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The Organic Acidemias: An Overview

, MD
Department of Genetics
Yale University School of Medicine
New Haven, Connecticut

Initial Posting: ; Last Update: December 22, 2009.

Summary

Disease characteristics. The term "organic acidemia" or "organic aciduria" (OA) applies to a group of disorders characterized by the excretion of non-amino organic acids in urine. Most organic acidemias result from dysfunction of a specific step in amino acid catabolism, usually the result of deficient enzyme activity. The majority of the classic organic acid disorders are caused by abnormal amino acid catabolism of branched-chain amino acids or lysine. They include maple syrup urine disease (MSUD), propionic acidemia, methylmalonic acidemia (MMA), methylmalonic aciduria and homocystinuria, isovaleric acidemia, biotin-unresponsive 3-methylcrotonyl-CoA carboxylase deficiency, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency, ketothiolase deficiency, and glutaricacidemia type I (GA I). A neonate affected with an OA is usually well at birth and for the first few days of life. The usual clinical presentation is that of toxic encephalopathy and includes vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma. Outcome is enhanced by diagnosis and treatment in the first ten days of life. In the older child or adolescent, variant forms of the OAs can present as loss of intellectual function, ataxia or other focal neurologic signs, Reye syndrome, recurrent ketoacidosis, or psychiatric symptoms.

Diagnosis/testing. Clinical laboratory findings that suggest an organic acidemia include acidosis, ketosis, hyperammonemia, abnormal liver function tests, hypoglycemia, and neutropenia. First-line diagnosis in the organic acidemias is urine organic acid analysis using gas chromatography with mass spectrometry (GC/MS), utilizing a capillary column. The urinary organic acid profile is nearly always abnormal in the face of acute illness with decompensation; however, in some disorders diagnostic analytes may be present only in small or barely detectable amounts when the affected individual is not acutely ill. Depending on the specific disorder, plasma amino acid analysis using a quantitative method such as column chromatography, high-performance liquid chromatography (HPLC), or GC/MS can also be helpful. A plasma or serum acylcarnitine profile can also provide a rapid clue to the diagnosis. Urine acylcarnitine profiling is more complex and interpretation can be difficult. Confirmatory testing involves assay of the activity of the deficient enzyme in lymphocytes or cultured fibroblasts and/or molecular genetic testing.

Management. Treatment of manifestations: The aim of therapy is to restore biochemical and physiologic homeostasis. Neonates require emergency diagnosis and treatment depending on the specific biochemical lesion, the position of the metabolic block, and the effects of the toxic compounds. Treatment strategies include: (1) dietary restriction of the precursor amino acids and (2) use of adjunctive compounds to (a) dispose of toxic metabolites or (b) increase activity of deficient enzymes. Frequent monitoring of growth, development, and biochemical parameters is essential. Decompensation caused by catabolic stress (e.g., from vomiting, diarrhea, febrile illness, and decreased oral intake) requires prompt and aggressive intervention. Liver transplantation has been successful in a small number of affected individuals. Post-partum monitoring of women with an OA is important in this time of metabolic stress.

Genetic counseling. The organic acidemias considered in this overview are inherited in an autosomal recessive manner. At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known. Prenatal diagnosis for pregnancies at increased risk varies by disorder and may include measurement of analytes in amniotic fluid, measurement of enzyme activity, or molecular genetic testing in cells obtained by CVS or amniocentesis.

Definition

The term "organic acidemia" or "organic aciduria" (OA) applies to a diverse group of disorders characterized by the excretion of non-amino organic acids in urine. The organic acidemias share many clinical similarities.

Most organic acidemias result from dysfunction of a specific step in amino acid catabolism, and are usually the result of deficient enzyme activity at that step. The pathophysiology results from accumulation of precursors and deficiency of products of the affected pathway.

The accumulated precursors are themselves toxic or are metabolized to produce toxic compounds. The pathophysiology of these disorders is the result of toxicity of small molecules to brain, liver, kidney, pancreas, retina, and other organs.

