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Organic acidemias: An overview and specific defects

Organic acidemias: An overview and specific defects
Author:
Olaf A Bodamer, MD, PhD, FAAP, FACMG
Section Editors:
Sihoun Hahn, MD, PhD
Marc C Patterson, MD, FRACP
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Jun 2022. | This topic last updated: Jan 11, 2022.

INTRODUCTION — Organic acidemias, also known as organic acidurias, are a class of inborn errors of metabolism characterized by accumulation of abnormal (and usually toxic) organic acid metabolites and increased excretion of organic acids in urine. They result primarily from deficiencies of specific enzymes in the breakdown pathways of amino acids. Most organic acidemias become clinically apparent during the newborn period or early infancy, although there are milder forms that may not present until adolescence or adulthood or not come to medical attention at all. After an initial period of well-being, affected children develop a life-threatening episode of metabolic acidosis characterized by an increased anion gap. This presenting episode may often be mistaken for sepsis and, if unrecognized, is associated with significant mortality. Metabolic decompensation can occur during episodes of increased catabolism, such as intercurrent illness, trauma, surgery, or prolonged episodes of fasting.

This topic gives an overview of the clinical presentation, diagnosis, and management of organic acidemias. The more prevalent organic acidemias are also reviewed in detail here, including propionic acidemia (PA), isovaleric acidemia (IVA), 3-methylcrotonylglycinuria (3-MCG), 3-methylglutaconic aciduria (3-MGA), and glutaric acidemia type 1 (GA1). Methylmalonic acidemia (MMA) is reviewed in detail separately. (See "Methylmalonic acidemia".)

The broader category of inborn errors of metabolism is also reviewed in detail in several separate topics:

(See "Inborn errors of metabolism: Classification".)

(See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features".)

(See "Inborn errors of metabolism: Identifying the specific disorder".)

(See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

CLASSIFICATION — Organic acidemias can be classified as follows [1-3]:

Branched-chain organic acidemias, including methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (IVA), 3-methylcrotonylglycinuria (3-MCG), and 3-methylglutaconic aciduria (3-MGA) (figure 1 and figure 2)

Multiple carboxylase deficiency (inborn errors of biotin metabolism), including holocarboxylase synthetase deficiency and biotinidase deficiency (see "Overview of the hereditary ataxias", section on 'Disorders of pyruvate and lactate metabolism')

Cerebral organic acidemias, including glutaric acidemia type 1 (GA1), aspartoacylase deficiency (Canavan disease), and 4-hydroxybutyric aciduria

CLINICAL PRESENTATION — Patients with organic acidemia, with some exceptions, most notably the most common, clinically relevant organic acidemias such as glutaric acidemia type 1 (GA1) and 3-methylcrotonylglycinuria (3-MCG), typically present during the first one to two weeks after birth with poor feeding, vomiting, floppiness, muscular hypotonia, and increasing lethargy that progresses to coma. Expanded newborn screening (NBS) by tandem mass spectrometry (MS/MS) in the United States, Australia, Europe, and Asia identifies organic acidemias in affected newborn infants within the first week of life [4]. The advent of NBS has led to a significant reduction of symptomatic newborn infants with organic acidemias through early diagnosis and timely initiation of treatment and management [3]. Mothers affected with GA1 and 3-MCG respectively have been identified coincidentally [5,6].

The initial presentation in older infants, children, and even adults is variable but also can include lethargy, vomiting, failure to thrive (FTT), encephalopathy, or seizures. Older patients usually present with acute decompensation associated with increased catabolism due to an intercurrent illness or other factors that result in severe metabolic acidosis, hyperammonemia, and ketosis. Pancytopenia may develop during propionic acidemia (PA) or methylmalonic acidemia (MMA) metabolic crises and typically resolves after the metabolic state normalizes [7]. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

INITIAL EVALUATION — The initial evaluation of an infant with suspected organic acidemia includes measurement of pH, carbon dioxide tension, bicarbonate, ammonia, lactate, pyruvate, glucose, electrolytes, creatinine, urea, and ketones. Infants typically have severe metabolic acidosis with an increased anion gap, ketosis, and hyperammonemia. Other common findings include hypoglycemia and electrolyte and other abnormalities associated with volume depletion. A complete blood count and differential are performed to detect neutropenia, thrombocytopenia, or pancytopenia, which occur frequently because of bone marrow suppression [8]. (See "Approach to hypoglycemia in infants and children" and "Approach to the child with metabolic acidosis" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Initial evaluation' and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Evaluation of specific critical presentations' and "Inborn errors of metabolism: Identifying the specific disorder".)

Pregnancy and perinatal history frequently are uncomplicated. Family history may reveal consanguinity and/or siblings who died during the neonatal period [7,9]. Some organic acidemias may present with a characteristic odor secondary to metabolite accumulation (table 1).

