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1.
J Inherit Metab Dis ; 42(5): 809-817, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177572

RESUMO

The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra-rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low-normal branched-chain keto acids (BCKAs) with undetectable l-allo-isoleucine. Interestingly, unlike in MSUD, none of the individuals with BCAT2 deficiency developed acute encephalopathy even with exceptionally high BCAA levels. We observed wide-ranging clinical phenotypes in individuals with BCAT2 deficiency. While one adult was apparently asymptomatic, three individuals had presented with developmental delay and autistic features. We show that the biochemical characteristics of BCAT2 deficiency may be amenable to protein-restricted diet and that early treatment may improve outcome in affected individuals. BCAT2 deficiency is an inborn error of BCAA catabolism. At present, it is unclear whether developmental delay and autism are parts of the variable phenotypic spectrum of this condition or coincidental. Further studies will be required to explore this.

2.
J Inherit Metab Dis ; 42(1): 128-139, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30740731

RESUMO

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

3.
J Pediatr ; 205: 77-82, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30529133

RESUMO

OBJECTIVES: To evaluate the timing of a delayed rise in thyroid-stimulating hormone (TSH) levels in preterm infants with congenital hypothyroidism, and to determine whether cases of congenital hypothyroidism would be missed by using current consensus guidelines of repeat screening at approximately 2 weeks of age or 2 weeks after the first screening. STUDY DESIGN: The study was performed over a 13-year period (January 2004-December 2016). Whole-blood TSH samples were collected between 72 and 120 hours after birth. Repeat samples were collected weekly in preterm infants until the infant was term-corrected (37 weeks' gestation). Patients were followed up to determine whether congenital hypothyroidism was permanent or transient. RESULTS: Twenty-seven (50.9%) preterm infants born at <33 weeks of gestation who were diagnosed with congenital hypothyroidism had delayed TSH elevation and would not have been detected on first newborn screen. Twelve of these infants (40.7%) with delayed TSH elevation had decompensated hypothyroidism at diagnosis (free thyroxine [FT4] <10 pmol/L), and 4 had severe congenital hypothyroidism (FT4 <5.5 pmol/L) at diagnosis. If screening had been repeated only at 2 weeks of life, 13 infants (48%) with delayed TSH elevation would not have been identified. Of the 27 infants with delayed TSH elevation, 6 (22%) have permanent congenital hypothyroidism, and another 12 will be reevaluated at age 3 years. CONCLUSION: Repeat screening for congenital hypothyroidism in preterm infants is necessary to avoid missing cases of congenital hypothyroidism with delayed TSH elevation. Repeat screening once at 2 weeks of life will miss infants with delayed TSH elevation and decompensated permanent congenital hypothyroidism.

4.
Pediatrics ; 142(4)2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30242075

RESUMO

BACKGROUND AND OBJECTIVES: Congenital hypothyroidism (CHT) is one of the most common preventable causes of learning disability. Newborn screening with whole-blood thyroid-stimulating hormone measurements was introduced in the Republic of Ireland in 1979 and is coordinated from a single center with an unchanged protocol since its inception. Our objective in this study was to describe the incidence of CHT in the Republic of Ireland over the past 37 years in the context of a complete national population and an unchanged screening protocol. METHODS: The newborn screening records of all individuals who were diagnosed with CHT between 1979 and 2016 were reviewed. Infants with positive screening results had a whole-blood thyroid-stimulating hormone value of ≥15 mU/L at 72 to 120 hours of life; values of 8 to 15 mU/L required a repeat whole-blood screening test. RESULTS: Of 2 361 174 infants who were screened between July 1979 and December 2016, 1063 (662 girls) were diagnosed with CHT (incidence: 0.45 cases per 1000 live births). The number of detected cases increased from 0.27 cases per 1000 live births treated between 1979 and 1991 to 0.41 cases per 1000 live births treated between 1992 and 2004 to 0.65 cases per 1000 live births treated between 2005 and 2016. The increase in detected cases of CHT was predominantly in the normal or hyperplastic gland category. CONCLUSIONS: The incidence of CHT has increased significantly in the Republic of Ireland over the past 37 years despite a consistent screening cutoff. The increased rate was not explained by an increased survival rate of preterm infants or a changing population heterogeneity.

