Jamie Titus, BS, MLT(ASCP)

• Adjunct Instructor
• Medical Laboratory Technology Program
• Seward County Community College/Area Technical School
• Allied Health Department
• Liberal, Kansas

The murmur is generally high pitched cholesterol define discount 20mg pravachol free shipping, peaks in late systole cholesterol levels chart in uk generic 20mg pravachol mastercard, and continues well through the S2 cholesterol hdl levels discount pravachol line. Beyond the neonatal period cholesterol foods cause high discount pravachol generic, treatment is surgical ligation or device closure during cardiac catheterization cholesterol levels explained australia purchase discount pravachol. Because the shunt occurs outside the heart cholesterol test strips & accu-chek generic pravachol 20 mg free shipping, the murmur is continuous and high pitched if the defect is restrictive and the pulmonary artery pressures are low. The turbulence and thus the intensity of the murmur are directly proportional to the flow and pressure difference between the ventricles. The most common type is the muscular defect, which commonly occurs in the anterior trabecular area of the septum. The perimembranous (often called membranous) defect occurs in the regions of the pars membranacea, or the embryonic bulboventricular foramina. The subarterial outlet, or supracristal defect, extends to the fibrous ring of the semilunar valves. The inlet or atrioventricular septal defect is that of the atrioventricular canal or embryonic atrioventricularis communis. A ventricular septal defect is a communication between the high-pressure left ventricle and the lower-pressure right ventricle. The shunt flow begins with the onset of ventricular contraction before the period of ejection (isovolumic contraction) and consequently gives rise to a holosystolic murmur that obscures the first and often the second heart sounds. The murmur is high pitched if the defect is restrictive, and the right-sided heart pressures are low; however, the murmur may be low pitched or even inaudible if the defect is large or if the pulmonary artery pressures are high, as occurs in the newborn. Location the perimembranous defect is best heard at the left sternal edge in the third left intercostal space. The extra volume of blood returning from the pulmonary circulation to the left side of the heart creates this murmur of "relative" (not true anatomic) mitral valve stenosis. Pulmonary Hypertension High pressure in the pulmonary artery limits left-to-right shunt flow and murmur intensity. Blood is ejected from the left ventricle to the right ventricle throughout systole, giving rise to a classical full-length, or "holosystolic," murmur. The larger the defect, the higher the pulmonary artery pressure and the earlier and louder the P2 are. Thus, the split of S2 may become very narrow, or the S2 may even become single, a finding of great concern. In large defects, a balance exists between delayed P2, caused by large pulmonary blood flow, and early P2 caused by high pulmonary artery pressure. The wider the split of S2, the less the concern is, because pulmonary vascular resistance is then likely to be low. The intensity or loudness of a murmur relates to the combination of both flow and gradient across the defect. Thus, very small defects with small left-to-right shunt flow may have a soft, high-pitched murmur. In moderate-sized defects, the murmur is loud, often associated with a palpable thrill. In large defects with no restriction between the right and left ventricle, the murmur is low pitched and less intense as the pulmonary artery and right-sided heart pressures equate with the left-sided heart pressure. In patients who develop increased pulmonary vascular resistance and a reduction in shunt flow and who are at risk for progressing to Eisenmenger syndrome (irreversible pulmonary vascular disease and cyanosis with right-to-left ventricular level shunt), the murmur also becomes quieter. Maturation of the pulmonary arteries and small muscular arteries is delayed in children with Down syndrome, and elevated pulmonary vascular resistance early in life is common. Therefore, the lesion may be missed early in life because signs of congestive heart failure may not occur. It is recommended that all children with Down syndrome undergo echocardiographic evaluation. Often, mitral regurgitation is present and is apparent as an apical holosystolic murmur that obscures S1. If the amount of mitral valve insufficiency is large, a mid-diastolic flow rumble of increased filling may be heard. The atrioventricular septal malformations vary markedly between a large atrial component with a restrictive ventricular communication to a large unrestrictive inlet ventricular septal defect. Consequently, their clinical manifestations also vary from that of an atrial septal defect to that of an unrestrictive ventricular septal defect. Right ventricular hypertrophy the functional significance of this anomaly is related to the degree of right ventricular outflow tract obstruction. There is a harsh ejection systolic murmur, heard best in the pulmonary area but also widely transmitted through the chest. The right ventricular outflow obstruction is most frequently a combination of muscular, annular, and valvular narrowing. The prominent systolic murmur in tetralogy of Fallot is therefore not caused by the septal defect. Patients with tetralogy of Fallot may present with moderate to severe degrees of right ventricular outflow obstruction, right-to-left ventricular level shunting, and varying degrees of cyanosis. Alternatively, the outflow obstruction may be mild, providing a predominant left-to-right shunt and causing the "acyanotic" or "pink" form of tetralogy of Fallot. In these patients, the degree of outflow obstruction becomes progressive; bidirectional flow develops and, finally, a dominant right-to-left shunt emerges. The cardiac murmur in tetralogy, a harsh loud ejection systolic murmur, arises from the turbulence generated in the right-sided heart outflow. In this condition, the murmur most often detected is a holosystolic murmur of a communicating ventricular septal defect or an ejection systolic murmur related to an obstructing pulmonary outflow. One aspect of tetralogy physiology is the variable degree of desaturation that may occur as a consequence of the reactive nature of the right ventricular outflow obstruction. The sudden development of severe reactive obstruction in response to temperature, fever, illness, dehydration, or intense crying may precipitate a hypercyanotic or tetralogy spell. Either increased infundibular reactivity or decreased systemic vascular resistance is responsible for the diminished pulmonary blood flow. This life-threatening event manifests as profound cyanosis, tachypnea, and