Newborn screening for X-linked adrenoleukodystrophy: further evidence high throughput screening is feasible.

X-linked adrenoleukodystrophy (ALD) is characterized by adrenal insufficiency and neurologic involvement with onset at variable ages. Plasma very long chain fatty acids are elevated in ALD; even in asymptomatic patients. We demonstrated previously that liquid chromatography tandem mass spectrometry measuring C26:0 lysophosphatidylcholine reliably identifies affected males. We prospectively applied this method to 4689 newborn blood spot samples; no false positives were observed. We show that high throughput neonatal screening for ALD is methodologically feasible.

A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta.

PURPOSE: Deficiency of prolyl 3-hydroxylase 1, encoded by LEPRE1, causes recessive osteogenesis imperfecta (OI). We previously identified a LEPRE1 mutation exclusively in African Americans and contemporary West Africans. We hypothesized that this allele originated in West Africa and was introduced to the Americas with the Atlantic slave trade. We aimed to determine the frequency of carriers for this mutation among African Americans and West Africans, and the mutation origin and age. METHODS: Genomic DNA was screened for the mutation using PCR and restriction digestion, and a custom TaqMan genomic single-nucleotide polymorphism assay. The mutation age was estimated using microsatellites and short tandem repeats spanning 4.2 Mb surrounding LEPRE1 in probands and carriers. RESULTS: Approximately 0.4% (95% confidence interval: 0.22-0.68%) of Mid-Atlantic African Americans carry this mutation, estimating recessive OI in 1/260,000 births in this population. In Nigeria and Ghana, 1.48% (95% confidence interval: 0.95-2.30%) of unrelated individuals are heterozygous carriers, predicting that 1/18,260 births will be affected with recessive OI, equal to the incidence of de novo dominant OI. The mutation was not detected in Africans from surrounding countries. All carriers shared a haplotype of 63-770 Kb, consistent with a single founder for this mutation. Using linkage disequilibrium analysis, the mutation was estimated to have originated between 650 and 900 years before present (1100-1350 CE). CONCLUSION: We identified a West African founder mutation for recessive OI in LEPRE1. Nearly 1.5% of Ghanians and Nigerians are carriers. The estimated age of this allele is consistent with introduction to North America via the Atlantic slave trade (1501-1867 CE).

Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method.

Newborn screening for X-linked adrenoleukodystrophy (X-ALD) has until now been limited in implementation because of the lack of an accepted standard methodology. We have previously reported a technique using LC-MS/MS analysis that could provide the basis for screening of newborns for X-ALD. The target analyte diagnostic for X-ALD and other peroxisomal disorders of peroxisomal beta-oxidation is 1-hexacosanoyl-2-lyso-sn-3-glycero-phosphorylcholine (26:0-lyso-PC). We report here the validation of the analytical method using an authentic standard of the target compound. The method possesses sensitivity of <1.0fmole injected on column with a correlation coefficient (R(2)) of 0.9987. A tetradeuterated analog of 26:0-lyso-PC served as the internal standard. The sensitivity of this clinical method was confirmed using 17 newborn samples of individuals with peroxisomal disorders retrieved from state newborn screening programs. These samples were run masked with over 1000 newborn samples. All affected individuals were identified with one exception. One sample which was retrieved as an affected did not have the biochemical or genetic abnormality of X-ALD and thus is considered an error in sample identity. These studies clearly show that the method is highly sensitive and accurate in identifying individuals with a defect in peroxisomal beta-oxidation such as X-ALD.

Birth delivery mode modifies the associations between prenatal polychlorinated biphenyl (PCB) and polybrominated diphenyl ether (PBDE) and neonatal thyroid hormone levels.

BACKGROUND: Developing infants may be especially sensitive to hormone disruption from chemicals including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). OBJECTIVE: We investigated relationships between cord serum levels of PCBs and PBDEs and thyroid hormones measured in cord blood serum and neonatal blood spots. METHODS: We measured PCBs and PBDEs, thyrotropin (TSH), thyroxine (T4) and free T4 (FT4) in cord blood serum from 297 infants who were delivered at the Johns Hopkins Hospital in 2004-2005. We abstracted results of total T4 (TT4) measured in blood spots collected in the hospital and at neonatal visits. We used delivery mode (augmented vaginal deliveries and nonelective cesarean deliveries) as a surrogate for intrapartum stress, which is known to alter cord blood thyroid hormones. RESULTS: In the full study population, no compounds were associated with a change in average TSH, FT4, or TT4. BDE-100 was associated with increased odds of low cord TT4, BDE-153 with increased odds of low cord TT4 and FT4, and no compounds were associated with increased odds of high TSH. For infants born by spontaneous, vaginal, unassisted deliveries, PCBs were associated with lower cord TT4 and FT4 and lower TT4 measured in neonatal blood spots. PBDEs showed consistent but mainly nonsignificant negative associations with TT4 and FT4 measurements. CONCLUSIONS: Prenatal PCB and PBDE exposures were associated with reduced TT4 and FT4 levels among infants born by spontaneous, unassisted vaginal delivery. Intrapartum stress associated with delivery mode may mask hormonal effects of PCBs and PBDEs.

Maternal, infant, and delivery factors associated with neonatal thyroid hormone status.

BACKGROUND: Thyroid function is dynamic during the perinatal period with many factors potentially influencing maternal, fetal and neonatal TSH and thyroid hormone levels. We sought to identify the impact of numerous maternal, fetal and delivery attributes on thyroid parameters in newborns. METHODS: This was a cross sectional study of 300 newborns. Detailed information was obtained from medical records and multiple characteristics from the record were tested as predictors of cord blood serum total T4, free T4 and TSH and infant T4 levels from the Maryland newborn screening program. MAIN OUTCOME: Outcomes are levels of thyroid stimulating hormone (TSH), thyroxine (T(4)), and free T(4) in newborn cord serum and total T(4) in postnatal heelstick bloodspot samples. RESULTS: Multivariate models identified a number of variables that are independently associated with thyroid hormone levels: higher birth order (lower cord TSH); older maternal age (lower cord total T(4)); pregnancy-induced hypertension and/or preeclampsia (lower cord total T(4) and free T(4)); gestational diabetes (higher cord free T(4)); sexually transmitted disease during pregnancy (lower cord TSH); alcohol use during pregnancy (lower cord TSH); thyroid condition/medications (higher bloodspot total T(4), both neonatal and subsequent); Asian ancestry (higher cord TSH); male sex (higher TSH and lower neonatal bloodspot total T(4)); and C-section (lower cord TSH). Gestational age was independently associated with lower cord TSH, higher cord total T(4), and higher neonatal and subsequent bloodspot total T(4). CONCLUSIONS: Fetal and newborn thyroid hormone levels during the perinatal period are dynamic and influenced by several biological and delivery related factors. Efforts to identify fetal thyroid disruptors in late gestation must carefully consider these factors.