5.
Horm Res Paediatr ; 89(4): 265-270, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29804122

RESUMO

BACKGROUND: Congenital hypothyroidism (CHT) has a reported incidence of approximately 1 in 2,000-4,000 births. There is no consensus on the optimal cut-off whole-blood thyroid-stimulating hormone (TSH) concentration that should be used for newborn screening (NBS). The NBS programme in the Republic of Ireland has used a cut-off of 8 mU/L since 1979. The aim of this study was to determine if raising the cut-off to 10 mU/L would have resulted in undetected cases of permanent or decompensated CHT. METHODS: All cases of CHT with a screening whole-blood TSH concentration between 8.0 and 9.9 mU/L were identified from the Republic of Ireland's NBS programme. Baseline demographics and imaging results were recorded. All cases over 3 years of age were evaluated to determine if CHT was permanent or transient. RESULTS: Of 2,361,174 infants screened in the Republic of Ireland between July 1979 and December 2016, a total of 1,063 babies were diagnosed with CHT and treated with levothyroxine. This included 33 (3.5%) infants with a whole-blood TSH concentration between 8 and 9.9 mU/L. Thirteen of these 33 infants had decompensated hypothyroidism with low plasma free thyroxine level at diagnosis and 9 (41%) of the 21 evaluable cases have confirmed permanent CHT. CONCLUSION: Although lowering screening TSH cut-offs can increase the cost of NBS, as well as anxiety for families, many infants with borderline increases in whole-blood TSH concentrations on NBS have persistent CHT and low thyroxine concentrations in infancy. We recommend that this is considered when developing and reviewing NBS protocols for identifying infants with CHT.


Assuntos
Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/epidemiologia , Tireotropina/sangue , Feminino , Humanos , Recém-Nascido , Irlanda , Masculino , Programas de Rastreamento , Estudos Retrospectivos
6.
Am J Med Genet A ; 176(5): 1115-1127, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29575569

RESUMO

Short-chain enoyl-CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile-onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteristic abnormal biochemical findings are secondary to dysfunction of valine metabolism. We describe four patients from two consanguineous families (one Pakistani and one Irish Traveler), who presented in infancy with LS. Urine organic acid analysis by GC/MS showed increased levels of erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconate (3-MGC). Increased urine excretion of methacrylyl-CoA and acryloyl-CoA related metabolites analyzed by LC-MS/MS, were suggestive of SCEH deficiency; this was confirmed in patient fibroblasts. Both families were shown to harbor homozygous pathogenic variants in the ECHS1 gene; a c.476A > G (p.Gln159Arg) ECHS1variant in the Pakistani family and a c.538A > G, p.(Thr180Ala) ECHS1 variant in the Irish Traveler family. The c.538A > G, p.(Thr180Ala) ECHS1 variant was postulated to represent a Canadian founder mutation, but we present SNP genotyping data to support Irish ancestry of this variant with a haplotype common to the previously reported Canadian patients and our Irish Traveler family. The presence of detectable erythro-2,3-dihydroxy-2-methylbutyrate is a nonspecific marker on urine organic acid analysis but this finding, together with increased excretion of 3-MGC, elevated plasma lactate, and normal acylcarnitine profile in patients with a Leigh-like presentation should prompt consideration of a diagnosis of SCEH deficiency and genetic analysis of ECHS1. ECHS1 deficiency can be added to the list of conditions with 3-MGA.

7.
J Nutr Metab ; 2017: 8570469, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29270317

RESUMO

A low methionine diet is the mainstay of treatment for pyridoxine nonresponsive homocystinuria (HCU). There are various guidelines for recommended protein intakes for HCU and clinical practice varies. Poor growth has been associated with low cystine levels. This retrospective review of 48 Irish pyridoxine nonresponsive HCU patients assessed weight, height, body mass index (BMI), protein intake, and metabolic control up to 18 years at nine set time points. Patients diagnosed through newborn screening (NBS) were compared to late diagnosed (LD) patients. At 18 years the LD group (n = 12, mean age at diagnosis 5.09 years) were heavier (estimated effect +4.97 Kg, P = 0.0058) and taller (estimated effect +7.97 cm P = 0.0204) than the NBS group (n = 36). There was no difference in growth rate between the groups after 10 years of age. The HCU population were heavier and taller than the general population by one standard deviation with no difference in BMI. There was no association between intermittently low cystine levels and height. Three protein intake guidelines were compared; there was no difference in adult height between those who met the lowest of the guidelines (Genetic Metabolic Dietitians International) and those with a higher protein intake.

