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Methylmalonic Acidemia

Synonyms: Methylmalonic Aciduria, Methylmalonicaciduria. Includes: MCEE-Related Methylmalonic Acidemia, MMAA-Related Methylmalonic Acidemia, MMAB-Related Methylmalonic Acidemia, MMADHC-Related Methylmalonic Acidemia, MUT-Related Methylmalonic Acidemia

, MD, PhD and , MD, PhD.

Author Information
, MD, PhD
Genetics and Molecular Biology Branch
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland
, MD, PhD
Genetics and Molecular Biology Branch
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: September 28, 2010.

Summary

Disease characteristics. Isolated methylmalonic acidemia/aciduria is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD variant 2 type), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes demonstrate periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress.

In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death.

In the infantile/non-B12-responsive phenotype, the most common form, infants are normal at birth but develop lethargy, vomiting, dehydration, hepatomegaly, hypotonia, and encephalopathy.

An intermediate B12-responsive phenotype can occasionally present in neonates, but usually presents in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake.

Atypical and "benign"/adult methylmalonic acidemia are associated with increased, albeit mild, urinary excretion of methylmalonate; however, it is uncertain if some of these individuals will develop symptoms. Major secondary complications of methylmalonic acidemia include developmental delay (variable); tubulointerstitial nephritis with progressive renal failure; “metabolic stroke” (acute and chronic basal ganglia involvement); disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.

Diagnosis/testing. Definitive diagnosis of isolated methylmalonic acidemia relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Establishing the specific enzymatic subtype of methylmalonic acidemia requires studies on vitamin B12 responsiveness, 14C propionate incorporation assays, complementation analysis, and cobalamin distribution assays. As an alternative or complement to the cellular biochemical studies, the finding of two distinct mutations in one of the genes associated with methylmalonic acidemia, with confirmation of carrier status in the parents, can definitely establish the diagnosis. MUT, MMAA, MMAB, MCEE, and MMADHC are the genes known to be associated with isolated methylmalonic acidemia.

Management. Treatment of manifestations: Critically ill individuals are stabilized by restoring volume status and acid-base balance; reducing or eliminating protein intake; providing increased calories via high glucose-containing fluids and insulin to arrest catabolism; and monitoring serum electrolytes and ammonia, venous or arterial blood gases, and urine output. Management includes a high-calorie diet low in propiogenic amino acid precursors); hydroxocobalamin intramuscular injections; carnitine supplementation; antibiotics such as neomycin or metronidazole to reduce propionate production from gut flora; gastrostomy tube placement as needed; and treatment of infections. Other treatments used in a limited number of patients include N-carbamylglutamate for the treatment of acute hyperammonemic episodes; liver, kidney or combined liver and kidney transplantation; and antioxidants for the treatment of optic nerve atrophy.

Prevention of primary manifestations: In some cases, newborn screening allows for pre-symptomatic detection of affected newborns and early treatment.

Agents/circumstances to avoid: Fasting and increased dietary protein.

Other: Medic Alert® bracelets and easily accessed detailed emergency treatment protocols facilitate care.

Genetic counseling. Isolated methylmalonic acidemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual 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 using molecular genetic techniques is possible in families in which the disease-causing mutations are known. Prenatal diagnosis for pregnancies at increased risk is possible by enzyme analysis and metabolite measurements on cultured fetal cells (obtained by chorionic villus sampling or amniocentesis), and by molecular genetic testing in those families in which the disease-causing mutations are known.

Diagnosis

Clinical Diagnosis

For this review, the term "isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine without hyperhomocysteinemia or homocystinuria, resulting from the failure to convert methylmalonyl-CoA into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix (Figure 1). The methylmalonic acidemia associated with succinyl-CoA ligase deficiency, caused by mutations in SUCLA2 or SUCLG1, is discussed in SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Aciduria.

Figure 1

Figure

Figure 1. Major pathway of the conversion of propionyl-CoA into succinyl-CoA. The biotin-dependent enzyme propionyl-CoA carboxylase converts propionyl-CoA into D-methylmalonyl-CoA, which is then racemized into L-methylmalonyl-CoA and isomerized into succinyl-CoA, (more...)

Isolated methylmalonic acidemia results from ONE of the following:

  • Complete (mut0 enzymatic subtype) or partial (mut enzymatic subtype) deficiency of the enzyme methylmalonyl-CoA mutase encoded by MUT
  • Diminished synthesis of its cofactor 5’-deoxyadenosylcobalamin, associated with cblA, cblB, or cblD-variant 2 complementation groups caused by mutations in MMAA, MMAB, and MMADHC, respectively
  • Deficient activity of methylmalonyl-CoA epimerase encoded by MCEE

The phenotype of isolated methylmalonic acidemia is nonspecific and can be shared by several related conditions.

Testing

Specialized metabolic testing is required to diagnose methylmalonic acidemia. An overview of the steps of intracellular cobalamin metabolism is depicted in Figure 1; a flowchart for the work-up of a person with elevated methylmalonic acid in urine and/or plasma is provided in Figure 2.

Figure 2

Figure

Figure 2. The algorithm for follow up of a positive newborn screen for methylmalonic academia was modified to include the consideration of methylmalonyl-CoA epimerase deficiency and the use of in vivo vitamin B12 responsiveness in the evaluation of an (more...)

Organic acid analysis. Definitive diagnosis relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography with confirmation of peaks by mass spectrometry (GC/MS).

  • The concentration of methylmalonic acid (MMA) is massively increased in the plasma, urine, and cerebrospinal fluid (CSF) in severely affected individuals.
  • Whole-body MMA excretion is typically elevated 1000-fold.

Approximate concentrations of MMA in various body fluids are listed in Table 1.

Table 1. Methylmalonic Acid Concentration in Phenotypes and Enzymatic Subtypes of Methylmalonic Acidemia

Methylmalonic Acidemia Phenotype/Enzymatic Subtype 1 Methylmalonic Acid Concentration
Urine 2 BloodCSF
Infantile/non-B12-responsive 3
mut0, mut, cblB
1000-10,000 mmol/mol Cr100-1000 µMUsually higher than blood
B12-responsive 3 cblA, cblD-var2
cblB, mut(rare)
Tens - hundreds mmol/mol Cr5-100 µMND
"Benign" /adult methylmalonic academia 4 10-100 mmol/mol Cr100 µM ND
MCEE deficiency 550-1,500 mmol/mol Cr7 µMND
Normal 6 <4 mmol/mol Cr 7<0.27 µM 70.59 µM

CSF= Cerebrospinal fluid

ND = not determined

1. Concordance between biochemical parameters and clinical phenotype does not always exist, partly because renal function can influence plasma MMA concentration.

2. In some centers, analysis of urine by 1H-NMR spectroscopy can also be used to demonstrate increased methylmalonate concentration [Iles et al 1986].

3. Approximate numbers, representing the author's experience with >50 individuals with the B12-responsive and non-B12-responsive types

4. From Giorgio et al [1976] and converted into µM for plasma concentration

5. Bikker et al [2006], Dobson et al [2006], Gradinger et al [2007]

6. From Gradinger et al [2007]

7. Normal values have not been exclusively derived from children or neonates. Some laboratories report urine MMA concentrations in mg/g/Cr (normal: <3 mg/g/Cr) and serum concentrations in nmol/L (normal: <271 nmol/L). The molecular weight of MMA is 118 g/mol.

