Neonatal hypoglycemia is low blood sugar (glucose) in the first few days after birth. Causes Babies need sugar (glucose) for energy. Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising.
Newborn screening (NBS) has evolved significantly since its introduction in 1962 for one biochemical genetic disorder, phenylketonuria (PKU). Soon after Robert Guthrie developed newborn screening as a means of preventing mental retardation in PKU, he realized that several other biochemical genetic disorders fit the same mold, that is, the disorders are capable of producing mental retardation but are potentially preventable by newborn identification and dietary treatment. The keys to these additions and further developments in newborn screening are the dried blood filter paper specimen, now known as the Guthrie specimen, and the small amount of blood needed for the assays. The mass spectrometer is an analytical instrument that detects ions by virtue of their mass and charge.
Figure 1 Schematic diagram of a tandem mass spectrometer and the path of the molecules and ions. This group of disorders is marked by the accumulation of characteristic amino acids; each disorder is the result of an inherited defect in an enzyme that is responsible for conversion of an amino acid into its product.
The major confirmatory test following any newborn screening abnormality is a plasma amino acid analysis. Fatty acid oxidation primarily occurs in the mitochondria and is critical for energy generation in the fasting state or during exercise. Figure 2 Metabolism of fatty acids illustrating entrance into mitochondrion and intramitochon-drial j-oxidation. Disorders have been described for each of these transporters and enzymes except fatty acyl-CoA synthetase.
The most striking clinical feature in the FAOD phenotype is intolerance to fasting or to vigorous exercise. In contrast to amino acid concentrations, which increase in a time-dependent manner, the acylcarnitines decrease significantly with passage of time and with initiation of feeding. The defect in an OAD is usually in an enzyme within an amino acid degradative pathway that is responsible for conversion of an organic acid derivative of the amino acid to another organic acid. MSUD: An elevation of levels of leucine and variable increases in levels of valine, isoleucine, and alloisoleucine are the characteristics of MSUD.
As a secondary metabolite, however, the accumulation of methionine lags behind that of homocysteine.
MCADD: The levels of the primary analyte of MCADD, octanoylcarnitine (C8), can also be elevated because of valproate therapy or medium chain triglycerides (MCT) oil supplementation and is also an indicator of the fatty acid disorder multiple acyl-CoA dehydrogenase deficiency (MADD). SCADD: Elevations in butyrylcarnitine (C4) levels, characteristic of this disorder, are also seen in the fatty acid disorder, MADD.
Carnitine transporter defect: In this disorder, free carnitine level is decreased to less than 5% of normal levels. MADD (Glutaric Acidemia II): The acylcarnitines levels are only mildly increased in MADD, making the detection of this disorder difficult. Propionic acidemia (PA) and methylmalonic acidemia (MMA): C3 (propionyl-carnitine) level is elevated in both these conditions, but the level is typically higher in PA. Isovaleric acidemia (IVA): The indicating metabolite of isovaleric acidemia in newborn screening is C5 (isovalerylcarnitine). Much less frequent are infants with metabolic disorders that are identifiable by newborn screening but are undetected. The important message is that any patient in whom there is clinical suspicion of a biochemical genetic disorder could have a disorder, either because it was not included in the newborn screening schedule or because it was missed in the screening process. The application of molecular genetic techniques to screening for a wide spectrum of disorders has been made possible by the stability of DNA in the Guthrie card (McCabe etal., 1987). Currently, molecular testing in newborn screening is used as a second tier, through examination of Guthrie cards from infants in whom the primary screening result was abnormal. Inherited disorders of fatty acid oxidation account for an estimated 3-6 % of sudden unexpected deaths in infancy (Boles etal., 1998). Postmortem blood specimens from all infants, even those without a metabolic disorder, are characterized by increased carnitine, acylcarnitines, and amino acids. The newborn examination facilitates the early identification of anomalies and health problems that require immediate intervention.
Most of that glucose is used by the brain. The developing baby gets glucose from the mother through the placenta.
It now includes endocrinopathies, hemoglobinopathies, congenital infections, cystic fibrosis, and congenital deafness as well as many biochemical genetic disorders.
Among these disorders were homocystinuria, maple syrup urine disease (MSUD), and galactosemia – disorders that can also result in somatic complications. Consequently, tests can be added to newborn screening without the requirement for another specimen, provided the test can be performed on whole blood eluted from a small disk punched from the specimen. It has been used for many years to identify metabolites that are separated on columns in techniques such as capillary electrophoresis, gas chromatography, and HPLC. Nevertheless, the system has certain technical limitations: (1) The equipment needs proper maintenance and tuning, making trained technicians vital for its operation.
