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Velaglucerase alfa is a glucocerebrosidase produced by gene activation technology in a human fibroblast cell line (HT-1080), and it is indicated as an enzyme replacement therapy (ERT) for the treatment of Gaucher disease type 1 (GD1). This multicenter, open-label, 12-month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase. Eligible patients, ≥2 years old and clinically stable on imiglucerase therapy, were switched to velaglucerase alfa at a dose equal to their prior imiglucerase dose. Infusion durations were 1 hr every other week. Forty patients received velaglucerase alfa (18 male, 22 female; four previously splenectomized; age range 9-71 years). Velaglucerase alfa was generally well tolerated with most adverse events (AEs) of mild or moderate severity. The three most frequently reported AEs were headache (12 of 40 patients), arthralgia (9 of 40 patients), and nasopharyngitis (8 of 40 patients). No patients developed antibodies to velaglucerase alfa. There was one serious AE considered treatment-related: a grade 2 anaphylactoid reaction within 30 min of the first infusion. The patient withdrew; this was the only AE-related withdrawal. Hemoglobin concentrations, platelet counts, and spleen and liver volumes remained stable through 12 months. In conclusion, adult and pediatric patients with GD1, previously treated with imiglucerase, successfully transitioned to velaglucerase alfa, which was generally well tolerated and demonstrated efficacy over 12 months' treatment consistent with that observed in the velaglucerase alfa phase 3 clinical trial program.
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Terapia de Reposição de Enzimas , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/deficiência , Adolescente , Adulto , Idoso , Criança , Esquema de Medicação , Substituição de Medicamentos , Feminino , Doença de Gaucher/enzimologia , Doença de Gaucher/genética , Glucosilceramidase/genética , Glucosilceramidase/farmacologia , Glucosilceramidase/uso terapêutico , Hemoglobinas/análise , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
Purpose. The purpose of this study was to assess the desirability of Duchenne muscular dystrophy (DMD) screening, the effectiveness of the consent process, and the feasibility of conducting DMD screening in a pediatric office. Methods. Infant males who attended a 12-month routine well-child visit at a participating pediatric clinic were screened for DMD. Parents and providers completed post-screening questionnaires to assess their experiences with and attitudes toward screening. Results. A total of 264 male infants were screened for DMD. Approximately 78% of parents indicated support of voluntary DMD screening and 91% of providers were in favor of screening for DMD. About 75% of parents correctly answered three of five questions testing their knowledge of DMD screening. Conclusion. DMD screening is feasible in a pediatric office when conducted as part of a research study. Infant screening for DMD eventually could be offered in pediatric health care provider offices as an optional public health service outside of newborn screening.
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PURPOSE: The Mucopolysaccharidosis Type I (MPS I) Registry is an international observational database that tracks the natural history and the outcomes of patients with MPS I. The Registry was a regulatory requirement following the approval of laronidase enzyme replacement therapy for MPS I in 2003. All data are collected voluntarily after informed consent from the patient or family. Data are checked through queries, monthly reviews, and electronic audits to identify missing, inconsistent, or invalid data. This analysis sought to determine overall data accuracy in the Registry through source document verification (SDV). METHODS: Two phases of SDV were performed. In each phase, Registry data were compared against source documents at sites in Europe, Latin America, and North America. Three patients were randomly selected for SDV at each of the selected sites among all patients enrolled ≥18 months and ever receiving laronidase. Key parameters central to MPS I and its treatment were examined from the baseline and the last available assessments. RESULTS: Results indicate an overall source-to-database error rate in the MPS I Registry of 2.7% (47 discrepancies out of 1715 items; 95% confidence interval [2.2%, 3.5%]) in Phase 1 and 3.7% (64 discrepancies out of 1732 items; 95% confidence interval [2.9%, 4.7%]) in Phase 2. No systematic errors were found. CONCLUSIONS: The overall error rates in both phases of SDV demonstrate acceptable data accuracy in the MPS I Registry within the data fields that were assessed. Copyright © 2011 John Wiley & Sons, Ltd.