Nonspecific findings on biochemical testing include the following:

  • 3-hydroxypropionate, 2-methylcitrate, and tiglylglycine detected in GC/MS analysis of urine
  • High anion gap metabolic acidosis in arterial or venous blood gas testing and huge quantities of ketone bodies and lactate in the urine that are detected in the decompensated state
  • Hyperammonemia
  • Increased concentration of glycine detected on plasma amino acid analysis
  • Elevated plasma concentration of propionylcarnitine (C3) and variable elevations in C4-dicarboxylic or methylmalonic/succinyl-carnitine (C4DC), measured by tandem mass spectrometry

Other nonspecific laboratory findings:

  • Neutropenia, thrombocytopenia, anemia

Establishing the specific enzymatic subtype of methylmalonic acidemia requires the following studies:

• Vitamin B12 responsiveness. In vivo responsiveness to vitamin B12 should be determined in all affected individuals. No standard regimen has been documented. When stable, affected individuals can be given 1.0 mg of hydroxocobalamin (OH-Cbl)* intramuscularly or intravenously every day for five days followed by assessment of production of MMA and related metabolites (3-OH-propionic, 2-methylcitrate) by serial urine organic acid analyses and /or measurements of plasma concentrations of MMA, propionylcarnitine, and homocysteine. A significant (more than 50%) reduction in metabolite production and plasma concentration(s) is considered to indicate responsiveness [Fowler et al 2008].

*Note: Hydroxocobalamin (not the cyano form) is the preferred preparation for treatment of methylmalonic acidemia.

14C propionate incorporation assay. The cellular assay of propionate conversion indirectly measures the activity of the enzyme methylmalonyl-CoA mutase by assessing the incorporation of the 14C radiolabel in the precursor, propionate, into macromolecules following its intramitochondrial activation to propionyl-CoA and subsequent emersion into the Krebs cycle (tricarboxylic acid cycle) in cultured skin fibroblasts. The technique involves incubating cells from the affected individual with 14C-labeled propionic acid, which is converted as indicated in Figure 1 into succinyl-CoA, then through the Krebs cycle into amino acids, and then into protein. A block (mutation) at any of the steps can reduce incorporation of 14C into protein; hence, this assay is not specific for methylmalonyl-CoA mutase deficiency [Morrow et al 1975].

The following methylmalonyl-CoA mutase deficiency enzymatic subtypes are recognized:

  • mut0 enzymatic subtype, in which enzymatic activity is non-detectable
  • mut enzymatic subtype, in which residual enzymatic activity is present

Note: In addition, this in vitro assay can be used to provide insight into responsiveness to exogenous administration of cobalamin, particularly if in vivo studies are questionable or borderline; however, it should be noted that the in vitro results do not always predict cofactor responsiveness in vivo.

In a recent study in vivo response was reported in all individuals with cblA and only rare individuals with cblB [Hörster et al 2007].

• Complementation analysis. This assay assigns a genetic group or class to the enzymatic block (i.e., mut0/mut, cblA, cblB, cblD variant 2) using heterokaryon rescue or enzymatic cross-correction [Gravel et al 1975]. The cell line from the affected individual is mixed with a panel of established cell lines of known status (e.g., mut0, cblA). Assignment of the enzymatic block to a particular complementation group is especially important if the abnormality is not in MUT, the gene encoding L-methylmalonyl-CoA mutase. For more details about complementation analysis, click here (pdf).

• Cobalamin distribution. This assay uses radioactive CN-[57Co] cobalamin to assess uptake, intracellular amounts, and relative proportions of CN-Cbl, OH-Cbl, adenosyl-Cbl (AdoCbl), and methyl-Cbl (MeCbl) by HPLC [Fowler & Jakobs 1998].

Newborn screening. In the past several years, the implementation of tandem mass spectrometry (MS/MS) in newborn screening (NBS) by many states in the US and countries worldwide has identified newborns with methylmalonic acidemia through detection of elevated concentration of blood propionylcarnitine (C3), a metabolite increased in the blood of individuals with methylmalonic acidemia and the related disorder, propionic acidemia [Chace et al 2001].

Note: Since propionylcarnitine is one of the analytes most frequently responsible for false positive results, ratios including C3/C2, C3/C0, C3/C16, and new biomarkers such as C16:1OH are recommended in combination with high blood concentration of C3 as decision criteria for “positive” testing in newborn screening acylcarnitine analysis by MS/MS for methylmalonic acidemia and propionic acidemia [Lindner et al 2008].

Second-tier testing of 3-hydroxypropionic, methylmalonic, and/or 2-methylcitric acids could be used to reduce the costs and anxiety associated with false positive results [Matern et al 2007, La Marca et al 2008].

  • If C3 and C5OH are increased, the diagnosis of holocarboxylase deficiency and/or biotinidase deficiency needs to be considered.
  • Elevated C4-dicarboxylic acylcarnitine (C4DC) is a marker for both methylmalonyl- and succinylcarnitine, and can indicate methylmalonic aciduria associated with succinyl-CoA ligase deficiency [Fowler et al 2008, Morava et al 2009].

Recommended action (ACT) sheet and confirmatory algorithm describing the basic necessary steps involved in the follow up of an infant who has screened positive are available; see the American College of Medical Genetics (ACMG) Newborn screening Web site and the National Academy of Clinical Biochemistry Guidelines (pdf) [National Academy of Clinical Biochemistry 2009].

Molecular Genetic Testing

Genes. MUT, MMAA, MMAB, MCEE, and MMADHC are the genes currently known to be associated with isolated methylmalonic acidemia.

Clinical testing

  • Sequence analysis of MUT, MMAA, MMAB, MMADHC, and MCEE
  • Deletion/duplication analysis. No data are available on mutation detection frequency.
  • Targeted mutation analysis for MUT mutation c.322C>T for individuals of Hispanic descent

Table 2. Summary of Molecular Genetic Testing Used in Isolated Methylmalonic Acidemia

Gene 1Approximate % of All Isolated MMA Attributed to Mutations in This GeneTest MethodMutations Detected 2Mutation Detection Frequency by Test Method 3,4
MUT60%
(78% mut0 enzymatic subtype, 22% mut enzymatic subtype)
Sequence analysisSequence variants 595%
Deletion / duplication analysis 6Exonic and whole-gene deletionsUnknown
Targeted mutation analysisSee footnote 7See footnote 7
MMAA25% Sequence analysisSequence variants 598%
Deletion / duplication analysis 6Exonic and whole-gene deletionsUnknown
MMAB12% Sequence analysisSequence variants 5Unknown
Deletion / duplication analysis 6Exonic and whole-gene deletionsUnknown
MCEEUnknownSequence analysisSequence variants 5Unknown
MMADHCUnknownSequence analysisSequence variants 5Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Based on Worgan et al [2006] and Hörster et al [2007]

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. For individuals of Hispanic descent, targeted mutation analysis for the MUT mutation c.322C>T is possible.