Some of these molecules, such as the glutaric acid metabolites, are thought to be excitotoxic to neurons and may affect N-methyl-D-asparate (NMDA) receptors [Hoffmann & Zschocke 1999].

Respiratory chain deficiencies measured in tissues of persons with propionic and methylmalonic acidemia suggest that secondary mitochondrial damage plays a role in the organ damage seen in some affected individuals [Chandler et al 2009, de Keyzer et al 2009].

In maple syrup urine disease (MSUD), leucine is believed to be toxic to neurons, but in some cases high concentrations of leucine have not been associated with brain damage [Nyhan et al 1998, Kolker et al 2000, Wajner et al 2000].

In addition, because catabolism of amino acids provides energy for other cellular processes, energy deficiency during metabolic crisis may contribute to the clinical syndrome.

As coenzyme A derivatives form a complex with carnitine, deficiency of carnitine may develop and contribute to disordered homeostasis.

Clinical Manifestations

Presentation. A neonate affected with an organic acidemia (OA) is usually well at birth and for the first few days of life. The usual clinical presentation is that of toxic encephalopathy and includes vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma. This nondistinct clinical picture may initially be attributed to sepsis, poor breast-feeding, or neonatal asphyxia. Outcome is enhanced by diagnosis in the first ten days of life [Acosta & Ryan 1997, Baric et al 1998, Saudubray & Charpentier 2001, Kamboj 2008].

Several rare OAs present with neurologic signs without concomitant biochemical findings such as hyperammonemia and acidosis; however, these disorders have a distinctive pattern of organic acids. They include 4-hydroxybutyric aciduria, D-2-hydroxyglutaric aciduria, 3-methylglutaconic aciduria caused by 3-methylglutaconic acid dehydratase deficiency, and malonic aciduria.

Methylmalonic aciduria, cblC variant, may present with developmental delay, minor dysmorphology, and hypotonia without acidosis.

Late-onset 3-methylcrotonyl carboxylase deficiency may present as developmental delay without Reye-like syndrome, in contrast to the early-onset form.

In the older child or adolescent, variant forms of the OAs can present as loss of intellectual function, ataxia or other focal neurologic signs, Reye syndrome, recurrent ketoacidosis, or psychiatric symptoms.

A variety of MRI abnormalities have been described in the OAs, including distinctive basal ganglia lesions in glutaricacidemia type I (GA I), white matter changes in maple syrup urine disease (MSUD), and abnormalities of the globus pallidus in methylmalonic acidemia. Macrocephaly is common in GA I.

Clinical course. Even with appropriate management, individuals with organic acidemias have a greater risk of infection and a higher incidence of pancreatitis, which can be fatal [Bultron et al 2008].

Methylmalonic acidemia is associated with an increased frequency of renal failure and the cblC variant of methylmalonic acidemia is associated with pigmentary retinopathy and poor developmental outcome in the early-onset form [Al-Bassam et al 1998, Al Essa et al 1998, Nicolaides et al 1998, Biancheri et al 2001].

Establishing the Diagnosis

Clinical laboratory findings that should suggest an organic acidemia (Table 1):

Acidosis. Serum bicarbonate lower than:

  • 22 mmol/L in individuals younger than age one month
  • 17 mmol/L in neonates

Note: In most organic acidemias, the acidosis is severe, with an anion gap higher than 20. Early in the course, however, the acidosis may be less severe and the anion gap smaller.

Ketosis

  • A positive (not trace) urine dipstick for ketones or Acetest® tablet (Ames), which detects acetoacetic acid and acetone

    OR
  • A urine organic acid profile containing excess β-hydroxybutyrate and acetoacetic acid as defined by the norms of the laboratory performing the test

Note: Because neonates do not normally produce much acetoacetate, ketosis detected in neonates by dipstick or Acetest® tablet should prompt serious consideration of an organic acidemia.

