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1.
Ir J Psychol Med ; 39(1): 74-84, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-30777583

RESUMO

OBJECTIVES: Our principle objective was to examine the personal and professional impact of service user (SU) suicide on mental health professionals (MHPs). We also wished to explore putative demographic or clinical factors relating to SUs or MPHs that could influence the impact of SU suicide for MHPs and explore factors MHPs report as helpful in reducing distress following SU suicide. METHODS: A mixed-method questionnaire with quantitative and thematic analysis was utilised. RESULTS: Quantitative data indicated SU suicide was associated with personal and professional distress with sadness (79.5%), shock (74.5%) and surprise (68.7%) particularly evident with these phenomena lasting less than a year for more than 90% of MHPs. MHPs also reported guilt, reduced self-confidence and a fear of negative publicity. Thematic analysis indicated that some MHPs had greater expertise when addressing SU suicidal ideation and in supporting colleagues after experiencing a SU suicide. Only 17.7% of MHPs were offered formal support following SU suicide. CONCLUSION: SU suicide impacts MHPs personally and professionally in both a positive and negative fashion. A culture and clear pathway of formal support for MHPs to ascertain the most appropriate individualised support dependent on the distress they experience following SU suicide would be optimal.


Assuntos
Saúde Mental , Suicídio , Pessoal de Saúde/psicologia , Humanos , Autoimagem , Suicídio/psicologia , Inquéritos e Questionários
2.
Clin Genet ; 89(3): 275-84, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26283276

RESUMO

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.


Assuntos
Exoma , Genes , Doenças Genéticas Inatas/diagnóstico , Mutação , Análise de Sequência de DNA , Canadá , Criança , Doenças Genéticas Inatas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
3.
Diabetes Metab ; 40(4): 310-3, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24503189

RESUMO

AIM: To describe the atypical phenotype and genotype of an adolescent girl with symptomatic exercise-induced hyperglycaemia, responsive to sulfonylurea treatment. METHODS: Chart review, gene sequencing, and blinded continuous glucose monitoring (Medtronic iPro2) were used to characterise the case. RESULTS: A novel heterozygous mutation p.Q219x (c.655C>T) in exon 6 of the glucokinase gene (NM_000162.3) was confirmed in the patient and father. Initiation of gliclazide 20mg twice daily was associated with resolution of symptoms and normalization of haemoglobin A1C (5.6%). Blinded continuous glucose monitoring demonstrated significantly less time spent in the hyperglycaemic range (sensor glucose>8.0 mmol/L) when on twice daily gliclazide versus intermittent or no gliclazide (mean minutes/day with sensor glucose > 8 mmol/L: 53.6 ± 90.0 vs. 307.9 ± 246.6; P=0.04). CONCLUSIONS: This novel mutation in the glucokinase gene led to atypical symptomatic exercise-induced hyperglycaemia that was responsive to low dose sulfonylurea with self-reported additional benefit after reduction of carbohydrate intake. We postulate that her atypical clinical presentation was related to the intense elite-level physical activity combined with carbohydrate loading before exercise.


Assuntos
Exercício Físico , Glucoquinase/genética , Hiperglicemia/tratamento farmacológico , Hiperglicemia/enzimologia , Mutação , Compostos de Sulfonilureia/uso terapêutico , Adolescente , Glicemia/fisiologia , Feminino , Humanos , Hiperglicemia/genética
4.
J Laryngol Otol ; 128 Suppl 2: S55-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24460913

RESUMO

INTRODUCTION AND AIMS: Cochlear implants have enabled an improved quality of life for many patients with deafness. Implant extrusion and skin flap necrosis are the most common complications associated with implant use. We report our management of patients presenting with complications as a result of cochlear implant insertion. The goal of surgery was to achieve a stable, healed wound for use as a cochlear device implantation site. METHODS AND RESULTS: We describe a series of patients presenting with skin flap necrosis and/or extrusion of their cochlear implant. The reconstructive options employed are discussed. CONCLUSION: Surgeons should be aware of the reconstructive options available in such circumstances, and should choose appropriate management depending on the clinical situation, in order to optimise the functional result for the patient.


