clinical manual for inborn errors of metabolism

clinical manual for inborn errors of metabolism

Our payment security system encrypts your information during transmission. We don’t share your credit card details with third-party sellers, and we don’t sell your information to others. Please try again.Please try again.Please try again. In spite of the improvements in health care and diagnostic facility, no substantial gain is noticed in infant mortality and morbidity rates as genetic disorders have emerged as leading causes after considerable control of Communicable Diseases. However, in the absence of any screening programme, the treatable metabolic disorders continue to affect large number of infants in the country. A rough estimate indicates that 5-15% of new born babies may have a metabolic problem. Realising the need for a national new born screening programme for Inborn Metabolic Disorders(lMDs) the Council constituted a National Task Force to create a comprehensive programme for laboratory diagnosis and clinical management of IMDs. In the shortest time, the Task Force Group has conducted a series of laboratory hands on training workshops at Bangalore and clinical workshop at New Delhi for capacity building in laboratory and clinical methodologies. This was followed by a multicentric new born screening programme for identified metabolic disorders. I congratulate the National Task Force on Inborn Metabolic Disorders under the chairmanship of Prof. S. S. Agarwal, Lucknow for their achievements in this area. I appreciate the efforts of Dr. Taranath Shetty, Bangalore in compiling the laboratory manual and Dr. Veena Kalra, New Delhi and her team for this excellent Clinical Manual which will be the first one of its kind in the Country. This will go a longway in helping the professionals in accurate diagnosis and appropriate clinical management. I am sure this document will ben Then you can start reading Kindle books on your smartphone, tablet, or computer - no Kindle device required.

• clinical manual for inborn errors of metabolism.

To calculate the overall star rating and percentage breakdown by star, we don’t use a simple average. Instead, our system considers things like how recent a review is and if the reviewer bought the item on Amazon. It also analyzes reviews to verify trustworthiness. There are a large number of conditions included in this group of disorders. Management of metabolic disorders can be very complicated and should always involve close liaison with a metabolic physician. Most of these disorders are inherited as autosomal recessive. Many metabolic disorders present in the newborn period or shortly thereafter. Patients may present later, for example during intercurrent illnesses. High index of suspicion required to make diagnosis as the clinical presentation of most metabolic disorders is non-specific. Do not store in a plastic envelope.Metabolic Conditions (p475) Death of a child with a suspected metabolic disorder See. Please enable it to take advantage of the complete set of features!Get the latest public health information from CDC. Get the latest research from NIH. Find NCBI SARS-CoV-2 literature, sequence, and clinical content:.This makes it essential that the practicing pediatrician be familiar with the clinical presentation of these disorders. A practical clinical approach to the recognition of inborn errors of metabolism in the young infant is presented in this review. Indications for specific laboratory studies are discussed. Guidelines are provided for the stabilization and emergency treatment of critically ill infants. This approach will identify those infants who will benefit from additional evaluation and specific treatment. Many of the inborn errors of metabolism, including urea cycle defects, organic acidemias, and certain disorders of amino acid metabolism, present in the young infant with symptoms of an acute or chronic metabolic encephalopathy. Typical symptoms include lethargy, poor feeding, apnea or tachypnea, and recurrent vomiting.

Therefore, appropriate laboratory testing for metabolic disorders should be performed in any infant who exhibits these findings. Although sepsis may be the initial consideration in a neonate with these symptoms, inborn errors of metabolism should always be in the differential diagnosis, particularly in a full-term infant with no specific risk factors. Hypoglycemia may be the predominant finding in a number of inborn errors of metabolism, including glycogen storage disorders, defects in gluconeogenesis, and fatty acid oxidation defects. The latter disorders, among the most common encountered, exhibit marked clinical variability and also may present as a sudden death, a Reye's-like episode, or a cardiomyopathy. Jaundice or other evidence of hepatic dysfunction is the mode of presentation of another important group of inborn errors of metabolism including galactosemia, hereditary tyrosinemia, neonatal hemochromatosis, and a number of other conditions. A subset of lysosomal storage disorders may present very early with coarse facial features, organomegaly, or even hydrops fetalis. Specific patterns of dysmorphic features and congenital anomalies characterize yet another group of inherited metabolic disorders, such as Zellweger syndrome and the Smith-Lemli-Opitz syndrome. Each of these symptom complexes, and the appropriate evaluation of the affected infants, is discussed in more detail in this review. Correspondence to: Ruben Bonilla Guerrero. Copyright 2018 Annals of Translational Medicine. All rights reserved. This article has been cited by other articles in PMC. Abstract The diagnosis of inborn errors of metabolism (IEM) takes many forms. Due to the implementation and advances in newborn screening (NBS), the diagnosis of many IEM has become relatively easy utilizing laboratory biomarkers. For the majority of IEM, early diagnosis prevents the onset of severe clinical symptoms, thus reducing morbidity and mortality.