DIAGNOSIS — The diagnosis should be suspected in patients who present with lethargy, vomiting, poor feeding, failure to thrive (FTT), hypotonia, or seizures in the first couple weeks of life or in association with an intercurrent illness in older patients. Specific organic acidemias are suggested by measurement of organic acids solely in urine by gas chromatograph-mass spectrometry (GC-MS) or tandem mass spectrometry (MS/MS) and confirmed by molecular testing that identifies compound heterozygous or homozygous pathogenic variants in the respective disease gene [3,4]. Additional studies, including analysis of enzyme activities in lymphoblasts or fibroblasts, are only used on a case-by-case basis. The specific profile seen in each organic acidemia is discussed in the disease-specific sections below.

Prenatal diagnosis or preimplantation diagnostic testing following in vitro fertilization (IVF) is available for all organic acidemias through molecular analysis, provided the genotype of the affected index patient and the carrier status of the parents are documented [10,11]. This approach is preferred over the detection of diagnostic compounds in amniotic fluid and/or analysis of enzyme activities in amniocytes or chorionic villi for prenatal diagnosis [3].

The diagnosis of an organic acidemia in a newborn infant can be suspected following expanded newborn screening (NBS) using MS/MS in the United States, Australia, Europe, and Asia [4]. Additional testing including urine organic acids, plasma acylcarnitine profile, plasma amino acids, and molecular analysis is necessary to confirm the diagnosis of an organic acidemia. (See "Newborn screening".)

Diagnosis of organic acidemias following initial presentation in adolescents or adults may be delayed or missed due to the variable presentation and lack of awareness that these disorders can present in older children and adults.

DIFFERENTIAL DIAGNOSIS — In neonates, the differential diagnosis includes sepsis, congenital viral infection, duct-dependent heart disease, drug withdrawal, and congenital adrenal hyperplasia. In older children and adults, the differential diagnosis includes diabetes, ingestion or intoxication, encephalitis, and adrenal insufficiency. Most of these are distinguished from organic acidemias by laboratory findings specific to each disorder. (See appropriate topic reviews for the individual disorders.)

Lethargy and coma may occur in amino acid disorders, organic acidemias, urea cycle disorders (UCDs), fatty acid oxidation defects, mitochondrial disorders, and disorders of carbohydrate metabolism (usually in the context of acute or episodic decompensation as described above). Depending upon the disorder, patients may be entirely neurologically normal prior to an acute metabolic decompensation or may have a longstanding history of developmental delay. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Identifying the specific disorder".)

Recurrent episodes of vomiting and dehydration (particularly if related to intake of protein or specific carbohydrates) are features of amino acid disorders, organic acidemias, and UCDs. Patients may also present with poor feeding and/or failure to thrive (FTT). FTT can range from severe to mild, depending upon the specific disorder and the severity of the defect.

Abnormal organic acid profiles may also be observed in patients with:

Fatty acid oxidation defects (see "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders")

Disorders of energy (carbohydrate) metabolism (see "Overview of inherited disorders of glucose and glycogen metabolism")

Mitochondrial disorders (see "Mitochondrial myopathies: Clinical features and diagnosis")

REFERRAL — All patients with suspected or confirmed organic acidemias need to be referred to a biochemical geneticist who is part of a multidisciplinary team that is experienced in the diagnosis and management of organic acidemias. This team should ideally be an integral part of a tertiary pediatric facility with access to subspecialists (eg, nephrology, intensive care, neurology).

MANAGEMENT — Management consists of treatment of the metabolic decompensation, followed by continuing care after recovery. Children with an organic acidemia are susceptible to metabolic decompensation during episodes of increased catabolism, such as intercurrent illness, trauma, surgery, prolonged and vigorous exercise, or prolonged episodes of fasting. Parents/caregivers and clinicians must be well informed about the initial signs of decompensation and trained in applying an emergency regimen [3]. Surgeons and anesthesiologists should be aware of potential complications and their prevention during anesthesia and surgery. An experienced metabolic nutritionist should be involved in the dietary management. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Approach to the child with metabolic acidosis".)

Treatment of metabolic decompensation — The aim is to prevent catabolism, provide sufficient calories to sustain metabolism, and correct metabolic acidosis and hyperammonemia [3]. Concurrent illness (eg, infection) is treated according to standard of care. A central line for intravenous therapy and admission to a level II to III intensive care unit experienced with acute therapy of episodes of metabolic decompensation is recommended.

Protein is withheld for 24 to a maximum of 48 hours during the acute illness and rapidly reintroduced as a low-protein diet (see 'Diet' below). Intravenous hydration is started at 1.25 to 1.5 times maintenance fluid requirements with 10 percent dextrose in appropriate electrolyte solutions (eg, D10 0.45% NaCL) to provide the following age-dependent glucose rates [3]:

Zero to 12 months – 8 to 10 mg/kg/min

One to 3 years – 7 to 8 mg/kg/min

Four to 6 years – 6 to 7 mg/kg/min

Seven to 12 years – 5 to 6 mg/kg/min

Adolescents – 4 to 5 mg/kg/min

Adults – 3 to 4 mg/kg/min

The tonicity of intravenous fluids is critical to prevent the development of hyponatremia [12].

