Funded by the NIH  •  Developed at the University of Washington, Seattle

 

Initial Posting: 27 June 2001

Last Update: 9 December 2003

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 result from dysfunction, usually because of deficient enzyme activity, of a specific step in amino acid catabolism. The majority of the classic organic acid disorders result from abnormal amino acid catabolism of branched chain amino acids or lysine. They include maple syrup urine disease (MSUD), propionic acidemia, methylmalonic acidemia (MMA), isovaleric acidemia, biotin-unresponsive 3-methylcrotonyl-CoA carboxylase deficiency, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency, ketothiolase deficiency, and glutaric acidemia 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 a 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 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 keto-acidosis, or psychiatric symptoms. A variety of MRI abnormalities have been described in the OAs, including distinctive basal ganglia lesions in GA I, white matter changes in MSUD, and abnormalities of the globus pallidus in methylmalonic acidemia.

Diagnosis/testing.  Clinical laboratory findings that should suggest an organic acidemia include acidosis, ketosis, hyperammonemia, abnormal liver function tests, hypoglycemia, and neutropenia. Propionic acidemia may present with isolated hyperammonemia early in its course. 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 organic acids found in the urine provide a high degree of suspicion for the specific pathway involved. 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 patient is not acutely ill. Depending on the specific disorder, plasma amino acid analysis can also be helpful. Plasma amino acid analysis requires a quantitative method such as column chromatography, high-performance liquid chromatography (HPLC), or GC/MS. Once the detection of specific analytes narrows the diagnostic possibilities, the activity of the deficient enzyme is measured in lymphocytes or cultured fibroblasts as a confirmatory test.

Genetic counseling.  The organic acidemias considered in this overview are inherited in an autosomal recessive manner. The parents are obligate heterozygotes and, therefore, carry a single copy of a disease-causing mutation. Heterozygotes are asymptomatic. At conception, the sibs of a proband have a 25% chance of being affected, a 50% chance of being unaffected and carriers, and a 25% chance of being unaffected and not carriers. The unaffected sibs of an affected individual have a two-thirds chance of being heterozygous. Three approaches to prenatal diagnosis are possible, depending on the disorder. These include measurement of analytes in amniotic fluid, measurement of enzyme activity in cells obtained by chorionic villus sampling or in cultured amniocytes, or molecular genetic testing of cells obtained by CVS or amniocentesis to identify the relevant mutations. For some disorders, molecular genetic testing may be available through laboratories offering custom prenatal testing.

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 NMDA receptors [Hoffman & Zschocke 1999]. Evidence suggests that methylmalonic acid is excitotoxic to neurons. 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 [Riviello et al 1991 , Nyhan et al 1998 , Kolker et al 2000 , Wajner et al 2000]. In addition, since catabolism of amino acids provides energy for other cellular processes, energy deficiency during metabolic crisis may contribute to the clinical syndrome. Since 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 a toxic encephalopathy and includes vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma. This non-distinct clinical picture may initially be attributed to sepsis, poor breast-feeding, or neonatal asphyxia. While a family history of neonatal death should prompt consideration of an organic acidemia, a negative family history does not exclude the possibility. Outcome is enhanced by diagnosis in the first ten days of life [Clarke 1996 , Acosta & Ryan 1997 , Baric et al 1998 , Saudubray & Charpentier 2001].

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 due to 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 keto-acidosis, or psychiatric symptoms. A variety of MRI abnormalities has been described in the OAs, including distinctive basal ganglia lesions in glutaric acidemia type I (GA I), white matter changes in MSUD, and abnormalities of the globus pallidus in methylmalonic acidemia. Macrocephaly is common in GA I.

Clinical course.  Despite appropriate management, patients with organic acidemias have a greater risk of infection and a higher incidence of pancreatitis, which can be fatal. Methylmalonic acidemia is associated with an increased frequency of renal failure and the cblC variant of methylmalonic acidemia is associated with pigmentary retinopathy [Kaplan et al 1991 , Peinemann & Danner 1994 , Leonard 1995 , Al-Bassam et al 1998 , Al Essa et al 1998 , Nicolaides et al 1998].

Establishing the Diagnosis

Clinical laboratory findings that should suggest an organic acidemia include acidosis, ketosis, hyperammonemia, abnormal liver function tests, hypoglycemia, and neutropenia. 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 patients. It is important to remember that these tests are screening tests, and the diagnosis must be confirmed using an independent GC/MS analysis of urinary organic acids as well as other appropriate tests when available [Goodman & Markey 1981 , Chalmers & Lawson 1982 , Blau et al 1996 , Seashore 1998].

Gas chromatography/mass spectrometry (GC/MS).  First-line diagnosis in the organic acidemias is urine organic acid analysis using gas chromatography with mass spectroscopy (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 methymalonic acid. When in excess, some of the co-enzyme 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 patient is not acutely ill. Thus obtaining a urine sample during the acute phase of the illness is crucial, even if it needs to be frozen and saved until the testing can be performed.

Because many laboratories have difficulty performing and/or interpreting urine organic acids on a 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.

• Mevalonic aciduria, a disorder of cholesterol biosynthesis, shows mevalonic acid in the urine.
• Glutaric acidemia 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 Disease 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) due to mutations in the gene encoding glutamate dehydrogenase need to be considered, although the urinary organic acid profile usually excludes them.