However, due to molecular, biochemical, and clinical variability of IEM, not all disorders included in NBS programs will be detected and diagnosed by screening alone. This article provides a general overview and simplified guidelines for the diagnosis of IEM in patients with and without an acute metabolic decompensation, with early or late onset of clinical symptoms. The proper use of routine laboratory results in the initial patient assessment is also discussed, which can help guide efficient ordering of specialized laboratory tests to confirm a potential diagnosis and initiate treatment as soon as possible. Keywords: Metabolic, inborn, disorder, diagnosis, laboratory Introduction The term “inborn errors of metabolism” (IEM) was first described by Sir Archibald Garrod in 1908 ( 1 ) to describe those diseases caused by a block in a metabolic pathway due to the deficient activity of a specific enzyme. These new technologies have also allowed for the expansion and improvement of newborn screening (NBS) on a global scale. In the United States (US), the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) (part of the US Department of Health and Human Services) recommends that all newborns be screened for 34 core disorders as well as 26 secondary disorders. Approximately 80% of the disorders tested in NBS are IEM ( 2 ). However, there is still the need to identify individuals whose defect was missed by NBS, or who were born before widespread screening was available. Background IEM can be classified into two broad categories: those which affect energy production, and those which affect the synthesis or degradation of specific molecules or compounds. Although carbohydrates, fats, and proteins are all used as energy sources, the degree to which a specific fuel is utilized depends on the organ or tissue type.

A disruption to a metabolic process that affects one type of fuel leads to the increased utilization of an alternate fuel type; this compensatory shift in energy production can lead to a pattern of abnormal metabolites observed in patients with these disorders, which is key to making the diagnosis. Due to the complex regulation of metabolic processes throughout the body, the accumulation of a substrate from a blocked metabolic step will engage alternate metabolic pathways that are otherwise minimally utilized under normal circumstances, leading to an increase in the production and accumulation of potentially harmful intermediate metabolites in patients with IEMs. These intermediates may also interfere with normal metabolism through activation or inhibition of enzymatic processes, or through competitive action, leading to additional clinical symptoms and pathognomonic patterns of elevated analytes. Most organic acidurias, amino acidopathies, peroxisomal disorders, lysosomal storage disorders (LSD), glycogen storage disorders (GSD), and mitochondrial fatty acid oxidation disorders are examples of defects in degradative pathways, in which specific enzymes break down substrates (glycogen, organic acids, amino acids, or fatty acids) to produce energy or to generate basic building blocks utilized in subsequent synthetic processes (i.e., creatine synthesis). In contrast, the porphyrias, cerebral creatine deficiencies, and congenital disorders of glycosylation are examples of defects in synthetic pathways, which impact the production of heme, creatine, and glycoproteins respectively. Transporters and channel proteins which mobilize substrate fall into both categories ( 3 - 6 ). General approach to diagnosing IEM Patients with inherited metabolic disorders can create a familiar diagnostic dilemma in clinical practice.