The addition of intralipid (eg, 2 g/kg/day) to parenteral therapy to provide additional calories ideally is started immediately. Triglyceride levels and platelets need to be monitored. Disorders of fatty acid oxidation have to be ruled out.

The maximum blood glucose concentration should not exceed 130 to 150 mg/dL. Insulin supplementation starting with 0.01 to 0.02 units/kg/hour may be needed in some instances to avoid hyperglycemia as well as lactic acidemia and to promote protein synthesis. Lactic acid levels should be monitored daily until they return to the patient's baseline levels [3].

Acidosis is corrected with sodium bicarbonate according to standard management guidelines for metabolic acidosis. Frequently, acidosis corrects through adequate rehydration and provision of calories. Hyperammonemia may require treatment with ammonium scavengers or carglumic acid (in case of methylmalonic acidemia [MMA] or propionic acidemia [PA]) [3,13]. Hemodialysis or hemofiltration is rarely indicated. Peritoneal dialysis is obsolete [14]. In some situations, children require mechanical ventilation.

Long-term management — Continuing care after recovery includes dietary management and medications to help prevent future episodes of metabolic decompensation.

Diet — Within one to two days after the initiation of therapy, a specific low-protein diet is introduced gradually to achieve protein required for growth and development. This diet may be supplemented with an amino acid mixture that excludes the offending amino acids. If the infant remains dependent upon parenteral nutrition, an amino acid mixture providing a minimum of 0.5 g/kg/day of protein is given to avoid catabolism. Sufficient energy should be provided with carbohydrate and fat, and the amount of protein should be increased, if tolerated. Long fasts are avoided. In children, for example, a late-night snack and/or early breakfast are given to limit the duration of overnight fasting. However, there are concerns regarding the amino acid composition of medical foods used for dietary treatment of MMA and PA. The increase in leucine concentration in these foods may lead to adverse growth deficiencies due to iatrogenic amino acid deficiencies [15]. Plasma amino acid levels should therefore be monitored carefully.

Medications — Medications are given to reduce the formation or increase the excretion of toxic metabolites. Plasma carnitine levels are usually low in patients with organic acidemia. L-carnitine (100 to 300 mg/kg per day given intravenously or 100 to 300 mg/kg per day divided into three doses given orally during acute decompensation) is given to enhance the formation and excretion of acylcarnitine conjugates thought to be toxic to the brain, liver, and kidneys. L-carnitine even at higher doses is generally well tolerated. Multivitamins and calcium supplements also are provided to avoid deficiencies that may result from the low-protein diet.

Carglumic acid is an option in cases of MMA and PA when significant hyperammonemia (eg, >400 micromol/L) is present [16,17]. Accumulation of propionyl-CoA in these disorders leads to reduced synthesis of N-acetyl-glutamate, the physiologic activator of carbamoyl phosphate synthetase 1. Carglumic acid, a molecular analog, may reduce hyperammonemia through direct activation of carbamoyl phosphate synthetase 1 [16,17].

Additional medications are given for the specific disorders as described below.

Follow-up — Patients should be seen at least twice and up to six times per year by a multidisciplinary team led by a biochemical geneticist familiar with the management of organic acidemias. Infants or those with poor metabolic control are evaluated more frequently. A dietitian experienced in dietary therapy of inborn errors of metabolism should manage the specific low-protein diet. Follow-up should include the following, which may need to be adapted based upon the individual organic acidemia [3]:

Monitoring metabolic function – Metabolic laboratory tests including plasma amino acids following a four-hour fast, plasma free carnitine, ammonia, blood gas, and lactate. Plasma MMA (in patients with MMA).

Monitoring of diet and nutritional status – Growth, dietary history, and laboratory studies including electrolytes, folic acid, vitamin D, cobalamin, albumin, prealbumin, and zinc.

Prevention of complications – Monitoring kidney function, cardiac function, neurodevelopment, ophthalmology, and hearing, as well as preventive dentistry.

PROGNOSIS — Early diagnosis by newborn screening (NBS) is associated with lower mortality but no decrease in morbidity in long-term survivors [18]. As an example, the number of metabolic crises and overall neurologic outcome were not different in 20 patients with propionic acidemia (PA) identified through NBS compared with 35 patients identified through selective metabolic screening [18].

RESOURCES — Support groups are good sources of additional information for parents/caregivers (Organic Acidemia Association).

SPECIFIC DISORDERS — The more prevalent organic acidemias, including propionic acidemia (PA), isovaleric acidemia (IVA), 3-methylcrotonylglycinuria (3-MCG), 3-methylglutaconic aciduria (3-MGA), and glutaric acidemia type 1 (GA1), are reviewed in this section. Methylmalonic acidemia (MMA) is mentioned briefly here and reviewed in detail separately. (See "Methylmalonic acidemia".)

