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1.
Haematologica ; 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846500

RESUMO

Children with immune thrombocytopenia ≥6 months completing a romiplostim study received weekly subcutaneous romiplostim (1-10 mg/kg targeting platelet counts of 50-200x109/L) in this extension to examine romiplostim's long-term safety and efficacy. Sixty-five children received romiplostim for a median (range) of 2.6 (0.1-7.0) years. Median baseline age was 11 (3-18) years and platelet count was 28 (2-458)x109/L. No patient discontinued treatment for an adverse event. Median average weekly dose was 4.8 (0.1-10) mg/kg; median platelet counts remained >50x109/L, starting at week 2. Nearly all patients (94%) had ≥1 platelet response (≥50x109/L, no rescue medication in the prior 4 weeks), 72% responded at ≥75% of visits, and 58% responded at ≥90% of visits. Treatment-free response (platelets ≥50x109/L ≥24 weeks without immune thrombocytopenia treatment) was seen in 15/65 patients while withholding romiplostim doses. At onset of treatment-free response, the nine girls and six boys had a median immune thrombocytopenia duration of 4 (1-12) years and had received romiplostim for 2 (1-6) years. At last observation, treatment-free responses lasted for a median of 1 (0.4-2.1) year, with 14/15 patients still in treatment-free response. Younger age at first dose and platelet count >200x109/L in the first 4 weeks were associated with treatment-free responses. In this 7-year open-label extension, three-fourths of the patients responded ≥75% of the time, and romiplostim was well tolerated, with no substantial treatment-related adverse events. Importantly, 23% of children maintained treatment-free platelet responses while withholding romiplostim and all other immune thrombocytopenia medications for ≥6 months. (ClinicalTrials.gov #NCT01071954).

2.
Lancet Haematol ; 5(3): e117-e126, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29396092

RESUMO

BACKGROUND: Treatment options for thrombocytopenia in myelodysplastic syndromes are scarce. As described previously in a randomised phase 2 study (n=250), 58 weeks of romiplostim treatment in patients with International Prognostic Scoring System (IPSS)-defined lower-risk (low-risk or intermediate-1 risk) myelodysplastic syndromes led to reduced platelet transfusions (p<0·0001) and increased International Working Group-defined haematological improvement-platelet rates (p<0·0001) versus placebo. However, the study drug was discontinued because of the potential risk for progression to or incorrect diagnosis or treatment for acute myeloid leukaemia, based on an acute myeloid leukaemia interim hazard ratio (HR) of 2·5; the subsequent 58-week acute myeloid leukaemia HR was 1·2 (95% CI 0·4-3·8). METHODS: This study is a 5-year follow-up of a phase 2, multicentre, double-blind trial of romiplostim treatment in patients with lower-risk myelodysplastic syndromes. Eligible patients were recruited at 109 centres in North America, Europe, Russia, and Australia, were aged 18-90 years, and had platelets of 20 × 109 per L or less with or without a history of bleeding or 50 × 109 platelets per L or less with a history of bleeding. Patients were randomly assigned by interactive voice response system with stratification by baseline platelet count (≥20 × 109 per L or <20 × 109 per L) and IPSS risk (low or intermediate-1) to receive either placebo or 750 µg romiplostim subcutaneously once per week for 58 weeks. The primary outcomes for this long-term follow-up were survival and progression to acute myeloid leukaemia. Progression to acute myeloid leukaemia was defined as either 20% blasts or more after 4 weeks from romiplostim discontinuation; as per pathology; or by initiation of antileukaemia treatment. The primary outcome was assessed per protocol in all patients with available data. This study is registered with ClinicalTrials.gov, NCT00614523. FINDINGS: Patients were recruited from July 21, 2008, to Dec 16, 2010. 167 patients were assigned to receive romiplostim treatment and 83 were assigned to receive placebo. 210 (84%) of 250 patients entered the 5-year long-term follow-up (139 patients in the romiplostim group and 83 in the placebo group). At the end of follow-up, proportions of patients with acute myeloid leukaemia (20 [12%] of 167 in the romiplostim group vs nine [11%] of 83 in the placebo group; HR 1·06 [95% CI 0·48-2·33]; p=0·88) and proportions who died (93 [56%] vs 54 [54%]; HR 1·03 [0·72-1·47]; p=0·89) were not significantly different between the two groups. INTERPRETATION: Following the decision to stop the study drug, 5-year long-term follow-up HRs for transformation to acute myeloid leukaemia and HRs for death did not differ between patients treated with romiplostim and those treated with placebo, indicating that use of romiplostim is probably not associated with any increased risk of acute myeloid leukaemia or death, despite initial concerns. FUNDING: Amgen Inc.