Testing Strategy

Confirmation of the diagnosis in a proband

  • Molecular genetic testing can be used in some settings to establish the diagnosis, specifically if two pathogenic mutations are identified in the proband and confirmed in the parents. Because the phenotype of isolated MMA can be identical regardless of the gene involved, molecular genetic testing can be performed in the following order: MUT and MMAB in B12-non-responsive individuals and MMAA in B12-responsive individuals. Molecular genetic testing of MCEE should be considered if testing of the other three genes is unrevealing and the 14C-propionate incorporation studies fail to assign a complementation class.

    Molecular genetic test results may also provide insight into genotype/phenotype associations.
  • Cellular biochemical testing including 14C-propionate incorporation studies and/or complementation analysis is the preferred method to establish the diagnosis; however, both require a skin biopsy to construct a primary fibroblast cell line and neither is widely available. Of note, these tests can (a) confirm the biochemical defect at the cellular level; (b) eliminate other diagnoses; and (c) test for B12 responsiveness in vitro. The 14C propionate incorporation assay is performed first to confirm the presence of a block in the pathway, and the complementation analysis second to assign a class to the lesion, especially if a diagnosis based on DNA testing is not definitive. Results of the complementation analysis can guide molecular genetic testing for the less common types of isolated methylmalonic acidemia, including those types caused by mutation of MMAA, MMAB, and MMADHC.

    If the in vivo response to intramuscular OH-Cbl is questionable or borderline, vitamin B12 administration should be continued until the results of the in vitro studies are available.

Note: A modified algorithm to include the consideration of methylmalonyl-CoA epimerase and succinyl-CoA ligase deficiencies, as well as the use of in vivo B12 responsiveness in the work-up of an individual who is found to have elevated methylmalonic acid at any age, is provided (Figure 2).

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

The phenotypes of isolated methylmalonic acidemia described below that are associated with the genetic variants mut0 enzymatic subtype, mutenzymatic subtype, cblA, cblB, and cblD variant 2 share clinical presentations and a natural history of periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress.

Infantile/ (non-B12-responsive) phenotype (mut0 enzymatic subtype, cblB). The most common phenotype of isolated methylmalonic acidemia presents during infancy. Infants are normal at birth, but rapidly develop lethargy, vomiting, and dehydration. Upon presentation, they exhibit hepatomegaly, hypotonia, and encephalopathy. Laboratory findings typically show a severe, high anion gap metabolic acidosis, ketosis and ketonuria, hyperammonemia, and hyperglycinemia [Matsui et al 1983]. Dialysis may be needed especially if hyperammonemia is significant and persistent. Thrombocytopenia and neutropenia, suggestive of neonatal sepsis, can be seen.

Catastrophic neonatal presentation of isolated methylmalonic acidemia can result in death, despite aggressive intervention. Rarely, infants with the B12-responsive mutenzymatic subtype or cblA can also present with an acute neonatal crisis.

Partially deficient or B12-responsive phenotype (mut enzymatic subtype, cblA, cblB [rare], cblD-variant 2). This intermediate phenotype of isolated MMA can occur in the first few months or years of life. Affected infants can exhibit feeding problems (typically anorexia and vomiting), failure to thrive, hypotonia, and developmental delay. Some have protein aversion and/or clinical symptoms of vomiting and lethargy after protein intake. These infants are at risk for a catastrophic decompensation, as can occur in the neonate, until the diagnosis is established and treatment initiated.

Less common is a phenotype characterized by early childhood presentation. Typically, clinical evidence of disease is not present before the first episode of vomiting, dehydration, lethargy, or coma that is often associated with respiratory distress, hepatomegaly, and seizures. As with the phenotypes in other metabolic diseases, such an episode may mimic sepsis or Reye syndrome.

During an episode of metabolic decompensation, the child may die despite intensive intervention if prompt treatment specific for MMA is not instituted. Establishing the diagnosis of MMA may be delayed, especially if a coexisting medical condition confounds the clinical picture [Ciani et al 2000].

"Benign"/adult form of isolated methylmalonic acidemia. A "benign" form of isolated methylmalonic acidemia is associated with increased, albeit mild, urinary excretion of methylmalonate [Giorgio et al 1976]. Affected individuals have been viewed as stable but may be prone to acute metabolic decompensation [Shapira et al 1991]. The etiology of this form of methylmalonic acidemia has not been fully established.

Methylmalonyl-CoA epimerase deficiency. Mutations in MCEE are a rare cause (6 individuals reported to date) of persistent moderate methylmalonic aciduria. Findings range from an initial presentation of severe metabolic acidosis with increased MMA and 2-methylcitrate and ketones in the urine to those more mildly affected. Symptoms include ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures. The first identified individual was the product of a consanguineous union and also had a DOPA-responsive dystonia, which resulted from a fortuitous homozygous mutation in SPR, the gene encoding sepiapterin reductase [Bikker et al 2006].

Secondary complications. Despite increased knowledge about isolated methylmalonic acidemia and possibly earlier symptomatic diagnosis, isolated methylmalonic acidemia continues to be associated with substantial morbidity and mortality [De Baulny et al 2005, Dionisi-Vici et al 2006] that correlates with the underlying defect [Hörster et al 2007]. Individuals with the mut0 enzymatic subtype and the cblB subtype have a higher rate of mortality and neurologic complications than those with the mut enzymatic subtype and cblA. The major secondary complications include:

  • Intellectual disability. Intellectual disability is not always present even in those who have severe disease. Intellectual disability may be related to the decompensated state, and may depend on the magnitude and duration of hyperammonemia. In a retrospective, survey-based review, about 50% of individuals with the mut0 enzymatic subtype and 25% of those with the cblA/cblB enzymatic subtype had an IQ below 80 and significant neurologic impairment [Baumgarter & Viardot 1995]. More recently, about 50% of individuals with mut0, 85% with mut, 48% with cblA, and 70% with cblB had an IQ above 90 [Hörster et al 2007].
  • Tubulointerstitial nephritis with progressive impairment of renal function. All individuals with isolated methylmalonic acidemia, even those who are mildly affected or who have received a liver allograft [Nyhan et al 2002] are thought to be at risk of developing renal insufficiency; direct nephrotoxicity of methylmalonic acid is hypothesized. End-stage renal disease (ESRD) was common in the mut0 enzymatic subtype (61%) and the cblB (66%) enzymatic subtype, but occurred less frequently in the cblA (21%) enzymatic subtype [Hörster et al 2007].

    An acute renal syndrome, seen in the setting of metabolic decompensation, may also exist [Stokke et al 1967] and requires further clinical delineation. Moreover, renal tubular dysfunction presenting as a decrease in urine concentrating ability and acidification, hyporeninemic hypoaldosteronism, tubular acidosis type 4, and hyperkalemia have been reported in a number of affected individuals [Walter et al 1989, D’Angio et al 1991, Pela et al 2006].
  • Neurologic findings. Some individuals develop a “metabolic stroke” or infarction of the basal ganglia, characteristically the globus pallidus, during acute metabolic decompensation, which can produce an incapacitating movement disorder [Korf et al 1986, Heidenreich et al 1988]. Of the survivors in one series, 20% had choreoathetosis and lesions in the basal ganglia [Baumgarter & Viardot 1995].