dyspnea, progressing to acidosis, unconsciousness, and death. During a spell, the outflow tract murmur disappears with the diminution in pulmonary blood flow. Tetralogy of Fallot is a consequence of developmental anterior displacement of the conal or outlet septum and failure to adjoin with the muscular trabecular interventricular septum. In cases in which there is a predominant left-to-right shunt, the murmur is a long, loud ejection systolic murmur and may overwhelm and obscure the S1. The murmur extends up the left sternal border (pulmonary area) and throughout both lung fields. The right ventricle is at systemic pressure, and the pitch of the murmur is quite high. There is a right ventricular parasternal impulse and often a palpable thrill in the pulmonary outflow region. In cyanotic tetralogy of Fallot, the loudness or intensity of the murmur diminishes as the pulmonary blood flow decreases. The right ventricle is usually very small; the left ventricle compensates and is large. All systemic venous blood returning to the right atrium must pass across at atrial septal level to enter the left atrium and then the left ventricle. The softer and shorter the murmur, the less the pulmonary blood flow is, so that, just as in tetralogy of Fallot, the softer the murmur, the more severe the cyanosis is. The cardiac impulse in hypoplastic right ventricle with pulmonary atresia may be right ventricular even though the dominant ventricle is the left. The source of the pulmonary blood flow in the neonate is a ductus arteriosus with left-to-right shunt. The murmur is high pitched, because the right ventricular pressures are very high. In both disorders, left ventricular hypertrophy is present, but in pulmonary atresia, there is a normal inferior vector. Intravenous prostaglandin therapy is required to ensure ductal patency and pulmonary blood flow in the neonatal period. In transposition of the great arteries, desaturated systemic venous blood returns to the right atrium, passes to the right ventricle, and is returned to the aorta and thus to the systemic circulation. Any oxygenation occurring in this setting is the result of mixing of blood with the pulmonary circulation at the ductal, atrial, or ventricular level. The aorta in this condition arises anteriorly, giving rise to a loud, single second heart sound. Many profoundly cyanotic full-term newborns with no audible murmur have transposition of the great arteries. In the first day or two after birth, the neonate may not be recognized as being ill if the ductus arteriosus remains open and the right ventricular output contributes to the systemic output. When the ductus begins to close, perfusion deteriorates, the pulses are diminished, acidosis develops, and death ensues. There may be considerable pulmonary blood flow and a dynamic right ventricle impulse. The heart function may be very poor, and the precordial and auscultatory examination findings may be quiet. After intravenous prostaglandin E1 has been given, causing opening of the ductus arteriosus, a reasonable systemic output and palpable pulses should return. Treatment includes the staged Norwood palliative repair to singleventricle Fontan operation or heart transplantation. There is a pronounced right ventricular impulse, and the A2 is loud because it is anterior. There may be a faint soft short ejection murmur that is audible along the left sternal border as a result of increased pulmonary blood flow. Such infants usually become ill at 2-3 weeks of age as a result of congestive heart failure rather than hypoxia. The examination findings are very different, because both ventricles are very hyperdynamic. The more severe the stenosis, the higher the intraventricular pressure is until cardiac failure occurs. This condition is characterized by an ejection systolic murmur, heard best in the pulmonary area. With increasing valvular obstruction, the murmur becomes louder and higher pitched and peaks later in systole. The P2 is very helpful because the more severe the pulmonary valve stenosis, the more delayed and less intense the P2 is. An ejection click, caused by abrupt arrest of leaflet excursion in early systole, frequently precedes the ejection systolic murmur. The more severe the pulmonary valve stenosis, the earlier and softer the pulmonary ejection click is. In other forms of right ventricular outflow obstruction, such as supravalvular stenosis and subvalvular stenosis, or in the setting of a dysplastic or malformed pulmonary valve, an ejection click is not audible. In newborns with very severe critical pulmonic stenosis, cyanosis, and low cardiac output, the examination findings may be quite different. There may be no pulmonary ejection click, and the murmur may be very short, soft, or both. Palpation in pulmonic valve stenosis may reveal a palpable thrill in the pulmonary area and an abnormal right ventricular impulse (except in mild cases). The apex beat is of a thrusting character and is not displaced in the absence of left-sided heart failure. In this condition, the systemic circulation is supplied from the right ventricle via the ductus arteriosus. The continuous murmur of ductal flow that may be heard is generally low pitched as a result of equal pulmonary and aortic pressures. The ejection systolic murmur from aortic valve stenosis is audible both at the apex and in the aortic area. Note that a quiet and low-pitched murmur may suggest poor ventricular function and low output. Pulmonary valve stenosis gives rise to a rough ejection systolic murmur that is most prominent in the pulmonary area and radiates equally to both lung fields. The presence of an ejection click distinguishes valve obstruction from subvalvular or supravalvular stenosis. The murmur of aortic stenosis is a rough, harsh, diamond-shaped ejection systolic murmur. It is heard best in the aortic area but often extends into the neck and throughout the precordium. A soft, short ejection murmur that peaks in systole indicates a mild degree of valve obstruction, whereas a loud, long, and late-peaking murmur, often associated with a palpable thrill, reflects more severe stenosis. The click intensity is inversely proportional to the severity of the valve narrowing. A loud aortic valve ejection click is often present in patients with a two-leaflet or bicuspid aortic valve even if there is no valve stenosis. The paradoxical split, occurring when there is a large delay of A2, is quite rare in children and young adults; it is seen in older people with calcific aortic valve stenosis and a failing left ventricle. In newborns with severe or critical aortic stenosis and low cardiac output, the examination findings may be very different. There is often no aortic ejection click, and, strikingly, the murmur may be short, soft, or both.