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

The majority of the classic organic acid disorders results 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).

Genotype/Phenotype Correlations

Mutations that have been reported can affect the active site of the enzyme, the binding site to the substrate, or the binding site for a cofactor. Although molecular specification of the gene mutations explains the response or lack of response to administration of cofactors of the deficient enzyme in some disorders that are cofactor responsive, much work remains to be done in developing genotype-phenotype correlations in the organic acidemias.

• In methylmalonic acidemia, the specific MUT mutation correlates with enzyme activity and designates the mut^- or mut⁰ form of the disorder. Enzyme activity correlates with clinical severity. Another specific mutation in the adenosylcobalamin binding site correlates in responsiveness to vitamin B₁₂ [Crane et al 1992 , Crane & Ledley 1994 , Ledley & Rosenblatt 1997 , Adjalla et al 1998 , Andersson & Shapira 1998].
• PCCA or PCCB can cause propionic acidemia. Some mutations are specific to particular ethnic, e.g., Spanish populations [Ugarte et al 1999 , Muro et al 2000].
• Expression data in over 60 mutations in GCDH in patients with glutaric acidemia I have shown little or no correlation between genotype and clinical phenotype, but some correlation with the excretion of glutaric acid metabolites is seen [Goodman et al 1998].

Evaluation Strategy

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

Plasma amino acid analysis.  Depending on the specific disorder, plasma amino acid analysis can be helpful, since specific abnormalities in plasma amino acid concentrations provide an important clue in identifying the disordered pathway. Plasma amino acid analysis requires a quantitative method such as column chromatography, high-performance liquid chromatography (HPLC), or GC/MS.

Enzyme analysis.  Once the detection of specific analytes narrows the diagnostic possibilities, the activity of the deficient enzyme is measured in lymphocytes or cultured fibroblasts as a confirmatory test.

Molecular genetic testing.  Molecular genetic testing can be used to confirm the diagnosis in some patients. The genes causing the organic acid disorders and the availability of molecular genetic testing are listed in Table 3 .

Compound heterozygosity for two different mutations is common in these autosomal recessive disorders. Carrier detection using molecular methods can be difficult if both mutations in a proband cannot be identified.

As with many other genetic conditions, particular sets of mutations are prevalent within specific ethnic groups. Examples include MSUD in the Old Order Amish and specific mutations in many organic acidurias among Arab populations in Saudi Arabia.

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 or cultural 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

This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis. —ED.

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, the sibs have a 25% chance of being affected, a 50% chance of being unaffected and carriers, and a 25% chance of being unaffected and not carriers.
• 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.  The sibs of obligate heterozygotes (the sibs of a proband's parents) have a 50% chance of being heterozygotes.

Carrier testing

• Carrier testing using molecular genetic techniques is not offered because it is not clinically available.
• 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. This has been well shown for propionic acidemia and seems true for methylmalonic acidemia.

Related Genetic Counseling Issues

Family planning.  The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

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 until the presence of the disorder is confirmed or excluded, is prudent.

DNA banking.  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. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Three approaches to prenatal diagnosis are possible, depending on the disorder. These include measurement of analytes in amniotic fluid, measurement of enzyme activity in cells obtained by chorionic villus sampling or in cultured amniocytes, or molecular genetic testing of cells obtained by CVS or amniocentesis to identify the relevant mutations if the two disease-causing mutations in the previously affected child are known. Amniocentesis is performed at 16-18 weeks' gestation* and chorionic villus sampling (CVS) at about 10-12 weeks' gestation.

• In propionic acidemia, methylmalonic acidemia and isovaleric acidemia, amniotic fluid measurements of the appropriate analytes using stable isotope dilution methods provide accurate and reliable identification of an affected fetus.
• In MSUD, enzyme activity in fetal cells obtained by chorionic villus sampling (CVS) or amniocentesis is reliable, but if cells from CVS are used, extreme care must be taken to assure that they are fetal, not maternal.

No laboratories offering molecular genetic testing for prenatal diagnosis of any of the organic acidemias discussed in this entry are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see .

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

Management

Many of the organic acidemias respond to treatment, and in the neonate especially, they demand emergency diagnosis and management. The aim of therapy is to restore biochemical and physiological homeostasis [Clarke 1996 , 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: 1) dietary restriction of the precursor amino acids; 2) use of adjunctive compounds to dispose of toxic metabolites; or 3) use of adjunctive compounds to 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 this must be done with great care and frequent monitoring of 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.

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 glutaric acidemia 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. 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].

Liver transplantation.  Successful liver transplantation has been performed on relatively few patients and cannot be considered a first-line treatment. However, successful outcome has been achieved in many of the small number of patients who have undergone transplantation. In the case of mutase-deficient methylmalonic acidemia, combined liver-kidney transplantation has corrected the renal disease that many such patients suffer and resulted in nearly normal metabolic status. In propionic acidemia, liver transplantation alone ameliorates the disease, but does not completely eliminate the disorder because the kidney also makes propionic acid. The usual complications of liver transplantation, such as cyclosporin toxicity and rejection, have been reported [Schlenzig et al 1995 , Burdelski & Ullrich 1999 , Saudubray et al 1999].

Pregnancy.