Epigenomic newborn screening for conditions with intellectual disability and autistic features in Australian newborns.

This study describes a protocol to assess a novel workflow called Epi-Genomic Newborn Screening (EpiGNs) on 100,000 infants from the state of Victoria, Australia. The workflow uses a first-tier screening approach called methylation-specific quantitative melt analysis (MS-QMA), followed by second and third tier testing including targeted methylation and copy number variation analyzes with droplet digital PCR, EpiTYPER system and low-coverage whole genome sequencing. EpiGNs utilizes only two 3.

Counting Conditions on Newborn Bloodspot Screening Panels in Australia and New Zealand.

A greater number of screened conditions is often considered to equate to better screening, whereas it may be due to conditions being counted differently. This manuscript describes a harmonised Australasian approach to listing target conditions found on bloodspot screening panels. Operational definitions for target disorders and incidental findings were developed and applied to disorder lists.

Further delineation of short-chain enoyl-CoA hydratase deficiency in the Pacific population.

Short-chain enoyl-coA hydratase (SCEH) deficiency due to biallelic pathogenic ECHS1 variants was first reported in 2014 in association with Leigh syndrome (LS) and increased S-(2-carboxypropyl)cysteine excretion. It is potentially treatable with a valine-restricted, high-energy diet and emergency regimen. Recently, Simon et al.

Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies.

Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children.

A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.

Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation.

Efficacy and safety of factor Xa inhibitors in low body weight patients.

Study Objective: The purpose of this study is to provide evidence for the safety and efficacy of factor Xa inhibitors in patients with a weight ≤60 kg or BMI < 18.5 kg/m .

Design: Multicenter, retrospective, cohort study.

Interstitial lung disease and pancreatic exocrine insufficiency in CADDS: Phenotypic expansion and literature review.

Contiguous / deletion syndrome (CADDS) is a rare deletion syndrome involving two contiguous genes on Xq28, and (formerly known as ). Only nine individuals with this diagnosis have been reported in the medical literature to date. Intragenic loss-of-function variants in cause the deafness, dystonia, and cerebral hypomyelination syndrome (DDCH).

MOGS-CDG: Quantitative analysis of the diagnostic Glc Man tetrasaccharide and clinical spectrum of six new cases.

Congenital disorders of glycosylation (CDG) are a clinically and biochemically heterogeneous subgroup of inherited metabolic disorders. Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening. Combined with the clinical heterogeneity of reported cases, diagnosing MOGS-CDG can be challenging.

Free urinary sialic acid levels may be elevated in patients with pneumococcal sepsis.

Objectives: Urine free sialic acid (UFSA) is an important diagnostic biomarker for sialuria ( variants) and infantile sialic acid storage disease/Salla disease ( variants). Traditionally, UFSA has been measured using specific single-plex methodology in relatively small cohorts of patients with clinical symptoms suggestive of these disorders. The use of multiplex tandem mass spectrometry urine screening (UMSMS) has meant that UFSA can be measured semi-quantitatively in a much larger cohort of patients being investigated for suspected metabolic disorders.

Loss of mitochondrial fatty acid β-oxidation protein short-chain Enoyl-CoA hydratase disrupts oxidative phosphorylation protein complex stability and function.

Short-chain enoyl-CoA hydratase 1 (ECHS1) is involved in the second step of mitochondrial fatty acid β-oxidation (FAO), catalysing the hydration of short-chain enoyl-CoA esters to short-chain 3-hyroxyl-CoA esters. Genetic deficiency in ECHS1 (ECHS1D) is associated with a specific subset of Leigh Syndrome, a disease typically caused by defects in oxidative phosphorylation (OXPHOS). Here, we examined the molecular pathogenesis of ECHS1D using a CRISPR/Cas9 edited human cell 'knockout' model and fibroblasts from ECHS1D patients.

The relationship between beta-ureidopropionase deficiency due to UPB1 variants and human phenotypes is uncertain.

Background: Beta-ureidopropionase deficiency, caused by variants in UPB1, has been reported in association with various neurodevelopmental phenotypes including intellectual disability, seizures and autism.

Aim: We aimed to reassess the relationship between variants in UPB1 and a clinical phenotype.

Methods: Literature review, calculation of carrier frequencies from population databases, long-term follow-up of a previously published case and reporting of additional cases.

Ethylmalonic encephalopathy masquerading as meningococcemia.

Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in (MIM #608451), characterized by global developmental delay, infantile hypotonia, seizures, and microvascular damage. The microvascular changes result in a pattern of relapsing spontaneous diffuse petechiae and purpura, positional acrocyanosis, and pedal edema, hemorrhagic suffusions of mucous membranes, and chronic diarrhea. Here, we describe an instructive case in which ethylmalonic encephalopathy masqueraded as meningococcal septicemia and shock.

Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD.

Background And Aims: NAFLD and its more-advanced form, steatohepatitis (NASH), is associated with obesity and is an independent risk factor for cardiovascular, liver-related, and all-cause mortality. Available human data examining hepatic mitochondrial fatty acid oxidation (FAO) and hepatic mitochondrial turnover in NAFLD and NASH are scant.