    Delayed myelination, incomplete opercularization, subcortical white matter changes, and brain stem and cerebellar changes have been described [Harting et al 2008, Radmanesh et al 2008]. Of note, individuals who have undergone liver and/or kidney transplantation can develop acute lesions without overt metabolic decompensation, suggesting that the enzyme deficiency in the brain remains unchanged and trapping of toxic metabolites in the CNS compartment can lead to injury despite other systemic benefits of the transplantation [Chakrapani et al 2002].
  • Pancreatitis. The incidence of pancreatitis in isolated methylmalonic acidemia is unknown, but it is a well-recognized complication [Kahler et al 1994]. It can occur acutely or chronically. Pancreatitis may be under-recognized because it can manifest nonspecifically with vomiting and abdominal pain.
  • Growth failure. Growth failure may be caused by both chronic illness and relative protein malnutrition. Many infants are less than three standard deviations below normal for both length and weight.

    Some children have documented growth hormone (GH) deficiency, but may not have an optimal response to GH therapy unless titration to the replacement dose is carefully adjusted [Bain et al 1995]. The indications for GH replacement therapy and the response to GH replacement in treated individuals require further investigation.
  • Functional immune impairment. This results in an increased susceptibility to severe infections, particularly by fungal and gram-negative organisms [Oberholzer et al 1967, Wong et al 1992].
  • Optic nerve atrophy. Late-onset optic atrophy associated with acute visual loss, resembling the presentation of the mitochondrial disorder Leber hereditary optic neuropathy (LHON), has been reported in isolated methylmalonic acidemia [Wasserstein et al 1999, Williams et al 2009], as well as in propionic acidemia [Williams et al 2009].

Survival in isolated methylmalonic acidemia has improved over time [Matsui et al 1983, van der Meer et al 1994, Baumgarter & Viardot 1995, Nicolaides et al 1998].

In those with the mut0 enzymatic subtype, survival at age one year has improved from 65% in the 1970s to over 90% in the 1990s; five-year survival has improved from 33% in the 1970s to over 80% in the 1990s.

In a recent series, the median age of death of those with the mut0 enzymatic subtype was compared over time: 100% died at a median age of 1.6 years in the 1970s, 50% died at a median age of 7.6 years in the 1980s, and a 20% died at a median age of 2.2 years in the 1990s. Overall mortality was about 50% for those with the mut0 enzymatic subtype (median age of death 2 years) as compared to 50% for the cblB enzymatic subtype (median age of death 2.9 years), 40% for the mut enzymatic subtype, (median age of death 4.5 years) and about 5% for the cblA enzymatic subtype (1 death at 14 days) [Hörster et al 2007].

Effect of newborn screening. The limited number of infants detected by newborn screening (NBS) and the short duration of their follow up do not allow conclusions regarding the effect of NBS on the long-term outcome of methylmalonic acidemia [Leonard et al 2003, Dionisi-Vici et al 2006]. Moreover, it must be emphasized that a significant number of individuals with the mut0 enzymatic subtype may present clinically before the NBS results become available. Limited observations in sibs with the cblA enzymatic subtype suggest that the IQs of the individuals treated from the newborn period were significantly better than those of their older affected sibs who were diagnosed after the onset of symptoms [Hörster et al 2007].

The natural history of isolated methylmalonic acidemia requires further study, particularly with respect to medical complications including renal disease, the effect of solid organ transplantation, and molecular pathology.

Genotype-Phenotype Correlations

Precise genotype-phenotype correlations are difficult to ascertain because most individuals are compound heterozygotes.

Homozygosity for the p.Arg108Cys MUT mutation is frequently associated with severe mutase deficiency (i.e., the mut0 enzymatic subtype) [Acquaviva et al 2005].

Homozygosity for the p.Gly717Val MUT mutation is associated with the mut enzymatic subtype [Worgan et al 2006].

Nonsense mutations usually result in a severe mut0 enzymatic subtype; however, a milder enzymatic subtype with a homozygous Arg727* MUT mutation, which falls in the terminal exon, has been reported in one patient [Oyama et al 2007].

There are reports of individuals with the mut enzymatic subtype presenting with acute metabolic crisis [Worgan et al 2006].

Because the clinical phenotype depends on whole-body enzyme activity, in vivo responsiveness to cobalamin, environmental factors, and perhaps the efficiency and activation of alternative propionyl-CoA disposal pathways, a better understanding of clinical correlations in isolated methylmalonic acidemia could be achieved by estimating the amount of whole-body residual metabolic capacity based on stable isotope studies [Leonard 1997].

Prevalence

Several studies have estimated the birth prevalence of isolated methylmalonic acidemia [Sniderman et al 1999]. Urine screening for isolated methylmalonic acidemia in Quebec identified "symptomatic methylmalonic aciduria" in approximately 1:80,000 newborns screened [Sniderman et al 1999], which approximates the observation of Chace et al [2001] of ten cases of isolated methylmalonic acidemia identified in a sample of 908,543 newborns screened by mass spectrometry in the US.

In Japan, the birth prevalence may be as high as 1:50,000 [Shigematsu et al 2002].

It appears that the prevalence of isolated methylmalonic acidemia may therefore fall between 1:50,000 and 1:100,000. However, larger studies are required to confirm this.

Differential Diagnosis

"Benign" methylmalonic acidemia. Newborn screening in the province of Quebec identified infants with mild-to-moderate urinary methylmalonic acid excretion. Follow up revealed resolution in more than 50% of children, as well as an apparently benign, persistent, low-moderate hypermethylmalonic acidemia in some [Sniderman et al 1999]. Additional individuals with a relatively benign type of methylmalonic acidemia have been reported [Martens et al 2002]. Caution is necessary in follow up of these individuals as some with the mut enzymatic subtype can present with acute metabolic crisis [Shapira et al 1991]. The long-term outcome and clinical phenotype of these individuals awaits further description. Some had a combined biochemical genetic phenotype of malonic and methylmalonic acidemia and therefore may not have a defect in methylmalonyl-CoA mutase activity or cobalamin metabolism [Sniderman et al 1999].

Combined methylmalonic acidemia and homocystinuria. Disorders that interfere with the intake, uptake, absorption, intestinal transport, delivery, and early metabolism of cobalamin can cause a perturbation in the synthesis of adenosylcobalamin and/or methylcobalamin. However, these conditions are usually accompanied by clinically significant hyperhomocysteinemia. The following are included in this group of disorders:

  • Cobalamin C deficiency (cblC) perhaps the most common inborn error of intracellular cobalamin metabolism. Individuals with this disorder almost always have increased plasma concentrations of homocysteine and methylmalonic acid, with low levels of methionine, while they frequently develop a pigmentary retinopathy and a “bull’s eye” maculopathy.
  • Deficiency of complementation group cblD and group cblF are extremely rare disorders.
    • CblF deficiency is caused by mutations in LMBRD1, which encodes a putative lysosomal cobalamin exporter [Rutsch et al 2009], affecting the synthesis of the cofactors for the enzyme methylmalonyl-CoA mutase (encoded by MUT) and the enzyme methyltetrahydrofolate: homocysteine methyltransferase, also known as methionine synthase (MS) (encoded by MTR).
    • CblD deficiency is heterogeneous [Suormala et al 2004]. Coelho et al [2008] identified the gene (C2ORF25) responsible for cblD and determined genotype/phenotype correlations:
      • Mutations that caused the mut enzymatic subtype only (cblD type 2) were nonsense and frame-shifting mutations in exons 3 and 4;
      • Mutations that caused the MTR enzymatic subtype only (cblD type1) were missense mutations in exons 6-8 ;
      • Mutations that cause a combined mut/MTR- enzymatic subtype (cblD) are frame-shifting mutations in exon 5, exon 8, and intron 7.

