989CHAPTER 81 Inborn Errors of Metabolism complex molecules in the heart, as occurs in the hypertrophic cardiomyopathy of mucopolysaccharidoses, such as Hurler syn drome Cardiomyopathy occurs as the s[.]
CHAPTER 81 Inborn Errors of Metabolism complex molecules in the heart, as occurs in the hypertrophic cardiomyopathy of mucopolysaccharidoses, such as Hurler syndrome Cardiomyopathy occurs as the sole initial clinical manifestation in a relatively restricted list of metabolic diseases, including autosomal recessively inherited deficiency of the cellular carnitine transporter, fatty acid oxidation disorders, glycogenosis types II and IX, and disorders of oxidative phosphorylation The carnitine transporter defect is caused by deficiency of the sodium-dependent transporter OCTN2, which is responsible for transporting carnitine from the circulation into tissues, including cardiac and skeletal muscle.27 Dilated cardiomyopathy with symptoms of heart failure generally presents within the first years of life and is associated with severely low plasma total carnitine levels Cardiac function improves dramatically after carnitine supplementation, and cardiomyopathy rarely recurs if carnitine is continued Hypertrophic cardiomyopathy resulting from myocardial steatosis may be an isolated presenting feature in several disorders of fatty acid oxidation, particularly those affecting long-chain fatty acid metabolism such as VLCAD or mitochondrial trifunctional protein deficiencies Saudubray and colleagues28 examined a series of 107 patients with fatty acid oxidation defects and found that cardiac involvement, including hypertrophic cardiomyopathy or arrhythmia, was apparent at presentation in 51% of cases Fatty acid oxidation disorders are most reliably detected by analysis of plasma acylcarnitine profiles by tandem mass spectrometry Longchain fatty acids are activated to CoA derivatives and then esterified to carnitine prior to transport into mitochondria for b-oxidation In fatty acid oxidation disorders, especially during acute metabolic decompensation, acylcarnitine species accumulate in plasma and provide a diagnostic profile that is specific to a given enzyme deficiency Confirmation of the diagnosis requires molecular DNA analysis of a panel of fatty acid oxidation genes Once the diagnosis of a long-chain fatty acid oxidation disorder has been established, restriction of dietary long-chain fat intake and provision of medium-chain triglyceride (MCT) oil as an alternative fuel source for the myocardium often reverses cardiomyopathy Cardiac support measures, including extracorporeal membrane oxygenation, may be necessary for as long as to weeks after presentation before heart function improves Feeding with triheptanoin, a triglyceride containing odd-chain seven carbon long fatty acids, was associated with some improvement in cardiac function over standard MCT oil feeding in a recent controlled clinical trial in adults with long-chain fatty acid oxidation disorders.29 Glycogen storage disease type II (acid a-glucosidase deficiency; Pompe disease) is a disorder of lysosomal glycogen accumulation that frequently presents as hypertrophic cardiomyopathy, yielding the classic boot-shaped radiographic appearance of the cardiac silhouette Skeletal myopathy manifesting as severe hypotonia may complicate the presentation Confirmation of the diagnosis requires measurement of enzyme activity in skeletal or cardiac muscle or cultured fibroblasts In the past, treatment has been supportive only, but enzyme replacement therapy is now the standard of care Intravenous infusion of recombinant acid a-glucosidase every other week has led to improved cardiac function, neuromuscular development, and survival in infants with Pompe disease.30 Several states have initiated newborn screening for Pompe disease in order to detect symptomatic infants and initiate enzyme replacement as early as possible However, antibody formation against the drug in some infants with subsequently decreased treatment effectiveness remains a clinical problem The cross-reactive immunologic material status of the infant needs to be determined 989 prior to starting enzyme replacement to predict which infant will develop neutralizing antibodies Myocardial function is highly dependent on mitochondrial oxidative phosphorylation; up to 30% of the total myocardial volume is composed of mitochondria.31 Dilated or hypertrophic cardiomyopathy is a frequent presenting feature in infants with severe defects of mitochondrial oxidative phosphorylation Skeletal muscle myopathy, liver dysfunction, renal tubulopathy, bone marrow failure, or CNS abnormalities may occur Chronic lactic acidosis, if present, is an important indicator of mitochondrial dysfunction Screening metabolic laboratory studies demonstrate nonspecific abnormalities associated with chronic lactic