They are broadly classified into amino acid, organic acid, and fatty acid oxidation disorders. In PKU, for instance, the neonate is clinically normal and remains so until developmental delay, irritability, and autistic features appear during the latter half of the first year. Table 1 lists the amino acid disorders that can be identified in expanded screening according to the screening abnormalities that bring them to attention and highlights their biochemical and clinical phenotypes. The sequence of fatty acid oxidation from transport into mitochondria through j-oxidation is depicted in Figure 2.
Normally, reduction of glucose in the fasting state or the requirement for additional glucose during exercise triggers the compensatory production of ketones to supply energy.
Since carnitine transport defect limits both the transport of free carnitine from the intestinal lumen and its reabsorption in the kidneys, the blood carnitine concentration is very low. Consequently, during the first days of life, the methionine level can remain normal or below the cutoff level for identifying it as being abnormal even if the infant has homocystinuria (Peterschmitt et al., 1999). Thus, in order to increase the sensitivity of the screening, a low threshold for identifying increased tyrosine must be set.
Citrullinemia and argininosuccinic acidemia are identified on the basis of increased citrulline levels, more pronounced in cit-rullinemia than in argininosuccinic acidemia.
Additionally, free carnitine is decreased, and the ratio of C16 to carnitine is a useful diagnostic marker.
In fact, in MMA the C3 elevation may be just at or even below the screening cutoff, rendering MMA very difficult to detect. 2-methylbutyryl-CoA dehydrogenase deficiency (2-MBDD) also produces an elevation of C5 but is not as striking an elevation as does IVA.


Segments of genes can be amplified directly from the filter paper matrix using the polymerase chain reaction (PCR) without prior extraction.
The purpose of this is to sort the affected infants from those whose primary screening abnormality was due to some reason other than the targeted disorder. Among this group, MCADD is the most frequent, and death during the initial presentation has been noted in 25-33% of the cases (Iafolla etal., 1994). Consequently, identification of biochemical genetic disorders from postmortem specimens must utilize criteria that are different from those used for the interpretation of metabolic profiles in newborn screening.
Emergencies and Common Abnormalities Involving the Abdomen, Pelvis, Extremities, Genitalia, and SpineA  A more recent article on this topic is available. A careful examination is also appropriate after a newborn has completed the transition from fetal to neonatal life.
Chordee (ventral curvature of the penis) without hypospadias occurs less frequently and may be due to skin tethering or a short urethra.
A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. Consequently, he modified his bacterial assay for phenylalanine, the analytical marker for PKU, to render it responsive to increases in other metabolites and to allow for the detection of these disorders (Guthrie, 1968). Over the years, many investigators have become aware of the possibility that this system could be used to screen newborns for disorders in their areas of interest, and several have succeeded in modifying existing assays to meet the specifications of newborn screening.
Several programs adopted neonatal urine screening using paper or thin-layer chromatography to expand coverage (Bamforth et al., 1999). This requirement for prior separation of metabolites, however, meant that mass spectrometry could not be used in screening since separation would be much too time consuming for the rapid throughput that routine screening requires. Homocystinuria may present with a similar picture, subsequently producing somatic features that include ectopia lentis, skeletal changes, and thromboembolism.
It begins with the mobilization of very long chain and long chain fatty acids from adipose tissue. The most frequently detected in expanded newborn screening has been medium chain acyl-CoA dehydrogenase deficiency (MCADD), with an incidence of 1:20 000, which is similar to that for PKU. In CPT-I deficiency, acylcarnitines are not formed, so the concentration of free carnitine is high but that of the acylcarnitines are low. The rate of decrease of the long chain acylcarnitines is more rapid than that of the short chain acylcarnitines (Chace et al., 2003).
This is especially likely when the Guthrie screening sample is collected at less than 24 hours after birth. Nevertheless, since many or most affected infants have normal blood tyrosine levels during the first days of life, they are still missed. Since cobalamin (B12) is a cofactor for methylmalonyl-CoA mutase, vitamin B12 deficiency can also result in increased methylmalonic acid and C3. Attempts are being made to include these categories in newborn screening, the most notable of which is the development of feasible screening methods to detect lysosomal disorders in the newborn (Chamoles et al., 2001), but, so far, methodologies suitable for routine screening have not emerged. These amplified segments can be examined for mutations relevant to the disorder(s) screened using identification techniques such as restriction analysis or single-nucleotide polymorphism (SNP) methodology.