Hyperammonemia. Plasma ammonium concentration exceeding the reference range for the laboratory performing the test and the age of the affected individual, usually greater than:

  • 150 µg/dL in neonates
  • 70 µg/dL in infants to age one month
  • 35-50 µg/dL in older children and adults

Abnormal liver function tests

  • Hypoglycemia. Serum glucose lower than:
    • 40 mg/dL in term and preterm infants
    • 60 mg/dL in children
    • 76 mg/dL over age 16 years
  • Neutropenia. Absolute neutrophil count (ANC) less than 1500/mm3. Total white cell counts vary with age and local laboratory reference ranges may need to be taken into account.

Note: Reference ranges listed are taken from Robertson & Shilkofski [2005]. However, the clinician should note the reference ranges in the laboratory used for testing, as reference ranges and units may vary among laboratories.

Table 1. Clinical Findings in Organic Acidemias Caused by Abnormal Amino Acid Catabolism

DisorderDistinctive Features
KetosisAcidosisOther
Maple syrup urine disease (MSUD) 1XMaple syrup odor
Propionic academia 2 XXNeutropenia
Methylmalonic acidemia (MMA)XXNeutropenia
Methylmalonic aciduria and homocystinuria, cblC typeRareRareVomiting, poor feeding, neurologic symptoms
Isovaleric academia 1XSweaty feet odor
Biotin-unresponsive 3-methylcrotonyl-CoA carboxylase deficiencyXHypoglycemia
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiencyReye syndrome, hypoglycemia
Ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase deficiency)XXHypoglycemia
Glutaricacidemia type I (GA I)Basal ganglia injury with movement disorder

1. In MSUD and isovaleric acidemia, distinctive odors in urine, sweat, and even the affected individual's room suggest the diagnosis.

2. Propionic acidemia may present with isolated hyperammonemia early in its course.

Newborn screening tests. The increasing performance of expanded newborn screening using tandem mass spectrometry to diagnose organic acidemias may result in earlier diagnosis of more affected individuals. Most states in the United States are now performing newborn screening tests for as many as 30 inborn errors of metabolism, including organic acidemias [Dott et al 2006, National Newborn Screening Status Report].

These tests are screening tests, and the diagnosis must be confirmed using an independent gas chromatography with mass spectrometry (GC/MS) analysis of urinary organic acids as well as other appropriate tests when available [Seashore 1998, Rhead & Irons 2004].

Gas chromatography/mass spectrometry (GC/MS). First-line diagnosis in the organic acidemias is urine organic acid analysis by GC/MS, utilizing a capillary column. Organic acids can be measured in any physiologic fluid. However, it is most effective to use urine to identify the organic acids that signal these disorders, as semi-quantitative methods may not identify the important compounds in plasma. The organic acids found in the urine provide a high degree of suspicion for the specific pathway involved (Table 1).

In special circumstances, quantitative methods using such techniques as stable isotope dilution may allow quantitation of specific organic acids, such as methylmalonic acid. When in excess, some of the coenzyme A derivatives of the organic acids that accumulate are conjugated with carnitine or glycine; thus, assessment of the plasma acylcarnitine profile and quantitation of urinary acylglycines is helpful in establishing a specific diagnosis.

The urinary organic acid profile is nearly always abnormal in the face of acute illness with decompensation. However, in some disorders the diagnostic analytes may be present only in small or barely detectable amounts when the affected individual is not acutely ill. Thus, it is critical to obtain a urine sample during the acute phase of the illness, even if the sample needs to be frozen and saved until the testing can be performed.

Many laboratories have difficulty performing and/or interpreting urine organic acid analysis by GC/MS; it is important that the biochemical genetic testing be performed in an experienced laboratory and interpreted by an individual trained in biochemical genetics.

Differential Diagnosis

The organic acidemias are important in the differential diagnosis of metabolic and neurologic derangement in the neonate and of new-onset neurologic signs in the older child.

Organic aciduria. Several disorders, not classified as primary disorders of organic acid metabolism, have a characteristic urinary organic acid profile that suggests the appropriate diagnosis.