Continuous glucose monitoring using a subcutaneously placed microdialysis sensor has been validated in adults and children with diabetes cholesterol pork generic pravachol 10 mg fast delivery. The feasibility free cholesterol test orlando buy generic pravachol 10mg online, safety cholesterol test app purchase 20 mg pravachol overnight delivery, and usefulness of these techniques have been examined in babies with low birth weight cholesterol test san jose generic 10mg pravachol mastercard. However cholesterol hdl ratio uk order pravachol 20 mg line, these methods cannot measure glucose levels less than 45 mg/dL with confidence cholesterol hdl ratio sheffield table discount pravachol 10 mg online, and the variance is large at high glucose concentrations. Thus far, these techniques have been used only for research studies, and their associated potential risks require further evaluation. If low glucose levels are observed during this time, frequent glucose determinations should be obtained to demonstrate recovery. The definition of hypoglycemia for preterm infants should not be any different from that for full-term infants. Finally, hypoglycemia in the neonate should be described as transient or persistent, and in either or both of these cases, as symptomatic or asymptomatic. Such a description has implications for both clinical management and long-term consequences. Transient hypoglycemia implies low glucose values that last only a short time if not corrected and that are confined to the newborn period. In contrast, persistent and recurrent hypoglycemia implies a form that requires prolonged management (glucose infusions for several days at high rates of infusion) and perhaps pharmacologic intervention. Several of these hypoglycemia syndromes may continue throughout infancy and childhood. The clinical manifestations of hypoglycemia are nonspecific and similar to those of many disorders in newborn infants (Box 95-1). The clinical signs and symptoms of hypoglycemia should improve with correction of the low glucose concentration. In addition, careful attention should be given to ensure that other associated disorders. Because of its implications for both long-term prognosis and clinical management, it is worthwhile to consider two types of neonatal hypoglycemia: those cases limited to the newborn period (transient hypoglycemia) and those cases continuing over an extended period of time or occurring more than once (persistent or recurrent hypoglycemia) (Box 95-2). Transient hypoglycemia is often a consequence of changes in the metabolic environment in utero or ex utero, whereas persistent or recurrent Hypoglycemia Perturbations in glucose metabolism after birth caused by failure to adapt to the extrauterine environment, as a result of either alterations in maternal metabolism or intrinsic metabolic problems in the neonate, often result in hypoglycemia. Lengthy debate has occurred among investigators regarding the definition of hypoglycemia. Finally, a convincing relationship between asymptomatic hypoglycemia in the neonate and long-term neurologic sequelae has not been demonstrated. The presence or absence of such signs cannot be used reliably to define neonatal hypoglycemia owing to immaturity of counter-regulatory hormonal stress response responsible for classic symptoms of hypoglycemia in older children and adults. Because the clinical signs of hypoglycemia in the neonate are not specific to alterations in glucose concentration, this approach has not been successful. The statistical definition of hypoglycemia is based on surveys of large numbers of infants. Abnormality is defined as a blood glucose concentration that falls outside a prescribed limit, for example, outside two standard deviations from the norm. In addition, the routine use of intravenous dextrose-containing fluids in preterm infants has confounded the ability to study glucose concentration in these small babies. Using 95% confidence intervals of the mean, Srinivasan and colleagues88 showed that normal, healthy, fullterm infants who were fed early achieved plasma glucose values of higher than 40 mg/dL within 4 hours after birth and higher than 45 mg/dL within 24 hours after birth. A cutoff value (although arbitrary) of 40 mg/dL has been developed by the American Academy of Pediatrics for the treatment with intravenous glucose of infants with symptomatic hypoglycemia, a value that is higher than the physiologic nadir and higher than concentrations usually associated with clinical signs. Studies in animals have shown that fetal hyperinsulinism, caused by either direct infusion of insulin to the fetus or fetal hyperglycemia, results in an increased metabolic rate in the fetus, fetal hypoxemia, and metabolic acidosis. Therefore, caution should be exercised in the administration of glucose to the mother during labor and delivery (see Chapter 28). Blood glucose concentrations in the mother should not be allowed to exceed those observed in the normal physiologic range. Maternal Pharmacologic Treatment the antidiabetic drugs tolbutamide and chlorpropamide cross the placenta and produce pancreatic beta-cell hyperplasia and increased insulin release. Tolbutamide has a markedly prolonged half-life in the neonate and has been found in higher concentrations in the newborn after delivery than those found in maternal blood. Although they are not used extensively in the United States, these drugs are used in other countries to treat gestational diabetes. Exchange transfusion was required in one infant whose mother received chlorpropamide and in whom hypoglycemia was not responsive to any conventional method of management. Newer formulations of these drugs have been shown to be safer because they do not cross the placenta as readily as the previous products. Benzothiadiazide diuretics may cause neonatal hypoglycemia by stimulation of fetal beta cells or secondary to an elevation in maternal glucose levels. Salicylates may cause hypoglycemia by uncoupling mitochondrial oxidative phosphorylation. Oral beta-sympathomimetic tocolytic drugs such as terbutaline and ritodrine have caused sustained hypoglycemia and elevated cord blood insulin levels in infants delivered within 2 days after termination of tocolytic therapy (see Chapter 19). These agents may cause neonatal hypoglycemia through maternal hyperglycemia and fetal hyperglycemia and hyperinsulinemia. Beta-adrenergic blocking agents such as propranolol cross the mammalian placenta, and their effects on the fetus are easily demonstrated. These drugs are used during pregnancy for the treatment of hypertension, hyperthyroidism, cardiac arrhythmia, and other conditions. They may interfere with the effects of the normal surge in catecholamine levels at birth. In animal studies, propranolol has been shown to impair fetal growth and may cause neonatal hypoglycemia and impair the thermogenic response to cold exposure. Intermittent hyperglycemia in the mother results in hyperglycemia in the fetus, which in turn causes hypertrophy of the fetal pancreatic islets and beta cells and increased secretion of insulin. Because of the lack of significant transfer of insulin from the mother to the fetus in humans, the circulating insulin in the fetal compartment is mostly of fetal origin. However, two studies have demonstrated that in insulin-dependent diabetes, in the presence of antibodies to insulin, a small amount of insulin exogenously administered to the mother may be transported to the fetus. The consequences of fetal hyperinsulinemia have been documented in experimental animal models. Direct insulin infusion into the normal rhesus monkey fetus induces fetal hyperinsulinemia, resulting in macrosomia, cardiomegaly, and an increase in adipose tissue. Chronic fetal hyperinsulinemia also results in an increase in the metabolic rate and oxygen