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BACKGROUND: Phenylketonuria (PKU) results from impaired breakdown of phenylalanine (Phe) due to deficient phenylalanine hydroxylase (PAH) activity. Sapropterin dihydrochloride (sapropterin, Kuvan®) is the only US- and EU-approved pharmaceutical version of naturally occurring 6R-BH(4), the cofactor required for PAH activity. Sapropterin enhances residual PAH activity in sapropterin-responsive PKU patients and, in conjunction with dietary management, helps reduce blood Phe concentrations for optimal control. Approval was based on the positive safety and efficacy results of four international clinical studies, the longest of which was 22 weeks in duration. OBJECTIVE: To evaluate the safety of long-term treatment with sapropterin in PKU subjects who participated in previous Phase 3 sapropterin trials. METHODS: PKU-008 was designed as a Phase 3b, multicenter, multinational, open-label, 3-year extension trial to evaluate the long-term safety of sapropterin in patients with PKU who were classified as sapropterin responders and participated in prior Phase 3 sapropterin studies: 111 subjects aged 4-50 years completed prior studies and were subsequently enrolled in study PKU-008. Routine safety monitoring was performed at 3-month intervals and included adverse event reporting, blood Phe monitoring, clinical laboratory evaluations, physical examinations and vital sign measurements. RESULTS: Average exposure during PKU-008 was 658.7±221.3 days (range, 56-953; median, 595). The average total duration of participation in multiple studies (PKU-001, PKU-003, PKU-004, and PKU-008; or PKU-006 and PKU-008) was 799.0±237.5 days (range, 135-1151). The mean sapropterin dose was 16.2±4.7 mg/kg/day. Most adverse events were considered unrelated to treatment, were mild or moderate in severity, and were consistent with prior studies of sapropterin. No age-specific differences were observed in adverse event reporting. Three subjects discontinued treatment due to adverse events that were considered possibly or probably related to study treatment (one each of difficulty concentrating, decreased platelet count, and intermittent diarrhea). No deaths were reported. Of seven reported serious adverse events, one was considered possibly related to study treatment (gastroesophageal reflux). There were no laboratory or physical examination abnormalities requiring medical interventions. For most subjects, blood Phe concentrations were consistently within target range, confirming the durability of response in subjects undergoing extended treatment with sapropterin. CONCLUSION: Sapropterin treatment was found to be safe and well tolerated at doses of 5 to 20mg/kg/day for an average exposure of 659 days. This study supports the safety and tolerability of sapropterin as long-term treatment for patients with PKU.
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Biopterinas/análogos & derivados , Fenilcetonúrias/tratamento farmacológico , Adolescente , Adulto , Biopterinas/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Pessoa de Meia-Idade , Fenilalanina/sangueAssuntos
Coleta de Amostras Sanguíneas/métodos , Doenças por Armazenamento dos Lisossomos/diagnóstico , Triagem Neonatal/métodos , Comitês Consultivos , Diagnóstico Precoce , Política de Saúde , Humanos , Indicadores e Reagentes , Recém-Nascido , Triagem Neonatal/legislação & jurisprudência , Atenção Primária à Saúde , Saúde Pública , Espectrometria de Massas em TandemRESUMO
Four unrelated families with the same unbalanced translocation der(4)t(4;11)(p16.2;p15.4) were analyzed. Both of the breakpoint regions in 4p16.2 and 11p15.4 were narrowed to large â¼359-kb and â¼215-kb low-copy repeat (LCR) clusters, respectively, by aCGH and SNP array analyses. DNA sequencing enabled mapping the breakpoints of one translocation to 24 bp within interchromosomal paralogous LCRs of â¼130 kb in length and 94.7% DNA sequence identity located in olfactory receptor gene clusters, indicating nonallelic homologous recombination (NAHR) as the mechanism for translocation formation. To investigate the potential involvement of interchromosomal LCRs in recurrent chromosomal translocation formation, we performed computational genome-wide analyses and identified 1143 interchromosomal LCR substrate pairs, >5 kb in size and sharing >94% sequence identity that can potentially mediate chromosomal translocations. Additional evidence for interchromosomal NAHR mediated translocation formation was provided by sequencing the breakpoints of another recurrent translocation, der(8)t(8;12)(p23.1;p13.31). The NAHR sites were mapped within 55 bp in â¼7.8-kb paralogous subunits of 95.3% sequence identity located in the â¼579-kb (chr 8) and â¼287-kb (chr 12) LCR clusters. We demonstrate that NAHR mediates recurrent constitutional translocations t(4;11) and t(8;12) and potentially many other interchromosomal translocations throughout the human genome. Furthermore, we provide a computationally determined genome-wide "recurrent translocation map."