Methylmalonic acidemia — MMA (also called methylmalonic aciduria) encompasses a heterogeneous group of disorders that are characterized by impaired metabolism of methylmalonic acid generated during the metabolism of certain amino acids (isoleucine, methionine, threonine, or valine) and odd-chain fatty acids (figure 1). These disorders are caused by a deficiency of the adenosylcobalamin-dependent enzyme methylmalonyl-CoA mutase (mut), a dimer of identical subunits encoded on chromosome 6p12 [19], or its cofactor, cobalamin (cbl, vitamin B12), which is required for the isomerization of methylmalonyl-CoA to succinyl CoA. MMA is discussed in greater detail separately. (See "Methylmalonic acidemia".)

Propionic acidemia — As with methylmalonyl-CoA, propionyl-CoA is formed through the catabolism of isoleucine, valine, threonine, methionine, odd-chain fatty acids, thymidine, uracil, and cholesterol (figure 1). In addition, a significant amount of propionyl-CoA may be generated by gut bacteria. PA is caused by a deficiency of propionyl-CoA carboxylase, a dimer of two different subunits (alpha chain on chromosome 13q32 and beta chain on chromosome 3q13.3). Numerous mutations have been identified in the genes encoding both chains in patients with PA [20,21]. PA occurs in approximately 1 in 100,000 newborns.

Clinical manifestations of PA — Affected patients typically present in the neonatal period with the signs of organic acidemia (see 'Clinical presentation' above), although a few present at an older age [3]. Some patients have hepatomegaly or develop seizures. Less severe forms of the disease may present in later childhood or adulthood with episodes of vomiting and lethargy, failure to thrive (FTT), protein intolerance, seizures, or psychomotor abnormalities, such as floppiness and hypotonia.

Cardiomyopathy, both dilated and hypertrophic, occurs in approximately one-quarter to one-half of patients and develops independent of any specific metabolic profile [22-25]. Conduction abnormalities may occur. In one review of 10 children with PA who were evaluated with electrocardiogram, exercise testing, and echocardiography, the heart rate-corrected QT (QTc) interval was prolonged (>440 milliseconds) in seven, and four had reduced left ventricular function [26].

Other reported manifestations include pancreatitis [27] and optic nerve atrophy (in male patients) [28]. Some infants with PA have dysmorphic facial features including high forehead; broad nasal bridge; epicanthal folds; long, smooth philtrum; and triangular mouth. (See "Methylmalonic acidemia".)

Diagnosis of PA — Measurement of organic acids in the urine by gas chromatograph-mass spectrometry (GC-MS) shows high concentrations of metabolites of propionyl-CoA, including propionic acid, methylcitrate, 3-OH propionic acid, tiglic acid, tiglylglycine, and propionylglycine. Plasma concentrations of carnitine are reduced, and plasma acylcarnitine analysis shows a markedly elevated concentration of methylmalonyl/propionyl carnitine (C3-acylcarnitine).

Quantitative measurements of amino acids in plasma and urine typically show increased glycine concentration, which results from inhibition of the synthesis of the glycine cleavage enzyme by propionyl-CoA, leading to reduced glycine oxidation [3]. However, glycine values can be normal, even in an infant with previously abnormal levels. Alanine can also be elevated.

High ammonia concentrations, similar to those seen in urea cycle disorders (UCDs), can be seen and may be secondary to inhibition of N-acetylglutamate synthesis through accumulating propionyl-CoA [17].

Demonstration of deficient activity of propionyl-CoA carboxylase in skin fibroblasts or peripheral blood leukocytes or molecular confirmation of two pathogenic mutations in either the propionyl-CoA carboxylase subunit alpha (PCCA) or propionyl-CoA carboxylase subunit beta (PCCB) gene establishes a definitive diagnosis. Molecular confirmation provides an opportunity for genetic counseling and informed decision about future pregnancies for the family.

Prenatal diagnosis or preimplantation diagnostic testing following in vitro fertilization (IVF) [3,10,11] is discussed above. (See 'Diagnosis' above.)

Management of PA — Specific treatment for PA consists of a low-protein diet containing the minimum natural protein required for growth. Restriction to 8 to 12 grams/day is recommended for the first three years, with a slow increase to 15 to 20 grams/day by six to eight years of age, taking into account weight, metabolic control, and plasma levels of essential amino acids [3]. The diet usually is supplemented with an amino acid mixture that does not contain isoleucine, methionine, threonine, or valine to provide up to 1.5 grams/kg/day of total protein. The intake of odd-chain fatty acids and polyunsaturated fat also is restricted [29].

Gastrostomy tube placement may be indicated, particularly when feeding is difficult and/or when the infant/child with PA is at risk for frequent episodes of metabolic decompensation [30].

Parents/caregivers should be taught how to recognize early signs of metabolic decompensation, how to increase fluid and energy intake while at home, and when to take the individual with PA to an emergency department. The treating metabolic disease specialist needs to provide a letter detailing the emergency regimen on how to treat PA [31].

Electrocardiograms and echocardiography should be performed regularly [26,32]. Regular cardiac evaluation is warranted because prolonged QTc in patients with PA may lead to life-threatening events [32].

Patients with more severe forms of PA often do not respond to routine medical treatment for the disease. These patients are candidates for liver transplantation.

Medications for PA — Treatment with biotin (5 to 10 mg/day orally), an essential cofactor, may be initiated and the patient observed for a biochemical response. However, there is only one case report of a patient with documented biotin-responsive PA [3,33].

