, 1, or >1) was assessed on neuropathologic examination, completed in 192 individuals at the time of analyses. RESULTS: On postmortem examination, chronic cerebral infarcts were found in 89 (42 with 1, 47 with >1). Higher harm avoidance was associated with higher likelihood of infarcts (odds ratio = 1.083, 95% confidence interval = 1.040-1.128). A moderately high level of the trait (score = 17, 75th percentile) was associated with a 2.4-fold increase in the likelihood of infarction compared with a moderately low level of the trait (score = 6, 25th percentile). These associations persisted in models that controlled for other cardiovascular risk factors. CONCLUSION: Higher level of the harm avoidance trait may be a risk factor for cerebral infarction.


Assuntos
Ansiedade/complicações , Ansiedade/psicologia , Infarto Cerebral/complicações , Personalidade , Idoso de 80 Anos ou mais , Infarto Cerebral/epidemiologia , Feminino , Humanos , Masculino , Fatores de Risco
17.
Mol Genet Metab ; 101(2-3): 172-7, 2010 Oct-Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20675163

RESUMO

Methionine adenosyltransferases (MAT's) are central enzymes in living organisms that have been conserved with a high degree of homology among species. In the liver, MAT I and III, tetrameric and dimeric isoforms of the same catalytic subunit encoded by the gene MAT1A, account for the predominant portion of total body synthesis of S-adenosylmethionine (SAM), a versatile sulfonium ion-containing molecule involved in a variety of vital metabolic reactions and in the control of hepatocyte proliferation and differentiation. During the past 15years 28 MAT1A mutations have been described in patients with elevated plasma methionines, total homocysteines at most only moderately elevated, and normal levels of tyrosine and other aminoacids. In this study we describe functional analyses that determine the MAT and tripolyphosphatase (PPPase) activities of 18 MAT1A variants, six of them novel, and none of them previously assayed for activity. With the exception of G69S and Y92H, all recombinant proteins showed impairment (usually severe) of MAT activity. Tripolyphosphate (PPPi) hydrolysis was decreased only in some mutant proteins but, when it was decreased MAT activity was always also impaired.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Isoenzimas/genética , Metionina Adenosiltransferase/genética , Metionina/sangue , Hidrolases Anidrido Ácido/genética , Adulto , Humanos , Lactente , Recém-Nascido , Isoenzimas/metabolismo , Masculino , Metionina Adenosiltransferase/metabolismo
18.
Pediatr Neurol ; 43(3): 205-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20691944

RESUMO

A number of medications have been used with varying success to treat the symptoms of generalized, focal, and paroxysmal dyskinesias; these agents include anticonvulsant, benzodiazepine, neuroleptic, dopaminergic, dopamine antagonist, and carbonic anhydrase inhibitor types. The carbonic anhydrase inhibitor drug group is best represented by acetazolamide, which has been widely applied in the treatment of paroxysmal dyskinesias. Zonisamide, which has several putative pharmacologic mechanisms of action, is a member of the carbonic anhydrase inhibitor drug group. Zonisamide was chosen for treatment of secondary paroxysmal dystonia in a patient with pyruvate dehydrogenase deficiency (case 1) and in two patients with neonatal hemochromatosis and family history of neonatal hemochromatosis (cases 2 and 3). Although zonisamide ameliorated the symptoms of secondary paroxysmal dystonia in these three patients, the precise biochemical mechanism remains unclear, and further studies are needed to substantiate and explain this finding.


Assuntos
Antioxidantes/uso terapêutico , Distúrbios Distônicos/tratamento farmacológico , Isoxazóis/uso terapêutico , Adolescente , Criança , Feminino , Hemocromatose/complicações , Hemocromatose/tratamento farmacológico , Humanos , Masculino , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/tratamento farmacológico , Zonisamida
19.
Nat Genet ; 39(9): 1127-33, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17704778

RESUMO

Nonsense-mediated mRNA decay (NMD) is of universal biological significance. It has emerged as an important global RNA, DNA and translation regulatory pathway. By systematically sequencing 737 genes (annotated in the Vertebrate Genome Annotation database) on the human X chromosome in 250 families with X-linked mental retardation, we identified mutations in the UPF3 regulator of nonsense transcripts homolog B (yeast) (UPF3B) leading to protein truncations in three families: two with the Lujan-Fryns phenotype and one with the FG phenotype. We also identified a missense mutation in another family with nonsyndromic mental retardation. Three mutations lead to the introduction of a premature termination codon and subsequent NMD of mutant UPF3B mRNA. Protein blot analysis using lymphoblastoid cell lines from affected individuals showed an absence of the UPF3B protein in two families. The UPF3B protein is an important component of the NMD surveillance machinery. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Mutação , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Sequência de Aminoácidos , Linhagem Celular Transformada , Códon sem Sentido , Análise Mutacional de DNA , Saúde da Família , Feminino , Perfilação da Expressão Gênica , Humanos , Immunoblotting , Masculino , Retardo Mental Ligado ao Cromossomo X/patologia , Dados de Sequência Molecular , Linhagem , Estabilidade de RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Síndrome
20.
J Int Neuropsychol Soc ; 11(4): 400-7, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16209420

RESUMO

Little is known about the relative benefits of cognitively stimulating activities at different points in the lifespan. In a cohort of 576 older persons without dementia, we assessed current and past (childhood, young adulthood, middle age) frequency of cognitive activity; availability of cognitively stimulating resources in the home in childhood and middle age; and 5 domains of cognitive function. Past cognitive activity and cognitive resources were positively correlated with both current cognitive activity and current cognitive function. The association with cognitive function was reduced after controlling for current cognitive activity, however. Current cognitive activity was associated with better cognitive function, especially semantic memory and perceptual speed, even after controlling for past activity. The results suggest that past cognitive activity contributes to current cognition principally through its association with cognitive activity in old age.


Assuntos
Atividades Cotidianas , Cognição/fisiologia , Avaliação Geriátrica , Vida , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estudos Longitudinais , Masculino , Memória/fisiologia , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Testes Neuropsicológicos , Percepção/fisiologia , Psicometria/métodos , Desempenho Psicomotor/fisiologia
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