Organic Acidemias

Recognition and thus prompt effective management of organic acidemias is often challenging for pediatricians who have not received specialist training. Delayed diagnosis and treatment may result in significantly poorer outcomes for infants and children with organic acidemias. Pediatricians should be aware of the common presentations and clues to diagnosis, including laboratory findings on routine investigations, and should know the principles of emergency and long-term management.After completing this article, readers should be able to: Recognize important and common presenting symptoms of organic acidemias.Recognize the importance of early diagnosis and management.Recognize findings on routine laboratory investigations that should increase suspicion for organic acidemias.Recognize the importance of early and ongoing collaboration with a metabolic specialist.Understand the relevant basic metabolic investigations.Understand the principles of emergency and long-term management.Organic acidemias (OAs) are inherited disorders of protein metabolism. Most are autosomal recessive disorders caused by a deficiency of enzymes or cofactors involved in the catabolic pathways of amino acids that result in the accumulation and excretion in urine of non-amino, carboxylic OAs.Although individually OAs are rare, together they are more common, with estimates of 3.7 to 12.5 per 100,000 live births. (1)(2)Acute presentations often mimic common pediatric conditions such as sepsis and may be missed or have delayed diagnosis if clues are not actively sought. If not recognized and treated urgently, children with OAs may experience severe metabolic decompensation resulting in irreversible neurologic damage or death. It is, therefore, important for pediatricians to be aware of how OAs present and to exercise a high index of suspicion.Although OAs frequently present in the neonatal period, the initial presentation may occur at any age, often with acute decompensation precipitated by an otherwise minor illness or fasting. Typically, OAs present acutely with lethargy or encephalopathy with elevated anion gap metabolic acidosis and often hyperammonemia.Children with OAs need careful management during illnesses and perioperatively to prevent decompensation and may also develop acute or chronic complications. It is, therefore, essential for pediatricians to have knowledge of OAs and to recognize the importance of continued close collaboration with metabolic physicians.In this review we detail how OAs present, when to suspect OAs, and the principles of emergency and long-term management.The consequences of severe metabolic decompensation can be devastating. Thus, OAs are included in newborn screening (NBS) protocols in several countries with the aim of improving outcomes by diagnosing OAs and initiating management before infants present symptomatically.The Recommended Uniform Screening Panel in the United States screens for several OAs, including glutaric aciduria type 1 (GA1), isovaleric acidemia (IVA), methylmalonic acidemia (MMA), propionic acidemia (PA), and maple syrup urine disease (MSUD). There are other, very rare OAs that are not detected by NBS.Although screening programs, cutoff values, and timing vary in different jurisdictions, all involve the identification of abnormally elevated specific acylcarnitines by tandem mass spectrometry.Positive NBS requires confirmatory metabolic testing to distinguish true-positive from false-positive screening results. NBS does not detect all affected patients, and it is important to highlight that normal NBS does not definitively exclude an OA, and thus if there is clinical suspicion, appropriate investigations must be undertaken. An important example is the GA1 low excretor phenotype, for which the sensitivity of NBS has been reported to be 84% compared with almost 100% for high excretors. (3)It is also important to be aware that some severe OAs may present symptomatically before the results of NBS becoming available. (4)It is critical that pediatricians maintain a high index of suspicion for OAs. Their presentations are usually nonspecific and may be attributed to more common neonatal or pediatric conditions such as sepsis, gastroenteritis, or hypoxic ischemic encephalopathy.Approximately two-thirds of individuals with classic OAs (MMA, PA, IVA) present in the neonatal period; however, one-third with variant phenotypes present later in infancy, childhood, or even adulthood. (5)Typically, severe phenotypes present with features suggestive of early-onset neonatal metabolic intoxication. After an initial symptom-free interval, infants may develop poor feeding, lethargy or irritability, and vomiting. If not recognized early, this progresses to encephalopathy and coma, with elevated anion gap metabolic acidosis and often hyperammonemia. Encephalopathy and cerebral edema due to an elevated ammonium level, leucine in MSUD, or other neurotoxic metabolites