As with MMA, antibiotics can be used to suppress gut bacteria and reduce propionic acid production. (See "Methylmalonic acidemia", section on 'Reduction of anaerobic bacteria in the gut'.)

Therapy with carglumic acid is an option in cases of MMA and PA when significant hyperammonemia (eg, >400 micromol/L) is present [17]. Carglumic acid, a molecular analog, may reduce hyperammonemia through direct activation of carbamoyl phosphate synthetase 1 [17]. This is typically given as a 100 mg/kg oral bolus followed by 25 to 62 mg/kg every six hours [3]. (See 'Medications' above.)

Liver transplantation — Liver transplantation has been performed in a few patients with frequent and severe episodes of metabolic decompensation despite good dietary therapy, a history of previous sibling death, or cardiomyopathy [30,34-37]. In one series, all five transplanted children had sustained normal graft function [34]. One child had a single metabolic event posttransplantation. The patients otherwise had no metabolic decompensations on a protein-unrestricted diet. Auxiliary liver transplantation is an alternative approach to orthotopic liver transplantation that preserves the native liver [38]. Cardiomyopathy is reversible after liver transplantation [23,39].

Prognosis for PA — Similar to those with MMA, patients severely affected with PA can die in the newborn period or during a later episode of metabolic decompensation. Mortality is high in patients with cardiomyopathy. Significant neurodevelopmental handicap occurs often in those who survive, although some patients have normal cognitive development [40]. Seizures may occur, and acute basal ganglia infarction has been reported [3].

Other complications include recurrent hypoglycemia; infection, including moniliasis; and osteoporosis with secondary fractures [3,41]. Pancreatitis may be a complication of organic acidemias and should be suspected if patients develop abdominal pain, vomiting, encephalopathy, or shock [3].

Isovaleric acidemia — Isovaleric acidemia (IVA) is caused by a deficiency of isovaleryl-CoA dehydrogenase, the mitochondrial flavoenzyme that converts isovaleryl-CoA to 3-methylcrotonyl CoA in the breakdown pathway of leucine (figure 2) [9,42].

Clinical manifestations of IVA — IVA typically presents in the neonatal period with signs of organic acidemia (see 'Clinical presentation' above). In addition, the accumulation of isovaleric acid results in the characteristic odor described as "sweaty feet" [9]. Some patients present later in the first year with vomiting, ketoacidosis, lethargy, and coma. IVA rarely is identified in children who develop pancreatitis.

Diagnosis of IVA — Measurement of organic acids in urine by GC-MS demonstrates increased concentrations of oxidation and conjugation products of isovaleric acid, including isovalerylglycine and 3-hydroxyisovaleric acid. Acylcarnitine profiles show increased levels of isovaleryl/2-methylbutyryl-carnitine (C5). Elevated ammonia levels may initially suggest a UCD. Demonstration of deficient activity of isovaleryl-CoA dehydrogenase in skin fibroblasts or peripheral blood leukocytes confirms the diagnosis.

IVA can be diagnosed prior to the onset of symptoms by newborn screening (NBS). However, NBS can also identify a mild, potentially asymptomatic form of IVA, which has implications for counseling and management [43]. (See "Newborn screening".)

Treatment of IVA — Specific treatment of IVA consists of a low-protein diet containing the minimum natural protein required for growth. As with MMA and PA, the protein intake is increased gradually as tolerated depending on age, growth, development, metabolic control, and plasma levels of essential amino acids. The diet usually is supplemented with an amino acid mixture that does not contain leucine.

Glycine 150 to 250 mg/kg/day orally can be given to enhance the formation and excretion of isovalerylglycine in severe forms of IVA [44]. There have been no reports of glycine toxicity. Glycine is given in addition to L-carnitine (100 to 200 mg/kg/day given intravenously or 100 to 300 mg/kg/day divided into three doses given orally).

Prognosis for IVA — IVA has a better prognosis than do MMA and PA, and the majority of children who survive develop normally [9]. However, an estimated one-half of patients who present in the newborn period do not survive.

3-methylcrotonylglycinuria — Isolated biotin-resistant 3-MCG (also known as 3-methylcrotonyl CoA carboxylase deficiency) is caused by a deficiency of 3-methylcrotonyl CoA carboxylase (MCC), which catalyzes the conversion of 3-methylcrotonyl CoA to 3-methylglutaconyl CoA in the catabolic pathway of leucine (figure 2) [9,45]. 3-MCC is a biotin-dependent carboxylase that belongs to the same group of enzymes as do propionyl-CoA carboxylase, pyruvate carboxylase, and acetyl CoA carboxylase [45]. 3-MCG is one of the most common organic acidemias detected by tandem mass spectrometry (MS/MS) in NBS programs. It occurs in approximately 1 in 50,000 newborns [4].

3-MCC deficiency also can result from multiple carboxylase deficiency secondary to a deficiency of holocarboxylase synthetase or biotinidase [9]. In contrast to 3-MCG, these disorders may be biotin responsive [9].