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Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 4/genética , Recombinação Genética , Translocação Genética , Quebra Cromossômica , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Mapeamento Cromossômico/métodos , Hibridização Genômica Comparativa , Família , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Família Multigênica , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Reação em Cadeia da Polimerase/métodos , Receptores Odorantes/genética , Duplicações Segmentares Genômicas/genética , Análise de Sequência de DNARESUMO
BACKGROUND: Cerebral palsy is a heterogeneous group of neurodevelopmental brain disorders resulting in motor and posture impairments often associated with cognitive, sensorial, and behavioural disturbances. Hypoxic-ischaemic injury, long considered the most frequent causative factor, accounts for fewer than 10% of cases, whereas a growing body of evidence suggests that diverse genetic abnormalities likely play a major role. METHODS AND RESULTS: This report describes an autosomal recessive form of spastic tetraplegic cerebral palsy with profound intellectual disability, microcephaly, epilepsy and white matter loss in a consanguineous family resulting from a homozygous deletion involving AP4E1, one of the four subunits of the adaptor protein complex-4 (AP-4), identified by chromosomal microarray analysis. CONCLUSION: These findings, along with previous reports of human and mouse mutations in other members of the complex, indicate that disruption of any one of the four subunits of AP-4 causes dysfunction of the entire complex, leading to a distinct 'AP-4 deficiency syndrome'.
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Anormalidades Múltiplas/genética , Complexo 4 de Proteínas Adaptadoras/deficiência , Paralisia Cerebral/genética , Deficiência Intelectual/genética , Microcefalia/genética , Anormalidades Múltiplas/patologia , Complexo 4 de Proteínas Adaptadoras/genética , Paralisia Cerebral/patologia , Genes Recessivos , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/patologia , Análise em Microsséries , Microcefalia/patologia , Linhagem , SíndromeRESUMO
The incidence of neonatal vitamin B12 (cobalamin) deficiency because of maternal deficiency was determined by surveying state newborn screening programs. Thirty-two infants with nutritional vitamin B12 deficiency were identified (0.88/100,000 newborns). Pregnant women should be assessed for their risk of inadequate intake/malabsorption of vitamin B12.