may result in a bulging fontanelle and a mistaken diagnosis of meningitis. Children with variant phenotypes may present with similar intoxication symptoms but later in childhood.Due to respiratory compensation for metabolic acidosis, individuals with OAs may demonstrate increased respiratory effort and tachypnea. In addition, mild to moderate hyperammonemia is a respiratory stimulant, thus causing tachypnea. Other features may include temperature instability with hypothermia, abnormal tone (generalized hypotonia or central hypotonia with peripheral hypertonia), jitteriness, abnormal movements (including lip smacking and cycling or boxing movements; typical for MSUD), apneas, and seizures.A characteristic odor may occasionally provide a clue to some OAs, including the odor of sweaty feet in IVA or maple syrup/burnt sugar in MSUD, which may be smelled in the cerumen as early as 12 hours of age. (6)GA1, when not detected by NBS, typically presents in infancy with acute neurologic crises with lethargy or encephalopathy, poor feeding, hypotonia, weakness, or seizures. (7) GA1 does not present with other systemic features, hyperammonemia, or metabolic acidosis.A rare but important presentation in GA1 is progressive macrocephaly and subdural hemorrhages, therefore risking the mistaken diagnosis of nonaccidental injury. (8)Older children with OAs may have a history of recurrent episodes of vomiting (being misdiagnosed as cyclic vomiting) or recurrent episodes of ataxia, or they may present with complications such as pancreatitis, cardiomyopathy, or renal impairment. Rarely, some OAs may mimic diabetic ketoacidosis, presenting with hyperglycemia and ketoacidosis. In addition, older children or adults may present with acute episodes of behavioral change or even psychosis.The least common presentations of OAs are the chronic progressive phenotype, which can include failure to thrive, chronic vomiting, developmental delay, progressive neurologic impairment, movement disorders, or psychiatric symptoms. With these presentations, the likelihood of an underlying inborn error of metabolism (IEM) or OA is low, but suspicion should be increased with a suggestive history such as consanguinity, previously affected siblings, protein avoidance, or recurrent episodes of vomiting, encephalopathy, or acidosis.Late-onset GA1 may present with more subtle and nonspecific neurologic signs and symptoms, including headache, macrocephaly, seizures, tremor, ataxia, or peripheral neuropathy.In summary, OAs frequently masquerade as more common childhood disorders, and a high index of suspicion is required to avoid diagnostic delay and poor outcomes. An OA should be considered in any severely unwell neonate, infant, or child without an obvious cause, particularly those with encephalopathy or those not responding to initial management. Moreover, infants or children with acute encephalopathy must have IEMs, including OAs, actively sought and excluded.The diagnostic evaluation includes a complete history, physical examination, and biochemical assessment.The history and physical examination may reveal clues that are suggestive of an OA as noted previously herein and detailed in Table 1.As previously noted, OAs should be considered in any critically unwell or encephalopathic infant or child. Investigations performed routinely in critically ill patients may indicate an IEM or OA, prompting further metabolic investigation.Basic biochemical screening by the pediatrician at the time of the initial evaluation of infants or children with encephalopathy should include a blood gas (with sodium and chloride to calculate anion gap), lactate, glucose, ammonium, liver enzymes, and urine ketones.Patients with OAs with acute decompensation usually demonstrate elevated anion gap metabolic acidosis (resulting from the accumulating OAs), with or without hyperammonemia. Hyperammonemia is generally defined as an ammonium level greater than 140 µg/dL (>100 μmol/L) in neonates or greater than 70 µg/dL (>50 μmol/L) after the neonatal period. Hyperammonemia typically causes altered consciousness at levels greater than 280 µg/dL (>200 μmol/L). (9) In OAs, the hyperammonemia is a secondary effect resulting from inhibition of the urea cycle by accumulation of intermediary metabolites. (9)The accumulation of intermediary metabolites and deficiency of products in OAs also may inhibit pyruvate dehydrogenase and the tricarboxylic acid cycle, resulting in lactic acidosis. (9) In addition, patients with OAs frequently present with ketosis and ketonuria, and they may also develop hypoglycemia or hyperglycemia. Ketonuria in neonates is highly suggestive of an OA and is an important clue to diagnosis. Elevated urine ketone levels may be the only significant finding on basic biochemical analysis in MSUD, which unlike the classic OAs, frequently does not present with hyperammonemia and in which acidemia is uncommon (although there may be an elevated anion