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PubMed2006

Time course of acylcarnitine elevation in neonatal intrahepatic cholestasis caused by citrin deficiency.

Citrin is a mitochondrial membrane aspartate-glutamate carrier, and citrin deficiency causes both hyperammonaemia in adults (adult-onset type II citrullinaemia, CTLN2) and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), with metabolic derangements in gluconeogenesis, aerobic glycolysis, urea synthesis, UDP-galactose epimerase activity, and possibly fatty acid synthesis and utilization. Through neonatal screening and case review, four patients with NICCD who had an acylcarnitine profile during infancy were all found to have an elevation of free carnitine, C2-carnitine, and long-chain acylcarnitines. These metabolic abnormalities appeared after the rise of citrulline and bilirubin, but before the elevation of alanine aminotransferase and aspartate aminotransferase. Although the rise of free carnitine and acylcarnitines seems to be a benign condition, the sequential changes of these metabolic derangements may give clues to the pathogenesis of this interesting disorder.

Alanine↗

PubMed2006

[Phenylketonuria].

Phenylketonuria is a hereditary metabolic disease, characterized by deficiency of phenylalanine hydroxylase, an enzyme necessary for the transformation of phenylalanine into tyrosine. Untreated, phenylketonuria leads to mental retardation, sometimes profound, as well as hypopigmentation. Dietary phenylalanine restriction allows patients to lead almost normal lives. Phenylalanine is toxic to fetal development and severe disorders occur in the children of women whose phenylketonuria is untreated during pregnancy. These women must be informed that they must plan pregnancy and begin dietary restrictions in the preconceptional period. France has set up routine neonatal screening in view of the incidence of this disease (1/17000 in France) and the existence of effective treatment. Since 1970, approximately 1600 infants with phenylketonuria have thus been diagnosed and treated. Strict metabolic control is necessary during the first 10 years of life, after which the diet can be progressively enlarged. Dietary restriction must resume before any pregnancy. Advances in treatment: a study published in 2002 showed that some patients deficient in phenylalanine hydroxylase are sensitive to pharmacological doses of tetrahydrobiopterin (BH4), a cofactor of this 'enzyme essential to the transformation of phenylalanine into tyrosine. Some patients treated by this cofactor have normal levels of phenylalanine intake. While only a few patients have so far received this alternative treatment, intermediate and long-term experiments are currently being evaluated.

Diagnosis, Differential↗

PubMed2006

Molecular epidemiology of phenylalanine hydroxylase deficiency in Southern Italy: a 96% detection rate with ten novel mutations.

Hyperphenylalaninemia (HPA) comprises a group of autosomal recessive disorders mainly caused by phenylalanine hydroxylase (PAH) gene mutations. We investigated PAH mutations in 126 HPA patients from Southern Italy who were identified in a neonatal screening program. The promoter, coding and exon-flanking intronic sequences of the PAH gene were amplified and sequenced. Mutations were identified in 240/249 alleles (detection rate: 96.4%). We found 60 gene variants; the most frequent were p.R261Q (15.7% of alleles), p.A403V (11.6% of alleles) and c.1066-11G > A (8.8% of alleles). The remaining mutations were rare, and ten are novel. This mutation epidemiology differs from that reported for Northern Italy and other European countries. We also identified several discordant genotype/phenotype correlations. About two-thirds of all mild phenylketonuria patients showed at least one tetrahydrobiopterin (BH4)-responsive mutation, and are thus candidates for a customized therapeutic approach.

Alleles↗

PubMed1991

Congenital hypothyroidism and pericardial effusion.