Assuntos
Implantes Cocleares/efeitos adversos , Retalhos Cirúrgicos/patologia , Idoso , Idoso de 80 Anos ou mais , Implante Coclear/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Necrose/etiologia , Falha de Prótese , Reoperação/métodos , Pele/patologia
5.
Clin Genet ; 86(2): 172-6, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23844659

RESUMO

Whole-exome sequencing (WES) has proven its utility in finding novel genes associated with rare conditions and its usefulness is being further demonstrated in expanding the phenotypes of well known diseases. We present here a family with a previously undiagnosed X-linked condition characterized by progressive restriction of joint range of motion, prominence of the supraorbital ridge, audiology issues and hernias. They had an average stature, normal occipitofrontal circumference and intelligence, absence of dysostosis multiplex and otherwise good health. A diagnosis of Hunter syndrome was determined using WES and further supported by biochemical investigations. The phenotype of this family does not correspond to either the severe or attenuated clinical subtypes of Hunter syndrome. As further atypical families are reported, this classification will need to be modified. Our findings highlight the utility of WES in expanding the recognized phenotypic spectrum of known syndromes.


Assuntos
Exoma/genética , Mucopolissacaridose II/genética , Análise de Sequência de DNA , Adulto , Criança , Pré-Escolar , Família , Feminino , Humanos , Lactente , Masculino , Mucopolissacaridose II/diagnóstico por imagem , Mutação/genética , Linhagem , Fenótipo , Radiografia , Reprodutibilidade dos Testes , Crânio/diagnóstico por imagem
6.
Neurogenetics ; 14(3-4): 181-8, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23733235

RESUMO

We describe the clinical and genetic features of a well-characterized cohort of patients with autosomal recessive hereditary spastic paraplegia (ARHSP) in the province of Ontario. Patients with documented corticospinal tract abnormalities were screened by whole gene sequencing and multiplex ligation probe amplification for mutations in nine genes known to cause ARHSP. Of a cohort of 39 patients, a genetic diagnosis was established in 17 (44 %) and heterozygous mutations were detected in 8 (21 %). Mutations were most frequent in SPG7 (12 patients), followed by SPG11 (10 patients), PNPLA6 (SPG39, 2 patients), and ZFYVE26 (SPG15, 2 patients). Although there are associations between some clinical manifestations of ARHSP and specific genes, many patients are tested at an early stage of the disease when phenotype/genotype correlations are not obvious. Accurate molecular characterization of well-phenotyped cohorts of patients will be essential to establishing the natural history of these rare degenerative disorders to enable future clinical trials.


Assuntos
Mutação , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Idoso , Criança , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Tratos Piramidais/patologia , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/patologia , Adulto Jovem
7.
J Appl Physiol (1985) ; 109(5): 1424-31, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20689094

RESUMO

Cerebral autoregulation adjusts cerebrovascular resistance in the face of changing perfusion pressures to maintain relatively constant flow. Results from several studies suggest that cardiac output may also play a role. We tested the hypothesis that cerebral blood flow would autoregulate independent of changes in cardiac output. Transient systemic hypotension was induced by thigh-cuff deflation in 19 healthy volunteers (7 women) in both supine and seated positions. Mean arterial pressure (Finapres), cerebral blood flow (transcranial Doppler) in the anterior (ACA) and middle cerebral artery (MCA), beat-by-beat cardiac output (echocardiography), and end-tidal Pco(2) were measured. Autoregulation was assessed using the autoregulatory index (ARI) defined by Tiecks et al. (Tiecks FP, Lam AM, Aaslid R, Newell DW. Stroke 26: 1014-1019, 1995). Cerebral autoregulation was better in the supine position in both the ACA [supine ARI: 5.0 ± 0.21 (mean ± SE), seated ARI: 3.9 ± 0.4, P = 0.01] and MCA (supine ARI: 5.0 ± 0.2, seated ARI: 3.8 ± 0.3, P = 0.004). In contrast, cardiac output responses were not different between positions and did not correlate with cerebral blood flow ARIs. In addition, women had better autoregulation in the ACA (P = 0.046), but not the MCA, despite having the same cardiac output response. These data demonstrate cardiac output does not appear to affect the dynamic cerebral autoregulatory response to sudden hypotension in healthy controls, regardless of posture. These results also highlight the importance of considering sex when studying cerebral autoregulation.


