Inborn

Public health newborn screening (NBS) programs provide population-scale ascertainment of rare, treatable conditions that require urgent intervention. Tandem mass spectrometry (MS/MS) is currently used to screen newborns for a panel of rare inborn errors of metabolism (IEMs)1-4. The NBSeq project evaluated whole-exome sequencing (WES) as an innovative methodology for NBS. We obtained archived residual dried blood spots and data for nearly all IEM cases from the 4.5 million infants born in California between mid-2005 and 2013 and from some infants who screened positive by MS/MS, but were unaffected upon follow-up testing. WES had an overall sensitivity of 88% and specificity of 98.4%, compared to 99.0% and 99.8%, respectively for MS/MS, although effectiveness varied among individual IEMs. Thus, WES alone was insufficiently sensitive or specific to be a primary screen for most NBS IEMs. However, as a secondary test for infants with abnormal MS/MS screens, WES could reduce false-positive results, facilitate timely case resolution and in some instances even suggest more appropriate or specific diagnosis than that initially obtained. This study represents the largest, to date, sequencing effort of an entire population of IEM-affected cases, allowing unbiased assessment of current capabilities of WES as a tool for population screening.

The specialty of inherited metabolic disease is at the forefront of progress in medicine, with new methods in metabolomics and genomics identifying the molecular basis for a growing number of conditions and syndromes. This review presents an updated pathophysiologic classification of inborn errors of metabolism and a method of clinical screening in neonates, late-onset emergencies, neurologic deterioration, and other common clinical scenarios. When and how to investigate a metabolic disorder is presented to encourage physicians to use sophisticated biochemical investigations and not miss a treatable disorder.

Inborn

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A food product that is not broken down into energy can build up in the body and cause a wide range of symptoms. Several inborn errors of metabolism cause developmental delays or other medical problems if they are not controlled.

Shchelochkov OA, Venditti CP. An approach to inborn errors of metabolism. In: Kliegman RM, St. Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson Textbook of Pediatrics. 21st ed. Philadelphia, PA: Elsevier; 2020:chap 102.

Recent innovations in medical technology have changed newborn screening programs in the United States. The widespread use of tandem mass spectrometry is helping to identify more inborn errors of metabolism. Primary care physicians often are the first to be contacted by state and reference laboratories when neonatal screening detects the possibility of an inborn error of metabolism. Physicians must take immediate steps to evaluate the infant and should be able to access a regional metabolic disorder subspecialty center. Detailed knowledge of biochemical pathways is not necessary to treat patients during the initial evaluation. Nonspecific metabolic abnormalities (e.g., hypoglycemia, metabolic acidosis, hyperammonemia) must be treated urgently even if the specific underlying metabolic disorder is not yet known. Similarly, physicians still must recognize inborn errors of metabolism that are not detected reliably by tandem mass spectrometry and know when to pursue additional diagnostic testing. The early and specific diagnosis of inborn errors of metabolism and prompt initiation of appropriate therapy are still the best determinants of outcome for these patients.

Improvements in medical technology and greater knowledge of the human genome are resulting in significant changes in the diagnosis, classification, and treatment of inherited metabolic disorders. Many known inborn errors of metabolism will be recognized earlier or treated differently because of these changes. It is important for primary care physicians to recognize the clinical signs of inborn errors of metabolism and to know when to pursue advanced laboratory testing or referral to a children's subspecialty center.

The principles of population screening to identify persons with biologic markers of disease and to apply interventions to prevent disease progression are well established. Screening tests must be timely and effective with a high predictive value. Current approaches to detecting inborn errors of metabolism revolve around laboratory screening for certain disorders in asymptomatic newborns, follow-up and verification of abnormal laboratory results, prompt physician recognition of unscreened disorders in symptomatic persons, and rapid implementation of appropriate therapies.

Table 4 lists some of the more common inborn errors of metabolism, classified by type of metabolic disorder. Such prototypical inborn errors of metabolism include PKU, ornithine transcarbamylase deficiency, methylmalonicaciduria, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, galactosemia, and Gaucher's disease.

Often, empiric therapeutic measures are needed before a definitive diagnosis is available. In a critically ill infant, aggressive treatment before the definitive confirmation of diagnosis is lifesaving and may reduce neurologic sequelae. Infants with a treatable organic acidemia (e.g., methylmalonicacidemia) may respond to 1 mg of intramuscular vitamin B12. Metabolic acidosis should be treated aggressively with sodium bicarbonate. Seizures in infancy should be treated initially with traditional antiepileptic drugs, but patients with rare inborn errors of metabolism may respond to other treatments (e.g., oral pyridoxine in a dosage of 5 mg per kg per day) if rare disorders such as pyridoxine-dependent epilepsy are clinically suspected by the consulting neurologist.