Assuntos
Leucemia Mieloide Aguda/epidemiologia , Síndromes Mielodisplásicas/epidemiologia , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/epidemiologia , Trombopoetina/uso terapêutico , Progressão da Doença , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/etiologia , Masculino , Síndromes Mielodisplásicas/etiologia , Contagem de Plaquetas , Prognóstico , Receptores Fc/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Medição de Risco , Análise de Sobrevida , Trombocitopenia/complicações , Trombocitopenia/diagnóstico , Trombopoetina/administração & dosagem , Trombopoetina/efeitos adversos , Resultado do Tratamento
3.
J Am Vet Med Assoc ; 253(12): 1623-1629, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668260

RESUMO

CASE DESCRIPTION A 7-year-old sexually intact female snow leopard (Panthera uncia) was examined because of blepharospasm, periocular discharge, ventral deviation of the upper eyelid cilia, third eyelid prolapse, and corneal opacity of the right eye. CLINICAL FINDINGS An ophthalmic examination performed with the patient anesthetized revealed a 3 × 3-mm ulcer that extended approximately 60% of the depth of the right cornea and was accompanied by perilesional and intralesional cellular infiltrates and active vascularization. The upper eyelid of the right eye also had a previously repaired coloboma resulting in trichiasis. TREATMENT AND OUTCOME Surgical intervention was elected after 5 weeks of medical management including topical administration of autologous serum and topical, subconjunctival, and systemic administration of antimicrobials failed to yield any improvement in the ulcer. Equine amniotic membrane free-island graft placement and eyelid revision surgeries were performed. Two and a half weeks later, a descemetocele was diagnosed ventrolateral to the original ulcer, and a second equine amniotic membrane free-island grafting procedure was performed. Both grafts healed without further intervention. CLINICAL RELEVANCE Equine amniotic membrane free-island grafts were used to successfully repair a corneal ulcer and descemetocele in a snow leopard. The grafting procedure spared the affected globe and resulted in satisfactory cosmesis and functional vision. This procedure should be considered as an option for corneal repair in nondomestic species for which postoperative care and medical treatment options are limited.


Assuntos
Âmnio/transplante , Úlcera da Córnea/veterinária , Felidae , Animais , Úlcera da Córnea/cirurgia , Feminino , Cavalos
4.
J Zoo Wildl Med ; 48(1): 224-227, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28363069

RESUMO

An adult male Bornean orangutan ( Pongo pygmaeus ) was diagnosed with invasive, poorly differentiated grade 9/9 mammary gland adenocarcinoma from a subcutaneous mass that was surgically removed during a routine preventative health examination. The tumor was tested for estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), and HER2 fluorescence in situ hybridization (HER2 FISH). Whole blood was tested for breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes. The orangutan was treated orally with two common human breast cancer drugs; tamoxifen and anastrozole. The orangutan lived for 4.5 yr postdetection, dying from an unrelated cause. This is the first reported case of mammary gland adenocarcinoma in a male great ape.


Assuntos
Adenocarcinoma/veterinária , Doenças dos Símios Antropoides/diagnóstico , Neoplasias Mamárias Animais/diagnóstico , Pongo pygmaeus , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Anastrozol , Animais , Antineoplásicos Hormonais/uso terapêutico , Doenças dos Símios Antropoides/tratamento farmacológico , Doenças dos Símios Antropoides/patologia , Doenças dos Símios Antropoides/cirurgia , Masculino , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Animais/cirurgia , Neoplasias Hormônio-Dependentes/diagnóstico , Neoplasias Hormônio-Dependentes/patologia , Neoplasias Hormônio-Dependentes/terapia , Neoplasias Hormônio-Dependentes/veterinária , Nitrilos/uso terapêutico , Tamoxifeno/uso terapêutico , Triazóis/uso terapêutico
5.
Haematologica ; 102(8): 1342-1351, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28411254