Assuntos
Artéria Cerebral Anterior/fisiopatologia , Débito Cardíaco , Circulação Cerebrovascular , Hipotensão/fisiopatologia , Artéria Cerebral Média/fisiopatologia , Coxa da Perna/irrigação sanguínea , Adulto , Artéria Cerebral Anterior/diagnóstico por imagem , Pressão Sanguínea , Ecocardiografia , Eletrocardiografia , Feminino , Frequência Cardíaca , Homeostase , Humanos , Hipotensão/diagnóstico por imagem , Masculino , Artéria Cerebral Média/diagnóstico por imagem , Fotopletismografia , Fluxo Sanguíneo Regional , Fatores Sexuais , Decúbito Dorsal , Fatores de Tempo , Ultrassonografia Doppler Transcraniana , Resistência Vascular , Adulto Jovem
8.
Am J Med Genet A ; 152A(3): 732-6, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20186791

RESUMO

Dopamine beta-hydroxylase (DBH) deficiency is characterized by a lack of sympathetic noradrenergic function. Affected individuals exhibit profound deficits in autonomic regulation of cardiovascular function. The diagnosis of DBH deficiency is based on clinical findings, biochemical studies, and sequencing of DBH gene. We report here the characterization of a mosaic cytogenetic abnormality detected by array-CGH in a 16-year-old female with primary DBH deficiency together with dysmorphic features. These features could not be explained by DBH deficiency leading to further investigation. Karyotype was reported normal (46,XX), while a targeted genomic array-CGH revealed a mosaic loss for a segment of at least 1 Mb across 11p13. This segmental loss included the PAX6 and WT1 genes within the WAGR syndrome critical region. Interestingly, the derivative chromosome 11 was observed only in about 28% of cells analyzed. Utilizing a genome-wide oligonucleotide-based array, the deletion segment was estimated to encompass a segment of approximately 10 Mb. Mosaic deletions of 11p13 in WAGR are extremely uncommon. In this case it is distinctly possible that the patient's bilateral iris colobomata might be a manifestation, albeit abbreviated, of the haploinsufficiency for PAX6. This case highlights the importance of cytogenetic analysis when a mutation alone cannot account for the complete phenotype. It also emphasizes the enhanced ability of high-resolution array-CGH techniques in accurately detecting subtle rearrangements in a mosaic form. Finally, it demonstrates the possible phenotypic effects of low-level PAX6 haploinsufficiency in a dosage-sensitive manner.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Dopamina beta-Hidroxilase/deficiência , Mosaicismo , Anormalidades Múltiplas/genética , Adolescente , Coloboma/genética , Hibridização Genômica Comparativa , Proteínas do Olho/genética , Feminino , Dosagem de Genes , Genes do Tumor de Wilms , Proteínas de Homeodomínio/genética , Humanos , Hipotensão Ortostática/enzimologia , Hipotensão Ortostática/genética , Hibridização in Situ Fluorescente , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Proteínas Repressoras/genética
9.
J Minim Access Surg ; 5(1): 14-6, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19547686

RESUMO

Splenic cysts are rare lesions with around 800 cases reported in the world literature. Traditionally splenectomy was the treatment of choice. However, with the recognition of the important immunological function of the spleen, new techniques to preserve splenic function have been developed. This case emphasizes that in selected cases splenic preservation is appropriate.

10.
Surgeon ; 6(1): 57-60, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18318091

RESUMO

A 50-year-old man who had suffered several episodes of early morning sweats and tremors was diagnosed as having hyperinsulinaemic hypoglycaemia. Cross-sectional imaging and endoscopic ultrasound revealed no pancreatic lesion. A selective intra-arterial calcium infusion study showed a two-fold increase of insulin secretion after infusion of the splenic and superior mesenteric arteries. Laparotomy was performed, no lesion was identified after full mobilisation of the pancreas, and nothing was evident with intra-operative ultrasound. A distal pancreatectomy was performed. Microscopically, the pancreas exhibited diffuse islet cell hyperplasia consistent with nesidioblastosis. The patient remains euglycaemic eight months post-operatively.


