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Some neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ might prevent this. Gestational hypoxia caused low birth-weight and changes in young adult offspring brain, mimicking those in human neuropsychiatric disease. Exposure of cultured neurons to fetal plasma or to secretions from the placenta or from model trophoblast barriers that had been exposed to altered oxygenation caused similar morphological changes. The secretions and plasma contained altered microRNAs whose targets were linked with changes in gene expression in the fetal brain and with human schizophrenia loci. Molecular and morphological changes in vivo and in vitro were prevented by a single dose of MitoQ bound to nanoparticles, which were shown to localise and prevent oxidative stress in the placenta but not in the fetus. We suggest the possibility of developing preventative treatments that target the placenta and not the fetus to reduce risk of psychiatric disease in later life.

Newborn screening in England is a national program with laboratories adhering to common screening algorithms. Until recently, screening for inherited metabolic disorders was provided by ten laboratories using laboratory-developed tests (LDTs) and three using commercial assays: harmonization of results proved challenging. Introduction of hereditary tyrosinemia type 1 screening meant LDTs required modification to include the measurement of succinylacetone, and subsequent re-validation. This provided an opportunity to implement a single commercial reagent kit in all laboratories. It was anticipated that this would improve analytical performance and harmonization. This study aimed to determine whether these goals were achieved. Verification across the 13 laboratories revealed that the commercial kit reduced inter-laboratory variation for all analytes demonstrating improved harmonization. However, this was achieved by applying instrument-specific correction factors to all analytes, the magnitude of which were significant, indicating a lack of standardization. Performance of succinylacetone was limited by instrument-dependent background interference from the methionine stable isotope label, underscoring the need to establish evidence-based screening cut-off values (COV) rather than adopting published thresholds. This study emphasizes the need for traceable reference materials to improve laboratory quality and the value of screening outcome data.

Background Vascular complications in homocystinuria have been known for many years, but there have been no reports to date on involvement of the ascending aorta. Methods We conducted a cross-sectional study of patients with homocystinuria, known to a single metabolic centre, and evaluated in 2016 with a transthoracic echocardiogram. Aortic root dilation was defined as Z-score ≥ 2.0 SD, and graded mild (Z-score 2.0–3.0), moderate (Z-score 3.01–4.0) and severe (Z-score > 4.0). Results The study population included 34 patients, median age of 44.3 years (IQR 33.3–52.2), 50% males, 69% diagnosed aged <18 years and 29% pyridoxine-responsive. Eight (24%) had a history of hypertension. Seven patients (21%) were found to have a dilation of the aortic root, mild in two cases (6%), moderate in four (12%) and severe in one (3%). None had dilation of the ascending aorta. Significant aortic regurgitation, secondary to moderate aortic root dilation, was documented in two patients. A single patient had significant mitral regurgitation due to prolapse of both valve leaflets, as well as mild aortic root dilation. Comparing patients with a dilation of the aortic root to those without, there were no significant clinical, laboratory or echocardiographic differences, with the only exception being that the diameter of the ascending aorta was larger in the group with a dilated aortic root, albeit within normal limits. Conclusions A subset of patients with homocystinuria have isolated dilation of the aortic root similar to that observed in Marfan syndrome.

Background: Barth syndrome (BTHS) is a serious X-linked, metabolic, multisystem disorder characterized by cardiomyopathy, neutropenia, myopathy, and growth delay. Because early diagnosis and appropriate treatment are of key importance for the survival of affected boys, we developed a biochemical BTHS screening method based on analysis of the monolysocardiolipin:cardiolipin ratio in bloodspots. Methods: We performed chloroform/methanol extraction on quarter-inch punches of dried bloodspots on Guthrie cards from BTHS patients and controls. Extracts were dried (60 °C, N2) and reconstituted in CHCl3/methanol/H2O [50:45:5 vol/vol/vol, 0.1% NH3 (25%)]. HPLC–tandem mass spectrometry analysis was performed with a normal-phase HPLC column and multiple reaction monitoring transitions for monolysocardiolipin (MLCL) and cardiolipin (CL) with a total run time of 10 min. The ratio of MLCL and CL was used as screening parameter. Results: All BTHS patients (n = 31) had monolysocardiolipin:cardiolipin ratios >0.40 and all controls (n = 215) had monolysocardiolipin:cardiolipin ratios <0.23. Using a cutoff point of 0.30, a blind test of 206 samples (199 controls, 7 BTHS) had sensitivity and specificity of 100%. Bloodspots could be stored at 4 °C or room temperature for >1 year without affecting the test outcome. Three neonatal Guthrie cards of BTHS patients taken 3.6 to 5.8 years previously were correctly identified as positive for BTHS. Conclusions: HPLC–tandem mass spectrometry analysis of dried bloodspots is an unambiguous screening test for BTHS with potential for rapid screening of neonates suspected of having BTHS, making remote and retrospective diagnosis accessible for a disease that is almost certainly underdiagnosed.