RESUMO

Primary immune thrombocytopenia is an autoimmune disorder characterized by increased platelet destruction and insufficient platelet production without another identified underlying disorder. Splenectomy may alter responsiveness to treatment and/or increase the risk of thrombosis, infection, and pulmonary hypertension. The analysis herein evaluated the safety and efficacy of the thrombopoietin receptor agonist romiplostim in splenectomized and nonsplenectomized adults with primary immune thrombocytopenia. Data were pooled across 13 completed clinical studies in adults with immune thrombocytopenia from 2002-2014. Adverse event rates were adjusted for time of exposure. Results were considered different when 95% confidence intervals were non-overlapping. Safety was analyzed for 1111 patients (395 splenectomized; 716 nonsplenectomized) who received romiplostim or control (placebo or standard of care). At baseline, splenectomized patients had a longer median duration of immune thrombocytopenia and a lower median platelet count, as well as a higher proportion with >3 prior immune thrombocytopenia treatments versus nonsplenectomized patients. In each treatment group, splenectomized patients used rescue medications more often than nonsplenectomized patients. Platelet response rates (≥50×109/L) for romiplostim were 82% (310/376) for splenectomized and 91% (592/648) for nonsplenectomized patients (P<0.001 by Cochran-Mantel-Haenszel test). Platelet responses were stable over time in both subgroups. Exposure-adjusted adverse event rates were higher for control versus romiplostim for both splenectomized (1857 versus 1226 per 100 patient-years) and nonsplenectomized patients (1052 versus 852 per 100 patient-years). In conclusion, responses to romiplostim were seen in both splenectomized and nonsplenectomized patients, and romiplostim was not associated with an increase in the risk of adverse events in splenectomized patients. clinicaltrials.gov Identifier: 00111475(A)(B), 00117143, 00305435, 01143038, 00102323, 00102336, 00415532, 00603642, 00508820, 00907478, 00116688, and 00440037.


Assuntos
Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Esplenectomia , Trombopoetina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/cirurgia , Proteínas Recombinantes de Fusão/efeitos adversos , Trombopoetina/efeitos adversos , Resultado do Tratamento
6.
Lancet ; 388(10039): 45-54, 2016 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-27103127

RESUMO

BACKGROUND: The thrombopoietin receptor agonist romiplostim could be an effective treatment in symptomatic children with persistent or chronic immune thrombocytopenia. We aimed to assess whether romiplostim is safe and effective in children with immune thrombocytopenia of more than 6 months' duration. METHODS: In this phase 3 double-blind study, eligible participants were children with immune thrombocytopenia aged 1 year to 17 years and mean platelet counts 30 × 10(9)/L or less (mean of two measurements during the screening period) with no single count greater than 35 × 10(9)/L, and were recruited from 27 sites in the USA, Canada, and Australia. Participants were randomly assigned (2:1) through the interactive voice response system to receive weekly romiplostim or placebo for 24 weeks stratified by age (1 year to <6 years, 6 years to <12 years, 12 years to <18 years), adjusting the dose weekly from 1 µg/kg to 10 µg/kg to target platelet counts of 50-200 × 10(9)/L. Patients and investigators were blinded to the treatment assignment. The primary analysis included all randomised patients and the safety analysis included all randomised patients who received at least one dose of investigational product. The primary endpoint, durable platelet response, was defined as achievement of weekly platelet responses (platelet counts ≥50 × 10(9)/L without rescue drug use in the preceding 4 weeks) in 6 or more of the final 8 weeks (weeks 18-25). This study is registered with ClinicalTrials.gov, NCT 01444417. FINDINGS: Between Jan 24, 2012, and Sept 3, 2014, 62 patients were randomly assigned; 42 to romiplostim and 20 to placebo. Durable platelet response was seen in 22 (52%) patients in the romiplostim group and two (10%) in the placebo group (p=0·002, odds ratio 9·1 [95% CI 1·9-43·2]). Durable platelet response rates with romiplostim by age were 38% (3/8) for 1 year to younger than 6 years, 56% (10/18) for 6 years to younger than 12 years, and 56% (9/16) for 12 years to younger than 18 years. One (5%) of 19 patients in the placebo group had serious adverse events compared with 10 (24%) of 42 patients in the romiplostim group. Of these serious adverse events, headache and thrombocytosis, in one (2%) of 42 patients in the romiplostim group, were considered treatment related. No patients withdrew due to adverse events. INTERPRETATION: In children with chronic immune thrombocytopenia, romiplostim induced a high rate of platelet response with no new safety signals. Ongoing romiplostim studies will provide further information as to long-term efficacy, safety, and remission in children with immune thrombocytopenia. FUNDING: Amgen Inc.