Even when there is a strong suspicion of an underlying metabolic defect, the sheer number of disorders and the variability in clinical features can render diagnostic test selection difficult. Clinical phenotypes of IEM are broad and often non-specific, mimicking more common conditions, and the onset of symptoms can occur at any age from fetus to adult. Although the classical presentation of most IEM involves an acutely ill newborn or young infant, this scenario is encountered less frequently now that advances in tandem mass-spectrometry-based NBS have decreased the number of acute episodes and consequent sequelae for many of the conditions identified by the screening test. However, because patients with milder mutations and subtle biochemical phenotypes may be missed by the cut-off values used to determine positive screening results, a normal newborn screen should not exclude these disorders from the differential diagnosis in a patient whose clinical presentation is suggestive of an inherited metabolic defect. Both clinical and biochemical phenotypes of IEM in children have been studied for decades; conversely, late onset or adult onset variants were largely unrecognized. In recent years, adult onset forms of many inherited metabolic disorders have been increasingly identified as true mild phenotypes, where symptoms in childhood were not severe enough to merit investigation. In these late onset variants of metabolic disorders, some not presenting until well into adulthood, the clinical features may be significantly different from the classical features associated with the underlying disorder, which, along with the patient’s age, could lead to a significant delay in diagnosis. Appropriate and prudent test selection must be driven by a combination of the patient’s clinical presentation and the results of routine first tier laboratory tests, which can help guide more specific testing.

When evaluating a patient for a possible IEM, routine laboratory tests can identify underlying patterns suspicious for a metabolic defect. Common findings include hypoketotic hypoglycemia, lactic acidosis, metabolic acidosis, ketosis, hyperammonemia, or metabolic acidosis in combination with hyperammonemia. Evaluating these blood and urine test results in conjunction with the clinical presentation can narrow the focus toward a particular subset of metabolic disorders. Among the clues that should lead clinicians to suspect an IEM are scenarios such as a critically ill neonate with a history of deterioration following an uncomplicated pregnancy, episodes of illness or fluctuating symptoms of lethargy or other neurological symptoms precipitated by intercurrent illness or stress, multisystem involvement, failure to thrive, developmental delay, progressive neurological signs or bizarre neurological symptoms with or without psychological problems in patients in whom the usual etiologies have been excluded, particularly in adults ( 7 ). Although biochemical genetic and molecular genetic tests are required to confirm a diagnosis, basic laboratory tests are still important and often provide the first clues to a possible underlying IEM. Medical and family history, clinical symptoms, and basic labs are usually adequate to categorize an IEM and provide initial treatment before the results of more specific testing are available, especially in an emergency situation. The first step in helping to select the appropriate laboratory investigation to rule out an IEM is to determine whether the condition is likely due to defects in small molecule metabolism (such as disorders of amino acids, organic acids, purines and pyrimidines, the urea cycle, mitochondrial energy metabolism) or defects of organelle metabolism (such as lysosomes or peroxisomes) ( 8 - 10 ). Patients with small molecule disorders usually present with acute illness requiring emergency intervention.

Patients with disorders of organelle metabolism commonly present with neurological and neuromuscular manifestations, organomegaly, hepatic dysfunction, with or without dysmorphism. Small molecule metabolism defects Patients with defects of small molecule metabolism may first present with acute illness. Basic laboratory tests should be performed in every child with an acute illness in whom an underlying metabolic disorder is a possibility. The following tests are examples of basic but nevertheless critical investigations to be considered when evaluating a patient for a potential IEM, as results can be directly affected by these disorders. Results of basic testing can provide direction into the underlying etiology and help in the selection of further more specific tests ( Table 1 ). In addition, enzymes in blood can deaminate amino acids causing elevation of ammonia. Therefore, measurement of ammonia can be challenging. A free-flowing blood sample should be collected into preferable pre-chilled tubes. The sample should be transported on ice to the laboratory and separated as soon as possible, preferably within 15 minutes. Specimen should be analyzed as soon as possible. IEM, inborn errors of metabolism. Acid-base status to determine the anion gap Metabolic acidosis is a disturbance in the body’s acid-base balance through the loss of bicarbonate, reduced renal excretion, or increased production of acids. Determining the acid-base status is important in the assessment of a patient with a potential inherited metabolic defect, because high anion gap metabolic acidosis is usually caused by the accumulation of organic acids including lactic acid, ketone bodies, or unusual acids and their derivatives. In contrast, diarrhea and renal tubular acidosis are the main causes of metabolic acidosis with a normal anion gap ( 11 ).