consumption, leading to relative hypoxemia, which in turn results in an increase in the synthesis of erythropoietin and an increase in red blood cell mass and polycythemia. In addition, hyperinsulinemia has been shown to suppress the production of surfactant in the lung and thus predispose to respiratory distress syndrome after birth (see Chapter 70). The increased concentration of these nutrients in the fetal circulation stimulates fetal insulin secretion, which in turn stimulates excessive fetal growth. Such a metabolic picture suggests a persistent insulin action and the lack of a counter-regulatory hormonal response. The combination of hyperinsulinism and insufficient counter-regulation results in decreased hepatic glucose production, increased peripheral glucose uptake, and impaired lipolysis. Several of these metabolic and morphologic abnormalities can be reversed with fastidious management of diabetes in the mother. It should be recognized that the clinical manifestations described here relate to diabetic mothers whose metabolism has not been well controlled. Data from a study7 in which maternal diabetes was rigorously managed by either an insulin infusion pump or split-dose insulin therapy are shown in Table 95-1. Despite rigorous management and reduced maternal hyperglycemia, significant morbidity may persist. Careful management of maternal metabolism tends to reduce the incidence of macrosomia but does not prevent it. The incidence of congenital malformations is increased twofold to threefold in the infants of insulin-dependent diabetic mothers compared with the normal population. The frequency of congenital anomalies is not increased in the infants of gestationally diabetic mothers or in those of diabetic fathers. A K score of 1 represents the 90th percentile for weight; scores of 0 and -1 represent the 50th and 10th percentiles, respectively. This syndrome consists of agenesis or hypoplasia of the femora in conjunction with agenesis of the lower vertebrae and sacrum. The frequency of congenital anomalies is significantly increased in mothers with poor metabolic control, as evidenced by increased hemoglobin A1c levels early in gestation,67 and a significant decrease in congenital malformations has been reported with rigorous metabolic regulation in the periconceptional period (see Chapter 19). Immediately after birth, there is a significant decrease in plasma glucose concentration, reaching a nadir between 30 and 90 minutes and followed by a spontaneous recovery in most infants. Irrespective of symptoms, the current recommendation is to correct the hypoglycemia with an appropriate glucose infusion. It should be underscored that hypoglycemia in the newborn does not necessarily reflect the magnitude of antepartum metabolic control of the mother and may simply be the consequence of hyperglycemia during labor and delivery. Alterations in calcium and magnesium homeostasis occur in about 50% of infants born to insulin-dependent diabetic mothers. Unlike hypoglycemia, hypocalcemia becomes apparent between 48 and 72 hours after birth. Both hypocalcemia and hypomagnesemia may be manifested with jitteriness and may require supplemental calcium therapy. In addition, data in asymptomatic infants of gestationally diabetic mothers have shown alterations in diastolic function and decreased passive compliance of the ventricular myocardium. By serially evaluating cardiac growth in utero in the fetuses of diabetic mothers, it has been shown that despite good metabolic control, cardiac hypertrophy developed in late gestation (34-40 weeks). Otherwise minor functional changes, such as impaired diastolic filling, have been reported in infants of gestational diabetic mothers and are usually not clinically significant. Preconceptional and early postconceptional metabolic control may decrease the incidence of congenital malformations. Improving maternal compliance, preventing ketoacidosis, and recognizing and treating pregnancy-induced hypertension and pyelonephritis are particularly important. Attempts should be made to maintain maternal fasting plasma glucose values at less than 80 mg/dL and 2-hour postprandial plasma glucose values at less than 120 mg/dL. With appropriate ambulatory support, hospitalization is not required in most mothers. Indications for hospitalization include pregnancy-induced hypertension, acute or chronic polyhydramnios, infections, and poor metabolic control. Follow-up ultrasonography is useful in the evaluation of amniotic fluid volume, fetal growth, and placental grading. Tests of fetal well-being begin in the second trimester (28-32 weeks of gestation). These tests usually include daily fetal movement counts and biweekly biophysical testing (non-stress testing, biophysical profile, or both) or non-stress testing combined with an amniotic fluid index (see Chapter 13). Delivery in insulin-dependent women is indicated after documentation of fetal lung maturity by amniocentesis (see Chapter 70). With appropriate care and fetal surveillance, most patients are now monitored expectantly for the spontaneous onset of labor at term. Vaginal delivery is preferred, but obstetric factors may justify cesarean delivery. Caution should be exercised in the delivery of a macrosomic fetus at risk for traumatic complications. During labor, glucose and insulin therapy should be adjusted to maintain normoglycemia in the mother. Delivery should take place in a hospital, where the newborn can be carefully monitored. Glucose values are checked during the first 3 hours after birth (typically between 30 and 60 minutes), sporadically before feedings, and any time symptoms are suspected. Feedings may be started as soon as the infant is stable, usually within 2 to 4 hours after birth, and continued at 3- to 4-hour intervals. Even though physiologic and clinical data clearly demonstrate a marked reduction in fetal and neonatal morbidity and mortality in pregnancy with diabetes, studies from the United Kingdom failed to show that such a goal was achieved in clinical practice. Improvements in antepartum care, fetal monitoring, rigorous control of maternal metabolism, and maternal education have all resulted in reduced perinatal mortality and morbidity. However, certain morbidities, such as hypoglycemia, macrosomia, and polycythemia, persist. The cumulative risk for the development of insulin-dependent diabetes mellitus before 20 years of age was 2. Another study revealed that the children of diabetic mothers, with and without macrosomia in the newborn period, had higher body mass indexes, higher blood pressures, and higher glucose and insulin levels on glucose tolerance testing when evaluated at age 18 to 26 years. These data need to be confirmed and their health consequences determined in a large cohort of carefully monitored children. Intellectual delay at ages 3 and 5 years in infants born to women with acetonuria (a marker of poor metabolic control) has been observed. Since these early studies, much improvement in the antepartum management of maternal diabetes has occurred. However, when correlation analyses were performed, a negative correlation was observed by Rizzo and colleagues80 between second- and third-trimester glycemic regulation (hemoglobin A1c and fasting plasma glucose levels) and the newborn behavior dimensions of the Brazelton Neonatal Behavioral Assessment and between third-trimester ketonuria and mental developmental index scores at 2 years of age and Stanford-Binet scores at 3 to 5 years of age. They did not find any correlation between neonatal blood glucose levels or the duration of hypoglycemia and neurologic abnormalities. With the increasing incidence of obesity in the general population, the number of such babies continues to increase. The exact mechanism of impaired glucose homeostasis in these infants has not been examined.