Assuntos
Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Lactente , Masculino , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Resultado do Tratamento
7.
Pediatr Blood Cancer ; 63(7): 1232-7, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27037553

RESUMO

BACKGROUND: Chronic immune thrombocytopenia (ITP) in children can negatively impact their health-related quality of life (HRQoL) and impose a burden on their parents. This study sought to examine the effect of romiplostim on HRQoL and parental burden in children with primary ITP. PROCEDURE: This was a phase 3, randomized, double-blind, placebo-controlled study. Children aged <18 years with ITP ≥6 months were randomly assigned to receive romiplostim or placebo for 24 weeks. The Kids' ITP Tool (KIT) was used to measure HRQoL and was administered to patients and/or their parents at baseline and weeks 8, 16, and 25. Mean KIT scores at each assessment and mean changes in KIT scores from baseline were calculated overall by treatment group and platelet response status. Psychometric properties of the KIT were evaluated and the minimally important difference (MID) was estimated for different KIT versions. RESULTS: Sixty-two patients (42 romiplostim and 20 placebo) were enrolled. Changes in KIT scores by treatment group showed numerically greater and more often statistically significant improvements from baseline to each assessment for children receiving romiplostim versus placebo. Mixed-effects analysis demonstrated statistically significantly greater reduction in parental burden from baseline in the romiplostim group versus placebo. Ranges for the MID were estimated as 9-13 points for the Child Self-Report version and 11-13 points for the Parent Impact version. CONCLUSIONS: The treatment with romiplostim may be associated with improved HRQoL in children with primary ITP and reduced burden to their parents.


Assuntos
Efeitos Psicossociais da Doença , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Qualidade de Vida , Receptores Fc/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Trombopoetina/administração & dosagem , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino , Pais , Proteínas Recombinantes de Fusão/efeitos adversos , Trombopoetina/efeitos adversos
8.
J Zoo Wildl Med ; 45(1): 143-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24712173

RESUMO

An adult male Amur tiger (Panthera tigris altaica) with confirmed inflammatory bowel disease developed acute severe icterus, bilirubinuria, bilirubinemia, and elevated bile acids after a diet change. Liver biopsies showed moderate lymphoplasmacytic cholangiohepatitis (lymphocytic cholangitis). The tiger developed neurologic signs including ataxia, tremors, and seizures, as well as epistaxis. Therapy consisted of antibiotics, a steroid anti-inflammatory, vitamins, pro-coagulants, and liver-supportive medicines. The tiger improved from acute liver failure within 3 wk, while the epistaxis began at 3.5 wk and did not resolve until 10.5 wk. The long-term maintenance plan consists of oral prednisolone, metronidazole, ursodiol, and an all muscle-meat beef diet.


Assuntos
Colangite/veterinária , Falência Hepática/veterinária , Tigres , Animais , Animais de Zoológico , Anti-Infecciosos/uso terapêutico , Colagogos e Coleréticos/uso terapêutico , Colangite/complicações , Colangite/patologia , Glucocorticoides/uso terapêutico , Falência Hepática/etiologia , Falência Hepática/patologia , Masculino , Metronidazol/uso terapêutico , Prednisolona/uso terapêutico , Ácido Ursodesoxicólico/uso terapêutico
9.
Am J Intellect Dev Disabil ; 117(2): 167-79, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22515830

RESUMO

Few studies exist of developmental trajectories in children with intellectual disability, and none for those with subtelomeric deletions. We compared developmental trajectories of children with Wolf-Hirschhorn syndrome to other genetic disorders. We recruited 106 children diagnosed with fragile X, Williams-Beuren syndrome, or Wolf-Hirschhorn syndrome, assessing their intellectual and adaptive behavior abilities. We retested 61 children 2 years later. We compared Time 1 and Time 2 difference scores related to genetic disorder, age, initial IQ, or adaptive behavior composite. Results show genetic disorder and initial IQ score were significant factors for IQ differences, but only genetic disorder affected adaptive behavior differences. Results suggest different gene-brain-behavior pathways likely exist for these genetic disorders. Different developmental trajectories will influence the type and intensity of intervention implemented by caregivers.