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Mães , Triagem Neonatal/métodos , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/epidemiologia , Adulto , Feminino , Humanos , Recém-Nascido , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Troca Materno-Fetal , Gravidez , Complicações na Gravidez/epidemiologia , Fatores de Risco , Inquéritos e Questionários , Estados Unidos/epidemiologia , Deficiência de Vitamina B 12/etiologiaRESUMO
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficiency of alpha-galactosidase A. In addition to the debilitating physical symptoms of FD, there are also under-recognized and poorly characterized psychiatric features. As a first step toward characterizing psychiatric features of FD, we administered the Achenbach adult self report questionnaire to 30 FD patients and the Achenbach adult behavior checklist questionnaire to 28 partners/parents/friends of FD patients. Data from at least one of the questionnaires were available on 33 subjects. Analysis focused on social-adaptive functioning in various aspects of daily life and on criteria related to the Diagnostic and statistical manual of mental disorders IV (DSM-IV). Adaptive functioning scale values, which primarily measure social and relationship functioning and occupational success, showed that eight FD patients (six female and two male) had mean adaptive functioning deficits as compared to population norms. Greater rates of depression (P < 0.01), anxiety (P = 0.05), depression and anxiety (P = 0.03), antisocial personality (P < 0.001), attention-deficit/hyperactivity (AD/H; P < 0.01), hyperactivity-impulsivity (P < 0.01), and aggressive behavior (P = 0.03) were associated with poorer adaptive functioning. Decreased social-adaptive functioning in this study was not statistically significantly associated to disease severity, pain, or level of vitality. This study shows for the first time that FD patients, particularly women, are affected by decreased social-adaptive functioning. Comprehensive treatment plans for FD should consider assessments and interventions to evaluate and improve social, occupational, and psychological functioning. Attention to the behavioral aspects of FD could lead to improved treatment outcome and improved quality of life. Individuals affected by Fabry disease exhibited social-adaptive functioning deficits that were significantly correlated with anxiety, depression, antisocial behavior, and AD/H problems in a sampling of our male and female patients aged between 18 years and 59 years.
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Doença de Fabry/psicologia , Saúde Mental , Ajustamento Social , Atividades Cotidianas , Adaptação Psicológica , Adolescente , Adulto , Fatores Etários , Agressão , Transtorno da Personalidade Antissocial/epidemiologia , Transtorno da Personalidade Antissocial/psicologia , Ansiedade/epidemiologia , Ansiedade/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Lista de Checagem , Depressão/epidemiologia , Depressão/psicologia , Doença de Fabry/diagnóstico , Doença de Fabry/epidemiologia , Doença de Fabry/genética , Feminino , Amigos/psicologia , Georgia/epidemiologia , Humanos , Comportamento Impulsivo/epidemiologia , Comportamento Impulsivo/psicologia , Relações Interpessoais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Escalas de Graduação Psiquiátrica , Fatores de Risco , Autorrelato , Fatores Sexuais , Cônjuges/psicologia , Adulto JovemRESUMO
Newborn screening has become an integral part of the evaluation of more than 4 million newborns a year in the United States and of most newborns in industrialized countries and many in developing countries. Because the term "newborn screening" refers to many procedures performed in a nursery such as screening for hearing loss or congenital heart disease, this discussion is limited to screening for genetic or congenital disorders with blood spotted on filter paper cards. This discussion reflects primarily the experiences and current status of NBS programs in the United States.
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Doenças Genéticas Inatas/diagnóstico , Testes Genéticos , Triagem Neonatal , Análise Custo-Benefício , História do Século XX , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Triagem Neonatal/economia , Triagem Neonatal/ética , Triagem Neonatal/história , Triagem Neonatal/legislação & jurisprudência , Fenilcetonúrias/diagnósticoRESUMO
Ornithine transcarbamylase (OTC) deficiency is an X-linked inborn error of metabolism characterized by impaired synthesis of citrulline from carbamylphosphate and ornithine. Previously reported data suggest that only approximately 80% of OTC deficiency (OTCD) patients have a mutation identified by OTC gene sequencing. To elucidate the molecular etiology in patients with clinical signs of OTCD and negative OTC sequencing, we subjected their DNA to array comparative genomic hybridization (aCGH) using a custom-designed targeted 44k oligonucleotide array. Whenever possible, parental DNA was analyzed to determine the inheritance or to rule out copy number variants in the OTC locus. DNA samples from a total of 70 OTCD patients were analyzed. Forty-three patients (43/70 or 61.5%) were found to have disease-causing point mutations in the OTC gene. The remaining 27 patients (27/70 or 38.5%) showed normal sequencing results or failure to amplify all or part of the OTC gene. Among those patients, eleven (11/70 or 15.7%) were found to have deletions ranging from 4.5kb to 10.6Mb, all involving the OTC gene. Sixteen OTCD patients (16/70 or 22.8%) had normal sequencing and oligoarray results. Analysis of the deletions did not reveal shared breakpoints, suggesting that non-homologous end joining or a replication-based mechanism might be responsible for the formation of the observed rearrangements. In summary, we demonstrate that approximately half of the patients with negative OTC sequencing may have OTC gene deletions readily identifiable by the targeted oligonucleotide-based aCGH. Thus, the test should be considered in OTC sequencing-negative patients with classic symptoms of the disease.