  • Mevalonicaciduria, a disorder of cholesterol biosynthesis, shows mevalonic acid in the urine.
  • Glutaricacidemia type II (GA II, EMA-adipic aciduria), a disorder of fatty acid oxidation, has multiple organic acids in abnormal concentration in urine. These organic acids include ethylmalonic acid, glutaric acid, dicarboxylic acids, and glycine conjugates of medium chain dicarboxylic acids.
  • The fatty acylCoA-glycine conjugates that signal incomplete fatty acid oxidation may be identified during GC/MS analysis of urine and serve as signals to the diagnosis of MCAD deficiency and other disorders of fatty acid oxidation and transport.
  • Biotinidase deficiency, a disorder of biotin recycling, results in the urinary excretion of several unusual organic acids, including 3-hydroxy-isovaleric, 3-methylcrotonic, 3-hydroxypropionic, methylcitric, 3-hydroxybutyric acids, and acetoacetate. Propionyl glycine and tiglylglycine may also be seen.
  • Mitochondrial diseases (see Mitochondrial Disorders Overview) with disordered oxidative phosphorylation often demonstrate the presence of abnormal organic acids in the urine, including lactate and 3-methylglutaconic, 2-hydroxybutyric, 3-hydroxybutyric, 2-methyl-3-hydroxybutyric, and ethylmalonic acids.

Acidosis. The differential diagnosis includes all causes of acidosis including renal tubular acidosis and inherited metabolic disorders of lactate and pyruvate metabolism and oxidative phosphorylation. Disorders of the Krebs cycle can also cause neurologic symptoms, usually accompanied by metabolic acidosis with elevations of specific organic acids in urine. Fumarase deficiency (fumarate) and 2-ketoglutarate dehydrogenase deficiency (2-ketoglutarate) are two examples.

Non-genetic conditions, such as shock and sepsis, also cause acidosis [Rustin et al 1997].

Hyperammonemia. Disorders of the urea cycle (see Urea Cycle Disorders Overview) and the hyperammonemia-hypoglycemia syndrome (see Familial Hyperinsulinism) caused by mutations in the gene encoding glutamate dehydrogenase need to be considered, although the urinary organic acid profile is likely to be diagnostic in the organic acid disorders. In the urea cycle disorder OTC deficiency, and others later in the cycle, orotic acid may be identified in the urine organic acid profile.

Developmental delay. The differential diagnosis of developmental delay with other neurologic findings unaccompanied by acidosis or hyperammonemia is extremely long. A high index of suspicion is required to keep an organic acidemia in mind when these symptoms prevail.

Prevalence

While each individual disorder comprising the organic acidurias is rare, disorders of organic acid metabolism in the aggregate are not. More than 100 inborn errors of metabolism, many of which are organic acidemias, present in the neonatal period, with an approximate incidence of 1:1000 neonates [Saudubray & Charpentier 2001].

Causes

Heritable Causes

The majority of the classic organic acid disorders result from abnormal amino acid catabolism of branched-chain amino acids or lysine. Characteristics of the disorders are summarized in Table 1 (clinical findings), Table 2 (metabolic findings), and Table 3 (molecular genetics).

Table 2. Metabolic Findings in Organic Acidemias Caused by Abnormal Amino Acid Catabolism