Assuntos
Desenvolvimento Infantil/fisiologia , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/fisiopatologia , Síndrome de Wolf-Hirschhorn/epidemiologia , Síndrome de Wolf-Hirschhorn/fisiopatologia , Adaptação Psicológica/fisiologia , Adolescente , Criança , Comportamento Infantil/fisiologia , Pré-Escolar , Cognição/fisiologia , Feminino , Síndrome do Cromossomo X Frágil/epidemiologia , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Genótipo , Humanos , Deficiência Intelectual/genética , Modelos Lineares , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Síndrome de Williams/epidemiologia , Síndrome de Williams/genética , Síndrome de Williams/fisiopatologia , Síndrome de Wolf-Hirschhorn/genética , Adulto Jovem
10.
Am J Med Genet A ; 152A(6): 1498-509, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20503326

RESUMO

The course of cognitive-behavioral development in children with intellectual disabilities produced by genetic disorders has only recently begun to be examined systematically. Unfortunately, these studies are few in number. Previously, we examined cognitive-behavioral development in children with the fragile X (FMR1) mutation and found longitudinal decreases in both IQ and adaptive behavior (DQ) scores in most males and females with the full mutation. In this study, we examine longitudinal changes in IQ and DQ in children with neurofibromatosis type 1 (NF1) and Williams-Beuren Syndrome (WBS) by examining differences in composite IQ and DQ scores between the first test (T1) and retest (T2), and compare their developmental trajectory to children with the FMR1 mutation. Sixty-five children with the FMR1 mutation, or NF1, or WBS, ages 4-16 years, were retested two years after initial testing with the Stanford-Binet 4th Edition (SBFE) and the Vineland Adaptive Behavior Scale (VABS). In addition to significant longitudinal declines in IQ and DQ noted previously in children with the FMR1 mutation, we found significant decreases in IQ in males compared to females in the remainder of our sample. We also observed statistically significant decreases in DQ scores among children the FMR1 mutation, as noted previously, but not among children with NF1 or WBS. Moreover, significant declines were found only among males with the FMR1 mutation. Unlike declines in IQ scores, decreases in DQ were not significantly different between males and females.


Assuntos
Desenvolvimento Infantil , Cognição , Síndrome do Cromossomo X Frágil/psicologia , Neurofibromatose 1/psicologia , Síndrome de Williams/psicologia , Adolescente , Criança , Pré-Escolar , Feminino , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Humanos , Masculino , Mutação , Fatores Sexuais
11.
Proc Natl Acad Sci U S A ; 106(29): 12031-6, 2009 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-19597142

RESUMO

Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-of-the-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8-16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a <2-Mb interval. Furthermore, the map enabled us to present evidence against the necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS-i.e., the presence of a single DS consensus region and the sufficiency of DSCR1 and DYRK1A, or APP, in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 21/genética , Síndrome de Down/genética , Trissomia/genética , Humanos , Lactente , Metanálise como Assunto , Fenótipo
12.
Am J Med Genet A ; 143A(20): 2478-89, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17853466

RESUMO

Studies of age-related features of cognitive-behavioral deficits produced by genetic mutations permit us to draw inferences about how brain development may be related cognitive ability as the child ages. Except for Down syndrome (DS) and the fragile X mutation (FRAXA), little is known about the longitudinal changes in cognitive-behavioral development in individuals with genetic abnormalities producing learning disabilities (LD) or mental retardation (MR). The purpose of this prospective study was to compare and contrast age related to cognitive abilities, adaptive and maladaptive behaviors in children and adolescents in the same age range, diagnosed with one of three genetic disorders: the FRAXA mutation, Neurofibromatosis type 1 (NF1) or Williams-Beuren syndrome (WBS). We also sought to examine whether cognitive-behavioral abilities associated with these three genetic disorders were related systematically to age. We examined 108 children, ages 4-15 years, with FRAXA, WBS, or NF1. Results show that there is a significant negative correlation between age and IQ, and between age and adaptive behavior (DQ) scores, in children with FRAXA and WBS, but not in children with NF1. All three groups of children have unusually high proportions of maladaptive behavior, ranging from 1/6 children with NF1 to 2/3 children with FRAXA. Cognitive and adaptive behavior profiles of children with FRAXA and WBS were also surprisingly similar. Our findings suggest the need for examining longitudinal developmental cognitive-behavioral changes in children and adolescents with all genetic disorders that produce LD or MR.