Assuntos
Insulinoma/diagnóstico , Nesidioblastose/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Diagnóstico Diferencial , Endossonografia , Humanos , Hiperinsulinismo/diagnóstico , Hipoglicemia/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Ultrassonografia de Intervenção
11.
J Laryngol Otol ; 122(3): 296-8, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17470313

RESUMO

BACKGROUND: Non-attendance at out-patient clinics is a seemingly intractable problem, estimated to cost 65 pounds sterling (97 euros) per incident. This results in under-utilisation of resources and prolonged waiting lists. In an effort to reduce out-patient clinic non-attendance, our ENT department, in conjunction with the information and communication technology department, instigated the use of a mobile telephone short message service ('text') reminder, to be sent out to each patient three days prior to their out-patient clinic appointment. OBJECTIVE: To audit non-attendance rates at ENT out-patient clinics following the introduction of a text reminder system. STUDY DESIGN: Retrospective review. METHODS: Non-attendance at our institution's ENT out-patient clinics was audited, following introduction of a text message reminder system in August 2003. Rates of non-attendance were compared for the text message reminder group and a historical control group. RESULTS: Before the introduction of the text message reminder system, the mean rate of non-attendance was 33.6 per cent. Following the introduction of the system, the mean rate of non-attendance reduced to 22 per cent. CONCLUSION: Sending text message reminders is a simple and cost-effective way to improve non-attendance at ENT out-patient clinics.


Assuntos
Agendamento de Consultas , Telefone Celular , Cooperação do Paciente , Sistemas de Alerta/instrumentação , Telefone Celular/economia , Feminino , Humanos , Masculino , Ambulatório Hospitalar/economia , Cooperação do Paciente/estatística & dados numéricos , Sistemas de Alerta/economia , Estudos Retrospectivos
12.
Mol Genet Metab ; 92(4): 325-35, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17723315

RESUMO

Glycogen storage disease, type II (GSDII; Pompe disease; acid maltase deficiency) is an autosomal recessive disease caused by mutations of the GAA gene that lead to deficient acid alpha-glucosidase enzyme activity and accumulation of lysosomal glycogen. Although measurement of acid alpha-glucosidase enzyme activity in fibroblasts remains the gold standard for the diagnosis of GSDII, analysis of the GAA gene allows confirmation of clinical or biochemical diagnoses and permits predictive and prenatal testing of individuals at risk of developing GSDII. We have developed a clinical molecular test for the detection of GAA mutations based on cycle sequencing of the complete coding region. GAA exons 2-20 are amplified in six independent PCR using intronic primers. The resulting products were purified and sequenced. Preliminary studies using this protocol were conducted with DNA from 21 GSDII-affected individuals from five centers across Canada. In total, 41 of 42 mutations were detected (96.7% detection rate). Mutations spanned intron 1 through exon 19 and included nine novel mutations. Haplotype analysis of recurrent mutations further suggested that three of these mutations are likely to have occurred independently at least twice. Additionally, we report the identification of the c.-32-13T>G GAA mutation in an individual with infantile variant GSDII, despite reports of this mutation being associated almost exclusively with late-onset forms of the disease. The development of a clinical molecular test provides an important tool for the management and counseling of families and individuals with GSDII, and has provided useful information about the GAA mutation spectrum in Canada.


Assuntos
Predisposição Genética para Doença/genética , Doença de Depósito de Glicogênio Tipo II/genética , alfa-Glucosidases/genética , Alelos , Análise Mutacional de DNA , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/enzimologia , Humanos , Mutação , alfa-Glucosidases/deficiência
13.
Eur J Anaesthesiol ; 24(5): 454-63, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17261210

RESUMO

BACKGROUND: The objective of this study was to determine the intracranial, cardiovascular and respiratory changes induced by conversion to high-frequency oscillator ventilation from conventional mechanical ventilation at increasing airway pressures. METHODS: In this study, 11 anaesthetized sheep had invasive cardiovascular and intracranial monitors placed. Lung injury was induced by saline lavage and head injury was induced by inflation of an intracranial balloon catheter. All animals were sequentially converted from conventional mechanical ventilation to high-frequency oscillator ventilation at target mean airway pressures of 16, 22, 28, 34 and 40 cm H(2)O. The mean airway pressure was achieved by adjusting positive end expiratory pressure while on conventional mechanical ventilation, and continuous distending pressures while on high-frequency oscillator ventilation. Cerebral lactate production, oxygen consumption and venous oximetry were measured and analysed in relation to changes in transcranial Doppler flow velocity. Transcranial Doppler profiles together with other physiological parameters were measured at each airway pressure. RESULTS: Cerebral perfusion pressure was significantly lower during high-frequency oscillator ventilation than during conventional mechanical ventilation (CMV: 45, 34, 22, 6, 9 mmHg vs. HFOV: 33, 20, 19, 5, 5 mmHg at airway pressures mentioned above, P = 0.02). Intracranial pressure and cerebrovascular resistance increased with increasing intrathoracic pressures (P = 0.001). Cerebral metabolic indices demonstrated an initial increase in anaerobic metabolism followed by a decrease in cerebral oxygen consumption progressing to cerebral infarction as intrathoracic pressures were further increased in a stepwise fashion. Arterial PaCO(2) increased significantly after converting from conventional mechanical ventilation to high-frequency oscillator ventilation (P = 0.001). However, no difference was observed between conventional mechanical ventilation and high-frequency oscillator ventilation when intracranial pressure, metabolic and transcranial Doppler indices were compared at equivalent mean airway pressures. CONCLUSIONS: The use of high positive end expiratory pressure with conventional mechanical ventilation or high continuous distending pressure with high-frequency oscillator ventilation increased intracranial pressure and adversely affected cerebral metabolic indices in this ovine model. Transcranial Doppler is a useful adjunct to intracranial pressure and intracranial venous saturation monitoring when major changes in ventilation strategy are adopted.