Clinical manifestations of 3-MCG — Historically, patients with 3-MCG were reported to have developmental delay, hypoglycemia, acidosis, FTT, and other symptoms that usually presented between six months and three years of age. Less common presentations included a fatal illness characterized by seizures and muscular hypotonia in the newborn period [46] and a later-onset form with symptoms developing during an episode of increased catabolism, such as an intercurrent illness. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.)

However, studies have failed to identify a correlation between genotype or biochemical phenotype and outcomes [47]. In addition, it was not apparent to what extent the enzyme deficiencies were clinically significant or what degree of vulnerability they might afford. NBS has made it clear that the spectrum of symptoms in patients with 3-MCG is quite variable, with most infants identified by NBS appearing clinically normal. This raises the question of whether 3-MCG constitutes a disease or merely a biochemical phenotype [48]. It is also possible that this condition has a low penetrance or requires other genetic or environmental influences in order to manifest a phenotype or constitute a predisposition disorder [49]. In a retrospective study of 25 infants identified by NBS, six showed variable clinical symptoms including developmental delay. In another study of 16 infants with confirmed 3-MCG found on NBS, all remained asymptomatic for the 50-month study period, except for two who had complications related to severe prematurity [49,50]. A number of healthy affected mothers were also ascertained through NBS [50].

Diagnosis of 3-MCG — Urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine is increased during an acute episode. Total and free plasma carnitine levels can be reduced, with elevated concentration of 3-hydroxyisovalerylcarnitine. If 3-MCC deficiency is secondary to multiple carboxylase deficiency, urinary excretion of 3-methylcitrate, propionic acid, and propionylcarnitine is increased.

The diagnosis is confirmed by molecular testing. Measurement of deficient 3-MCC activity in leukocytes or fibroblasts may provide additional information in case of an uncertain molecular test result.

Treatment of 3-MCG — There is no consensus on the treatment of patients with 3-MCG [51]. No specific medication is available for treatment of 3-MCG. Biotin (5 to 10 mg/day, independent of age) is given until the possibility of multiple carboxylase deficiency is excluded. L-carnitine is recommended when the free carnitine is deficient.

Most patients do well with carnitine supplementation only, without developing decompensation. For symptomatic patients, specific treatment similar to that for IVA and a low-protein diet containing the minimum natural protein required for growth is an option if the symptoms, such as hyperammonemia or acidosis, are felt to be due to 3-MCC deficiency rather than some other cause (eg, multiple carboxylase deficiency). A specific low-protein diet including restriction of leucine is not indicated. (See 'Medications' above.)

Prognosis for 3-MCG — Most patients with this disorder have a good outcome with normal neurodevelopment.

3-methylglutaconic aciduria — There are five known types of 3-MGA:

3-MGA type I is a rare, autosomal-recessive organic aciduria caused by deficiency of 3-methylglutaconyl-CoA hydratase, an enzyme in the leucine degradation pathway converting 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA. As a consequence, patients with MGA type I excrete increased amounts of 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. The clinical spectrum ranges from asymptomatic infants diagnosed through expanded NBS to adults with progressive neurodegeneration. Less than 20 patients with MGA type I have been reported in the literature [52]. Supplementation with L-carnitine is recommended. Dietary therapy with restriction of leucine intake may be undertaken in patients with a more severe phenotype [53].

3-MGA type II (Barth syndrome) is an X-linked disorder due to pathogenic variants in the TAZ gene that encodes tafazzin. The phospholipid acyltransferase activity of tafazzin is responsible for remodeling of cardiolipin, an important component of the inner mitochondrial membrane and respiratory chain activity [54]. Clinical symptoms of Barth syndrome include cardiomyopathy (dilated, isolated noncompaction of the ventricular myocardium), neutropenia, skeletal myopathy, and growth delay. Phenotypic variability may be marked even within the same family [55]. Barth syndrome is usually suspected on the basis of clinical symptoms and a positive family history. Elevated 3-MGA excretion in urine further supports the diagnosis; however, the absence of this finding does not rule out the disorder. For all patients, molecular testing is recommended for confirmation of the diagnosis. Tetralinoleoyl-cardiolipin levels are low in individuals with Barth syndrome [56], although this test is only available in a few specialized diagnostic laboratories. Management is supportive only, with the main focus on treatment of cardiomyopathy and neutropenia [54,55].

3-MGA type III (Costeff syndrome) is a rare neuroophthalmologic syndrome associated with early-onset optic atrophy, neurologic symptoms, cognitive impairment, and 3-MGA [57]. Pathogenic variants in the OPA3 outer mitochondrial membrane lipid metabolism regulator (OPA3) gene are causative. Diagnosis of 3-MGA types III through V is confirmed by molecular testing. Urine organic acid analysis may reveal intermittent 3-MGA but can be within normal limits. Management is supportive only.

3-MGA type IV is a heterogeneous group of patients with intermittent 3-MGA who do not have an identified defect. Variants in the caseinolytic peptidase B homolog (CLPB) are associated with cataracts, neutropenia, epilepsy, and MGA [58]. A number of patients have had associated mitochondrial respiratory chain disorders [59,60]. Management is supportive only.