In the UK, Classical Galactosaemia (CG) is identified incidentally from the Newborn Screening (NBS) for phenylketonuria (PKU) using an “Other disorder suspected” (ODS) pathway when phenylalanine (Phe) and tyrosine (Tyr) concentrations are increased. We aimed to determine the efficacy of CG detection via NBS and estimate the incidence of CG in live births in the UK. A survey was sent to all UK NBS laboratories to collate CG cases diagnosed in the UK from 2010 to 2020. Cases of CG diagnosed were determined if detected clinically, NBS, or by family screening, as well as age at diagnosis. Cases referred via the ODS pathway were also collated, including the final diagnosis made. Responses were obtained from 13/16 laboratories. Between 2010 and 2020, a total of 6,642,787 babies were screened, and 172 cases of CG were identified. It should be noted that 85/172 presented clinically, 52/172 were identified by NBS, and 17/172 came from family screening. A total of 117 referrals were made via the ODS pathway, and 45/117 were subsequently diagnosed with CG. Median (interquartile range) age at diagnosis by NBS and clinically was 8 days (7–11) and 10 days (7–16), respectively (Mann–Whitney U test, U = 836.5, p-value = 0.082). The incidence of CG is 1:38,621 live births. The incidence of CG in the UK is comparable with that of other European/western countries. No statistical difference was seen in the timing of diagnosis between NBS and clinical presentation based on the current practice of sampling on day 5. Bringing forward the day of NBS sampling to day 3 would increase the proportion diagnosed with CG by NBS from 52/172 (30.2%) to 66/172 (38.4%).

Cortical necrosis is a rare cause of kidney failure, thought to arise from occlusion of afferent arterioles and interlobular arteries in the cortical vasculature.1 The radiological appearances are unusual, with a hypoechoic circumferential band adjacent to the renal capsule on sonography2 and a cortical rim sign on CT,3 both seen on our patient. Hyperhomocysteinaemia as a result of B12 deficiency has been associated with thrombotic events, including myocardial infarction.4,5 Severe hyperhomocysteinaemia, as a result of inherited enzyme defects, renal failure, or vitamin deficiency, is associated with an increased risk of endothelial activation, and arterial thrombosis.

Doc number: 105 Abstract Background: Genotyping requires biological sample collection that must be reliable, convenient and acceptable for patients and clinicians. Finding the most optimal procedure of sample collection for premature neonates who have a very limited blood volume is a particular challenge. The aim of the current study was to evaluate the use of umbilical cord (UC) tissue and newborn dried blood spot (DBS)-extracted genomic DNA (gDNA) as an alternative to venous blood-derived gDNA from premature neonates for molecular genetic analysis. All samples were obtained from premature newborn infants between 24-32 weeks of gestation. Paired blood and UC samples were collected from 31 study participants. gDNA was extracted from ethylenediaminetetraacetic acid (EDTA) anticoagulant-treated blood samples (~500 μl) and newborn DBSs (n = 723) using QIAamp DNA Micro kit (Qiagen Ltd., Crawley, UK); and from UC using Qiagen DNAeasy Blood and Tissue kit (Qiagen Ltd., Crawley, UK). gDNA was quantified and purity confirmed by measuring the A260 :A280 ratio. PCR amplification and pyrosequencing was carried out to determine suitability of the gDNA for molecular genetic analysis. Minor allele frequency of two unrelated single nucleotide polymorphisms (SNPs) was calculated using the entire cohort. Results: Both whole blood samples and UC tissue provided good quality and yield of gDNA, which was considerably less from newborn DBS. The gDNA purity was also reduced after 3 years of storage of the newborn DBS. PCR amplification of three unrelated genes resulted in clear products in all whole blood and UC samples and 86%-100% of newborn DBS. Genotyping using pyrosequencing showed 100% concordance in the paired UC and whole blood samples. Minor allele frequencies of the two SNPs indicated that no maternal gDNA contamination occurred in the genotyping of the UC samples. Conclusions: gDNAs from all three sources are suitable for standard PCR and pyrosequencing assays. Given that UC provide good quality and quantity gDNA with 100% concordance in the genetic analysis with whole blood, it can replace blood sampling from premature infants. This is likely to reduce the stress and potential side effects associated with invasive sample collection and thus, greatly facilitate participant recruitment for genetic studies.

Phosphorus and arsenic are also regarded as potentially nephrotoxic substances able to induce a renal cortical necrosis. [...] it would have been appropriate to rule out a potential metal intoxication in this interesting case of acute kidney injury.

Bohring–Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria for this condition, describe ten previously unreported patients, and update the natural history of four previously reported patients. This is the largest series reported to date, providing a unique opportunity to document the key clinical features and course through childhood. Investigations undertaken to try and elucidate the underlying pathogenesis of BOS using array comparative genomic hybridization and tandem mass spectrometry of cholesterol precursors did not show any pathogenic changes responsible.