8.
Brain Dev ; 39(6): 536-538, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28190537

RESUMO

d-Glyceric aciduria is caused by deficiency in d-glycerate kinase (GK) due to recessive mutations in the GLYCTK gene. GK catalyzes the conversion of d-glycerate to 2-phosphoglycerate which is an intermediary reaction in the catabolism of serine and fructose. Deficiency of GK leads to accumulation of d-glycerate, which may be detected in urine organic acid analysis. Debate exists as to whether this is a benign or disease-causing disorder as the reported phenotypes vary significantly. We report two siblings from a consanguineous Pakistani family. The index case is a 5year old boy with severe autism and global developmental delay. His urine organic acid analysis showed markedly increased excretion of glycerate, determined as d-form by enantioselective gas chromatography. There was no oxalic aciduria. His younger sister (3years old) is asymptomatic and developmentally normal (already bilingual). Her urine showed similar amounts of d-glycerate. Both children are homozygous for the novel mutation c.767C>G in exon 5 of the GLYCTK gene, predicted to affect the enzyme by replacing the evolutionarily conserved Proline with Arginine (P256R). Both parents are heterozygous carriers. These cases support the view that d-glycerate kinase deficiency is a benign disorder. Long term follow-up studies with a greater number of individuals may be required for further confirmation.


Assuntos
Mutação/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico por imagem , Erros Inatos do Metabolismo dos Carboidratos/genética , Pré-Escolar , Saúde da Família , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Fosfotransferases/deficiência , Fosfotransferases/genética
9.
J Inherit Metab Dis ; 40(1): 49-74, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27778219

RESUMO

Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 µmol/L. Nevertheless, we recommend keeping the concentration below 100 µmol/L because levels fluctuate and the complications associated with high levels are so serious.


Assuntos
Cistationina beta-Sintase/deficiência , Homocistinúria/dietoterapia , Homocistinúria/tratamento farmacológico , Betaína/metabolismo , Homocisteína/metabolismo , Humanos , Metionina/metabolismo , Piridoxina/uso terapêutico
10.
Clin Pediatr (Phila) ; 53(14): 1345-51, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25006113

RESUMO

BACKGROUND: Vitamin D has important skeletal and extraskeletal roles but those living at northerly latitudes are at risk of suboptimal levels because of reduced sunlight exposure. AIM: To describe the vitamin D status of Irish children and identify factors predictive of vitamin D status. METHODS: A prospective cross sectional study was undertaken over a 12 month period. Two hundred and fifty two healthy children attending for minor medical or surgical procedures were recruited. All had 25-hydroxyvitamin D (25OHD), parathyroid hormone and bone profiles measured. RESULTS: The mean (standard deviation) for 25OHD was 51(25) nmol/L (20.4 (10) ng/mL). Forty-five percent had levels >50 nmol/L (20 ng/mL). The following variables were significantly associated with 25OHD levels >50 nmol/L (20 ng/mL): sample drawn in April-September, use of vitamin D supplements, consumption of formula milk, and non-African ethnicity. CONCLUSION: More than half of the children in this study had 25OHD levels less than 50 nmol/L (20 ng/mL). Vitamin D status was significantly improved by augmented oral vitamin D intake.


Assuntos
Grupos de Populações Continentais/estatística & dados numéricos , Dieta , Suplementos Nutricionais , Alimentos Fortificados , Deficiência de Vitamina D/epidemiologia , Vitamina D/análogos & derivados , Adolescente , Densidade Óssea , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Irlanda , Masculino , Hormônio Paratireóideo/sangue , Estudos Prospectivos , Estações do Ano , Vitamina D/sangue
11.
Am J Med Genet A ; 158A(9): 2254-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22848014

RESUMO

We report on the case of a 2-year-old girl recently diagnosed with Methylenetetrahydrofolate reductase (MTHFR) deficiency who originally presented in the neonatal period with a distinctive rash. At 11 weeks of age she developed seizures, she had acquired microcephaly and developmental delay. The rash deteriorated dramatically following commencement of phenobarbitone; both rash and seizures abated following empiric introduction of pyridoxine and folinic acid as treatment of possible vitamin responsive seizures. We postulate that phenobarbitone in combination with MTHFR deficiency may have caused her rash to deteriorate and subsequent folinic acid was helpful in treating the rash and preventing further acute neurological decline as commonly associated with this condition.


Assuntos
Exantema/diagnóstico , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Pré-Escolar , Exantema/enzimologia , Exantema/etiologia , Feminino , Humanos
12.
Platelets ; 22(1): 65-73, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21133649

RESUMO

Elevated levels of plasma homocysteine (Hcy) are an independent risk factor for cardiovascular disease and thrombosis. The molecular basis for this phenomenon is not known but may relate to modification of cell surface thiols. The platelet specific integrin α(IIb)ß3 is a cysteine-rich cell adhesion molecule that plays a critical role in platelet aggregation and adhesion in haemostasis and thrombosis. In this study, we looked for evidence of a homocysteine-induced modification of α(IIb)ß3 using a fluorescently labeled PAC-1 antibody that recognizes the activated conformation of the integrin on the platelet surface. We show that exogenous Hcy (10-100 µM) and homocysteine thiolactone (HcyTL) (10-100 µM) increased PAC-1 binding to platelets in a concentration dependent manner in vitro. In parallel, we show subjects with clinical hyperhomocysteinemia exhibit a greater degree of activation of α(IIb)ß3 compared to age-matched controls. These findings demonstrate that circulating Hcy can modulate the activation state of the platelet integrin α(IIb)ß3, a key player in platelet aggregation and thrombosis.