A group of infants, affected by congenital hypothyroidism diagnosed through the neonatal screening program, was investigated with echocardiography to detect the presence of pericardial effusion. We studied the relationship between the effusion and the etiology of hypothyroidism, established through thyroid scintiscanning. Our data show a high prevalence of effusion in hypothyroid patients, without other clinical signs of cardiac involvement as well as a relationship between the etiology of hypothyroidism and the presence of effusion. This seems to be much more frequent in those forms which can imply a more severe hormonal defect, particularly during fetal life (agenesis/dyshormonogenesis). Furthermore, the high prevalence of pericardial effusion suggests to start the L-T4 replacement therapy with lower dosages as commonly advised, in order to avoid a cardiac involvement.

Congenital Hypothyroidism↗

PubMed2003

Twenty years experience in rapid identification of congenital adrenal hyperplasia in Hungary.

UNLABELLED: The aim of this study was to assess the effectivity of the identification of patients with congenital adrenal hyperplasia (CAH) in Hungary in the absence of systematic neonatal screening and to estimate the incidence. Dried blood-spot samples of patients clinically suspected at any age to have CAH were collected between 1978 and 1998 throughout the whole country. 17-Hydroxyprogesterone (17-OHP) was measured by radioimmunoassay. Age-specific cut-offs were used. The effectivity of the system was retrospectively assessed. Additional cases were sought to assess the overall incidence of CAH in Hungary. Among the 1,837 patients investigated, 185 cases of CAH were identified. The overall effectivity was 94.7%. The sensitivity and the specificity were 98.9% and 94.2%, respectively. Salt-wasting (SW) boys were, on average, diagnosed 2 weeks later than SW girls, while both boys and girls with the simple virilising (SV) form were diagnosed at similar ages (2 versus 2.5 years). An additional 19 cases were diagnosed during the study period using other methods (plasma and urinary steroid profiles without blood-spot 17-OHP measurements). The incidence of classical CAH in Hungary was 1:14,300 (CI 95% between 1:12,450 and 1:16,795). Presuming that the incidence of CAH is the same among boys and girls, one can calculate that the diagnosis was missed in 24 boys (2 SW, 22 SV). CONCLUSION: it is possible to identify the vast majority of classical cases of congenital adrenal hyperplasia without a neonatal mass screening programme. However, a significant number of boys with the simple virilising form missed whereas both salt-wasting boys and girls are diagnosed safely.

17-alpha-Hydroxyprogesterone↗

PubMed2005

Undetectable serum IgA and low IgM concentration in children with congenital hypothyroidism.

Some studies suggest thyroid hormones may regulate the human immune system. In order to evaluate the effect of thyroid hormone deficiency on antibody production, we evaluated serum IgA and IgM concentrations in 83 children with congenital hypothyroidism (CH), diagnosed by neonatal screening. Patients were compared to two healthy, age-matched control groups. Patients with permanent CH had a significantly higher frequency of undetectable IgA concentrations (thyroid agenesis, P<10(-5); thyroid ectopy, P=0.013) and lower concentrations of IgA (thyroid agenesis, P<10(-6); thyroid ectopy, P<10(-5); dyshormonogenesis, P=0.0002) and IgM (thyroid agenesis, P=0.0002; thyroid ectopy, P<10(-6); dyshormonogenesis, P=0.0017) compared to control group. No difference was observed between patients with transient hypothyroidism and controls. A significant correlation was observed between serum IgA and IgM concentrations and fT4 levels. IgA and IgM deficiency is correlated with the severity of congenital hypothyroidism and may help to evaluate the duration and severity of thyroid hormone deficiency during prenatal life.

Biomarkers↗

PubMed2005

Congenital hypothyroidism with gland in situ: diagnostic re-evaluation.