3-MGA type V is characterized by dilated cardiomyopathy, cerebellar ataxia, testicular dysgenesis, and growth failure in persons of Canadian Dariusleut-Hutterite ethnicity. It is due to mutations in the DnaJ heat shock protein family (Hsp40) member C19 (DNAJC19) gene that encodes a protein involved in import of other proteins into the mitochondria [61]. Management is supportive only.

Glutaric acidemia type 1 — GA1 is caused by deficiency of riboflavin-dependent glutaryl-CoA dehydrogenase (GCDH), the mitochondrial enzyme that converts glutaryl-CoA to crotonyl-CoA in the catabolic pathway of lysine, hydroxylysine, and tryptophan (figure 3) [9]. A variety of mutations have been identified in the GCDH gene [62]. In a mouse model, expression of GCDH in the brain was limited to neurons [63].

A Scandinavian study estimated the frequency as 1 in 30,000 newborns [64]. The prevalence is increased among the Ojibwa and Cree in northeastern Manitoba and northwestern Ontario [65] and among the Amish in Pennsylvania.

Clinical manifestations of GA1 — The presentation of GA1 is variable [65,66] and appears to be unrelated to biochemical phenotype or genotype [67]. In contrast to the other organic acidurias, GA1 rarely presents in the newborn period. Affected children typically have an episode of metabolic decompensation with ketoacidosis, hyperammonemia, hypoglycemia, and encephalopathy during the first year or later, often accompanied by infection and fever. In a series of 77 affected patients, decompensation occurred before 18 months of age, almost always during an infectious illness [68]. These children also develop an irreversible dystonic movement disorder with preserved cognitive function and often have feeding difficulties because of orofacial dyskinesia [9,69-71].

However, episodes of decompensation and encephalopathy are mild or absent in approximately 25 percent of affected children. These patients develop dystonia that often is diagnosed as cerebral palsy and have motor delay and intellectual disability [69]. Some children present with acute subdural hemorrhage or chronic subdural effusions that may be mistakenly attributed to child abuse or shaken baby syndrome [69,72-74]. A possible mechanism of the acute hemorrhage is increased fragility of bridging veins that are stretched because of cerebral atrophy. (See "Child abuse: Epidemiology, mechanisms, and types of abusive head trauma in infants and children" and "Child abuse: Eye findings in children with abusive head trauma (AHT)".)

Patients typically have microencephalic macrocephaly. When present at birth, it is the earliest sign of GA1 [68]. In some patients, the head circumference is normal at birth but increases rapidly during infancy [9,71]. Metabolic decompensation is associated with acute symmetric striatal necrosis that is similar to a stroke in time course, radiologic appearance, and irreversibility and results in dystonia [68,75]. Injury to the putamen is associated with sudden developmental arrest. Autopsy studies confirm the presence of microencephalic macrocephaly and striatal atrophy [76-83]. In one autopsy series of six patients ranging in age from 8 months to 40 years, the neuron loss appeared to occur shortly after the encephalopathic episode and to be nonprogressive [83]. In addition, all brain regions, not just the striatum, demonstrated markedly elevated concentrations of glutaric acid. This finding suggests that brain injury may be related to the efficiency of organic acid clearance [84]. (See "Macrocephaly in infants and children: Etiology and evaluation".)

Approximately 20 percent of children have seizures, and 20 to 30 percent have subdural hemorrhages or effusions [65,85]. Other symptoms include insomnia, hyperthermia, hyperhidrosis, and anorexia. Preliminary data suggest that kidney function declines in patients with GA1 over time, although long-term studies are lacking [86].

Diagnosis of GA1 — Urinary concentrations of glutaric acid and 3-hydroxyglutaric acid are increased [87]. Excretion of glutaconic acid and dicarboxylic acids may be more prominent than that of 3-hydroxyglutaric acid during episodes of ketosis [88]. Plasma concentrations of glutarylcarnitine (C5DC) are increased, and carnitine levels are low. Biochemically, there are two distinct forms. The classic form is associated with abnormal elevations of glutarate metabolites in blood and urine [68,75,89], while the low-excretor variant is associated with normal or very minimally elevated levels of glutarate metabolites and can be missed on NBS [67,90-92].

The diagnosis is confirmed by measurement of deficient GCDH activity in leukocytes or fibroblasts is deficient or identification of a pathogenic mutations using molecular techniques [93].

Treatment of GA1 — Presymptomatic treatment of GA1 significantly reduces the risk of neurologic sequelae [94,95]. Specific treatment for GA1 consists of a low-protein diet containing the minimum natural protein required for growth [87]. Similar to that of the other organic acidemias, the protein intake is increased gradually, as tolerated, depending on age, growth, development, and plasma levels of essential amino acids. The diet is supplemented with an amino acid mixture that does not contain tryptophan and lysine, typically until six years of age. Most untreated persons with GA1 experience acute encephalopathic crises during the first six years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. Dietary treatment is relaxed after age six years and should be supervised by specialized metabolic centers [2].