Note: Individuals with complementation cblD variant 1 [Coelho et al 2008], cblE (methionine synthase reductase), and cblG (methionine synthase) abnormalities do not have methylmalonic academia, but homocystinuria caused by impaired methyl-cobalamin synthesis.

Vitamin B12 deficiency. Individuals with vitamin B12 deficiency can have increased methylmalonic acidemia and homocystinuria. Maternal B12 deficiency can produce a methylmalonic acidemia syndrome in an infant that ranges from severe encephalopathy to elevated serum concentration of propionylcarnitine detected by newborn screening [Chace et al 2001]. This metabolic abnormality can occur in a breast-fed infant of a vegan mother and in an infant born to a mother with subclinical pernicious anemia. The mother does not necessarily have a very low serum concentration of vitamin B12. IM vitamin B12 replacement therapy to normalize vitamin B12 serum concentration reverses the metabolic abnormality.

Mitochondrial encephalomyopathy with elevated methylmalonic acid. Mild methylmalonic aciduria has been described in cases of succinate-ligase alpha subunit (SUCLG1 mutations) and succinate-ligase ADP-forming beta subunit (SUCLA2 mutations) associated with mitochondrial DNA depletion presenting with severe lactic acidosis and encephalomyopathy.

Succinyl-CoA ligase (SUCL) catalyzes the reversible conversion of succinyl-CoA and ADP or GDP to succinate and ATP or GTP, and is composed of an α subunit encoded by SUCLG1 and a β subunit encoded by either SUCLA2 or SUCLG2.

Mutations in SUCLG1 result in a severe phenotype, associated with lactic acidosis and early death in the first week of life.

SUCLA2 mutations are associated with hypotonia, muscle atrophy presenting around ages three to six months (with mtDNA depletion, complex I, III, and IV deficiency in the muscle), hyperkinesia, seizures, severe hearing impairment, and growth failure. Patients develop a Leigh syndrome-like disorder, cortical and basal ganglia atrophy, and dystonia. Some affected individuals can die in infancy; others have survived into their 20s. (See SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Aciduria.)

Methylmalonic aciduria ranges from 10 to 200 mmol/mol creatinine in these individuals and is accompanied by raised plasma concentrations of lactate, methylcitrate, 3-hydroxyproprionic and 3-hydroxyisovaleric acid, proprionylcarnitine, and C4-dicarboxylic carnitine (C4DC) [Elpeleg et al 2005, Carrozzo et al 2007, Ostergaard et al 2007, Morava et al 2009].

Reye-like syndrome. A Reye-like syndrome of hepatomegaly and obtundation in the face of a mild intercurrent infection can be seen as an unrecognized presentation of a number of inborn errors of metabolism, including isolated methylmalonic acidemia [Chang et al 2000].

Other entities that can display methylmalonic acidemia despite normal methylmalonyl-CoA mutase enzyme activity have been variably described:

  • “Atypical” methylmalonic acidemia has been reported with progressive neurodegenerative disease, microcephaly, and cataracts (two sibs) [Strømme et al 1995] or with a mitochondrial depletion syndrome/complex IV deficiency and combined propionic and methylmalonic acidemia (one person) [Yano et al 2003]. These cases have similarities with the phenotype caused by mutations in SUCLA2.
  • Benign methylmalonic acidemia with distal renal tubular acidosis (one sibship) [Dudley et al 1998]
  • Malonyl-CoA decarboxylase deficiency, usually associated with combined methylmalonic and malonic aciduria, with significantly higher malonic versus methylmalonic acid levels [Brown et al 1984]
  • Combined malonic and methylmalonic acidemia with methylmalonic acid predominating and normal malonyl-CoA decarboxylase activity [Gregg et al 1998]
  • Isolated methylmalonic acidemia, possibly caused by methylmalonic semialdehyde dehydrogenase deficiency [Roe et al 1998]
  • Isolated methylmalonic aciduria and normal plasma concentrations of methylmalonic acidemia (one family) [Martens et al 2002]

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with isolated methylmalonic acidemia, the following evaluations are recommended:

  • A serum chemistry panel (Na+, K+, CI, glucose, urea, creatinine, AST, ALT, alkaline phosphatase, bilirubin [T/U], triglycerides, and cholesterol); complete blood count with differential; arterial or venous blood gas; plasma ammonium concentration; formal urinalysis; quantitative plasma amino acids; and urine organic acid analysis by gas chromatography and mass spectrometry (GC-MS)
  • If possible, measurement of plasma concentrations of methylmalonic acid, methylcitrate, free and total carnitine, and an acylcarnitine profile to document propionylcarnitine (C3 species) concentration
  • Measurement of serum vitamin B12 concentration to determine if a nutritional deficiency is present in the patient or the mother (in newborns)

Treatment of Manifestations

Critically ill individuals must be stabilized in the following manner:

  • Volume replacement with isotonic solutions. Do not use Lactated Ringers.
  • All IV solutions should contain glucose, preferably D10 or D12.5. If hyperglycemia develops, an insulin infusion may be needed.
  • The total base deficit should be followed serially with repeat electrolyte and venous or arterial blood gas measurements and corrected by hydration and bicarbonate replacement, if needed.
  • Adequate kcals must be delivered. Central or peripheral total parenteral nutrition (TPN), which typically contains glucose and amino acids, and in some instances, lipids, may be required.
  • Carnitine may be administered intravenously.
  • Urine output and serum sodium concentration need to be monitored.
  • Dietary protein should be reintroduced as soon as is feasible given the clinical scenario and may need to be further augmented with TPN.
  • Hemodialysis may be required in the event of treatment failure (uncontrollable acidosis and/or hyperammonemia).

During times of illness, aggressive fluid, metabolic, and nutritional management is necessary. Most individuals require "sick day" management regimens, which typically consist of reducing or eliminating protein intake and increasing fluids and glucose to ensure delivery of adequate calories and to arrest lipolysis. Immediate hospitalization is usually required if signs suggest intercurrent infection.

Most affected individuals require gastrostomy tube placement because of anorexia and vomiting.

Prevention of Primary Manifestations

Dietary management. After stabilization, nutritional management is critical. This typically includes instituting a low-protein, high-calorie diet. Natural protein needs to be carefully titrated to allow for normal growth, while avoiding excessive propiogenic amino acid load into the pathway. In some patients with very low protein tolerance propiogenic amino acid precursors, such as isoleucine and valine, can be severely restricted, which can produce a nutritional deficiency state and requires vigilant monitoring of plasma amino acid concentrations. When stable, a typical neonate may be placed on a diet that provides 1.5 g/kg/day of whole protein plus a propiogenic amino acid-deficient formula such as PropimexTM. A protein-free formula, such as ProphreeTM, is given to some individuals to provide extra fluid and calories. As the infant grows, the total protein load is slowly reduced, based on growth, plasma amino acid concentrations, and plasma and urine methylmalonic acid concentrations.