This disorder can be confused with diabetic ketoacidosis or salicylism when it occurs in the older child cholesterol numbers ratio calculator generic 10 mg pravachol. The treatment for both disorders is a low-protein diet and possibly a low-fat diet cholesterol phospholipids and glycolipids are examples of buy pravachol 10mg line, especially during intercurrent illnesses cholesterol in shrimp mayo clinic buy pravachol 10mg free shipping. Patients who have hypoglycemia with ketosis should be evaluated for an organic acidemia cholesterol lowering foods for diabetes pravachol 10 mg amex. Methylmalonic acidemia and propionic acidemia cholesterol in salmon pravachol 10 mg cheap, two of the most common organic acid disorders cholesterol definition in hindi purchase pravachol 20 mg otc, are often associated with ketosis. These common organic acidemias may be associated with hypoglycemia, an increased anion gap, hyperammonemia, hyperglycinemia, and an increased ratio of acylcarnitine to free carnitine with an abnormal pattern of specific acylcarnitines, but none of these findings is present invariably. The most common organic acidurias in the newborn period are isovaleric acidemia, methylmalonic acidemia, and propionic acidemia (see Box 99-1). All three disorders are the consequence of defects in branched-chain amino acid metabolism, affecting the catabolism of isoleucine, leucine, or valine. Patients born with these disorders are generally healthy at birth and then become inexplicably ill on the second or third day of life. Biochemically, these disorders are characterized by a combination of many or all of the following features: severe ketoacidosis, hyperammonemia, lactic acidemia, hyperglycinemia, abnormal carnitine metabolism. Several organic acidurias represent compound phenotypes because the genetic defect affects the synthesis or functioning of several enzymes. The most common of these compound disorders is multiple carboxylase deficiency, which may be the consequence of either of two genetically distinct defects: biotinidase deficiency and holocarboxylase synthetase deficiency (see Newborn Screening Programs). Both enzyme deficiencies lead to functional deficiencies of four enzymes, all carboxylases: acetyl-CoA carboxylase, which is involved in fatty acid synthesis; 3-methylcrotonylCoA carboxylase deficiency, which is involved in branched-chain amino acid metabolism; propionyl-CoA carboxylase, which is also involved in branched-chain amino acid metabolism; and pyruvate carboxylase deficiency, which is involved in gluconeogenesis. Both forms of multiple carboxylase deficiency can cause lactic acidemia and a complex organic aciduria; both are also considered in the algorithm for lactic acidemia (see Lactic Acidemia). Both forms of multiple carboxylase deficiency can lead to severe metabolic encephalopathy and/or neonatal seizures, and require prompt diagnosis and treatment. The sick infant should be evaluated with plasma carnitine analysis, including an acylcarnitine profile, urine organic acid analysis, and serum biotinidine analysis. Treatment with oral biotin supplementation should be started at an initial dose of 20 to 40 mg/day. This disorder is characterized by dysmorphogenesis of the brain, face, and kidneys, as well as the more expected clinical and biochemical phenotype of a combined amino acid and fatty acid -oxidation defect. This disorder is also associated in many cases with lactic acidosis, especially during acute phases of the illness. Many of the other organic acidurias listed in Box 99-1 present in a different manner from the disorders listed in the preceding, and need to be evaluated and treated differently once they are identified by urine organic acid analysis. For example, mevalonic aciduria is associated with hepatosplenomegaly, diarrhea, anemia, hypocholesterolemia, and craniofacial dysmorphism. The underlying defect in this disorder is deficiency of mevalonate kinase, which is a peroxisomal enzyme that catalyzes the first committed step in the biosynthesis of cholesterol and nonsterol isoprenoids (see Dysmorphic Syndromes). Glutathione is a tripeptide involved in maintaining the redox status within the cell. This rare disorder produces acidosis but not ketosis or hypoglycemia in the newborn period. It leads to acidosis during intercurrent illnesses later in childhood and progressive neurologic abnormalities, including ataxia, spasticity, and mental retardation. The primary objective of treatment is to correct the acidosis and electrolyte imbalances associated with the disorder, especially during acute illnesses. In the neonatal period, it is also important to aggressively treat any anemia or hyperbilirubinemia that develops. Management of a patient with an organic acidemia that can produce a neurologic intoxication syndrome and metabolic encephalopathy. Carnitine is used in many of these disorders to remove toxic metabolites during the acute phase. During an acute crisis, it is probably best to provide intravenous carnitine at 100 to 200 mg/kg per day (larger doses are sometimes given) as a continuous drip or in four divided doses. Glycine has been given for similar reasons to patients with isovaleric acidemia and related disorders. Intralipid can be started after carnitine supplementation has begun and when it is certain that the patient does not have a defect of fatty acid -oxidation. In the absence of a specific diagnosis, a high-carbohydrate formula that contains proportionately reduced amounts of protein and fat should be started. As a rule, it is necessary to limit only protein intake or, more correctly, the intake of certain amino acids, but restriction of protein and fat intake may be required for some disorders. A range of special formulas is commercially available for these patients, but specialized diets should always be designed with the assistance of a dietitian experienced in managing patients with inborn errors of metabolism. Carnitine (100 mg/kg per day) and glycine (250 mg/kg per day) are also used during the maintenance phase of treatment. The various approaches to the acute and long-term management of organic acidemias have led to improved survival and outcome. However, the prognosis for patients with these disorders still varies widely for different disorders and for patients with the same disorder. This disorder can, therefore, be classified as an amino acid disorder and a fatty acid -oxidation defect, which is characterized by an abnormal urine organic acid pattern. The defect interferes with the major pathways of ketone body formation and consequently is a cause of severe nonketotic hypoglycemia and acidosis in the newborn infant. Patients generally have vomiting, hypotonia, or lethargy at presentation, but others present with seizures caused by the profound hypoglycemia associated with this disorder. This disorder is treated with frequent feedings of a combined low-fat/ leucine-restricted, low-protein diet, and carnitine supplementation. Other treatment modalities described above for the organic acidurias may also be helpful. Lactic Acidemia the lactic acidemias are a complex group of inborn errors of metabolism. The classification, diagnosis, and treatment of these disorders will almost certainly change as understanding of their pathogenesis improves. In particular, current understanding of the pathogenesis of defects of the respiratory or electron transport chain is evolving rapidly. Lactic acidemia may be the consequence of overproduction of lactate, underuse of lactate, or both. A prerequisite for evaluating a patient with lactic acidemia is to assess the adequacy of tissue oxygenation. After it has been established that tissue oxygenation is adequate, several laboratory studies should be performed to determine the cause of the lactic acidemia, including those for blood lactate and pyruvate, blood gases and electrolytes, serum glucose, blood ammonia, plasma amino acids, plasma and urinary ketones, plasma and urinary carnitine, and urinary organic acids. The differential diagnosis of the primary genetic lactic acidemias with onset in the neonatal period includes defects of gluconeogenesis, glycogenolysis, or pyruvate metabolism; defects of the Krebs (or tricarboxylic acid) cycle; and defects of the respiratory chain (Table 99-15). Many defects of fatty acid oxidation, organic acid metabolism, and the urea cycle are associated with lactic acidemia because of relationships among the various pathways of intermediary metabolism. These disorders are more properly considered secondary lactic acidemias and are discussed elsewhere in this chapter. Multiple carboxylase deficiency is an exception to this rule because the underlying defect impairs biotin metabolism, which may produce pyruvate carboxylase deficiency and lactic acidemia. The urinary organic acid pattern, along with the