gap from the branched-chain keto acids).In contrast, in urea cycle disorders (UCDs), which are the main differential diagnosis with OAs in hyperammonemia, typically the hyperammonemia with a resulting respiratory alkalosis and an inappropriately low blood urea level are the only biochemical abnormalities on routine investigations. Although the degree of hyperammonemia is not diagnostic, ammonium levels greater than 1,400 µg/dL (>1,000 μmol/L) are more likely to be seen in patients with UCDs; however, patients with OAs occasionally present with an ammonium level greater than 1,400 µg/dL (>1,000 μmol/L), but this is usually in the context of other laboratory abnormalities as noted previously herein (Table 2).In addition, in patients with OAs the complete blood cell count may demonstrate neutropenia and thrombocytopenia, reflecting bone marrow suppression resulting from the toxic effect of metabolite accumulation. Macrocytic anemia may suggest vitamin B12 deficiency or an IEM of intracellular cobalamin metabolism.Although most patients with OAs will have suspicious findings on routine investigations, some, such as those with GA1, may not; thus, even in the absence of laboratory abnormalities, the clinical findings may still warrant metabolic investigations.When suspicion of an OA or an IEM arises, more specific metabolic investigations should be considered after discussion with a metabolic specialist.Metabolic investigations include the following: Urine OA (UOA) analysis: Demonstrates key diagnostic abnormal OAs.Acylcarnitine profile (ACP): Identifies elevations in specific acylcarnitine species that may be diagnostic for OAs or fatty acid oxidation disorders (FAODs).Free and total carnitine: A reduced free carnitine fraction suggests conjugation of carnitine with toxic metabolites and increases suspicion of OAs or FAODs.Plasma amino acid (PAA) analysis: Diagnostic with elevations of branched-chain amino acids (BCAAs) and pathognomonic alloisoleucine in MSUD, and aids in the diagnosis of UCDs in patients with hyperammonemia. The glutamine level can also help differentiate between an OA and a UCD, with raised glutamine levels in UCDs, whereas the glutamine level tends to be normal or low normal in patients with OAs. The glycine level may be elevated in those with PA or MMA.Note that between episodes of metabolic crisis, UOA analysis and the ACP may not be diagnostic. Thus, for indications such as cyclic vomiting, samples should also be collected at the time of acute symptomatic presentation.The metabolic specialist may suggest additional investigations, such as urine orotic acid or homocysteine. Although approximately 60% of MMA is caused by deficiency of methylmalonyl-CoA mutase, a vitamin B12 (cobalamin)–dependent enzyme, note that rarer disorders of vitamin B12 transport or metabolism account for the remainder. (10) In combined disorders of cobalamin metabolism, the coenzyme of methionine synthase, methylcobalamin, is also affected, which results in an elevated homocysteine level in addition to MMA. Thus, homocysteine and B12 levels should always be measured in patients with elevated methylmalonic acid levels. Vitamin B12 deficiency should also be considered in the differential diagnosis of MMA, particularly in the setting of the breastfed infant of the vegetarian, vegan, or B12-deficient mother.The Figure shows the more common OAs caused by defects in the BCAA catabolic pathway and the principal diagnostic metabolites found on the ACP, PAA, and UOA investigations.GA1, not illustrated in the Figure, results from deficiency of glutaryl-CoA dehydrogenase, which disrupts lysine and tryptophan metabolism, resulting in the accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid, seen on UOA analysis, and elevated glutarylcarnitine on the ACP.Directed by the specific biochemical findings, the metabolic specialist may recommend molecular genetic testing (either a gene panel or sequencing of a specific gene). In some disorders there are genotype-phenotype correlations that may inform prognosis. A genetic diagnosis is important not only for treatment and prognosis but also because it may allow carrier detection and potential prenatal diagnosis.Emergency management should be started by the pediatrician as soon as hyperammonemia or a suspected OA has been identified and should not await diagnostic biochemical testing to be completed. Hyperammonemia is life-threatening and has significant associated mortality and neurodevelopmental morbidity. Poorer outcomes are seen in patients with peak ammonium levels greater than 1,400 µg/dL (>1,000 μmol/L), more than 3 days in a hyperammonemic coma, and evidence of raised intracranial pressure. (11)Early discussion with a metabolic center is critical, and urgent transfer to a unit with pediatric intensive care, hemodialysis capabilities, and metabolic expertise may be necessary.The following outlines the emergency management of an infant or child with