DisorderAmino Acid Pathway(s) AffectedEnzymeDiagnostic Analytes by GC/MS 1 and Quantitative Amino Acid Analysis
Maple syrup urine disease (MSUD)Leucine, isoleucine, valineBranched-chain ketoacid dehydrogenaseBranched-chain ketoacids and hydroxyacids in urine
Alloisoleucine in plasma
Propionic acidemiaIsoleucine, valine, methionine, threoninePropionyl CoA carboxylasePropionic acid, 3-OH propionic acid, methyl citric acid, propionyl glycine in urine
Propionyl carnitine, increased glycine in blood
Methylmalonic acidemia (MMA)Isoleucine, valine, methionine, threonineMethylmalonyl CoA mutaseMethylmalonic acid in blood and urine
Propionic acid, 3-OH propionic acid, methyl citrate in urine
Acyl carnitines, increased glycine in blood
Methylmalonic aciduria and homocystinuria, cblC typeIsoleucine, valine, methionine, threonineMMACHC proteinMethylmalonic acid in blood and urine
Total homocysteine in plasma
Isovaleric acidemiaLeucineIsovaleryl CoA dehydrogenase3-OH isovaleric acid, isovaleryl glycine in urine
Biotin-unresponsive 3-methylcrotonyl- CoA carboxylase deficiencyLeucine3-methylcrotonyl- CoA carboxylase3-hydroxy-isovaleric acid, 3-methylcrotonyl glycine in urine
3-hydroxy-3- methylglutaryl-CoA (HMG-CoA) lyase deficiencyLeucineHMG-CoA lyase3-OH-3-methyl glutaric acid, 3-methylglutaconate, 3-OH-isovalerate, 3-methylglutarate in urine
Ketothiolase deficiencyIsoleucineMitochondrial acetoacetyl-CoA thiolase2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine in urine
Glutaricacidemia type I (GA I)Lysine, hydroxylysine, tryptophanGlutaryl CoA dehydrogenaseGlutaric acid, 3-OH-glutaric acid in urine
Glutarylcarnitine in blood

1. Gas chromatography/mass spectrometry

Table 3. The Organic Acidemias: Molecular Genetics

DisorderGene SymbolProtein NameOMIM #
Maple syrup urine disease (MSUD) type IABCKDHA 2-oxoisovalerate dehydrogenase alpha subunit248600
608348
MSUD type IBBCKDHB 2-oxoisovalerate dehydrogenase beta subunit248611
MSUD type IIDBT Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex248610
Propionic acidemia type IPCCA Propionyl-CoA carboxylase alpha chain606054
232000
Propionic academia type IIPCCB Propionyl-CoA carboxylase beta chain232050
606054
Methylmalonic acidemia (MMA)MUTMethylmalonyl-CoA mutase251000
609058
MMAAMethylmalonic aciduria type A protein607481
251100
MMABCob(l)yrinic acid a,c-diamide adenosyltransferase607568
251110
Methylmalonic aciduria and homocystinuria, cblC typeMMACHC Methylmalonic aciduria and homocystinuria type C protein609831
277400
Isovaleric acidemiaIVD Isovaleryl CoA dehydrogenase243500
607036
Biotin-unresponsive 3-methylcrotonyl- CoA carboxylase deficiencyMCCC1Methylcrotonyl-CoA carboxylase subunit alpha 210200
609010
MCCC2 Methylcrotonyl-CoA carboxylase beta chain210210
609014
3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA) lyase deficiency
HMGCLHydroxymethylglutaryl-CoA lyase246450
Mitochondrial acetoacetyl-CoA thiolase deficiency
(β-ketothiolase deficiency)
ACAT1 Acetyl-CoA acetyltransferase203750
607809
Glutaricacidemia type I (GA I)GCDHGlutaryl-CoA dehydrogenase231670

Evaluation Strategy

Determining the specific cause of organic acidemia is important for establishing prognosis, appropriate treatment strategy, and genetic counseling.

Family history. While a family history of neonatal death in sibs of a proband should prompt consideration of an organic acidemia, a negative family history does not exclude the possibility.

Plasma amino acid analysis. Depending on the specific disorder, plasma amino acid analysis can be helpful because specific abnormalities in plasma amino acid concentrations provide an important clue to identifying the disordered pathway.

Assay of enzyme activity. Once the detection of specific analytes narrows the diagnostic possibilities, the activity of the deficient enzyme is assayed in lymphocytes or cultured fibroblasts as a confirmatory test. For many pathways, no single enzyme assay can establish the diagnosis. For others, tests such as complementation studies need to be done.

Molecular genetic testing. Molecular genetic testing can be used to confirm the diagnosis in some affected individuals. The genes in which mutation causes the organic acid disorders are listed in Table 3.