If acidosis is present, it should be evaluated in conjunction with other metabolic states such as hypo- and hyper-glycemia, ketosis, hyperlactatemia, and hyperammonemia. The majority of IEM that present with overwhelming metabolic acidosis and ketosis are organic acidemias (i.e., methylmalonic acidemia, propionic acidemia, isovaleric acidemia). On the other hand, metabolic acidosis with hypoglycemia and no ketosis can be the only finding in an underlying mitochondrial fatty acid oxidation defect, where rescue of hypoglycemia is impaired by the inability to produce energy from fatty acid metabolism and an increase in the production of non-physiological dicarboxylic acid intermediates ( 12 ). Metabolic acidosis and hyperlactatemia in the absence of elevated organic acids other than lactic acid and pyruvic acid can be found in disorders of pyruvic acid metabolism, as well as in respiratory chain defects ( Figure 1 ). Open in a separate window Figure 1 Metabolic Acidosis Workup Algorithm. PC, pyruvate carboxylase; UOA, urine organic acids; SC, serum carnitine; MSUD, maple syrup urinary disease; FOAD, fatty acid oxidation disorder; PAC, plasma acylcarnitines; FAA, free fatty acids; PAA, plasma amino acids; GDS 1, glycogen storage disorder type 1. Blood glucose Severe hypoglycemia is a life-threatening condition found in many metabolic disorders, including disorders of protein metabolism such as organic acidurias and certain amino acidopathies. However, critical hypoglycemia is a feature found in disorders directly affecting carbohydrate metabolism such as GSD, gluconeogenesis defects (glucose-6-phosphatase deficiency, fructose-1,6-biphosphate deficiency), and mitochondrial fatty acid oxidation defects, which produce a severe depletion of circulating and reserve carbohydrates secondary to defective alternative energy production ( Figure 2 ) ( 13, 14 ). Open in a separate window Figure 2 Hypoglycemia Workup Algorithm.

GDS 1, glycogen storage disorder type 1; HFI, hereditary fructose intolerance; UOA, urine organic acids; SC, serum carnitine; PAC, plasma acylcarnitines; PAA, plasma amino acids; UAA, urine amino acids; SI, serum insulin; FAA, free fatty acids. When evaluating hypoglycemia, a logical approach is to first consider whether the patient is ketotic or nonketotic. Disorders of mitochondrial fatty acid oxidation, carbohydrate metabolism, ketone body metabolism, and organic acidemias can all cause hypoglycemia. Disorders of mitochondrial fatty acid oxidation and ketogenesis including HMG-CoA lyase deficiency and HMG-CoA synthase deficiency as well as hyperinsulinemia are associated with hypoketotic hypoglycemia with or without severe metabolic acidosis, whereas other disorders such as organic acidemias, defect of ketone body metabolism and less commonly maple syrup urine disease (MSUD), typically cause ketotic hypoglycemia ( 15, 16 ). During normal physiological conditions when hypoglycemia ensues, there is the simultaneous onset of hepatic glycogen-to-glucose conversion and an increase in the catabolism of free fatty acids. Mitochondrial fatty acid oxidation defects produce profound hypoglycemia due to the depletion of circulating glucose and hepatic glycogen stores arising from the inability to metabolize fatty acids to meet energy requirements. In these defects, there is also the inability to rescue hypoglycemia and reduced production of acetyl-CoA due to decreased flux through the beta-oxidation spiral, which affects ketone body production. In GSD, there is impaired conversion of hepatic glycogen into circulating glucose during fasting, thus depleting available carbohydrates; the hypoglycemia is associated with hepatomegaly, mild to severe hepatic dysfunction, and hyperlactatemia.