a suspected OA. The initial 3 steps should be commenced immediately by the pediatric team in an acutely unwell, encephalopathic, or hyperammonemic infant or child when there is suspicion of an IEM, and metabolic specialist advice should be sought urgently without awaiting results of basic metabolic investigations.Treat the triggering illness (fever, infection, injury).Stop protein intake: Stop exogenous dietary protein or total parenteral nutrition.Decrease catabolism and promote anabolism: Provide a glucose infusion rate (GIR) sufficient to promote anabolism (neonate: 8–10 mg/kg per min). (12)If hyperglycemia ensues, an insulin infusion may be carefully started to further promote anabolism. Do not reduce the GIR. Careful monitoring of glucose, acid base, and lactate levels is important.Support anabolism with a lipid infusion once a FAOD is excluded.Management of hyperammonemia: Repeat level immediately with free-flowing sample sent on ice.Consider treatment with intravenous nitrogen scavengers (sodium benzoate or sodium phenylacetate/phenylbutyrate or combined as Ammonul® [Medicis Pharmaceutical Corp, Scottsdale, AZ]), given as an initial bolus followed by maintenance infusion. These remove ammonium by conjugation of benzoate with glycine to produce hippurate, and phenylacetate with glutamine to produce phenylacetylglutamine, which are then excreted in the urine. (12)Once an OA is confirmed, phenylbutyrate should be discontinued due to its mechanism of action through conjugating of ammonium with glutamine, which will further reduce glutamine concentration. (12)In undiagnosed significant hyperammonemia, intravenous arginine, which enhances the urea cycle, should also be considered. If an OA is confirmed, arginine can be discontinued. (12)If an OA is suspected, consider oral carglumic acid, a synthetic analogue of N-acetylglutamate, which activates the first step of the urea cycle. (12)If the ammonium level is greater than 700 µg/dL (>500 μmol/L), or not responding to medical management with a rapid decrease within 4 to 6 hours, then hemodialysis/hemofiltration should be commenced. Adults and older children have a greater risk of severe cerebral edema, so dialysis may need to be commenced at lower ammonium levels.If the ammonium level persists at greater than 1,400 µg/dL (>1,000 μmol/L), redirection of care may be considered in discussion with the metabolic specialist and the parents.If an OA is suspected or in undiagnosed hyperammonemia, intravenous l-carnitine is given to improve conjugation of toxic intermediates (once a FAOD is excluded). (12)Correction of acidosis:a. If significant acidosis and not responding to reversal of catabolism, the acidemia may be corrected cautiously with intravenous sodium bicarbonate.Management of hyperleucinosis (MSUD): The principal metabolites thought to be responsible for neurotoxicity in MSUD are leucine and 2-keto-isocaproic acid. Elevated leucine is associated with risk of cerebral edema. Infants or children with severe leucine encephalopathy may need dialysis.Trial of vitamins or cofactors: Occasionally IEMs and OAs may be vitamin or cofactor responsive (biotin, thiamine, riboflavin, vitamin B12, vitamin B6). In the severely affected patient, it is generally safe to initiate a trial in discussion with a metabolic specialist. Only rarely should a “cocktail” of vitamins, as opposed to a targeted trial, need to be started without a presumptive diagnosis or confirmed biochemical diagnosis.Hyperammonemia, hyperleucinosis, and severe acidosis increase the risk of cerebral edema, so neurologic status must be monitored closely.The long-term care of children with OAs will involve a metabolic specialist, a metabolic dietitian, a pediatrician, and other specialists where appropriate. The metabolic specialist and dietitian should supervise the ongoing care of all children with OAs, but the division of follow-up and monitoring will depend on several factors, including local resources, disease severity, and proximity to health-care facilities.General long-term management principles for OAs include the following: Dietary restriction of precursor amino acids:The primary management is to reduce the intake of the precursor amino acids proximal to the metabolic block (isoleucine, valine, methionine, threonine in MMA and PA, leucine in severe cases of IVA, BCAA in MSUD, lysine and tryptophan in GA1). This is achieved by restricting natural protein intake while supplying sufficient nutrients for growth, development and prevention of catabolism by supplementing with a medical formula free of the specific amino acids. Monitoring of PAA is important, along with regular dietary assessment to ensure nutritional sufficiency.Medications: Supplementation with oral l-carnitine in MMA, PA, IVA, and GA1 should be provided to conjugate with and reduce toxic metabolites. Carnitine supplementation is not given in MSUD.Oral glycine may also be provided in IVA to conjugate with