Note: While sequence analysis is generally the first-line molecular genetic testing for most disorders, certain mutations are prevalent within specific ethnic groups, and thus, targeted mutation analysis could be performed first in individuals from those populations. Examples include MSUD and glutaricaciduria types 1 and 3 in the Old Order Amish [Sherman et al 2008]. Several organic acidurias, especially propionic acidemia, are common among Arab populations in Saudi Arabia owing to consanguinity, estimated to be as high as 25%-70% [Kaya et al 2008].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The organic acidemias considered in this overview are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and, therefore, carry a single copy of a disease-causing mutation.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. All offspring of affected individuals are obligate carriers.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing using molecular genetic techniques is possible if the organic acidemia-causing mutations in the family are known. Note: Compound heterozygosity for two different mutations is common in these autosomal recessive disorders; thus, carrier detection can be difficult if only one mutation in a proband can be identified.

Methods other than molecular genetic testing are for the most part not reliable for carrier testing because the ranges of enzyme activity in carriers and non-carriers can overlap.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Diagnosis of newborn at-risk sibs. If prenatal diagnosis has not been performed in an at-risk pregnancy, immediate diagnostic testing of the newborn must be performed. Expectant treatment, including elimination of fasting stress or protein load until the presence of the disorder is confirmed or excluded, is prudent.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Three approaches to prenatal diagnosis may be possible, including measurement of analytes in amniotic fluid or use of cells obtained by CVS or amniocentesis to either assay enzyme activity or extract DNA for molecular genetic testing.

Biochemical genetic testing. Prenatal diagnosis for pregnancies at increased risk for propionic acidemia, methylmalonic acidemia, biotin-unresponsive 3-methylcrotonyl-CoA carboxylase deficiency, glutaricacidemia type 1, ketothiolase deficiency, methylmalonic aciduria and homocystinuria, cblC type, and isovaleric acidemia is possible by analysis of amniotic fluid if highly accurate quantitative methods are used to measure the appropriate analytes. Amniocentesis is usually performed at approximately 15 to 18 weeks' gestation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Prenatal diagnosis for pregnancies at increased risk for MSUD is possible by measurement of enzyme activity in fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15 to 18 weeks' gestation. (If cells from CVS are used, extreme care must be taken to assure that they are fetal rather than maternal cells.)

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation)..

Preimplantation genetic diagnosis may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Management

Treatment of Manifestations

Many of the organic acidemias respond to treatment, and in the neonate especially, early diagnosis and prompt management are essential to a good outcome. The aim of therapy is to restore biochemical and physiologic homeostasis [Acosta & Ryan 1997, Baric et al 1998, Saudubray & Charpentier 2001]. The treatments, while similar in principle, depend on the specific biochemical lesion and are based on the position of the metabolic block and the effects of the toxic compounds. Treatment strategies include the following:

  • Dietary restriction of the precursor amino acids
  • Use of adjunctive compounds to:
    • Dispose of toxic metabolites
    • Increase activity of deficient enzymes

Dietary. Table 2 indicates the amino acids involved in the classic disorders. The use of specific metabolic foods (formulas) deficient in the particular precursor amino acids for each disorder is a critical part of management as it provides the essential amino acids in an otherwise protein-deficient diet.

Adequate calories to inhibit catabolism are supplied as carbohydrate and fat and appropriate protein must be supplied to support anabolism. Total parenteral nutrition has been used during gastrointestinal illness or surgery but must be monitored with careful attention to biochemical parameters.

Adjunctive compounds to dispose of toxic metabolites. Examples include use of thiamine to treat thiamine-responsive MSUD and hydroxocobalamin (but usually not cyanocobalamin) to treat methylmalonic acidemia. For the disorders of propionate metabolism, intermittent administration of non-absorbed antibiotics can reduce the production of propionate by gut bacteria.

Long-term care. Ongoing care requires the support of knowledgeable nutritionists and physicians. Frequent monitoring of growth, development, and biochemical parameters is essential. Long-term outcome can be excellent in the organic acidemias. However, appropriate management does not guarantee a good outcome, as individuals affected with an OA are medically fragile [de Baulny et al 2005].