Assuntos
Homocisteína/metabolismo , Hiper-Homocisteinemia/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Trombose/metabolismo , Anticorpos/metabolismo , Sítios de Ligação de Anticorpos/efeitos dos fármacos , Plaquetas/metabolismo , Estudos de Casos e Controles , Feminino , Homocisteína/análogos & derivados , Homocisteína/farmacologia , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/fisiopatologia , Integrinas/metabolismo , Masculino , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Fatores de Risco , Compostos de Sulfidrila/metabolismo , Trombose/etiologia , Trombose/fisiopatologia
13.
J Inherit Metab Dis ; 34(1): 49-55, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20821054

RESUMO

Cystathionine ß-synthase (CBS) deficiency is usually confirmed by assaying the enzyme activity in cultured skin fibroblasts. We investigated whether CBS is present in human plasma and whether determination of its activity in plasma could be used for diagnostic purposes. We developed an assay to measure CBS activity in 20 µL of plasma using a stable isotope substrate - 2,3,3-(2)H serine. The activity was determined by measurement of the product of enzyme reaction, 3,3-(2)H-cystathionine, using LC-MS/MS. The median enzyme activity in control plasma samples was 404 nmol/h/L (range 66-1,066; n = 57). In pyridoxine nonresponsive CBS deficient patients, the median plasma activity was 0 nmol/ho/L (range 0-9; n = 26), while in pyridoxine responsive patients the median activity was 16 nmol/hour/L (range 0-358; n = 28); this overlapped with the enzyme activity from control subject. The presence of CBS in human plasma was confirmed by an in silico search of the proteome database, and was further evidenced by the activation of CBS by S-adenosyl-L-methionine and pyridoxal 5'-phosphate, and by configuration of the detected reaction product, 3,3-(2)H-cystathionine, which was in agreement with the previously observed CBS reaction mechanism. We hypothesize that the CBS enzyme in plasma originates from liver cells, as the plasma CBS activities in patients with elevated liver aminotransferase activities were more than 30-fold increased. In this study, we have demonstrated that CBS is present in human plasma and that its catalytic activity is detectable by LC-MS/MS. CBS assay in human plasma brings new possibilities in the diagnosis of pyridoxine nonresponsive CBS deficiency.


Assuntos
Cistationina beta-Sintase/deficiência , Cistationina beta-Sintase/metabolismo , Homocistinúria/diagnóstico , Plasma/enzimologia , Espectrometria de Massas em Tandem/métodos , Análise Química do Sangue/métodos , Análise Química do Sangue/normas , Calibragem , Estudos de Casos e Controles , Cromatografia Líquida , Estabilidade Enzimática , Homocistinúria/sangue , Homocistinúria/enzimologia , Humanos , Técnicas Imunoenzimáticas/métodos , Técnicas Imunoenzimáticas/normas , Plasma/química , Plasma/metabolismo , Fosfato de Piridoxal/farmacologia , S-Adenosilmetionina/farmacologia , Espectrometria de Massas em Tandem/normas
14.
Eur J Pediatr ; 169(8): 941-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20177701

RESUMO

Localised duplications, involving the MECP2 locus, at Xq28 have been associated with a syndrome comprising X-linked mental retardation, hypotonia and recurrent infections in males. We now present neuroradiological evidence that progressive cerebellar degenerative changes may also be a consistent feature of this syndrome, emerging in the second decade of life. We report seven affected males, from three different families who, in addition to the previously described clinical findings, have a reduction in the volume of the white matter and mild dilatation of the lateral ventricles. Three of the older patients show a consistent cerebellar degenerative phenotype. Furthermore, we describe the first female affected with the disorder. The female was mildly affected and shows X-inactivation in the ratio of 70:30, demonstrating that X-inactivation cannot be exclusively relied upon to spare the female carriers from symptoms. In conclusion, there is a radiological phenotype associated with Xq28 duplication which clearly demonstrates progressive degenerative cerebellar disease as part of the syndrome.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Duplicação Gênica , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/patologia , Proteína 2 de Ligação a Metil-CpG/genética , Inativação do Cromossomo X , Atrofia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Pré-Escolar , Cromossomos Humanos X/genética , Progressão da Doença , Família , Feminino , Humanos , Lactente , Ventrículos Laterais/diagnóstico por imagem , Ventrículos Laterais/patologia , Imagem por Ressonância Magnética , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico por imagem , Linhagem , Fenótipo , Fatores Sexuais , Tomografia Computadorizada por Raios X
16.
Thyroid ; 18(8): 883-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18651804