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Deleção de Genes , Rearranjo Gênico , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Ornitina Carbamoiltransferase/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Ornitina Carbamoiltransferase/metabolismo , Mutação Puntual , Alinhamento de Sequência , Adulto JovemRESUMO
In 1993, the first effective enzyme replacement therapy for a genetic disease, Ceredase (Genzyme Corporation, Cambridge, MA), was approved for use in patients with Gaucher disease. Over the next 13 years, enzyme replacement therapy became clinically available for the treatment of Fabry disease, mucopolysaccharidosis Type I, mucopolysaccharidosis Type II, mucopolysaccharidosis Type VI, and glycogen storage disease Type II. The development of enzyme replacement therapy to treat lysosomal storage diseases has resulted in an increasing number of genetic patients undergoing weekly or biweekly intravenous enzyme replacement therapy and an expanded role of the genetics team to include comprehensive care involving therapeutic intervention for lysosomal storage diseases. This article describes the development of two outpatient genetics-based infusion centers: the Northshore Genetics Infusion Clinic as part of the Children's Hospital of Wisconsin Lysosomal Diseases Treatment Center in conjunction with the Medical College of Wisconsin and the Emory Lysosomal Storage Disease Center for Genetic Infusions in the Emory University Department of Human Genetics.
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Instituições de Assistência Ambulatorial/economia , Instituições de Assistência Ambulatorial/organização & administração , Terapia Genética , Doenças por Armazenamento dos Lisossomos/terapia , Instituições de Assistência Ambulatorial/normas , Humanos , Infusões Intravenosas , Doenças por Armazenamento dos Lisossomos/enzimologia , Doenças por Armazenamento dos Lisossomos/genética , Recursos HumanosRESUMO
The mucopolysaccharidoses are a group of lysosomal storage disorders caused by defects in the degradation of glycosaminoglycans. Each disorder is characterized by progressive multi-system disease with considerable clinical heterogeneity. The clinical heterogeneity of these disorders is thought to be related to the degree of the metabolic block in glycosaminoglycan degradation which in turn is related to the underlying mutation at the respective locus. There are currently no objective means other than longitudinal clinical observation, or the detection of a recurrent genetic mutation to accurately predict the clinical course for an individual patient, particularly when diagnosed early. In addition, there are no specific disease biomarkers that reflect the total body burden of disease. The lack of specific biomarkers has made monitoring treatment responses and predicting disease course difficult in these disorders. The recent introduction of enzyme replacement therapy for MPS I, II, and VI highlights the need for objective measures of disease burden and disease responsiveness. We show that serum levels of heparin cofactor II-thrombin complex is a reliable biomarker of the mucopolysaccharidoses. Untreated patients have serum levels that range from 3- to 112-fold above control values. In a series of patients with varying severity of mucopolysaccharidosis I, the serum complex concentration was reflective of disease severity. In addition, serum heparin cofactor II-thrombin levels showed responsiveness to various treatment regimens. We propose that serum levels of heparin cofactor II-thrombin complex may provide an important assessment and monitoring tool for patients with mucopolysaccharidosis.