Assuntos
Traumatismos Craniocerebrais/fisiopatologia , Ventilação de Alta Frequência/métodos , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/fisiopatologia , Análise de Variância , Animais , Velocidade do Fluxo Sanguíneo , Dióxido de Carbono/sangue , Infarto Cerebral/etiologia , Circulação Cerebrovascular , Modelos Animais de Doenças , Feminino , Humanos , Pressão Intracraniana , Ácido Láctico/metabolismo , Monitorização Fisiológica/métodos , Oximetria/métodos , Consumo de Oxigênio , Respiração com Pressão Positiva/métodos , Pressão , Ovinos , Ultrassonografia Doppler Transcraniana/métodos , Resistência Vascular
14.
Clin Exp Dermatol ; 30(4): 363-5, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15953070

RESUMO

Identification of mutations in the hairless (HR) gene in patients with atrichia with papular lesions (APL) has proven of critical importance, as it provides a basis for the differentiation between APL and alopecia universalis. The establishment of the diagnostic criteria for APL has triggered the identification of a large number of APL patients among those suspected to suffer from alopecia universalis. This advancement has resulted in the discovery of an increasing number of hairless mutations in both consanguineous and nonconsanguineous APL families. Here, we report the identification of a homozygous mutation, 3434delC, in an APL patient of Arab-Palestinian descent. The proband is a 23-year-old female with generalized scalp and body alopecia. To confirm the diagnosis of APL and to identify the specific mutation, we sequenced the hairless gene. Sequencing of all exons of the hairless gene revealed a homozygous frameshift mutation, 3434delC, in exon 18. Interestingly, the same mutation was previously identified in an Arab-Israeli family. Our data suggest that the 3434delC mutation most likely represents a founder mutation in this geographical region.


Assuntos
Alopecia/genética , Mutação da Fase de Leitura/genética , Dermatopatias Genéticas/genética , Dermatopatias Papuloescamosas/genética , Fatores de Transcrição/genética , Adulto , Sequência de Bases , Feminino , Humanos , Dados de Sequência Molecular , Linhagem
15.
J Inherit Metab Dis ; 26(1): 89-91, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12872849

RESUMO

Hyperammonaemia is a common and serious complication of propionic acidaemia. Treatment of hyperammonaemia with sodium phenylacetate or phenylbutyrate has not been well studied in this disorder. We reviewed the medical records of 5 patients with propionic acidaemia over a 16-year period. We collected information on events where plasma amino acids and ammonium, plasma acids and acid-base balance, or all 3 parameters were obtained simultaneously. All patients were on protein-restricted diet and carnitine throughout the period. In contrast to hyperammonaemia in patients with a urea cycle disorder, plasma glutamine levels were below the normal mean and there was no correlation between plasma ammonium and glutamine levels. The absence of positive correlation between plasma glutamine and ammonium suggests that the routine use of sodium phenylacetate or phenylbutyrate to treat hyperammonaemia in propionic acidaemia should be questioned until further studies are done. Throughout follow-up of our propionic acidaemia patients, we have observed that plasma glycine levels correlated positively with serum bicarbonate. The association of high plasma glycine with good acid-base balance might have a potential role in management and warrants further investigation.