In the past, most congenital hypothyroidism (CH) children with thyroid gland in situ were considered to be affected by hormonogenesis defect. Nowadays, the improved sensitivity of neonatal screening, novel insights into the pathogenic mechanisms and the advances of genetic analyses have reopened the discussion about the etiology of CH with thyroid in situ. We report the etiological re-evaluation of 31 children with thyroid in situ, who had been identified by the CH screening program. The purposes of this re-evaluation were: a) to investigate the definitive diagnosis and pathogenetic mechanism of CH with thyroid in situ in eligible children suspected of dyshormonogenetic defect and b) to verify the adequacy of the treatment schedules. Thirty out of 31 children were affected with permanent hypothyroidism and only one child was euthyroid at re-evaluation (transient CH). Thyroid hormone organification defects were present in less than half of the CH patients with thyroid in situ (13/30); a higher prevalence of partial defects of iodine organification than severe or complete forms was found. An inactivating TSH-receptor gene mutation was found in only one patient without iodine organification defect. Some questions remain unanswered concerning the adequacy of the schedules of treatment, particularly about the proper treatment of mild and borderline forms of CH.

Congenital Hypothyroidism↗

PubMed2000

Longitudinal assessment of L-T4 therapy for congenital hypothyroidism: differences between athyreosis vs ectopia and delayed vs normal bone age.

To study the effects of LT4 dose on thyroid hormone serum levels, a prospective, longitudinal and comparative study was designed, including 56 term eutrophic 1-89 day-old infants with congenital hypothyroidism (CH) detected by neonatal screening. Patients were divided into four groups according to delayed or normal bone age at birth, and athyreosis or ectopic thyroid. All received an initial dose of 50 micrograms/day (12.9-13.7 micrograms/kg/day) LT4 and were followed bimonthly (first year) and quarterly (second year) with thyroid profile and bone age determinations at 6, 12 and 24 months. At diagnosis, hormone levels were higher in cases of ectopia than in athyreosis (p < 0.001), and T4 was lower in children with delayed than in normal bone age at birth (p < 0.05). During treatment, all groups were clinically euthyroid despite T4 and FT4 serum levels higher than the upper normal limit (p < 0.0.001), though T3 and FT3 were within the normal limit (p > 0.05). TSH normalized within 8 weeks. Bone age accelerated at 2 years in eight children of the bone age delayed group. No patient had craniosynostosis.

Age Determination by Skeleton↗

PubMed1992

Congenital anomalies concomitant with persistent primary congenital hypothyroidism.

The Israeli national neonatal screening program for congenital hypothyroidism (CH) was initiated in May 1978. The overall incidence of persistent primary congenital hypothyroidism (PPCH) during the first 10 years of screening was 1:2,950 live births. The purpose of this study was to ascertain the incidence of congenital extrathyroid anomalies (ETAs) among the infants with PPCH and to compare it with the Israeli Birth Defect Monitoring System data. Among 243 PPCH infants on whom adequate data were available, 38 infants (15.6%) had associated congenital anomalies. Fourteen infants had congenital cardiac anomalies (5.8%): VSD (n = 7), PDA (n = 3), PS (n = 2), one mitral insufficiency, and one congenital atrial flutter. Eight children (3.3%) had congenital dislocation of the hip; their M:F ratio was 3:5 similar to the M:F ratio in CH (unlike the ratio in the general population). Some additional anomalies were considerably more common than in the general population. It is reasonable to assume that teratogenic effects active during organogenesis may affect simultaneously many organs, including the developing thyroid, causing a relatively high percentage of CH infants with congenital ETA.

Congenital Abnormalities↗

PubMed2006

Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth.

BACKGROUND: Infections during fetal life or neonatal period, including infections with Toxoplasma gondii, may be associated with a risk for schizophrenia and other mental disorders. The objectives of this study were to study the association between serological markers for maternal and neonatal infection and the risk for schizophrenia, related psychoses, and affective disorders in a national cohort of newborns. METHODS: This study was a cohort-based, case-control study combining data from national population registers and patient registers and a national neonatal screening biobank in Denmark. Patients included persons born in Denmark in 1981 or later followed up through 1999 with respect to inpatient or outpatient treatment for schizophrenia or related disorders (ICD-10 F2) or affective disorders (ICD-10 F3). RESULTS: Toxoplasma gondii immunoglobulin G (IgG) levels corresponding to the upper quartile among control subjects were significantly associated with schizophrenia risk (odds ratio [OR] = 1.79, p = .045) after adjustment for urbanicity of place of birth, year of birth, gender, and psychiatric diagnoses among first-degree relatives. There was no significant association between any marker of infection and other schizophrenia-like disorders or affective disorders. CONCLUSIONS: Our study supports an association between Toxoplasma gondii and early-onset schizophrenia. Further studies are needed to establish if the association is causal and if it generalizes to cases with onset after age 18.