Hydroxocobalamin injections, 1.0 mg every day to every other day are usually required in individuals who are vitamin B12 responsive. The regimen of B12 injections needs to be individually adjusted according to the patient’s age and, possibly, weight.

Carnitine can be given at a dose of 50-100 mg/kg/day, up to approximately 300 mg/kg/day. As a dietary supplement, carnitine may increase intracellular CoA pools and enhance the excretion of propionylcarnitine. The contribution of propionylcarnitine excretion to the total propionate load is, however, small. The relief of intracellular CoA accretion may be the mechanism by which carnitine supplementation benefits some individuals.

Antibiotics. A variety of antibiotic regimens to reduce the production of propionate from gut flora can be used:

  • Oral neomycin, 250 mg by mouth four times a day, was the original regimen reported by Snyderman et al [1972].
  • Metronidazole at 10-15 mg/kg/day has also been used with success.

The intervals at which affected individuals are treated may vary, but typically feature one week to ten days of treatment per month.

Although oral antibiotics reduce the propionate load that derives from gut flora in affected individuals, chronic antibiotic therapy is not innocuous; it introduces the risk of repopulation of the individual with resistant flora. This could pose a serious infectious threat and could be especially dangerous to individuals with isolated methylmalonic acidemia, since most deaths are related to metabolic decompensation, often precipitated by infection.

Response to antibiotic administration should be determined in treated persons by demonstrating either a decrease in whole body output of methylmalonic acid on antibiotic therapy by a timed urine collection or a decrease in the plasma methylmalonic acid concentration compared to the baseline value for that individual.

Rotating antibiotic regimens may be required in some persons.

Antioxidants. One individual with isolated methylmalonic acidemia, documented to be glutathione deficient after a severe metabolic crisis, responded to ascorbate therapy [Treacy et al 1996]. Several recent studies document increased oxidative stress, glutathione depletion, and specific respiratory chain complex deficiencies in persons with the mut0 enzymatic subtype with methylmalonic acidemia [Schwab et al 2006, Atkuri et al 2009, Chandler et al 2009, de Keyzer et al 2009], suggesting a potential benefit of treatment with antioxidants or other mitochondria-targeted therapies in these patients.

A regimen of coenzyme Q10 and vitamin E has been shown to prevent progression of acute optic nerve involvement in a patient with MMA [Pinar-Sueiro et al 2010].

Organ transplantation. Preliminary data suggest that liver transplantation can protect against metabolic instability, but carries significant pre- and post-procedural risks and is not curative [Leonard et al 2001].

Because most of the metabolic conversion of propionate occurs in the liver, replacing the liver could contribute enough enzyme activity to avert metabolic decompensation. To date, few individuals with isolated methylmalonic acidemia have undergone living donor liver transplantation or combined liver-kidney transplantation in order to avoid continuing metabolic damage to the kidney [van Hoff et al 1998, Kayler et al 2002, Nyhan et al 2002, Hsui et al 2003, Kasahara et al 2006, Morioka et al 2007]. The underlying biochemical parameters and the frequency of metabolic decompensation improved significantly in individuals undergoing liver transplantation despite persistent metabolic abnormalities [Nyhan et al 2002], probably as a resut of increased extrahepatorenal methylmalonic acid production primarily from the skeletal muscle [Chandler et al 2007a]. Following liver transplantation, some individuals continued to have progressive renal failure as well as high CSF concentrations of methylmalonic acid [Kaplan et al 2006]. One had a metabolic infarction of the brain, supporting the hypothesis that methylmalonic acid is produced de novo in the CNS [Chakrapani et al 2002] and suggesting that adequate protein restriction should be continued after the transplantation.

Some individuals have received only renal allografts [Van Calcar et al 1998, Lubrano et al 2001]; the transplanted kidney in one person was claimed to provide enough enzyme activity to normalize methylmalonic acid excretion and allow for increased dietary protein tolerance [Lubrano et al 2001].

The number of individuals who have undergone liver and/or kidney transplantation, the detailed effects on the underlying metabolic disorder, and the overall outcome in those undergoing this procedure have yet to be determined. Inclusion of enzymatic and mutation information in case series of transplanted patients will allow better comparisons of the outcomes and genotype-phenotype associations that could inform decisions about the indication and timing of transplantation in individual cases.

Prevention of Secondary Complications

Frequent monitoring of plasma amino acids is necessary to avoid deficiency of essential amino acids (particularly isoleucine) as a result of excessive protein restriction and the development of acrodermatitis-enteropathica-like cutaneous lesions in methylmalonic aciduria, as in other organic acidurias (glutaric aciduria-I) and amino acid disorders (MSUD) [De Raeve et al 1994]. Adjusting dietary whole (complete) protein intake, based on clinical and laboratory findings, is needed throughout life for these patients.

Surveillance

During the first year of life, infants may need to be evaluated as frequently as every week. There are no guidelines regarding the recommended type or frequency of laboratory testing.

Agents/Circumstances to Avoid

The following should be avoided:

  • Fasting. During acute illness, intake of adequate calories is necessary to arrest/prevent decompensation.
  • Stress
  • Increased dietary protein

Evaluation of Relatives at Risk

Depending on the genotype and phenotype of the proband, evaluation of sibs at risk should be performed using biochemical testing and treatment instituted as soon as possible if the sibling is affected. Cellular enzymology and/or molecular genetic analysis typically can further confirm the results of biochemical studies.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Gene therapy: Preliminary studies in human-derived hepatocytes and animal models of methylmalonic acidemia suggest a potential benefit of gene therapy [Chandler et al 2007b, Chandler & Venditti 2008, Chandler & Venditti 2010, Carrillo-Carrasco et al 2010]. The effect of that therapeutic approach in patients and especially on the long-term complications of methylmalonic acidemia remains to be elucidated in appropriate clinical studies.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Medic Alert® bracelets and emergency treatment protocols outlining fluid and electrolyte therapy should be available for all affected individuals.

Although all of the treatments discussed above may be needed in fragile individuals, they still may not prevent death, the severe sequelae of metabolic decompensation (e.g., metabolic stroke of the basal ganglia), or renal disease. The correlation and identification of treatment patterns and outcomes is needed to develop more effective management protocols for individuals with isolated methylmalonic acidemia.

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

Isolated methylmalonic acidemia is 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 one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual 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. The offspring of an individual with isolated methylmalonic acidemia are obligate heterozygotes (carriers) for a disease-causing mutation.

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 in families in which the MUT, MMAA, MMAB, or MMADHC mutations are known.

Methods other than molecular genetic testing are not reliable for carrier testing.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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.

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

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).

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

Biochemical testing. Prenatal testing for pregnancies at 25% risk for isolated methylmalonic acidemia is possible by:

  • Amniotic fluid analysis of metabolites. The absolute positive predictive and negative predictive values of metabolite analysis only have yet to be determined. Elevation of metabolites below the range of affected fetuses can indicate a heterozygous status and should therefore be followed by confirmatory testing in cell studies.
  • Enzyme analysis of cultured fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Studies on chorionic villus cells can be false negative and should be followed up by studies on cultured amniocytes [Morel et al 2005]. Biochemical confirmation of the diagnosis in an affected family member must be obtained before prenatal testing can be performed.