acidosis Definitive diagnosis requires histologic evaluation of skeletal muscle with measurement of respiratory chain enzyme activities followed by molecular DNA analysis of a panel of both nuclear and mitochondrial genes associated with respiratory chain deficiency Isolated deficiency of cytochrome C oxidase (COX or complex IV) and reduced nicotinamide adenine dinucleotide (NADH)-ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain are the most common oxidative phosphorylation defects presenting with cardiomyopathy Although some protein subunits of complexes I and IV are encoded by mtDNA, most infant-onset isolated complex deficiencies probably are the result of autosomal recessively inherited deficiency of nuclear-encoded respiratory chain subunits or of chaperone proteins that ensure proper assembly of functional complexes For instance, hypertrophic cardiomyopathy caused by functional COX deficiency has been associated with mutations in nuclear COX subunit genes32,33 or nuclear genes for COX-associated proteins SCO1 and SCO2.34 Cardiomyopathy may be seen in several other IEMs However, in these disorders, other physical or biochemical features are generally apparent at initial clinical presentation For instance, dilated cardiomyopathy may complicate propionic acidemia during acute metabolic decompensation, but features of severe metabolic acidosis, vomiting, dehydration, coma, and possibly hyperammonemia are part of the initial clinical presentation Metabolic Myopathies and Rhabdomyolysis Rhabdomyolysis is a clinical syndrome resulting from skeletal muscle injury and release of potentially toxic substances into the circulatory system Acute onset of severe muscle pain associated with increased serum CK levels is the hallmark of the disorder In extreme cases, massive myoglobinuria may cause acute renal insufficiency Although trauma and direct muscle injury are by far the most common causes of rhabdomyolysis, inborn errors of muscle metabolism should be considered in the differential diagnosis of rhabdomyolysis occurring at any age In the absence of a history of trauma, the differential diagnosis of acute rhabdomyolysis should include drug or toxin exposure, muscle hypoxia (often associated with seizures), temperature alterations, inflammatory diseases, and IEMs Because muscle contraction depends on adenosine triphosphate (ATP) generated by the mitochondrial electron transport chain, it follows that any process that impairs muscle ATP synthesis or that results in energy expenditure that surpasses ATP production could lead to rhabdomyolysis The clinical history should lead to the appropriate diagnosis A family history that includes rhabdomyolysis or a history in which more than one episode of exercise-induced rhabdomyolysis has been observed should induce suspicion of a metabolic disorder Along with muscular dystrophy and endocrine etiologies (hypothyroidism, 990 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine hyperthyroidism, diabetic ketoacidosis, pheochromocytoma), glycolytic defects, fatty acid oxidation disorders, purine biosynthetic disorders, and disorders of mitochondrial oxidative phosphorylation should be considered if historical elements not point to the more common etiologies As described previously, the fatty acid oxidation disorders can be detected by urine organic acid analysis and plasma acylcarnitine profile Chronic lactic acidosis may be a clue to a disorder of oxidative phosphorylation Measurement of blood lactate level before and after an exercise treadmill protocol may help detect a respiratory chain defect if the postexercise lactate level is severely elevated Definitive diagnosis of a mitochondrial disorder requires histologic and enzymatic analysis of a fresh muscle biopsy The glycolytic defects of phosphofructokinase and phosphoglycerate mutase deficiencies along with myophosphorylase deficiency (glycogen storage disease type V or McArdle disease) cause severe recurrent rhabdomyolysis; their detection requires enzymatic analysis of muscle tissue Likewise, myoadenylate deaminase deficiency, a defect in purine catabolism, and CPT-II deficiency are also diagnosed by measurement of the enzyme activities in muscle All of these diagnoses may be confirmed by molecular DNA analysis of the associated genes Neonatal Screening Newborn screening for IEMs was first introduced in the 1960s, with screening for phenylketonuria Technologic advances, most significantly the introduction of tandem mass spectrometry for mass screening, have greatly increased the number of disorders that can be identified by analysis of a dried blood spot on a filter paper card.35 An expert review conducted in 2006 by the American College of Medical Genetics led to the recommendation that 29 core conditions—including several aminoacidopathies, fatty acid oxidation defects, and