Frequent episodes of decompensation can be devastating to the central nervous system. Any source of catabolic stress, such as vomiting, diarrhea, febrile illness, and decreased oral intake can lead to decompensation, which requires prompt and aggressive intervention. During acute decompensation, treatment strategies are directed toward elimination of the toxic amino acid precursors by restriction of their intake and the use of adjunctive measures such as hemodialysis. During acute decompensation, critical care support is often required, acidosis may need to be corrected, and careful and frequent biochemical monitoring is crucial.

The first episode of decompensation in glutaricacidemia type I (GA I) usually results in severe damage to the basal ganglia with resultant movement disorder. Early diagnosis with aggressive prevention of decompensation can prevent this damage. The pathophysiology may involve acute striatal necrosis; management of acute illness based on a model of stroke-like damage and brain energy deficiency has been advocated [Strauss & Morton 2003].

Early diagnosis of MSUD has a major effect on outcome.

The cblC form of methylmalonic acidemia does not appear to respond well to therapy, even when undertaken early [Rosenblatt et al 1997]. A late-onset form of cblC may respond better to treatment with hydroxocobalamin than the early-onset form [Bodamer et al 2001].

Liver transplantation. While liver transplantation has been performed on small numbers of affected individuals and thus cannot be considered a first-line treatment, the outcome has been successful in many cases. The usual complications of liver transplantation, including cyclosporin toxicity and rejection, have been reported [Burdelski & Ullrich 1999, Saudubray et al 1999]. Survival rates have been reported to be comparable to those in children undergoing transplant for non-metabolic diagnoses and quality of life is good [Leonard et al 2001, Kayler et al 2002].

Combined liver-kidney transplantation has an increasing role in the treatment of methylmalonic acidemia, since it has corrected the renal disease that many such individuals suffer and has resulted in near-normal metabolic status [McGuire et al 2008].

In mutase-deficient methylmalonic acidemia, combined liver-kidney transplantation is often used.

In propionic acidemia, liver transplantation alone ameliorates the disease, but does not completely eliminate the disorder because the kidney also makes propionic acid.

Pregnancy. With careful metabolic management, successful pregnancy has been achieved by women with isovaleric acidemia, MSUD, propionic acidemia, methylmalonic acidemia, and mitochondrial β-ketothiolase deficiency, without apparent adverse outcome to mother or fetus [Walter 2000, Deodato et al 2006]. Careful monitoring post partum, a period of particular metabolic stress for the mother, is crucial. While the likelihood that the infant will be affected is low, simple metabolic testing can be easily accomplished and may reassure anxious parents even before the newborn screening result is available.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

  1. Blau N, Duran M, Blaskovics ME, Gibson KM, Scriver CR. Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases. New York, NY: Springer; 2005.
  2. Dionisi-Vici C, Deodato F, Röschinger W, Rhead W, Wilcken B. 'Classical' organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: Long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis. 2006;29:383–9. [PubMed: 16763906]

Chapter Notes

Revision History

  • 22 December 2009 (me) Comprehensive update posted live
  • 26 June 2007 (cd) Revision: genetic testing (sequence analysis) for isovaleric academia available clinically and for prenatal diagnosis. Molecular genetic and biochemical testing clinically available for methylmalonic academia and homocystinuria, cb1C type and prenatal diagnosis.
  • 27 December 2006 (ms) Revision: biochemical prenatal diagnosis for ketothiolase deficiency available
  • 27 October 2006 (ms) Revision: targeted mutation analysis for p.A282V mutation clinically available
  • 2 May 2006 (ms) Revision: addition of methylmalonic aciduria and homocystinuria, cblC type
  • 24 March 2006 (me) Comprehensive update posted to live Web site
  • 28 June 2004 (cd) Revision: change in test availability
  • 9 December 2003 (me) Comprehensive update posted to live Web site
  • 27 June 2001 (ms) Overview posted to live Web site
  • 13 January 2001 (ms) Original submission
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