The most notable use of molecular testing is in screening for cystic fibrosis, wherein the primary screen, immunoreactive trypsinogen (IRT), can be increased for many reasons other than cystic fibrosis. Sudden death as a result of an inherited metabolic disorder may remain unexplained even after an autopsy and, hence, may get classified as sudden infant death syndrome (SIDS). If a newborn is found to have an abdominal wall defect, management includes the application of a warm, moist, and sterile dressing over the defect, decompression of the gastrointestinal tract, aggressive fluid resuscitation, antibiotic therapy, and prompt surgical consultation.
If one anatomic malformation is found, the newborn should be evaluated for associated anomalies. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. This article briefly reviews newborn screening and then focuses on the advances in neonatal identification of the biochemical genetic disorders.
This resulted in additional coverage but required collection of the specimen at several weeks of age rather than within the first day of life and examined only amino acids and a very limited number of organic acids. Tyrosinemia type I can produce liver disease in early infancy, whereas tyrosinemia type II can produce developmental delay without liver involvement. Cardiomyopathy is a particular feature of carnitine transporter defect and of defects in the j -oxidation of very long chain and long chain fatty acids. In CPT-II deficiency, the acylcarnitines are unchanged, so the long chain acylcarnitine levels are increased.
Effective screening, therefore, requires collection of the Guthrie specimen within 24-48 h of life and lowering of the cutoff value for repeat specimens. The unconjugated organic acid (and secondary organic acid metabolites) accumulate to very high levels and produce metabolic acidosis. This was recognized several years ago in Quebec and the newborn screening program was stimulated to apply an enzyme assay screening method for succinylacetone, the specific marker metabolite for tyrosinemia I, to the Guthrie specimen (Grenier etal., 1982), resulting in almost complete ascertainment. The other two urea cycle disorders, carbamyl phosphate synthetase deficiency (CPSD) and ornithine transcarbamylase deficiency (OTCD), could be determined by decreased citrulline levels, but, at present, this identification is limited by an excessively high false-positive rate. Neonates of mothers who ingested pivalic acid can thus mistakenly be thought to have IVA or 2-MBDD on newborn screening (Abdenur et al., 1998). In the false-negative category is the rare infant who had an abnormal level of the metabolite marker for a disorder but was missed because of program or laboratory error (Smith et al., 2001). Second tier testing of the abnormal specimens sorts out those infants who harbor one or more CFTR mutations known to be associated with cystic fibrosis. Early diagnosis is imperative because surgical correction can prevent irreversible neurologic damage.
However, until very recently, the only biochemical genetic disorder among these additions has been biotinidase deficiency (Heard et al., 1984).
Consequently, many serious disorders were not covered, or not covered in time for effective therapy, and the disorders that were most frequently identified were benign (Wilcken etal., 1980). The process of newborn screening begins with methanol extraction of blood from the specimen, followed by butanol derivatization of amino acids and acylcarnitines.
The fatty acyl-CoA moves to the mitochondrion, as does carnitine, which has entered the cell via a carnitine transporter.
The concentrations of multiple acylcarnitine markers and relative molar ratios are also important in the interpretation of a positive result.
This can present in the neonate as poor feeding, lethargy, vomiting, tachypnea, and seizures.
The plethora of mutations could be met by multiplex PCR coupled with microarrays using chip technology (Caggana etal., 1998), but heterozygote detection and perhaps the expense would continue to be major issues.
In expanded newborn screening, second tier molecular testing is also used to test the Guthrie specimen for the A985G mutation in MCAD, the major mutation associated with MCADD, when the primary screen reveals an increased level of C8.


In 66 specimens, diagnosis of a biochemical genetic disorder was considered likely (Chace etal., 2001). A newborn with developmental hip dysplasia should be evaluated by an orthopedist, and treatment may require use of a Pavlik harness.
It takes advantage of the principle that molecules fragment into predictable species depending on their structural properties. This phenotype is characteristic of the organic acid disorders (in which category MSUD is often included).
On the outer mitochondrial membrane, carnitine palmitoyltransferase I (CPT I) catalyzes an exchange of carnitine with the CoA to yield fatty acylcarnitine, releasing CoA. Other laboratory findings during acute episodes include metabolic acidosis, hyperammonemia, and elevations of the liver enzyme levels. After an acylcarnitine abnormality has been ascertained, usually by repeat screening, confirmatory testing is performed by analyses of plasma acylcarnitines and urine acylglycines.
Nevertheless, candidates for primary molecular screening include those with treatable disorders with few molecular etiologies such as factor V Leiden, sickle cell disease, and the mitochondrial MERRF and MELAS syndromes. In both these examples, second tier molecular testing substantially reduces the number of false-positive results. The presence of ambiguous genitalia is a medical emergency, and pituitary and adrenal integrity must be established. The ions enter the first MS, where the parent molecules are sorted by mass and charge and are then directed into the collision chamber. Other exceptions are the urea cycle disorders, in which the affected neonate may have severe hyperammonemia, producing lethargy that can rapidly progress to coma. The fatty acylcarnitine is transported to the inner mitochondrial membrane by a translocase where CPT II decouples and releases the carnitine and links the fatty acid to CoA again.