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Biomarcadores/sangue , Cofator II da Heparina/metabolismo , Mucopolissacaridoses/sangue , Trombina/metabolismo , Animais , Análise Química do Sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Cofator II da Heparina/análise , Humanos , Estudos Longitudinais , Masculino , Camundongos , Mucopolissacaridoses/terapia , Trombina/análiseRESUMO
Fabry disease is an X-linked lysosomal storage condition caused by a deficiency of alpha-galactosidase A. In order to determine the average number of family members who are diagnosed with Fabry disease following the diagnosis of a proband, four lysosomal storage disease centers across the United States reviewed the completed pedigrees of their Fabry disease patients. In addition, data from three Fabry disease families from other centers were submitted by patients directly. The pedigree review found 74 probands (54 males and 20 females) who had 357 diagnosed family members, of which 223 were female (60.5%) and 146 were male (39.5%). Analysis found that, on average, there were five family members diagnosed with Fabry disease for every proband. Now that enzyme replacement therapy (ERT) is available for the treatment of Fabry disease, this finding emphasizes the need for all health care professionals to ensure a detailed pedigree has been constructed for each patient affected by Fabry disease and to encourage testing and evaluation of all at-risk family members.
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Doença de Fabry/diagnóstico , Adolescente , Criança , Doença de Fabry/genética , Feminino , Humanos , Masculino , LinhagemAssuntos
Anormalidades Múltiplas/diagnóstico , Craniossinostoses/diagnóstico , Deficiência Intelectual/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Craniossinostoses/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , SíndromeRESUMO
OBJECTIVES: Mutations in the tafazzin (TAZ) gene at chromosomal locus Xq28 are responsible for Barth syndrome (BTHS), X-linked endocardial fibroelastosis (EFE), X-linked fatal infantile dilated cardiomyopathy (CMD3A), and familial isolated noncompaction of left ventricular myocardium (INVM). This evaluation was performed to determine if a known familial TAZ gene mutation might present with abnormal fetal cardiac pathology findings as early as the second trimester of pregnancy. METHODS: Prenatal diagnosis revealed that a male fetus was positive for a known familial arg94his TAZ gene mutation. An elective termination with subsequent fetal pathology examination was performed at 18 weeks' gestation. RESULTS: Fetal examination revealed cardiomegaly, EFE, and subendocardial vacuolization of the myocytes. CONCLUSION: Characteristic cardiac pathology findings of a TAZ gene mutation are seen in a fetus at 18 weeks' gestation. To our knowledge, this case provides the earliest fetal pathologic description of a TAZ cardiomyopathy.
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Cardiomiopatias/genética , Cromossomos Humanos X , Mutação Puntual , Proteínas/genética , Fatores de Transcrição/genética , Aciltransferases , Cardiomiopatias/congênito , Cardiomiopatias/patologia , Feminino , Humanos , Recém-Nascido , Masculino , Linhagem , Gravidez , Diagnóstico Pré-NatalRESUMO
In a previous report, we described the first liveborn with trisomy 4 mosaicism [Marion et al. (1990) Am J Med Genet 37:362-365]. To our knowledge, since our original report, there have been only four additional reports of a prenatal diagnosis of mosaic trisomy 4 resulting in a liveborn child [Hsu et al. (1997) Prenat Diag 17:201-242; Kuchinka et al. (2001) Prenat Diag 21:36-39; Wieczorek et al. (2003) Prenat Diag 23:128-133; Zaslav et al. (2000) Am J Med Genet 95:381-384]. Three of the more recent reports lacked confirmation of the mosaicism in tissue samples collected from the child after delivery, and likely represent cases of confined placental mosaicism. We recently examined our original patient, N.J., in an effort to provide long-term follow-up. N.J. is currently 14-years-old, and is enrolled in both special education and mainstream eighth grade classes at a local public middle school. Although she generally scores below average on standardized intellectual tests, her verbal skills and social interactions are more age appropriate. Our initial report described abnormalities of N.J.'s right hand and right ear, for which several reconstructive surgeries have been performed. A current medical concern is her entrance into puberty, as menarche has not yet occurred, and asymmetrical breast development is present. Overall, N.J. has developed into a generally healthy adolescent with low-normal intellect. This report demonstrates the importance of long-term follow-up in providing accurate counseling for rare chromosomal disorders.