However, hypoglycemia might be absent in GSD type II (Pompe disease, or lysosomal acid maltase deficiency) as cytoplasmic glycogen metabolism is spared and glycogen accumulates only in lysosomes and in the early stages of GSD type IV. Hypoglycemia can also be found in disorders of carbohydrate metabolism like the galactosemias or hereditary fructose intolerance. In classic galactosemia, accumulated galactose-1-phosphate inhibits phosphoglucomutase to impair glycolysis, whereas in hereditary fructose intolerance, accumulated fructose-1-phosphate inhibits both gluconeogenesis and glycogenolysis ( 17 - 20 ). A history of the time-based relationship of hypoglycemia to feeding can be helpful in making the diagnosis. Hypoglycemia in the postprandial state or after a short duration fast ( 8 hours) is suggestive of a fatty acid oxidation defect. Other basic laboratory findings may also be helpful; for example, hypoglycemia in the presence of hepatic fibrosis and cirrhosis might be the only finding in hereditary tyrosinemia type I. Ammonia Like hypoglycemia, hyperammonemia is also a life-threatening condition; therefore, the plasma ammonia level should be tested in all patients with alteration of consciousness and encephalopathy, particularly young children. Hyperammonemia can be caused by many non-metabolic conditions, including liver disease, portocaval shunt, glutamate dehydrogenase hyperactivity, or valproic acid toxicity. Although some organic acidemias and disorders of mitochondrial fatty acid oxidation may also cause hyperammonemia, it is usually less significant. Ammonia, the neurotoxic byproduct of amino acid deamination, is converted to excretable urea by the urea cycle in a series of enzymatic steps occurring either in the cytosol or in the mitochondrion.

Although very efficient under normal conditions, the urea cycle is a comparatively fragile metabolic process that can be affected by inherited metabolic disorders through a variety of different mechanisms ( Figure 3 ). Open in a separate window Figure 3 Hyperammonemia Workup Algorithm. UOA, urine organic acids; PAC, plasma acylcarnitines; SC, serum carnitine; PAA, plasma amino acids; ASA, argininosuccinic acid; UAA, urine amino acids. Urea cycle disorders are inherited deficiencies in any of the enzymes of the urea cycle, or in the production of the allosteric cofactor N-acetylglutamine, resulting in severe primary hyperammonemia. Hyperammonemia is also a relatively common secondary finding in organic acidurias, wherein accumulated substrates or organic acid intermediates inhibit the proximal urea cycle enzyme N-acetylglutamate synthase (NAGS), producing an overall reduction of the urea cycle detoxifying efficacy. Among the organic acidurias, propionic acidemia and methylmalonic acidemia in particular can present with intermittent secondary hyperammonemia due to the inhibitory capability of accumulated propionyl-CoA. Metabolic derangements in which circulating levels of ornithine, citrulline, or arginine are decreased due to renal losses or reduced endogenous production can also produce hyperammonemia, since all three are urea cycle intermediates. When circulating or intracellular levels of these amino acids fall, the efficiency of the urea cycle can decrease, resulting in hyperammonemia; the most profound losses of amino acids important to the urea cycle are found in cystinuria and lysinuric protein intolerance where the renal reabsorption of ornithine and arginine can be severely reduced due to competition for a shared dibasic amino acid transporter. In contrast, mitochondrial fatty acid oxidation disorders can present with hyperammonemia due to the combined effects of substrate depletion and urea cycle inhibition by toxic acylcarnitine species.

The level of acetyl-CoA, the end product of fatty acid beta oxidation, is decreased when overall flux through the pathway is reduced. Acetyl-CoA is required for the production of N-acetylglutamate, which allosterically activates the enzyme carbamoyl phosphate synthetase 1 (CPS1); CPS1 converts ammonia to carbamoyl phosphate in the rate-limiting first step of the urea cycle. In certain long-chain fatty acid oxidation defects, fatty acylation of an active site residue of CPS1 directly affects the urea cycle detoxification capacity. Finally, some disorders can produce hyperammonemia secondary to organ damage. For example, in lysosomal disorders including the mucopolysaccharidoses as well as in some peroxisomal disorders, the accumulation and storage of complex large molecules within the liver leads to hepatocellular damage, which in turn causes a decrease in urea cycle efficiency ( 21 - 26 ). Lactic acid The physiological balance of circulating lactic acid sustained by lactic acid production through cytoplasmic glycolysis and multi-tissue mitochondrial consumption can be disturbed by both non-metabolic and metabolic conditions. Lactic acidosis can occur due to an increase in lactate production, or a decrease in its metabolism. Most metabolic disorders presenting with hyperlactatemia have concurrent ketosis, with the exception of pyruvic dehydrogenase (PDH) deficiency, glycogenosis type-I or certain fatty acid oxidation disorders ( 27 ). Lactic acidosis is most often caused by tissue hypoxia due to poor circulation or inadequate oxygen supply from multiple causes, including cardiogenic or hypovolemic shock. Non-metabolic sources of hyperlactatemia are not usually accompanied by ketosis. However, several IEMs including organic acidurias, disorders of mitochondrial energy metabolism, or defects of gluconeogenesis can also present with lactic acidosis.