organic acidurias detectable by tandem mass spectrometry—should be included in the panel of disorders screened.36 Currently, the federal Advisory Committee on Heritable Disorders in Newborns and Children provides recommendations to the US Secretary of Health and Human Services, on the basis of available evidence, regarding which disorders should be included in newborn screening programs Their recommendations are published as part of the Recommended Uniform Screening Panel (RUSP; www.hrsa.gov/advisory-committees/ heritable-disorders/rusp/index.html) However, newborn screening continues to be executed at the state level; each state must individually decide whether and how to adopt the recommendations of the RUSP Screening for the lysosomal storage disorders Pompe disease and Hurler disease was added to the RUSP in 2019 because of clear evidence for the benefits of early detection and treatment However, implementation of screening for these disorders is not yet uniform across all states The cost versus benefits of expanded screening, whether to include specific rare or poorly treatable disorders in the screening panel, and the availability of adequate follow-up resources continue to be debated However, a general consensus has emerged that expanded newborn screening is an effective tool for identifying IEM early in life, allowing for the initiation of therapy, often before the infant becomes symptomatic, and allowing for prevention of morbidity and mortality associated with IEMs.37 It must be remembered, though, that newborn screening is just that—a screen—and both false-positive and false-negative results are possible Thus, the astute clinician must remain cognizant of the fact that in an ill infant, a normal newborn screen is reassuring but should not be taken as absolute proof positive that an IEM identifiable on newborn screening is not present Appropriate screening laboratory evaluation and emergency treatment should be instituted if clinical signs and symptoms of an IEM are present in a sick child Conclusions IEMs are individually rare but collectively will make not infrequent appearances in a busy pediatric intensive care unit The signs and symptoms of IEMs may be nonspecific and often overlap extensively with more common disorders When clinical suspicion of an IEM arises, screening biochemical genetic laboratory studies must be ordered Further confirmatory testing often is necessary if screening laboratory tests point to a specific disease Confirmatory testing and disease-specific therapy should be instituted following consultation with a biochemical genetics specialist If detected and treated early, the clinical outcome for many IEMs can be favorable Key References Fearing MK, Marsden D Expanded newborn screening Pediatr Ann 2003;32:509-515 Gilbert-Barness E, Barness LA, Farrell PM Metabolic Diseases: Foundations of Clinical Management, Genetics, and Pathology 2nd ed Amsterdam: IOS Press; 2017 Hoffmann GF, Zschocke J, Nyhan WL Inherited Metabolic Diseases: A Clinical Approach 2nd ed Heidelberg: Springer; 2017 LaFranchi S Hypoglycemia of infancy and childhood Pediatr Clin North Am 1987;34:961-982 Saudubray JM, Narcy C, Lyonnet L, et al Clinical approach to inherited metabolic disorders in neonates Biol Neonate 1990;58(suppl 1):44-53 Stark Z, Tan TY, Chong B, et al A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders Genet Med 2016;18:10901096 The full reference list for this chapter is available at ExpertConsult.com e1 References Eisensmith RC, Woo SL Population genetics of phenylketonuria Acta Paediatr Suppl 1994;407:19-26 Hoffmann GF, von Kries R, Klose D, et al Frequencies of inherited organic acidurias and disorders of mitochondrial fatty acid transport and oxidation in Germany Eur J Pediatr 2004;163:76-80 Hoffmann GF, Zschocke J, Nyhan WL Inherited Metabolic Diseases: A Clinical Approach 2nd ed Heidelberg: Springer; 2017 Gilbert-Barness E, Barness LA, Farrell PM Metabolic Diseases: Foundations of Clinical Management, Genetics, and Pathology 2nd ed Amsterdam: IOS Press; 2017 Phenylketonuria: screening and management NIH Consens Statement 2000;17:1-27 Baumgartner ER, Suormala T Multiple carboxylase deficiency: inherited and acquired disorders of biotin metabolism Int J Vitam Nutr Res 1997;67:377-384 Russo PA, Mitchell GA, Tanguay RM Tyrosinemia: a review Pediatr Dev Pathol 2001;4:212-221 Stark Z, Tan TY, Chong B, et al A prospective evaluation of wholeexome sequencing as a first-tier molecular test in infants with suspected monogenic disorders Genet Med 2016;18:1090-1096 Saudubray JM, Narcy C, Lyonnet L, et al Clinical approach to inherited metabolic disorders in neonates Biol Neonate 1990;58(suppl 1): 44-53 10 Hayasaka K, Tada K, Fueki N, et al Nonketotic hyperglycinemia: analyses of glycine cleavage system in typical and atypical cases J Pediatr 1987;110:873-877 11 