Assuntos
Adaptação Psicológica , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Neurofibromatose 1/diagnóstico , Síndrome de Williams/diagnóstico , Adolescente , Fatores Etários , Criança , Pré-Escolar , Seguimentos , Humanos , Masculino , Estudos Prospectivos
13.
Am J Hum Genet ; 79(6): 1119-24, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17186471

RESUMO

In a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), we identified two nonsense mutations and one consensus splice-site mutation in the AP1S2 gene on Xp22 in three families. Affected individuals in these families showed mild-to-profound mental retardation. Other features included hypotonia early in life and delay in walking. AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Aberrant endocytic processing through disruption of adaptor protein complexes is likely to result from the AP1S2 mutations identified in the three XLMR-affected families, and such defects may plausibly cause abnormal synaptic development and function. AP1S2 is the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.


Assuntos
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética , Retardo Mental Ligado ao Cromossomo X/genética , Mutação , Subunidades sigma do Complexo de Proteínas Adaptadoras/metabolismo , Adulto , Criança , Endossomos/metabolismo , Feminino , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/etiologia , Retardo Mental Ligado ao Cromossomo X/psicologia , Linhagem
14.
J Vet Diagn Invest ; 17(4): 331-40, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16130990

RESUMO

Selenium (Se) is an essential trace element that is often deficient in the natural diets of domestic animal species. The measurement of Se in whole blood or liver is the most accurate way to assess Se status for diagnostic purposes. This study was conducted to compare hydride generation atomic absorption spectroscopy (HG-AAS) with inductively coupled plasma-mass spectrometry (ICP-MS) for the detection and quantification of Se in liver samples. Sample digestion was accomplished with magnesium nitrate and nitric acid for HG-AAS and ICP-MS, respectively. The ICP-MS detection was optimized for 82Se with yttrium used as the internal standard and resulted in a method detection limit of 0.12 microg/g. Selenium was quantified by both methods in 310 samples from a variety of species that were submitted to the Toxicology Laboratory at New Bolton Center (Kennett Square, PA) for routine diagnostic testing. Paired measurements for each sample were evaluated by a mean difference plot method. Limits of agreement were used to describe the maximum differences likely to occur between the 2 methods. Results suggest that under the specified conditions ICP-MS can be reliably used in place of AAS for quantitation of tissue Se at or below 2 microg/g to differentiate between adequate and deficient liver Se concentrations.


Assuntos
Análise Química do Sangue/veterinária , Fígado/química , Espectrometria de Massas/veterinária , Selênio/análise , Espectrofotometria Atômica/veterinária , Animais , Análise Química do Sangue/métodos , Bovinos , Espectrometria de Massas/métodos , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Espectrofotometria Atômica/métodos
15.
Am J Hum Genet ; 77(1): 41-53, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15889350

RESUMO

Allan-Herndon-Dudley syndrome was among the first of the X-linked mental retardation syndromes to be described (in 1944) and among the first to be regionally mapped on the X chromosome (in 1990). Six large families with the syndrome have been identified, and linkage studies have placed the gene locus in Xq13.2. Mutations in the monocarboxylate transporter 8 gene (MCT8) have been found in each of the six families. One essential function of the protein encoded by this gene appears to be the transport of triiodothyronine into neurons. Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Infancy and childhood in the Allan-Herndon-Dudley syndrome are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or cupped. Some patients have myopathic facies. Generalized weakness is manifested by excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting. Cognitive development is severely impaired. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behavior tends to be passive, with little evidence of aggressive or disruptive behavior. Although clinical signs of thyroid dysfunction are usually absent in affected males, the disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations.


Assuntos
Deficiências do Desenvolvimento/genética , Retardo Mental Ligado ao Cromossomo X/genética , Transportadores de Ácidos Monocarboxílicos/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Cromossomos Humanos X , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/genética , Mutação , Paraplegia/genética , Linhagem
16.
Hum Mutat ; 23(2): 147-59, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14722918

RESUMO

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.


Assuntos
Regulação da Expressão Gênica/genética , Proteínas de Homeodomínio/genética , Mutação/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Agenesia do Corpo Caloso , Células Cultivadas , Corpo Caloso/patologia , Análise Mutacional de DNA/métodos , Feminino , Ligação Genética/genética , Genitália Feminina/anormalidades , Genitália Feminina/patologia , Genitália Masculina/anormalidades , Genitália Masculina/patologia , Genótipo , Proteínas de Homeodomínio/biossíntese , Humanos , Recém-Nascido , Linfócitos/química , Linfócitos/metabolismo , Linfócitos/patologia , Imagem por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Transtornos dos Cromossomos Sexuais/genética , Fatores de Transcrição/biossíntese
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