Note: The most prudent recommendation is to perform both metabolite analysis AND enzymatic assays of cultured CVS or amniocytes. Confirmation in postnatal fibroblasts should be routinely requested.

Preimplantation genetic diagnosis (PGD) 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.

  • National Library of Medicine Genetics Home Reference
  • Save Babies Through Screening Foundation, Inc.
    P. O. Box 42197
    Cincinnati OH 45242
    Phone: 888-454-3383
    Email: email@savebabies.org
  • Organic Acidemia Association
    PO Box 1008
    Pinole CA 94564
    Phone: 510-672-2476
    Fax: 866-539-4060 (toll-free)
    Email: carolbarton@oaanews.org
  • European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B. OMIM Entries for Methylmalonic Acidemia (View All in OMIM)

251000METHYLMALONIC ACIDURIA DUE TO METHYLMALONYL-CoA MUTASE DEFICIENCY
251100METHYLMALONIC ACIDURIA, cblA TYPE
251110METHYLMALONIC ACIDURIA, cblB TYPE
251120METHYLMALONYL-CoA EPIMERASE DEFICIENCY
277410METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblD TYPE
607481MMAA GENE; MMAA
607568MMAB GENE; MMAB
608419METHYLMALONYL-CoA EPIMERASE; MCEE
609058METHYLMALONYL-CoA MUTASE; MUT
611935MMADHC GENE; MMADHC

MMAA

Normal allelic variants. MMAA contains seven exons; the first is non-coding [Dobson et al 2002b].

Pathologic allelic variants. More than 20 mutations have been described, including missense, nonsense, and splicing mutations, deletions, and insertions [Dobson et al 2002a, Lerner-Ellis et al 2004, Yang et al 2004, Merinero et al 2008]. One common mutation, p.Arg145*, accounts for 43% of mutant alleles identified in one large study [Lerner-Ellis et al 2004]. This mutation resides on a common haplotype and has also been seen in Spanish individuals [Martinez et al 2005]. In Japan, a common deletion, c.503delC, has been observed [Yang et al 2004].

Table 3. Selected MMAA Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.64C>Tp.Arg22*NM_172250​.1
NP_758454​.1
c.161G>A p.Trp54*
c.266T>Cp.Leu89Pro
c.283C>Tp.Gln95*
c.358C>Tp.Gln120*
c. 397C>Tp.Gln133*
c.433C>Tp.Arg145*
c.503delCp.Thr168Metfs*9
c.562G>Cp.Gly188Arg
c.650T>Ap.Leu217*
c.653G>Ap.Gly218Glu
c.733+1G>A--
c.988C>Tp.Arg330*
c.1076G>Ap.Arg359Gln

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The gene is predicted to encode a protein of 418 amino acids. The predicted protein product possesses a mitochondrial leader sequence and appears to belong to the ArgK protein subfamily of G3E GTPases [Leipe et al 2002]. While this gene was originally proposed to function in cobalamin entry into the mitochondria [Dobson et al 2002a], it was recently characterized as a metallochaperone GTPase that acts to protect the methylmalonyl-CoA mutase enzyme from oxidative inactivation during catalytic cycles and to facilitate cofactor (adenosylcobalamin) binding [Korotkova & Lidstrom 2004, Hubbard et al 2007].

Abnormal gene product. The precise biochemical function of the MMAA protein product is unknown but suspected to be similar to homologs in bacteria. Missense mutations appear to fall in evolutionarily conserved residues or consensus splice sites. Environmental, dietary, and (possibly) epigenetic modifiers may operate to define the phenotype in this condition, especially since individuals homozygous for identical mutations can exhibit disparate phenotypes [Lerner-Ellis et al 2004].

MMAB

Normal allelic variants. MMAB contains nine exons. Two common normal allelic variants have been described: p.Arg19Gln and p.Met239Lys, which had frequencies of 36% and 46% in control alleles. The protein with the p.Met239Lys substitution has kinetic parameters that are physiologically appropriate [Leal et al 2004].

Pathologic allelic variants. Several missense, nonsense/frameshift, and splice-site mutations have been identified [Dobson et al 2002b, Yang et al 2004, Martinez et al 2005, Lerner-Ellis et al 2006]. More than half of the mutations were localized to exon 7 [Lerner-Ellis et al 2006]:

  • c.556C>T, the most common mutation in a large series [Lerner-Ellis et al 2006], accounted for 33% of all alleles and seen exclusively among affected individuals of European descent, was associated with early onset of symptoms (age <1 year).
  • Two African Americans with the c.403G>A, c.571C>T, and c.656A>G mutations had late presentation (ages 3 and 8 years) [Lerner-Ellis et al 2006].

Table 4. Selected MMAB Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.56_57delGCinsAAp.Arg19GlnNM_052845​.3
NP_443077​.1
c.287T>Cp.Ile96Thr
c.291-1G>A--
c.403G>Ap.Ala135Thr
c.556C>T p.Arg186Trp
c.568C>Tp.Arg190Cys
c.569G>Ap.Arg190His
c.571C>Tp.Arg191Trp
c.572G>Ap.Arg191Gln
c.656A>Gp.Tyr219Cys
c.197-1G>T--
c.700C>Tp.Gln234*
c.716T>Ap.Met239Lys

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The gene encodes the 250 amino acid protein Cob(I)alamin adenosyltransferase, an enzyme that transfers the adenosyl group from ATP to Co[+1] balamin [Leal et al 2003]. The crystal structure of a bacterial homologue has been determined [Saridakis et al 2004].

Abnormal gene product. The reported missense mutations fall into residues that are evolutionarily conserved [Dobson et al 2002b]. One mutation destroys a splice site [Dobson et al 2002b, Martinez et al 2005]. Several mutant alleles have been biochemically characterized [Saridakis et al 2004].

MUT

Normal allelic variants. MUT contains 13 exons. A number of intragenic polymorphisms at this locus exist, including p.His532Arg and p.Val671Ile [Ledley & Rosenblatt 1997, Worgan et al 2006].

Pathologic allelic variants. More than 190 mutations have been described, including 103 (54%) missense mutations; 27 (14%) nonsense mutations; 18 (9%) splicing mutations; 42 (22%) small insertions/deletions; and one large deletion of exon 12. The mutations are distributed throughout the entire coding sequence except for exon 1, which is untranslated [Crane et al 1992, Crane & Ledley 1994, Ogasawara et al 1994, Ledley & Rosenblatt 1997, Adjalla et al 1998, Fuchshuber et al 2000, Acquaviva et al 2001, Acquaviva et al 2005, Jung et al 2005, Martinez et al 2005, Worgan et al 2006, Gradinger et al 2007, Lempp et al 2007, Sakamoto et al 2007, Merinero et al 2008].

For a list of alleles that have been repeatedly identified in diverse populations, click here (pdf).

While some individuals are homozygous for a given mutation, most are compound heterozygotes. The phenomenon of interallelic complementation makes prediction of genotype/phenotype/enzyme activity difficult because some individuals who have two mutations can have a mut enzymatic subtype in the compound state but a mut0 enzymatic subtype in the homozygous state [Janata et al 1997, Ledley & Rosenblatt 1997, Acquaviva et al 2005].