and reduce toxic metabolites.In MMA and PA, intermittent oral metronidazole may help reduce the production of propionate by intestinal bacteria.Vitamins and cofactors: Some OAs may be responsive to cofactors or vitamins. Some individuals with MMA are responsive to cobalamin (vitamin B12), and all individuals diagnosed as having MMA should have an initial trial of B12 and if responsive require supplementation. Some individuals with MSUD are thiamine responsive.Monitoring: Regular follow-up is important to monitor metabolic control, growth, development, and nutritional sufficiency and to screen for potential complications.See Table 3 for the management and complications of the more common OA disorders.For all OAs, prompt management of intercurrent illness and catabolic stress is essential to prevent metabolic decompensation. Metabolic decompensations may be precipitated by inadequate adherence to medical management (diet, medical foods, medication) or by catabolic stress (illness, vaccinations, fasting, trauma, medications such as chemotherapy or corticosteroids, surgery). Aggressive illness management is particularly vital in children younger than 2 years with GA1 due to the high risk of neurologic crisis and damage with febrile illnesses.It may be possible to manage mild intercurrent illness at home through stopping protein intake, giving regimens that provide carbohydrates and sufficient calories to meet increased energy requirements, and giving antipyretics to manage fever.The primary metabolic team should provide all caregivers with written illness management instructions to assist them in providing appropriate care at home, in addition to contact details for an on-call metabolic team to supervise any home illness management, and criteria for when to attend the hospital.If enteral home illness management is not tolerated or is prolonged or the child is particularly unwell or has neurologic signs, hospital attendance is required. In addition to the home illness management letter, the metabolic team should provide parents with an emergency letter to present to any treating physician or emergency department. This letter should detail initial management when the child presents unwell or not tolerating enteral illness management, including required blood work and investigations, type and volume of intravenous fluids, and medication plan, in addition to the contact details for the metabolic team.The metabolic team should be advised of any acute admissions as well as any admissions or that may require so that a management can be to reduce the risk of metabolic management should always include early discussion with a metabolic specialist and of the following assessment with intravenous and blood work to include glucose, lactate, ammonium, complete blood cell urine consider and additional investigations by the any illness or protein catabolism with intravenous providing monitoring of neurologic lipid of hyperammonemia if significant or not responsive to the previously with carglumic acid or intravenous nitrogen scavengers (sodium as by a metabolic l-carnitine in may be increased as by a metabolic specialist during oral glycine in IVA is intravenous of acidosis if required significant acidosis and to the previously should be within hours to catabolism of individuals with recurrent severe decompensations or poor metabolic control, liver (MMA, PA, or combined liver and may be considered. does not the OAs but may improve control, reduce the risk for and of decompensation to be and improve of There including renal and neurologic complications (MMA, has been to improve in patients with In MSUD, liver usually branched-chain dehydrogenase to allow normal protein intake and significantly reduce the risk of hyperleucinosis at of however, during of catabolic stress there a risk of metabolic decompensation and complications include and failure to (MMA, complications are common, particularly in MMA and PA, and include developmental delay, seizures, movement disorders, and metabolic in MMA has been to be in patients identified by NBS, to of children with GA1 not treated with and emergency management during intercurrent illness an acute encephalopathic crisis, usually within the first 2 years of The of this metabolic decompensation is with movement disorders, significant and The of neurologic decompensations and movement disorders has reduced after NBS to to with dietary management and illness management. progressive neurologic have been reported in to with important complications in OAs include renal failure (MMA), and and in MMA of and have the importance of biochemical and monitoring of liver are rare disorders that require a high index of suspicion to and effective treatment is essential to neurologic and death. there is suspicion of an IEM, or when is it is essential that a metabolic specialist advice to the care of children with OAs or other

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