Animals↗

PubMed1993

The North American Collaborative Study of Maternal Phenylketonuria. Status report 1993.

Neonatal screening for phenylketonuria (PKU) has created an unexpected problem as females with PKU are reaching childbearing age. Surveys have revealed that maternal phenylalanine blood concentrations above 1200 mumol/L are associated with microcephaly, mental retardation, congenital heart defects, and intrauterine growth retardation among their offspring. It is estimated that as many as 3000 hyperphenylalaninemic females may be at risk for producing these fetal abnormalities. To examine this problem, the North American Maternal PKU Collaborative Study has been developed to evaluate the efficacy of a phenylalanine-restricted diet in reducing fetal morbidity. Preliminary findings indicate that phenylalanine restriction should begin before conception for females with PKU planning a pregnancy. Dietary control should maintain maternal blood phenylalanine levels between 120 and 360 mumol/L and should provide adequate energy, protein, vitamin, and mineral intake. Pregnant hyperphenylalaninemic females who achieved metabolic control after conception or by the 10th week of pregnancy had a better offspring outcome than anticipated.

Adolescent↗

PubMed2002

A population-based study on the frequency of additional congenital malformations in infants with congenital hypothyroidism: data from the Italian Registry for Congenital Hypothyroidism (1991-1998).

In the last decade a high frequency of other congenital anomalies has been reported in infants with congenital hypothyroidism (CH) detected by neonatal screening. In the present study the occurrence of additional congenital malformations (CM) in the population of CH infants detected in Italy between 1991 and 1998 (n = 1420) was investigated. In Italy all of the centers in charge of screening, treatment, and follow-up of CH adhere to the Italian National Registry of infants with CH. In this study a high prevalence of additional CM (8.4%), more than 4-fold higher than that reported in the Italian population (1-2%), was found in the population of CH infants. Cardiac anomalies represented the most frequent malformations associated with CH, with a prevalence of 5.5%. However, a significant association between CH and anomalies of nervous system, eyes, and multiple CM was also observed. In conclusion, the significantly higher frequency of extrathyroidal congenital malformations reported in the CH infants than in the general population represents a further argument supporting the role of a genetic component in the etiology of CH. Investigations of the molecular mechanisms underlying developmental events of formation of thyroid and other organs represent critical steps in the knowledge of CH etiology.

Abnormalities, Multiple↗

PubMed2005

Dried blood spots as a practical and inexpensive source for human immunodeficiency virus and hepatitis C virus surveillance.

Passive surveillance of infectious diseases with a high percentage of asymptomatic cases or long incubation periods, such as acquired immunodeficiency syndrome (AIDS), does not reflect the current transmission dynamics. Thus, a multi-strategic surveillance, such as the human immunodeficiency virus (HIV) sentinel surveillance proposed by the World Health Organization (WHO), is necessary. The Brazilian HIV sentinel surveillance was started in May 1992 with this purpose. The objectives of this study were to evaluate the feasibility and costs of HIV and hepatitis C virus (HCV) surveillance using dried blood spots (DBS) collected for neonatal screening of metabolic diseases in the state of Minas Gerais, Brazil. This was accomplished through the comparison of HIV and HCV seroprevalence with previous Brazilian studies. From December 2001 to June 2002, 24,905 newborns were tested for HIV and 4211 for HCV. HIV seroprevalence was 0.25% and the 95% confidence interval (CI) was 0.18, 0.31%; and HCV seroprevalence was 0.71% and the 95% CI was 0.46, 0.97%. These numbers are similar to previous Brazilian studies. Cost in this study was approximately USD 3.10 per sample, which was roughly one third of the cost of the same exam at the Brazilian HIV sentinel surveillance. We conclude that it is possible and more cost-effective to use DBS for infectious diseases surveillance, albeit it is still necessary to compare these results with the usual sentinel methodology in a concomitant trial.