blood ammonia concentration and plasma and urine carnitine analyses, provides a practical means for discriminating between the primary and secondary lactic acidemias. The urinary organic acid pattern is by definition abnormal in patients with an organic acidemia and is abnormal in many of the disorders of fatty acid -oxidation. Patients with fatty acid oxidation defects often excrete increased amounts of dicarboxylic acids, 3-hydroxydicarboxylic acids, or both. In contrast, the primary lactic acidemias are associated with a normal organic acid pattern or a nonspecific pattern of increased excretion of lactate and pyruvate, various Krebs cycle intermediates, dicarboxylic and 3-hydroxydicarboxylic acids, or 3-methylglutaconic acid. The dicarboxylic and 3-hydroxydicarboxylic acids are the consequence of secondarily impaired mitochondrial fatty acid -oxidation. The concentrations of urinary metabolites excreted in the primary lactic acidemias are generally less than those produced by the organic acidurias and fatty acid -oxidation defects. The plasma ammonia concentration and the plasma and urine carnitine analyses also provide useful information for distinguishing between the primary and secondary lactic acidemias. Patients with an organic aciduria or a fatty acid -oxidation defect often have hyperammonemia and relative carnitine insufficiency, with an increased acylcarnitine-to-free carnitine ratio and specific acylcarnitine abnormalities. The exception to this rule is the severe neonatal form of pyruvate carboxylase deficiency, because these patients can have hyperammonemia. Similarly, patients with a primary urea cycle defect could have lactic acidosis, but the degree of acidosis is relatively mild, especially early in the course of the disease, when respiratory alkalosis rather than metabolic acidosis is generally present (see Hyperammonemia). In practical terms, the first step in discriminating among the primary lactic acidemias is to examine the results of the lactate (L) and pyruvate (P) analyses in terms of the absolute and relative values of this pair of metabolites. Defects of gluconeogenesis or the pyruvate dehydrogenase complex are generally associated with a normal L: P ratio, whereas defects of the respiratory chain are often associated with an increased L: P ratio. These two groups of disorders can be distinguished from each other by the presence or absence of hypoglycemia and ketosis. Defects of gluconeogenesis are generally associated with hypoglycemia and ketosis, whereas patients with pyruvate dehydrogenase complex deficiency are generally normoglycemic and do not have ketosis (see Hypoglycemia). Less severe deficiencies are compatible with survival but lead to psychomotor retardation. Most patients with pyruvate dehydrogenase complex deficiency have an X-linked form of the disease, in which male patients are more severely affected than female patients. The rationale for this therapy is that glucose is catabolized through the glycolytic pathway to pyruvate and then requires the action of the pyruvate dehydrogenase complex before it can enter the Krebs cycle, whereas fatty acids enter the Krebs cycle without passing through the pyruvate dehydrogenase complex. Thiamine and lipoic acid are cofactors for the first and second components of the pyruvate dehydrogenase complex, respectively. Some patients have been treated with dichloroacetate, a drug that maintains the pyruvate dehydrogenase complex in its activated state. Four defects affecting the Krebs cycle have been described: -ketoglutarate dehydrogenase complex deficiency, fumarase deficiency, succinate dehydrogenase deficiency, and dihydrolipoamide dehydrogenase deficiency. The clinical presentations of -ketoglutarate dehydrogenase deficiency and fumarase deficiency are variable but always affect neurologic function. Similarly, individuals who are carriers for fumarase deficiency have an increased disposition for leiomyomatosis and renal cell cancer. Dihydrolipoamide dehydrogenase deficiency affects a protein that is a component of three different -ketoacid dehydrogenase complexes: the -ketoglutarate dehydrogenase complex. Dihydrolipoamide dehydrogenase deficiency is, therefore, a compound deficiency of these three -ketoacid dehydrogenase complexes and is associated with severe ketoacidosis and a pathognomonic organic aciduria. Defects of the respiratory chain are a complex group of disorders reflecting the large number of genes involved in this metabolic system. The common names, composition, and genetic origin of the subunits of the five respiratory chain complexes are listed in Table 99-16. The mitochondrial genome differs in several strategic ways from the nuclear genome. It is a circular, double-stranded genome that contains about 16,500 basepairs (16. Conversely, the number of nuclear genes involved in mitochondrial structure and function is far greater than the number of mitochondrial encoded genes, supporting the clinical observation that nuclear mutations are also a significant cause of mitochondrial disease, especially in children. An extraordinarily broad range of clinical phenotypes has been described among patients with respiratory chain defects. Thus, all patients suspected of having a respiratory chain disorder should undergo a comprehensive clinical evaluation to delineate the full pattern of organ involvement. Similarly, all patients suspected of having a respiratory chain disorder should undergo a metabolic evaluation for lactic acidemia and related biochemical abnormalities, as discussed in the beginning of this section (see Lactic Acidemia). These studies should be done in both the fasting and fed state (1 hour postprandial). The metabolic evaluation should include measurement of blood lactate and pyruvate, plasma and urine ketones (-hydroxybutyrate and acetoacetate), plasma amino acids (focusing on alanine, the transamination product of pyruvate), plasma carnitine analysis (including total carnitine, free carnitine, and the acylcarnitine profile), plasma coenzyme Q10 (which is required for normal functioning of the respiratory chain), and urine organic acid analysis. It is important to remember that the absence of lactic acidemia, or any of the other aforementioned biochemical findings, does not exclude the diagnosis of a respiratory chain disorder. Interpretation of the results of these diagnostic studies is complicated by the fact that many defects are tissue specific. In particular, many defects are not expressed biochemically in blood cells or cultured skin fibroblasts, which mandates the need for invasive studies to obtain a skeletal muscle, cardiac, or liver biopsy. Enzyme and polarographic analysis can implicate deficiency of one or more of the respiratory chain complexes, but they do not permit the clinician to determine whether the patient has a defect in a nuclear- or mitochondrialencoded subunit. In recent years, considerable progress has been made in identifying the nuclear genes that encode for the respiratory chain subunits and related mitochondrial processes, and genetic analysis is becoming increasingly available for many nuclear-encoded defects. A general consensus seems to have developed about the diagnostic evaluation of patients with a suspected respiratory chain disorder. If the patient appears likely to have a respiratory chain disorder and the clinical phenotype is characteristic of a specific, well-defined mitochondrial disorder that can be confirmed by genetic testing of a blood sample, then proceeding with such genetic testing is generally indicated. If, however, it appears that the patient has a mitochondrial respiratory chain disorder that does not have a recognizable clinical pattern, then performing additional, more specialized, invasive biochemical testing to define the underlying metabolic defect before initiating genetic testing is the preferred route to pursue. The key to learning the well-characterized clinical phenotypes that can be diagnosed by focused genetic testing using blood samples is to acquire an understanding of the current classification scheme for respiratory chain disorders. The traditional approach to classifying mitochondrial disorders was based on clinical phenotypes, pathologic findings, and biochemical findings. However, a clinically based classification system is limited by two well-established characteristics of mitochondrial respiratory chain disorders: a particular clinical phenotype can be caused by more than one genetic defect, and conversely, the same genetic defect can produce more than one clinical phenotype. Recognition of these limitations led to efforts to classify mitochondrial disorders according to their genetic bases. This approach to classification is also imperfect, but it is improving as current understanding of the genetic bases of these disorders becomes greater.