Gallagher RC, Van Hove JL, Scharer G, et al Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy Ann Neurol 2009;65:550-556 12 Marquardt T, Denecke J Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies Eur J Pediatr 2003;162:359-379 13 Opitz JM, Gilbert-Barness E, Ackerman J, Lowichik A Cholesterol and development: the RSH (“Smith-Lemli-Opitz”) syndrome and related conditions Pediatr Pathol Mol Med 2002;21:153-181 14 Millington DS, Kodo N, Norwood DL, Roe CR Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism J Inherit Metab Dis 1990;13:321-324 15 Yokota I, Indo Y, Coates PM, Tanaka K Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency An A to G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation J Clin Invest 1990;86:1000-1003 16 Sims HF, Brackett JC, Powell CK, et al The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy Proc Natl Acad Sci U S A 1995;92:841-845 17 Morton DH, Strauss KA, Robinson DL, et al Diagnosis and treatment of maple syrup disease: a study of 36 patients Pediatrics 2002;109:999-1008 18 Grompe M The pathophysiology and treatment of hereditary tyrosinemia type Semin Liver Dis 2001;21:563-571 19 Luijerink MC, Jacobs SM, van Beurden EA, et al Extensive changes in liver gene expression induced by hereditary tyrosinemia type I are not normalized by treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)1,3-cyclohexanedione (NTBC) J Hepatol 2003;39:901-909 20 LaFranchi S Hypoglycemia of infancy and childhood Pediatr Clin North Am 1987;34:961-982 21 Lteif AN, Schwenk WF Hypoglycemia in infants and children Endocrinol Metab Clin North Am 1999;28:619-646, vii 22 de Lonlay P, Giurgea I, Touati G, Saudubray JM Neonatal hypoglycaemia: aetiologies Semin Neonatol 2004;9:49-58 23 Stanley CA Hyperinsulinism in infants and children Pediatr Clin North Am 1997;44:363-374 24 Lipshultz SE, Sleeper LA, Towbin JA, et al The incidence of pediatric cardiomyopathy in two regions of the United States N Engl J Med 2003;348:1647-1655 25 Bonnet D, de Lonlay P, Gautier I, et al Efficiency of metabolic screening in childhood cardiomyopathies Eur Heart J 1998;19: 790-793 26 Ackerman MJ, VanDriest SL, Ommen SR, et al Prevalence and agedependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective J Am Coll Cardiol 2002;39: 2042-2048 27 Nezu J, Tamai I, Oku A, et al Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter Nat Genet 1999;21:91-94 28 Saudubray JM, Martin D, de Lonlay P, et al Recognition and management of fatty acid oxidation defects: a series of 107 patients J Inherit Metab Dis 1999;22:488-502 29 Gillingham MB, Heitner SB, Martin J, et al Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a doubleblinded, randomized controlled trial J Inherit Metab Dis 2017; 40:831-843 30 Nicolino M, Byrne B, Wraith JE, et al Clinical outcomes after longterm treatment with alglucosidase alfa in infants and children with advanced Pompe disease Genet Med 2009;11(3):210-219 31 Page E, Polimeni PI, Zak R, et al Myofibrillar mass in rat and rabbit heart muscle Correlation of microchemical and stereological measurements in normal and hypertrophic hearts Circ Res 1972;30: 430-439 32 Antonicka H, Leary SC, Guercin GH, et al Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency Hum Mol Genet 2003;12:2693-2702 33 Antonicka H, Mattman A, Carlson CG, et al Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy Am J Hum Genet 2003;72:101-114 34 Leary SC, Kaufman BA, Pellecchia G, et al Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase Hum Mol Genet 2004;13:1839-1848 35 Schulze A, Lindner M, Kohlmuller D, et al Expanded newborn screening for inborn errors of metabolism by electrospray ionizationtandem mass spectrometry: results, outcome, and implications Pediatrics 2003;111(6 Pt 1):1399-1406 36 Newborn screening toward a uniform screening panel and system, Genet Med 2006;8(suppl 1):1S-252S 37 Fearing MK, Marsden D Expanded newborn screening Pediatr Ann 2003;32:509-515 e2 Abstract: Inborn errors of metabolism, although individually rare, are not infrequent visitors to a busy pediatric intensive care unit This chapter presents a general approach to the clinical suspicion, differential diagnosis, emergency intervention, and definitive treatment of inborn errors of metabolism using neonatal onset disorders as a paradigm Diagnostic and treatment approaches to specific clinical scenarios—including metabolic acidosis, hypoglycemia, cardiomyopathy, and recurrent rhabdomyolysis—are discussed Key words: inborn errors of metabolism, hypoglycemia, metabolic acidosis, lactic acidosis, cardiomyopathy, rhabdomyolysis, coma, aminoacidopathy, organic acidemia 82 Progress Towards Precision Medicine in Critical Illness MARY K DAHMER AND MICHAEL W QUASNEY PEARLS • The goal of precision medicine in the context of critical care is for treatment strategies to be developed that take into account