Assuntos
Equilíbrio Ácido-Base/fisiologia , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Glutamina/sangue , Glicina/sangue , Propionatos/sangue , Compostos de Amônio Quaternário/sangue , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Bicarbonatos/sangue , Biomarcadores , Dieta com Restrição de Proteínas , Progressão da Doença , Seguimentos , Humanos , Acidemia Propiônica
16.
J Inherit Metab Dis ; 25(5): 333-46, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12408183

RESUMO

During 1967-1983, the Maternal and Child Health Division of the Public Health Services funded a collaborative study of 211 newborn infants identified on newborn screening as having phenylketonuria (PKU). Subsequently, financial support was provided by the National Institute of Child Health and Human Development (NICHD). The infants were treated with a phenylalanine (Phe)-restricted diet to age 6 years and then randomized either to continue the diet or to discontinue dietary treatment altogether. One hundred and twenty-five of the 211 children were then followed until 10 years of age. In 1998, NICHD scheduled a Consensus Development Conference on Phenylketonuria and initiated a study to follow up the participants from the original Collaborative Study to evaluate their present medical, nutritional, psychological, and socioeconomic status. Fourteen of the original clinics (1967-1983) participated in the Follow-up Study effort. Each clinic director was provided with a list of PKU subjects who had completed the original study (1967-1983), and was asked to evaluate as many as possible using a uniform protocol and data collection forms. In a subset of cases, magnetic resonance imaging and spectroscopy (MRI/MRS) were performed to study brain Phe concentrations. The medical evaluations revealed that the subjects who maintained a phenylalanine-restricted diet reported fewer problems than the diet discontinuers, who had an increased rate of eczema, asthma, mental disorders, headache, hyperactivity and hypoactivity. Psychological data showed that lower intellectual and achievement test scores were associated with dietary discontinuation and with higher childhood and adult blood Phe concentrations. Abnormal MRI results were associated with higher brain Phe concentrations. Early dietary discontinuation for subjects with PKU is associated with poorer outcomes not only in intellectual ability, but also in achievement test scores and increased rates of medical and behavioural problems.


Assuntos
Fenilcetonúrias , Adulto , Química Encefálica , Criança , Continuidade da Assistência ao Paciente , Escolaridade , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Fenilalanina/administração & dosagem , Fenilalanina/análise , Fenilalanina/sangue , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/complicações , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/dietoterapia , Fenilcetonúrias/psicologia , Análise de Regressão , Classe Social , Escalas de Wechsler
18.
Am J Med Genet ; 102(2): 161-8, 2001 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-11477610

RESUMO

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome caused by deletions in glypican 3 (GPC3). SGBS is characterized by pre- and postnatal overgrowth, a characteristic facial appearance, and a spectrum of congenital malformations which overlaps that of other overgrowth syndromes. We performed GPC3 deletion screening on 80 male patients with somatic overgrowth in the following categories: SGBS (n = 19), possible SGBS (n = 26), including families in which individuals had previously been diagnosed with other overgrowth syndromes, and Wiedemann-Beckwith syndrome (WBS) (n = 35). Using exon-specific PCR and Southern blot analysis, we identified seven GPC3 deletions. In most cases a clear X-linked family history was not present. In two cases, GPC3 deletions were identified in patients belonging to pedigrees published previously as other overgrowth syndromes: one with a diagnosis of Sotos syndrome and the other Perlman syndrome with nephroblastomatosis. A third patient developed hepatoblastoma, a tumor type not previously described in SGBS. No GPC3 deletions were identified among the WBS patients. Direct sequencing of all GPC3 exons in the remaining 13 SGBS patients without GPC3 deletions did not identify any further mutations, raising the possibility of alternative silencing mechanisms and/or other genes in the pathogenesis of SGBS. Our results validate the clinical specificity of the facial appearance, skeletal/hand anomalies, and supernumerary nipples in patients with GPC3 deletions. Our data also suggest that nephroblastomatosis and hepatoblastoma are included in the phenotypic spectrum of GPC3 deletions and SGBS, underscoring the importance of tumor surveillance in these children.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Transtornos do Crescimento/genética , Proteoglicanas de Heparan Sulfato/genética , Anormalidades Múltiplas/patologia , Southern Blotting , DNA/genética , Saúde da Família , Feminino , Deleção de Genes , Ligação Genética , Glipicanas , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Síndrome , Cromossomo X/genética
19.
Biol Psychiatry ; 49(8): 677-84, 2001 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-11313035