Blood Specimen Collection↗

PubMed2006

Frequencies of phenylalanine hydroxylase mutations I65T, R252W, R261Q, R261X, IVS10nt11, V388M, R408W, Y414C, and IVS12nt1 in Minas Gerais, Brazil.

In order to determine the phenylketonuria (PKU) mutation spectrum in the population of Minas Gerais State, Brazil, 78 unrelated PKU patients found by the neonatal screening program from 1993 to 2003 were tested for nine phenylalanine hydroxylase mutations. These mutations were selected due to their high frequencies in other Brazilian populations and in Portugal, where the largest contingent of the Caucasian component of the Brazilian population originated from. The most frequent mutations were V388M (21%), R261Q (16%), IVS10nt11 (13.4%), I65T (5.7%), and R252W (5%). The frequencies of the other four mutations (R261X, R408W, Y414C, and IVS12nt1) did not reach 2%. By testing these nine mutations, we were able to identify 64% of the PKU alleles in our sample. V388M frequency was higher than in any other known population and almost three times larger than that observed in Portugal, probably reflecting genetic drift. The mutation profile, as well as the relative frequency of the different mutations, suggest that the Minas Gerais population more closely resembles that of Portugal than do the other Brazilian populations that have already been tested.

Brazil↗

PubMed2006

Combined ultrasound and isotope scanning is more informative in the diagnosis of congenital hypothyroidism than single scanning.

BACKGROUND: Thyroid imaging is helpful in confirming the diagnosis of congenital hypothyroidism and in establishing the aetiology. Although isotope scanning is the standard method of imaging, ultrasound assessment may be complementary. AIM: To determine the strengths and weaknesses of thyroid ultrasound and isotope scanning in neonates with thyroid stimulating hormone (TSH) elevation. METHODS: Babies from the West of Scotland with raised capillary TSH (>15 mU/l) on neonatal screening between January 1999 and 2004 were recruited. Thyroid dimensions were measured using ultrasonography, and volumes were calculated. Isotope scanning was carried out with a pinhole collimator after an intravenous injection of 99m-technetium pertechnetate. RESULTS: 40 infants (29 female) underwent scanning at a median of 17 days (range 12 days to 15 months). The final diagnosis was athyreosis (n = 11), ectopia (n = 12), hypoplasia (n = 8; 3 cases of hemi-agenesis), dyshormonogenesis (n = 5), transient hypothyroidism (n = 2), transient hyperthyrotropinaemia (n = 1) and uncertain status with gland in situ (n = 1). 6 infants had discordant scans with no isotope uptake but visualisation of thyroid tissue on ultrasound. This was attributed to TSH suppression from thyroxine (n = 3); maternal blocking antibodies (n = 1); cystic degeneration of the thyroid (n = 1); and possible TSH receptor defect (n = 1). CONCLUSIONS: Isotope scanning was superior to ultrasound in the detection of ectopic tissue. However, ultrasound detected tissue that was not visualised on isotope scanning, and showed abnormalities of thyroid volume and morphology. We would therefore advocate dual scanning in newborns with TSH elevation as each modality provides different information.

Congenital Hypothyroidism↗

PubMed1996

PAH deficiency in Italy: correlation of genotype with phenotype in the Sicilian population.