the variability seen between individuals • Heterogeneity in the groups of patients with conditions seen most often in the intensive care unit (sepsis and acute respiratory distress syndrome) may explain the lack of significant progress in treatment of such syndromes • Studies related to genetics, transcriptomics, and plasma biomarkers have been used to begin to understand the heterogeneity in patients with sepsis or acute respiratory distress syndrome and to identify subgroups with common characteristics • Thus far, both studies using transcriptomic approaches and those using novel analytic approaches to serum biomarkers suggest that patients with septic shock and acute respiratory distress syndrome can be separated into at least two subgroups distinguished in part by characteristics of their immune response In 2015, the National Institutes of Health launched a Precision Medicine Initiative with the goal that both prevention and treatment strategies in medicine move toward an approach that takes into account the variability observed between individuals.1 To date, this has been used most successfully in the field of cancer, which has used genetics and transcriptomics to examine heterogeneity within cancer types and to identify subtypes based on specific molecular signatures Such studies have resulted in targeted treatments based on the underlying pathophysiology seen within a cancer subtype Although there is significant heterogeneity in many of the conditions seen in both pediatric and adult intensive care units (ICUs), studies are just beginning to address this heterogeneity by identifying subgroups at highest risk of poor outcome (prognostic enrichment) or subgroups with common underlying pathophysiology that may be more likely to benefit from a specific treatment (predictive enrichment) Two of the most common causes of admissions to ICUs are sepsis and acute respiratory distress syndrome (ARDS), two conditions known to have significant heterogeneity both in underlying triggers and in response to treatment Why one individual responds to treatment and another progresses to severe illness and even death is unclear This variability in response to treatment is thought to be due, at least in part, to the heterogeneity within these conditions In addition, the failure of many of the treatments tested in the last 20 years has been attributed, in part, to heterogeneity among these patients Simulation models indicate that heterogeneity in cohorts of patients with acute respiratory failure can significantly impact clinical trial results by showing no benefit for the entire cohort, although a high-risk subgroup of patients may actually benefit, or by showing benefit for the entire cohort, though a subgroup of patients may incur harm.2 The recent consensus in the field is that strategies aimed at prognostic and/or predictive enrichment should be leveraged in research related to critical illnesses to identify subgroups at highest risk and/ or distinguished by differences in the underlying pathophysiology to identify targeted therapies with a higher likelihood of reducing morbidity and mortality.3 This chapter will discuss results of studies related to genetic variation, gene expression, and plasma biomarkers designed to begin to address the heterogeneity seen in patients with sepsis and ARDS Genetic Variation and Critical Illness When contemplating the great diversity among humans, it is somewhat surprising to realize that the deoxyribonucleic acid (DNA) of two unrelated humans is more than 99.9% identical Although the vast majority of nuclear DNA is identical from one person to the next, a small fraction of DNA sequence (,0.1%) varies among individuals and is responsible for the genetically determined variation in our physical characteristics and physiology Genetic variability also appears to be involved with susceptibility to some diseases, therapeutic responses to treatment, and disease outcomes The sequencing of the human genome and advent of highthroughput sequencing and genotyping technologies have revolutionized the understanding of gene structure and genetic variation Many genes are polymorphic; that is, there are small differences (variations) in DNA sequence between individuals Single-nucleotide 991 ... between individuals.1 To date, this has been used most successfully in the field of cancer, which has used genetics and transcriptomics to examine heterogeneity within cancer types and to identify... to severe illness and even death is unclear This variability in response to treatment is thought to be due, at least in part, to the heterogeneity within these conditions In addition, the failure... Bonnet D, de Lonlay P, Gautier I, et al Efficiency of metabolic screening in childhood cardiomyopathies Eur Heart J 1998;19: 790-793 26 Ackerman MJ, VanDriest SL, Ommen SR, et al Prevalence and