Once a non-metabolic etiology of hyperlactatemia has been ruled out, the most common origins of hyperlactatemia secondary to mitochondrial energy disruption by toxic metabolites are fatty acid oxidation disorders, organic acidurias, and in very rare cases, urea cycle defects. Other inherited causes of persistent hyperlactatemia include disorders of glycogen metabolism, disorders affecting gluconeogenesis, and disorders directly affecting the Krebs cycle or pyruvic acid metabolism. In disorders affecting glycogen degradation, hyperlactatemia peaks postprandial. Hyperlactatemia can differ in disorders directly affecting pyruvic acid metabolism ( 28, 29 ). In pyruvate dehydrogenase (PDH) deficiency, alpha-ketoglutarate dehydrogenase deficiency, and respiratory chain disorders, hyperlactatemia usually occurs in the fed state, whereas in pyruvate carboxylase deficiency, hyperlactatemia occurs in both fasting and fed states. Ketones The ketone bodies 3-hydroxybutyric acid, acetoacetic acid, and acetone are the natural end products of mitochondrial fatty acid beta-oxidation. Ketonuria, an increase in the urinary excretion of ketones, is found physiologically in late infancy, childhood and adolescence, but is not considered normal in the neonate. Physiological ketosis is not accompanied by metabolic acidosis, hyperlactatemia, or hypoglycemia, markers of metabolic stress; it is a common finding following fasting, vomiting, consumption of a ketogenic diet, or states of increased catabolism. However, because ketones are organic acids, severe ketonuria that produces metabolic acidosis should not be considered physiological, and indicate an IEM. The timing of ketonuria in relation to feeding or fasting is an important differentiator that can point to the potential type of underlying metabolic disorder. For instance, severe ketonuria with fasting hypoglycemia, or postprandial hyperglycemia with hyperlactatemia are common findings in certain disorders of glycogenosis.

In contrast, pure marked ketonuria in fed and fasting states can occur in ketone body handling disorders such as succinyl-CoA transferase (SCOT) deficiency or beta-ketothiolase (BKT) deficiency. MSUD and organic acidemias like propionic acidemia and isovaleric acidemia can present with high anion gap metabolic acidosis and ketonuria. Unlike other markers of metabolic stress, ketosis is clinically relevant both when increased and when absent. While a severe reduction in the excretion of ketones along with low circulating glucose levels (hypoketotic hypoglycemia) is a common finding in vomiting, anorexia, or generalized catabolic states, this pattern is also a significant indicator of a potential disorder of mitochondrial fatty acid oxidation, with or without glucose overutilization. It is important to note, however, that several mitochondrial fatty acid oxidation disorders can present with intermittent episodes of mild to severe ketonuria when the affected enzyme is distal enough in the beta-oxidation degradative pathway that long-chain fatty acid metabolism is still capable of generating some ketones, as in the case of 3-hydroxyacyl-CoA dehydrogenase (HAD) deficiency or medium-chain-acyl-CoA dehydrogenase (MCAD) deficiency, or in very-long-chain-acyl-CoA dehydrogenase (VLCAD) deficiency, where the oxidation of unsaturated fatty acids is primarily affected, while the oxidation of saturated fatty acids remains mostly intact ( 15, 33 - 36 ). Additional considerations Aside from those investigations listed above, other important initial tests include CBC, liver function tests, coagulation studies, creatine kinase levels, renal function tests, BUN, uric acid, lipid profiles and CSF cell study and CSF glucose. Non-laboratory tests can also be critical to the diagnosis of an IEM.