The results of the neonatal screening for phenylalanine hydroxylase (PAH) deficiency in Sicily show that its incidence is higher than previously reported for mainland Italians and that non-PKU HPA is in excess of classical and mild PKU. The latter finding suggests that a high number of non-PKU HPA mutations would occur in the Sicilian population compared to populations with an inverted PKU/non-PKU HPA ratio. Previous studies have identified 40 mutations accounting for the majority (98%) of mutant alleles underlying PAH deficiency in Sicily. In order to study the molecular basis of the distribution of PAH deficiency phenotypes in the Sicilian population, we have correlated 31 of those mutations with clinical and metabolic phenotypes in 12 mentally retarded patients, 14 treated patients with classic or mild PKU, and 13 subjects presenting the non-PKU HPA phenotype. The present study proposes a tentative classification for a large number (26) of PAH gene mutations which may represent an additional tool for establishing a differential diagnosis for PAH deficiency in the Sicilian population.

Amino Acid Metabolism, Inborn Errors↗

PubMed2003

Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults.

OBJECTIVE: To describe intellectual, motor, and school-associated outcome in young adults with early treated congenital hypothyroidism (CH) and to study the association between long-term outcome and CH variables acting at different points in time during early development (CH severity and early L-thyroxine treatment levels [0-6 years]). METHODS: Neuropsychological tests were administered to all 49 subjects with CH identified during the first 3 years of the Norwegian neonatal screening program (1979-1981) at a mean age of 20 years and to 41 sibling control subjects (mean age: 21 years). RESULTS: The CH group attained significantly lower scores than control subjects on intellectual, motor, and school-associated tests (total IQ: 102.4 [standard deviation: 13] vs 111.4 [standard deviation: 13]). Twelve (24%) of the 49 CH subjects had not completed senior high school, in contrast to 6% of the control subjects. CH severity (pretreatment serum thyroxine [T4]) correlated primarily with motor tests, whereas early L-thyroxine treatment levels were related to verbal IQ and school-associated tests. In multiple regression analysis, initial L-thyroxine dose (beta = 0.32) and mean serum T4 level during the second year (beta = 0.48) predicted Verbal IQ, whereas mean serum T4 level during the second year (beta = 0.44) predicted Arithmetic. CONCLUSIONS: Long-term outcome revealed enduring cognitive and motor deficits in young adults with CH relative to control subjects. Verbal functions and Arithmetic were associated with L-thyroxine treatment variables, suggesting that more optimal treatment might be possible. Motor outcome was associated with CH severity, indicating a prenatal effect.

Adult↗

PubMed2005

Association between prenatal treatment and clinical manifestations of congenital toxoplasmosis in infancy: a cohort study in 13 European centres.

AIM: To determine the effectiveness of prenatal treatment for clinical manifestations of congenital toxoplasmosis. METHODS: We prospectively identified 255 live-born infants with congenital toxoplasmosis using prenatal or neonatal screening. We determined the effect of prenatal treatment on the risks of intracranial or ocular lesions in infancy, accounting for gestational age at maternal seroconversion. RESULTS: Prenatal treatment within 4 wk of seroconversion reduced the risk of intracranial lesions compared with no treatment (odds ratio, OR 0.28; 95% CI: 0.08-0.75), but there was no significant effect when initiated after 4 wk (OR 0.76; 95% CI: 0.35-1.59; overall p-value 0.19). Compared to spiramycin alone, no treatment doubled the risk of intracranial lesions (OR 2.33; 95% CI: 1.04-5.50), but the risk did not differ with pyrimethamine-sulphonamide treatment (overall p-value 0.52). There was no consistent relationship between the type or timing of treatment and the risk of ocular lesions. Gestational age at maternal seroconversion was inversely associated with the risk of intracranial but not ocular lesions. CONCLUSION: Only early versus no prenatal treatment for intracranial lesions showed a statistically significant benefit. A large randomized controlled trial and/or meta-analysis of individual patient data from cohort studies is required to confirm these findings.

Adult↗