Approach And Results: To investigate this relationship, liver biopsies were obtained from patients with obesity undergoing bariatric surgery and data clustered into four groups based on hepatic histopathological classification: Control (CTRL; no disease); NAFL (steatosis only); Borderline-NASH (steatosis with lobular inflammation or hepatocellular ballooning); and Definite-NASH (D-NASH; steatosis, lobular inflammation, and hepatocellular ballooning).

Feasibility of Screening for Chromosome 15 Imprinting Disorders in 16 579 Newborns by Using a Novel Genomic Workflow.

Importance: Newborn screening for Angelman syndrome (AS), Prader-Willi syndrome (PWS), and chromosome 15 duplication syndrome (Dup15q) may lead to benefit from early diagnosis and treatment.

Objective: To examine the feasibility of newborn screening for these chromosome 15 imprinting disorders at population scale.

Design, Setting, And Participants: In this diagnostic study, the validation data set for the first-tier SNRPN test, called methylation-specific quantitative melt analysis (MS-QMA), included 109 PWS, 48 AS, 9 Dup15q, and 1190 population control newborn blood spots (NBS) and peripheral tissue samples from participants recruited from January 2000 to December 2016.

Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings.

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation.

A Model Incorporating Serum Alkaline Phosphatase for Prediction of Liver Fibrosis in Adults with Obesity and Nonalcoholic Fatty Liver Disease.

We assessed the relationship between serum alkaline phosphatase (ALP) and liver fibrosis by histology, in addition to other noninvasive parameters, in obese patients undergoing metabolic surgery. Patients scheduled for elective bariatric surgery were prospectively recruited from a bariatric clinic. An intraoperative liver biopsy was performed, and liver histology was evaluated by a pathologist blinded to the patients' data.

Early-onset vitamin B-dependent epilepsy due to pathogenic variants in a premature infant: A case report and review of the literature.

Vitamin B-dependent epilepsies are a heterogeneous group of disorders characterized by decreased availability of the active cofactor pyridoxal-5'-phosphate (PLP). While pathogenic variants in or genes account for most cases of these disorders, biallelic pathogenic variants in have been shown to cause a form of early onset vitamin B-dependent epilepsy (EPVB6D). PLPBP is thought to play a role in the homeostatic regulation of vitamin B, by supplying PLP to apoenzymes while limiting side-reaction toxicity related to excess unbound PLP.

Newborn bloodspot screening in the time of COVID-19.

Purpose: A COVID-19 pandemic business continuity plan (BCP) was rapidly developed to protect the Victorian newborn screening (NBS) program. Here, we present the outcomes of our COVID-19 BCP and its impact on the Victorian NBS laboratory service.

Methods: Change management principles were used to develop a BCP that included mapping of NBS processes against staff resources, triaging priorities, technology solutions, supply chain continuity, gap analysis, and supporting maternity service providers.

Dig deeper when it does not make sense: Juvenile xanthomas due to sitosterolemia.

Sitosterolemia is an extremely rare autosomal recessive disease caused by mutations in either or , which encode for a sterol efflux transporter (sterolin) that pumps sterols out into the intestinal lumen or into bile. This leads to progressive accumulation of plant sterols in blood and tissues. Clinical presentation is variable and may include xanthoma, arthritis, thyroid dysfunction, premature atherosclerotic disease, splenomegaly, and hematologic manifestations.

Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature.

Lathosterolosis is a rare autosomal recessive disorder of cholesterol biosynthesis. It is caused by defects in the SC5D (sterol C5-desaturase) gene which encodes for the 3-beta-hydroxysteroid-delta-5-desaturase (also called sterol-C5-desaturase or lathosterol dehydrogenase). Only six cases have been described in the literature, but it is possible that a number of patients with milder forms of the condition might have been missed.

ECHS1 disease in two unrelated families of Samoan descent: Common variant - rare disorder.

Mutations in the short-chain enoyl-CoA hydratase (SCEH) gene, ECHS1, cause a rare autosomal recessive disorder of valine catabolism. Patients usually present with developmental delay, regression, dystonia, feeding difficulties, and abnormal MRI with bilateral basal ganglia involvement. We present clinical, biochemical, molecular, and functional data for four affected patients from two unrelated families of Samoan descent with identical novel compound heterozygous mutations.

Age, Sex, and Depot-Specific Differences in Adipose-Tissue Estrogen Receptors in Individuals with Obesity.

Objective: The aim of this study was to examine the effects of sex and menopausal status on depot-specific estrogen signaling in white adipose tissue (AT) in age-matched men and women with morbid obesity.

Methods: A total of 28 premenopausal women, 16 postmenopausal women, and 27 age-matched men undergoing bariatric surgery were compared for omental (OM) AT (OMAT) and abdominal subcutaneous (SQ) AT (SQAT) genes and proteins.

Results: With the exception of fasting nonesterified fatty acids being higher in women (P < 0.