Early detection by expanded newborn screening combined with treatment that includes avoidance of fasting, adherence to a low-fat diet, and carnitine supplementation has been effective in preventing sudden death and other complications in these disorders (Waisbren et al., 2003). Later complications include developmental delay, mental retardation, and other neurologic abnormalities.
An important difference, however, is the likely presence of increased valine levels in MSUD and normal valine levels in hydroxyprolinemia.
When increased tyrosine is flagged in newborn screening, the vast majority of infants have transient neonatal tyrosinemia, a benign finding (Wilcken et al., 2003).
Primary screening for severe combined immunodeficiency (SCID), fragile X syndrome, type I diabetes, acute lymphoblastic anemia, and hereditary hemochromatosis might also be considered. Early diagnosis of spinal lesions is imperative because surgical correction can prevent irreversible neurologic damage. In this chamber, collision-induced disassociation (CID) produces characteristic fragments because of collision between an inert gas and the ionized particles. Nevertheless, in all of the amino acid disorders, clinical signs of disease may not have appeared during the first few days of life.
A notable exception to this dramatic presentation is glutaric acidemia type I (GA I), in which the neonate appears to be normal (except for macrocephaly) but suddenly becomes dystonic later in the first or second year of life, often during an acute febrile illness or after an immunization.
Homocystinuria: Homocystinuria results in a primary elevation of homocysteine levels, with a secondary increase in methionine.
This is especially true for babies with lower-than-average weight or whose mothers have diabetes. Possible Complications Severe or long-term hypoglycemia may lead to brain damage, affecting normal mental function. Naylor subsequently used this system to greatly expand the number of biochemical genetic disorders identifiable in routine newborn screening (Naylor and Chace, 1999). Expanded newborn screening, revealing a specific amino acid elevation, can identify these infants and preventive therapy can be effective. The successive removal of two carbons via the j-oxidation cycle results in acetyl-CoA that is used to generate energy through the TCA cycle and the synthesis of ketones. Computer algorithms enable correlation between the mass spectra of the fragments in the second MS and the spectra of the intact parent molecules in the first MS.
Confirmation of an acylcarnitine screening abnormality that suggests an OAD includes urine organic acid analysis.
The data thus acquired can be scanned for characteristic fragments so that parent molecules corresponding with these fragments can be selectively analyzed. Different scanning modes can analyze the same data for other specific fragments, thereby resulting in identification of multiple classes of compounds in the same specimen.
Quantitative analysis is performed using the ratio of the metabolite to its isotopic analog (internal standard is added at the beginning of the process). The management of infants with this anomaly is described in Figure 4.15In female newborns, the clitoris can have a relatively prominent appearance, especially if the labia are underdeveloped or the infant is premature. Software programs are formatted to analyze the spectra, perform the calculations to determine the concentrations, and flag the abnormal values.
According to guidelines established by the American Academy of Pediatrics,10 an examination that is positive for developmental hip dysplasia should lead to an orthopedic referral. Though the automated system detects metabolite abnormalities, personnel familiar with metabolic disorders are essential for recognizing the metabolite profiles that indicate a disorder.
It may also be caused by increased maternal androgen production or maternal drug use.Withdrawal of maternal hormones in normal newborns may cause a milky, sometimes bloody secretion from the vagina. If the follow-up examination is positive or inconclusive, orthopedic referral is indicated.
The secretion may persist for several days but requires no treatment.Newborn with Unilateral Undescended TestisThe rightsholder did not grant rights to reproduce this item in electronic media. This defect is commonly associated with a fixed intrauterine position and may be associated with developmental hip dysplasia.
When the defect is marked and relatively rigid, it cannot be distinguished from talipes equinovarus, a condition characterized by adduction or inversion of the forefoot, inversion at the ankle, and equinus posturing (toes down, heel up, and malrotation of the calcaneus). This anomaly tends to be hereditary and is frequently lateral to the fifth digit on the hands or feet. The extra digits may have a nail and are attached by a small pedicle, which differentiates the defect from true polydactyly.
If bony tissue is not palpable, the application of a ligature around the pedicle allows the digit to fall off.True polydactyly more commonly occurs on the feet and may be present with malformation syndromes.
Syndactyly may involve soft tissue (simple synostosis) or fusion of bone (complex synostosis).
Features and management of these defects are summarized in Table 2.6,7Anal patency is assessed by inspection or by probing with a small finger.



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