RESUMO

BACKGROUND: Velocardiofacial syndrome, caused by a microdeletion on chromosome 22q.11, is associated with craniofacial anomalies, cardiac defects, learning disabilities, and psychiatric disorders. To understand how the 22q.11 deletion affects brain development, this study examined gray and white matter volumes in major lobar brain regions of children with velocardiofacial syndrome relative to control subjects. METHODS: Subjects were ten children with velocardiofacial syndrome and ten age- and gender-matched unaffected children. Coronal images were acquired with a 3-D spoiled gradient echo series and partitioned into 124, 1.5-mm contiguous slices. A stereotaxic grid was used to subdivide brain tissue into cerebral lobes, which were segmented into gray, white, and CSF compartments using an algorithm based on intensity values and tissue boundaries. Nonparametric statistics were used to compare lobar volumes of gray and white matter. RESULTS: Analyses indicated that children with velocardiofacial syndrome had significantly smaller volumes in nonfrontal, but not frontal, lobar brain regions. Volume reductions affected nonfrontal white matter to a greater extent than nonfrontal gray matter. CONCLUSIONS: The presence of white matter reductions may be related to disturbances in myelination or axonal integrity in velocardiofacial syndrome. Further work is required to delineate the nature and extent of white matter anomalies, and to link them to variation in the neurocognitive and neuropsychiatric phenotype of velocardiofacial syndrome.


Assuntos
Encéfalo/patologia , Cardiomiopatias/patologia , Deleção Cromossômica , Anormalidades Craniofaciais/patologia , Deficiências da Aprendizagem/patologia , Imageamento por Ressonância Magnética , Transtornos Mentais/patologia , Adolescente , Cardiomiopatias/genética , Criança , Cromossomos Humanos Par 22/genética , Anormalidades Craniofaciais/genética , Feminino , Humanos , Deficiências da Aprendizagem/genética , Masculino , Transtornos Mentais/genética , Síndrome
20.
Mol Genet Metab ; 72(4): 336-42, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11286508

RESUMO

In mammals, L-lysine is first catabolized to alpha-aminoadipate semialdehyde by the bifunctional enzyme alpha-aminoadipate semialdehyde synthase (AASS), followed by a conversion to alpha-aminoadipate by alpha-aminoadipate semialdehyde dehydrogenase. In Saccharomyces cerevisiae, which synthesize rather than degrade lysine, the latter activity requires two distinct genes. LYS2 encodes the alpha-aminoadipate reductase activity, while LYS5 encodes a phosphopantetheinyl transferase activity that is required to activate Lys2p. We have identified a full-length human cDNA homologous to the yeast LYS5 gene. The cDNA contains an open-reading frame of 930 bp predicted to encode 309 amino acids, and the human protein is 26% identical and 44% similar to its yeast counterpart. In Northern blot analysis the cDNA hybridizes to a single transcript of approximately 3 kb in all tissues except testis, where there is an additional transcript of 1.5 kb. Expression is highest in brain followed by heart and skeletal muscle, and to a lesser extent in liver. We further identified three human genomic BAC clones containing the human gene. Fluorescence in situ hybridization (FISH) analysis using the BAC clones mapped the gene to chromosome 11q22 while alignment of the cDNA and genomic sequences allowed partial identification of the intron-exon boundaries. Finally, using one-step homologous recombination in S. cerevisiae we generated a lys5 knockout strain. Complementation studies in the yeast knockout demonstrate that the human homolog encodes alpha-aminoadipate dehydrogenase phosphopantetheinyl transferase activity. We hypothesize that defects in this gene may result in pipecolic acidemia.


Assuntos
Aldeído Oxirredutases/genética , Proteínas Fúngicas/genética , Genes Fúngicos/genética , Lisina/genética , Saccharomyces cerevisiae/genética , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , Clonagem Molecular , Primers do DNA/química , DNA Complementar/análise , DNA Complementar/isolamento & purificação , Proteínas Fúngicas/química , Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , L-Aminoadipato-Semialdeído Desidrogenase , Dados de Sequência Molecular , Peso Molecular , Reação em Cadeia da Polimerase , Saccharomyces cerevisiae/enzimologia , Homologia de Sequência de Aminoácidos
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