RESUMO

BACKGROUND: The distribution of neonatal blood thyroid-stimulating hormone (TSH) concentrations has been used as an index reflecting population dietary iodine intake, with higher concentrations being indicative of lower iodine intake. We examined this distribution in neonates born in Ireland, where the pregnant population has shown a recent decline in urinary iodine (UI) excretion. Our objectives were to determine if any alteration was observed in the percentage of values > 5.0 mIU/L and whether a trend in neonatal blood TSH was apparent. METHODS: Samples drawn from the National Neonatal Screening Programme were assessed during the years 1995-2006 from winter (January n = 35,079) and summer (August n = 37,940) months, respectively, in view of the known seasonal variation in Irish dietary iodine intake. RESULTS: Apart from the first years studied (1995-1996), the proportion of individual blood TSH values >5.0 mIU/L did not exceed 3%, a value believed to be indicative of iodine deficiency. A significant declining trend in the proportion of blood TSH >5.0 mIU/L was observed in subsequent years (p < 0.01). While excluding severe iodine deficiency, these analyses failed to detect the slight but highly significant (p < 0.001) tendency toward increasing blood TSH within the 0-5.0 mIU/L interval in the study population between 1999 and 2006, which was greater in summer than in winter months (p < 0.001). CONCLUSIONS: These data support a link between fetal thyroid function and a fall in maternal iodine intake. While the findings of the proportion of blood TSH values >5.0 mIU/L exclude severe maternal or fetal iodine deficiency, a trend toward increasing TSH may provide an early indication of impending iodine deficiency. The findings assume greater importance in the context of declining UI reported from many developed countries even where the proportion of blood TSH values >5.0 mIU/L is <3%, thus excluding severe maternal and fetal iodine deficiency.


Assuntos
Iodo/deficiência , Triagem Neonatal , Tireotropina/sangue , Hipotireoidismo Congênito/diagnóstico , Deficiências Nutricionais/epidemiologia , Feminino , Humanos , Recém-Nascido , Iodo/urina , Irlanda/epidemiologia , Gravidez , Estações do Ano
18.
Mol Genet Metab ; 82(4): 345-7, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15308134

RESUMO

Anonymous population screening was carried out to detect the N314D, Los Angeles (D1), and Duarte (D2) alleles of the galactose-1-phosphate uridyltransferase gene in Ireland using 743 blood samples, covering the Traveller (n = 243) and non-Traveller (n = 500) population groups. The frequency of the N314D substitution was found to be 0.099 overall. D1 allele frequencies were found to be 0.031 and 0.023 in the Traveller and non-Traveller groups, respectively, while D2 allele frequencies were 0.058 and 0.076, respectively. No significant differences in allele frequency were detected between the Traveller and non-Traveller groups, or between the Irish population groups and the literature values for Northern and Western Europe.


Assuntos
Galactosemias/genética , Frequência do Gene , UTP-Hexose-1-Fosfato Uridililtransferase/genética , Alelos , Substituição de Aminoácidos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Galactosemias/diagnóstico , Galactosemias/etnologia , Humanos , Irlanda , Masculino , Síndrome
20.
Mol Genet Metab ; 81(2): 133-6, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14741195

RESUMO

Transferase-deficient galactosaemia is an inherited disorder of carbohydrate metabolism, caused by mutation at the galactose-1-phosphate uridyl transferase (GALT) locus. A denaturing high performance liquid chromatography (dHPLC) method was developed for variant scanning of the GALT gene. The method unequivocally identified the Duarte D1, D2, Q188R, and K285N GALT alleles and associated polymorphisms. Length polymorphism in an intronic Alu repeat was characterised and a novel Single Nucleotide Polymorphism (IVS10nt-322g-->t) associated with the D1 allele was identified.


Assuntos
Variação Genética , Polimorfismo de Nucleotídeo Único , UDPglucose-Hexose-1-Fosfato Uridiltransferase/genética , Elementos Alu , Cromatografia Líquida de Alta Pressão , Humanos , Polimorfismo Genético , UDPglucose-Hexose-1-Fosfato Uridiltransferase/sangue
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