Although riboflavin (100 to 300 mg/day) is not routinely given, it may be administered in addition to L-carnitine (100 to 200 mg/kg/day intravenously or 100 to 300 mg/kg/day orally divided in three doses) since it is also a cofactor of GCDH [9]. Treatment for the dystonia may include baclofen or valproic acid.

Treatment success in a GA1 mouse model correlated directly with control of brain glutaric acid levels and maintenance of glutamate and gamma amino butyric acid (GABA). Depletion of glutamate and GABA (a marker for impending brain injury) was detectable with proton magnetic resonance spectroscopy [63]. These findings may facilitate the development of improved treatment and monitoring strategies for patients with GA1.

Prognosis for GA1 — Children who are undiagnosed and untreated are likely to develop cerebral atrophy with developmental delay and pyramidal tract signs (brisk deep tendon reflexes, spastic tone, and extensor plantar response). Neuroimaging studies typically show extracerebral fluid collections and atrophy in the frontotemporal regions and diffuse hypodensities in the white matter. These may improve with dietary therapy [96]. Children with GA1 can develop normally if they are treated with L-carnitine and a low-protein diet when initially diagnosed through NBS and episodes of metabolic decompensation are avoided during intercurrent illnesses [97,98].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of metabolism".)

SUMMARY AND RECOMMENDATIONS

Organic acidemias, also known as organic acidurias, are a group of disorders characterized by increased excretion of organic acids in urine due to deficiencies of specific enzymes in the breakdown pathways of amino acids. (See 'Introduction' above.)

Patients with classic organic acidemias typically present during the first one to two weeks after birth with poor feeding, vomiting, increasing lethargy, hypotonia, and metabolic acidosis with increased anion gap. The exceptions are cerebral organic acidemias such as glutaric acidemia (or aciduria) type 1 (GA1), which rarely presents during the neonatal period. Older infants and children may present with lethargy, vomiting, failure to thrive, seizures, or acute metabolic decompensation associated with an intercurrent illness. (See 'Clinical presentation' above.)

The initial evaluation of an infant with suspected organic acidemia includes measurement of pH, carbon dioxide tension, ammonia, lactate, pyruvate, glucose, electrolytes, creatinine, urea, ketones, and complete blood count. Laboratory features of organic acidemia include severe metabolic acidosis with an increased anion gap, ketosis, and hyperammonemia. Other findings may include hypoglycemia, electrolyte and other abnormalities associated with dehydration, and evidence of bone marrow suppression. (See 'Initial evaluation' above.)

Specific organic acidemias are suggested by measurement of organic acids in the urine and confirmed by molecular testing (see 'Diagnosis' above):

Methylmalonic acidemia (MMA) – Increased plasma methylmalonic acid and increased urinary methylmalonic acid, methylcitrate, propionic acid, and 3-OH propionic acid (figure 1); deficient activity of methylmalonyl-CoA mutase or cobalamin deficiency (see 'Methylmalonic acidemia' above and "Methylmalonic acidemia")

Propionic acidemia (PA) – Increased urinary propionic acid, methylcitrate, 3-OH propionic acid, tiglic acid, tiglylglycine, and propionylglycine (figure 1); deficient activity of propionyl-CoA carboxylase (see 'Propionic acidemia' above)

Isovaleric acidemia (IVA) – Increased urinary isovalerylglycine and 3-hydroxyisovaleric acid (figure 2); deficient activity of isovaleryl-CoA dehydrogenase (see 'Isovaleric acidemia' above)

3-methylcrotonylglycinuria (3-MCG) – Increased urinary 3-hydroxyisovaleric acid and 3-methylcrotonylglycine (figure 2); deficient activity of 3-methylcrotonyl CoA carboxylase (MCC) (see '3-methylcrotonylglycinuria' above)

3-methylglutaconic aciduria (3-MGA) – Increased urinary 3-methylglutaconic acid (see '3-methylglutaconic aciduria' above)

Glutaric acidemia type 1 (GA1) – Increased urinary glutaric acid and 3-hydroxyglutaric acid (figure 3); deficient glutaryl-CoA dehydrogenase (GCDH) activity (see 'Glutaric acidemia type 1' above)

The initial management of a metabolic decompensation includes withholding protein from the diet or parenteral nutrition; intravenous hydration and provision of energy through glucose and intralipid; and correction of metabolic acidosis, hyperammonemia, hypoglycemia, and electrolyte abnormalities. Associated illnesses (eg, infections) also are treated. After one to two days of treatment, a specific low-protein diet that excludes the offending amino acids is gradually introduced. Medications may be given to reduce the formation or increase the excretion of toxic metabolites. (See 'Management' above and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

Children with organic acidemia are susceptible to metabolic decompensation during episodes of increased catabolism (eg, intercurrent illness, trauma, or surgery). Parents/caregivers and clinicians must be educated about the initial signs of decompensation and trained in applying an emergency regimen. (See 'Introduction' above and 'Management' above.)

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Topic 2927 Version 21.0

References