In a study in British Columbia, the overall incidence of the inborn errors of metabolism were estimated to be 40 per 100,000 live births or 1 in 2,500 births,[9] overall representing more than approximately 15% of single gene disorders in the population.[9] While a Mexican study established an overall incidence of 3.4: 1000 live newborns and a carrier detection of 6.8:1000 NBS.[10]

In October 2010, the NDSI-IEM program was launched in the Office of Dietary Supplements (ODS) to explore the research evidence supporting the use of nutrition and dietary supplement interventions for inborn errors of metabolism (IEM) and the infrastructure needed to carry out new research. In collaboration with the National Center for Advancing Translational Sciences (NCATS) and with input from a broad range of interested and involved parties, challenges and barriers to conducting research on nutritional treatments for IEM are being identified. Strategies will be developed to support evidence-based research on the safety and effectiveness of nutritional management modalities in IEM.

Decrease laboratory costs and improve data quality for the most complex matrices. Enable fast cleanup of complex matrices collected for inborn errors of metabolism by utilizing accelerated online sample preparation.

Objective: To determine the impact of surfactant use in an inborn (I) and outborn (O) population of infants 23-26 weeks gestation. Methods: All live born infants, 23-26 weeks gestation born in a perinatal center (I) and admitted to a teritary care unit (O) were considered; those with major congenital abnormalities were excluded. Data from 1982-87, presurfactant (Pre), were compared with 1991-94, postsurfactant (Post). Outcomes included mortality and gross morbidity (cerebral palsy, cognitive impairment, blindness &/or deafness) at 18-24 months corrected age. Intact survivors were those without gross morbidity, excluding those lost to follow up (N=66 (7%)). Statistical analyses of outcome between pre and post surfactant era and in surfactant treated and non treated patients were performed. Results: Pre I (N=321), Post I (N=241); Pre O (N=247), Post O (N=173). Mean birth weights and gender between I and O and Pre and Post were similar. In O, there were no significant differences Pre and Post in mortality and intact survival rates, although untreated patients in Post had a significantly better survival (p

Single nucleotide polymorphism arrays (SNP-A) are increasingly accepted as a karyotyping tool, but with systematic application of this technology to study clonal somatic chromosomal lesion came a realization as to how widespread are copy number variations (CNV) and copy-number neutral runs of homozygosity (ROH) through the human genome. Recognition of recurrent CNVs and ROH is of importance for distinction of truly somatic lesions but clearly both ROH and CNVs themselves could constitute risk factors for development of MDS and AML prediction as sites frequently affected by these changes could constitute fragile sites for chromosomal breaks and recombination events. Alternatively these inherited genomic variants could affect expression of corresponding genes and alter regulatory elements. They can physically disrupt a gene, potentially creating new isoforms and can have a subtle effect on gene expression, either through variable penetrance of gene dosage effects or through interaction between the CNV/ROH and the genetic background. As all ROH is unlikely to be explained by autozygosity, meiotic errors or early embryonic mitotic events could be responsible. The role of CNVs in disease, in particular immune-related disorders, has become increasingly apparent, while acquired ROH is well-recognized as playing a role in carcinogenesis and malignant evolution. However, CNVs and inborn ROH as predisposing factors in myeloid malignancies has not been explored in depth. SNP-A (for example Affymetrix 6.0 arrays) offer an opportunity to systematically investigate not only somatic unbalanced translocations but also copy neutral loss of heterozygosity (CN-LOH), including ROH.

To determine how CNVs and inborn ROH may affect predisposition to myeloid malignancies, we first studied an large cohort of control individuals (N=995) from internal and publicly-available sources. We identified 261 CNVs distributed across the entire genome; 15 were unique to our cohort and had not been previously reported. The remaining CNVs were verified against the Database of Genomic Variants ( ) and their frequency was established. We also identified 153 non-clonal regions of ROH in the normal cohort (9.8%), distributed across all chromosomes and mapped frequently occurring ROH. No correlation was found between chromosome size and size of ROH on that chromosome. ROH could be divided into two groups: interstitial (N=147) and telomeric (N=6). Interstitial ROH ranged in size from 0.29-64.9Mb with a median of 7.2Mb; the rare telomeric germline ROH was 2.5-13.2Mb with a median of 5.8Mb. There were 30 recurrent regions of ROH; the most frequent (at 0.4%) were at 4q13.1-q13.3 and 5q15-q21.1. We concluded that interstitial ROH be457b7860