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Cromossomos Humanos Par 4/genética , Mosaicismo , Trissomia/genética , Adolescente , Feminino , Dedos/anormalidades , Seguimentos , Humanos , Sindactilia/patologia , Fatores de Tempo , Dedos do Pé/anormalidadesRESUMO
OBJECTIVE: To conduct surveillance of the developmental status of children who screen positive and are diagnosed with a metabolic or endocrine disorder. STUDY DESIGN: The Centers for Disease Control and Prevention linked three data sources in Georgia: (1) Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP), (2) Special Education Database of Metropolitan Atlanta (SEDMA), and (3) State of Georgia Newborn Blood-Spot Screening Program (NBSP). RESULTS: When MADDSP and NBSP were linked (birth cohorts 1981-1991), of an estimated 147 infants who screened positive for a metabolic or endocrine disorder and were at risk for mental retardation if left untreated, only three children were identified with mental retardation. When SEDMA and NBSP were linked (birth cohorts 1981-1995), of an estimated 216 children who screened positive for a metabolic or endocrine disorder, nine children were identified as having a developmental disability less severe than mental retardation, eg, speech and language impairments. CONCLUSIONS: Although children found in MADDSP or SEDMA have a low occurrence of developmental disabilities attributable to these metabolic or endocrine disorders, our finding of cases of developmental disabilities of varying severity attributable to a metabolic or endocrine disorder suggests a need for ongoing population-based monitoring of the long-term developmental outcomes of children identified through newborn screening programs.
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Deficiências do Desenvolvimento/etiologia , Doenças do Sistema Endócrino/complicações , Erros Inatos do Metabolismo/complicações , Triagem Neonatal , Coleta de Dados , Doenças do Sistema Endócrino/congênito , Doenças do Sistema Endócrino/diagnóstico , Humanos , Recém-Nascido , Deficiência Intelectual/etiologia , Erros Inatos do Metabolismo/diagnósticoRESUMO
OBJECTIVES: Although several studies describe the 22q11.2 deletion, population-based data are scant. Such data are needed to evaluate properly the impact, distribution, and clinical presentation of the deletion in the population. Our goals were to assess the population-based birth prevalence of the 22q11.2 deletion and its associated phenotype and its impact on the occurrence of heart defects. METHODS: We evaluated data on infants who were born from 1994 through 1999 to women who resided in metropolitan Atlanta. We matched records from the Metropolitan Atlanta Congenital Defects Program (a population-based registry with active case ascertainment), the Sibley Heart Center at Children's Healthcare of Atlanta, and the Division of Medical Genetics at Emory University. We used birth certificate data for the denominators of the rates. RESULTS: We identified 43 children with laboratory-confirmed 22q11.2 deletion among 255 849 births. The overall prevalence was 1 in 5950 births (95% confidence interval: 1 in 4417 to 1 in 8224 births). The prevalence was between 1 in 6000 and 1 in 6500 among whites, blacks, and Asians and 1 in 3800 among Hispanics. Most affected children (81%) had a heart defect, and many (1 in 3) had major extracardiac defects (other than velopalatal anomalies), including anomalies of the central nervous system. Overall, the deletion contributed to at least 1 of every 68 cases of major heart defects identified in the total birth cohort and, in particular, to 1 of every 2 cases diagnosed with interrupted aortic arch type B, 1 of every 5 with truncus arteriosus, and 1 of every 8 with tetralogy of Fallot. CONCLUSIONS: The 22q11.2 deletion was common in this birth population. The clinical phenotype included a wide and variable spectrum of major cardiac and extracardiac anomalies. From these population-based data, one can estimate that at least 700 affected infants are born annually in the United States. Population-based estimates such as these should be useful to medical professionals and policy makers in planning for the optimal care of people with the 22q11.2 deletion.