Unfortunately cholesterol conversion buy generic pravachol, effective treatment is not available for all of the lysosomal storage disorders cholesterol food chart nhs buy pravachol australia. Mevalonic aciduria is caused by a rare defect cholesterol in cell membrane order pravachol 20mg line, mevalonate kinase deficiency cholesterol medication and apple cider vinegar discount 20mg pravachol amex, which catalyzes an early step in cholesterol biosynthesis cholesterol levels heart disease myth quality pravachol 20 mg. It can also be classified as a peroxisomal single enzyme disorder because mevalonate kinase is located within the peroxisome (see Peroxisomal Disorders) cholesterol test kit boots generic 20mg pravachol with amex. The pathogenesis of this disorder is complex because mevalonic acid has a role in several strategic pathways. In addition to its role as a precursor of cholesterol, mevalonic acid is a precursor of dolichol, which is required for glycoprotein biosynthesis; heme, which plays a key role in oxygen transport; and ubiquinone, a component of the respiratory chain (see Lactic Acidemia). Mevalonate kinase deficiency is a highly pleiotropic disorder associated in the newborn period with dysmorphic features. In severe cases, it leads to profound failure to thrive, developmental delay, and early death. Although the defect would be expected to lead to lactic acidosis because of decreased synthesis of ubiquinone and malfunctioning of the respiratory chain, lactic acidosis is not a common feature of the disorder. Alternatively, mevalonate kinase deficiency can produce a very different clinical phenotype, hyper IgD syndrome, which is one of the periodic fever disorders. Mevalonic aciduria and hyper IgD syndrome appear to be allelic forms of mevalonate kinase deficiency. The characteristic diagnostic feature is mevalonic aciduria, which can be documented by urinary organic acid analysis. No effective treatment exists for this disorder, although corticosteroids might be of some benefit. Multiple acyl-CoA dehydrogenase deficiency is a clinically heterogeneous disorder. The severe neonatal form of this disease is associated with metabolic abnormalities. Less severe later-onset forms can present at any age thereafter, and do not have congenital malformations. The diagnosis is initially made by urine organic acid analysis, and then confirmed by in vitro cell studies using cultured skin fibroblasts or genetic testing. There is no effective treatment for the severe neonatal form of disease, but more mildly affected patients may improve with riboflavin supplementation. The peroxisomal disorders are a highly diverse group of disorders, reflecting the metabolic diversity of the enzymes contained within this organelle. Many of these enzymes are involved in unusual oxidation reactions; the name of this organelle was derived from one such reaction involving hydrogen peroxide. The peroxisomal disorders can be classified into two groups: defects of peroxisome biogenesis and defects affecting a single enzyme (see Table 99-8). The first group consists of disorders associated with absent or severely reduced numbers of peroxisomes and multiple enzyme deficiencies. These disorders are caused by defects in peroxisomal biogenesis, which lead to impaired import of proteins and enzymes into the peroxisome. Epiphyseal stippling is an unusual radiographic finding of ectopic calcification found most characteristically in the ankle, patella, vertebrae, hips, and trachea (see Cholesterol Biosynthesis). Other peroxisomal assembly disorders include neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondrodysplasia punctata. Genetic studies have identified approximately 20 different genetic loci associated with peroxisomal biogenesis defects. Genetic complementation studies have shown that Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease represent allelic variants at many of these loci. Zellweger syndrome is the most severe variant, and infantile Refsum disease is the least severe variant. Rhizomelic chondrodysplasia punctata is the consequence of mutations at one of the other loci involved in peroxisomal biogenesis. Peroxisomal deficiencies have been found only in the rhizomelic form of chondrodysplasia punctata, which is an autosomal recessive disorder characterized by severe shortening of the proximal extremities (hence the term rhizomelic), craniofacial dysmorphism, congenital cataracts, joint contractures, and severe psychomotor retardation. The skeletal abnormalities of this form of dwarfism are evident in the neonatal period. The best known disorder in this group is X-linked adrenoleukodystrophy, which does not produce dysmorphism and does not manifest in the neonatal period and, therefore, is not discussed further. However, several other peroxisomal monoenzymopathies with onset in the neonatal period have been recognized. The best characterized of these disorders are acyl-CoA oxidase deficiency, bifunctional enzyme deficiency, and thiolase deficiency. These three enzymes share a common biochemical role in peroxisomal (rather than mitochondrial) fatty acid oxidation and bile acid biosynthesis. Many of the dysmorphic and laboratory abnormalities associated with Zellweger syndrome and its variants, therefore, can be attributed to abnormal fatty acid metabolism or abnormal bile acid metabolism. Similarly, defects affecting the enzymes that catalyze plasmalogen biosynthesis produce a clinical phenotype that resembles rhizomelic chondrodysplasia punctata. Several other single-enzyme deficiencies have been described that do not involve the peroxisomal pathways of fatty acid oxidation or plasmalogen biosynthesis. One of these disorders, mevalonic aciduria, is a defect in cholesterol biosynthesis and is described under Organic Acidurias. The various dysmorphic features of fetal warfarin syndrome and vitamin K epoxide reductase deficiency are consequences of impaired activity of the vitamin Kediated carboxylation reactions, which include proteins of the bone matrix and circulating coagulation factors. Vitamin K supplementation is an effective therapy for the coagulopathy associated with this disorder but might not be effective for the other manifestations because of their prenatal onset. It should begin with broadly focused screening tests, which are then followed by more specialized examinations. Laboratory findings helpful in the differential diagnosis of suspected metabolic disease are listed in Table 99-9. In the absence of this enzyme, the precursor of 3-hydroxyisobutyryl-CoA, methacrylyl-CoA, accumulates and is conjugated with cysteine to form two unusual metabolites that are excreted in the urine. This disorder is detected by urinary amino acid analysis, which reveals the unusual cysteine conjugates. This disorder appears to be caused by intracellular accumulation of methacrylyl-CoA or methacrylate, which is formed by nonenzymatic hydrolysis of methacrylylCoA. In addition to this defect, several patients with 3-hydroxyisobutyric aciduria did not have deacylase deficiency or another recognizable enzyme deficiency in the valine pathway. The clinical phenotype of these patients was similar to that of the patient with deacylase deficiency, including significant craniofacial and cerebral dysmorphism, which was accompanied in some cases by intracerebral calcifications. Although the underlying defect has not been identified in these patients, the presumption is that a defect in the metabolism of 3-hydroxyisobutyric acid led to the intracellular accumulation of methacrylate or a related teratogen. Vitamin K epoxide reductase deficiency is an autosomal recessive disorder that produces a phenocopy of the fetal warfarin embryopathy syndrome. However, there should be a core of tests available at all institutions that care for sick neonates. These laboratory tests are chosen because they provide a relatively rapid, inexpensive evaluation for a wide range of disorders. It is strongly recommended that the specific details of collection and handling of all samples be clearly understood before samples are obtained and that there be collaboration with laboratory personnel throughout the process. A number of blood studies are indicated, many of which are routinely performed during the care of sick neonates. The complete blood cell count should include examination of cell morphology and a differential cell count. Neutropenia and thrombocytopenia may be associated with a number of the organic acidemias, including isovaleric acidemia, methylmalonic acidemia, and propionic acidemia (see Hematologic Abnormalities). Megaloblastosis may be found in disorders of purine biosynthesis, such as some rare forms of homocystinuria or orotic aciduria. Electrolytes and blood gases are required to determine whether acidosis or alkalosis exists and, if so, whether the abnormality is associated with an increased anion gap. Pancytopenia Proximalrenaltubular dysfunction(seeTable99-14) Lactate and pyruvate analysis should be measured to identify the nature of any excess anions (see Lactate and Pyruvate Analysis). Hypoglycemia is a frequent finding in sick neonates, especially premature infants, but is also a critical finding in some metabolic disorders. Hypoglycemia should be investigated further when it is severe, when accompanied by other signs of metabolic disease, or when it proves refractory to conventional therapy. In particular, nonketotic or hypoketotic hypoglycemia is the hallmark of defects of fatty acid oxidation. The blood ammonia concentration should be determined in all neonates with evidence of unexplained lethargy and neurologic intoxication. Early recognition of the congenital hyperammonemias is crucial because they are a rapidly progressive group of disorders that can quickly lead to irreversible damage after hours rather than days. Effective treatment is available for many of these disorders, but it must be instituted early in the course of the disease. A blood uric acid test is a convenient screen for the few inborn errors of metabolism that are associated with hypouricemia or hyperuricemia. Type I glycogen storage disease is probably the most common inherited disorder associated with hyperuricemia (see Hypoglycemia), whereas xanthine oxidase deficiency associated with molybdenum cofactor deficiency causes hypouricemia (see Metabolic Seizures). In this event, a urine specimen should be sent directly for the more specialized testing. After a few hours at room temperature, the specimen should be smelled for evidence of an unusual odor. Several inborn errors of metabolism, especially the organic acidurias, are associated with characteristic odors (see Table 99-7). Urine specimens should be tested for reducing substances, which include principally the monosaccharides. The Clinitest reaction detects excess excretion of galactose and glucose but not fructose. False-positive reactions are found with ampicillin and related penicillin derivatives and with some other drugs that are excreted as their glucuronide conjugates. A specimen that shows a positive reaction with the Clinitest reaction should be investigated further by means of the Clinistix reaction. A specimen with positive Clinitest and negative Clinistix results should be analyzed specifically for galactose. The urine pH should be determined to characterize the renal response to an alteration in blood pH. In the face of a significant acidemia, the kidneys should produce an acidic urine (pH <5). A renal acidification disorder should be considered in the absence of an appropriate urine pH. Spot tests may be used to detect excessive urinary excretion of ketones, -ketoacids, or other metabolites. The ferric chloride reaction is also a useful test, although it is relatively insensitive and subject to potentially misleading false-positive reactions with several drugs. These studies include the nitrosonaphthol reaction, which detects certain tyrosine metabolites; the p-nitroaniline reaction, which is relatively specific for methylmalonic aciduria; and the Sulfitest, which detects excess sulfite excretion in patients with sulfite oxidase deficiency and molybdenum cofactor deficiency. In general, the more specialized tests require relatively sophisticated equipment and personnel to perform and interpret, take longer to perform (sometimes days to weeks), are more expensive, and are usually available in only a few centers. All physicians who might care for a sick neonate with a suspected inborn error of metabolism should develop their own referral system for patients with various metabolic abnormalities. It is a good idea to set up a referral system in advance of a specific emergency so that appropriate referral can be obtained more easily when the time comes. Because not all patients require transfer or tolerate transfer to a tertiary care center, plans should also be on hand for collecting samples for various specialized tests. It is truly unfortunate when the often extraordinary and well-intentioned efforts of those caring for a sick newborn infant are subverted by improper collection or handling of samples. Detailed requirements for collection and handling of samples for various metabolic analyses should be available in the nursery, and they should be kept in a place where they can be found in an emergency. The distinction between a screening study and a specialized follow-up test is not always clear. In some circumstances, the physician would proceed directly to performing a specialized study. Similarly, it is generally best to perform some of the specialized studies during an episode of acute metabolic decompensation, such as hypoglycemia, when they are most likely to be informative, rather than waiting until the results of the screening tests become available. As a rule, the sequence of ordering tests should be compressed in an acutely ill patient. The most commonly performed of the specialized studies is probably quantitative plasma and urinary amino acid analysis. Although this study may be useful, it does not substitute for a quantitative determination when the clinical findings suggest a disorder that is reflected in an abnormal amino acid pattern (Table 99-13). In most cases, a complete quantitative analysis is required, whereas in other situations, specific amino acids should be the focus of attention. This recommendation to inform the laboratory of the clinical context of the investigation applies equally to the other specialized studies discussed here. The plasma glycine level may be only minimally elevated in some patients with nonketotic hyperglycinemia. Plasma and urinary carnitine analysis is indicated for patients who show evidence of unexplained acidosis, hyperammonemia, hypoglycemia, or ketonuria when there might be a disorder accompanied by an abnormal organic aciduria, defect in fatty acid oxidation, or respiratory chain defect. In these settings, carnitine insufficiency or frank carnitine deficiency can develop. Many of the organic acidurias or fatty acid oxidation defects are associated with overproduction of specific acyl-CoAs. As they accumulate, these acyl-CoAs are transesterified with free carnitine to form acylcarnitines and free CoA.

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