Persons with two truncating mutations usually have the mut0 enzymatic subtype.

Nonsense mutations have been described in the following codons: 7, 18, 31, 54, 84, 117, 135, 152, 156, 161, 224, 228, 284, 342, 403, 413, 414, 426, 429, 451, 467, 474, 494, 511, 581, 589, 688, and 727.

Only a few mutations are seen frequently in homozygous form; p.Arg108Cys, p.Asn219Tyr, and p.Arg369His cause a mut0 enzymatic subtype when homozygous, while p.Gly717Val and p.Arg694Trp are associated with a mut enzymatic subtype when homozygous.

The mut enzymatic subtype is known to be associated mostly, but not exclusively, with mutations in the cobalamin binding domain of the mut protein. The mut enzymatic subtype mutation plays usually a dominant role when in compound heterozygote state with a mut0 enzymatic subtype mutation, given an OH-Cbl response in the in vitro assay [Lempp et al 2007].

Table 5. Selected MUT Missense Variants

Class of Variant AlleleMut Enzymatic Subtype (when Homozygous)DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
Normal--c.636A>Gp.= 2
(Lys212Lys)
NM_000255​.1
NP_000246​.1
c.1495G>Ap.Ala499Thr
c.1595A>Gp.His532Arg
c.2011G>Ap.Val671Ile
c.636A>Gp.= 2
(Lys212Lys)
c.1992G>Ap.= (Ala664Ala)
Pathologicmut0c.278G>Ap.Arg93His
mut0c.284C>Gp.Pro95Arg
mut0c.313T>Cp.Try105Arg
mut0c.322C>Tp.Arg108Cys
mut0c. 521T>Cp.Phe174Ser
mut0c.572C>Ap.Ala191Glu
mut0c.607G>Ap.Gly203Arg
mut0c.643G>Ap.Gly215Ser
mut0c.655A>Tp.Asn219Tyr
mut0c.935G>Tp.Gly312Val
mut0c.1105C>Tp.Arg369Cys
mut0c.1106G>A p.Arg369His
mut0c.1280G>A p.Gly427Asp
mut0c.1867G>Ap.Gly623Arg
mut¯c.281G>Tp.Gly94Val
mut¯c.299A>Gp.Tyr100Cys
mut¯c.691T>A p.Tyr231Asn
mut¯c.1097A>Gp.Asn366Ser
mut¯c.1867G>Ap.Gly623Arg
mut?c.2054T>Gp.Leu685Arg
mut¯c.2080C>Tp.Arg694Trp
mut¯c.2099T>Ap.Met700Lys
mut¯c.2150G>Tp.Gly717Val

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

mut0 = mut0 enzymatic subtype

mut= mut enzymatic subtype

1. Variant designation that does not conform to current naming conventions

2. p.= designates that protein has not been analyzed, but no change is expected

Normal gene product. Methylmalonyl-CoA mutase enzyme is a nuclear-encoded, mitochondrially localized enzyme that exists as a homodimer. The protein contains 750 amino acids and has an N-terminal mitochondrial leader sequence (residues 1-32) that is removed by the mitochondrial importation and processing machinery. The mitochondrial leader signal is followed by the N-terminal extended segment (residues 33-87), which is involved in subunit interaction. The N-terminal barrel is the substrate binding domain (residues 88-422) and is attached to the C-terminal adenosylcobalamin binding domain (residues 578-750) by a long linker region (423-577). The protein contains a mole of adenosylcobalamin per mole of subunit and performs a 1, 2 rearrangement reaction, isomerizing L-methylmalonyl-CoA into succinyl-CoA [Fenton et al 2001].

Abnormal gene product. Only selected mutations have been studied enzymatically. The methylmalonyl-CoA mutase protein has several functional domains and mutations have been described in each. A mitochondrial leader sequence lies at the amino terminus. Three nonsense mutations that fall into this domain have been described: p.Gln7* [Acquaviva et al 2005] and p.Gln18* and p.Arg31* [Worgan et al 2006]. One report noted that a truncated protein, likely translated from an internal AUG, arose from the p.Gln18* mutant allele. This mutant protein is "mis-targeted" and not functional. Adjacent to, but distinct from, the mitochondrial leader sequence is the putative dimerization domain of the enzyme subunits. The coenzyme-A binding pocket spans the middle of the second exon to the end of the sixth exon. Mutations that reside in this location, between amino acids 86 and 423, may destroy substrate binding and are predicted to impede catalysis by a variety of mechanisms. Some, such as p.Arg93His, can participate in interallelic complementation. The mechanism underlying this phenomenon is unclear [Worgan et al 2006]. A linker domain spanning residues 424-577 separates the C-terminal cobalamin-binding domain. Most of the mutations identified in this domain are splice-site or nonsense changes and have been associated with mut0 enzymatic subtype of methylmalonic acidemia [Acquaviva et al 2005], while the only missense mutation located in the middle of this segment c.1553T>C, p.Leu518Pro affects a highly conserved amino acid [Worgan et al 2006]. Most of the mut enzymatic subtype mutations reside in the cobalamin binding domain, which is located between amino acids 578 and 750. Some mutations in this region can display purely Km effects, as might be expected for a cofactor binding mutations, while others affect the Km and Vmax [Janata et al 1997]. This region also contains residues that can participate in interallelic complementation [Ledley & Rosenblatt 1997].

MCEE

Normal allelic variants. MCEE has four exons.

Pathologic allelic variants. After the initial identification of two individuals with methylmalonic aciduria who were homozygous for the MCEE c.139C>T mutation [Bikker et al 2006, Dobson et al 2006], an additional four of 229 individuals with elevated MMA of unknown etiology were reported to have mutations in MCEE [Gradinger et al 2007]. Two persons with decreased [14C]propionate incorporation were homozygous for the nonsense mutation c.139C>T in exon 2. Among 199 persons with normal [14C]propionate incorporation, one was homozygous for the novel missense mutation c.178A>C in exon 2, and two were heterozygous for the novel missense mutation c.427C>T in exon 3.

Table 6. Selected MCEE Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.139C>Tp.Arg47*NM_032601​.3
NP_115990​.3
c.178A>Cp.Lys60Gln
c.427C>Tp.Arg143Cys

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The human DL-methylmalonyl-CoA racemase gene on Chr 2p13.3 was cloned by Bobik & Rasche [2001] by analyzing prokaryotic gene arrangements.

The deduced 176-amino acid protein contains an N-terminal mitochondrial targeting sequence.

Abnormal gene product. The mutations described to date are either missense or nonsense and are predicted to decrease or eliminate function.

MMADHC

Normal allelic variants. MMADHC (formerly C2orf25) comprises eight exons and spans 18 kb [Coelho et al 2008].

Table 7. Selected MMADHC Pathologic Allelic Variants Associated with Isolated MMA

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.160C>Tp.Arg54*NM_015702​.2
NP_056517​.1
c.57_64delCTCTTTAGp.Ser20*
(Cys19fs*20)
c.307_324dupp.Leu103_Ser108dup
c.60_61insAT
(60insAT)
p.Leu21Ilefs*2
(L20fs*21)
c.455dupCp.Cys153Metfs*10
(T152fs*162)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Pathologic allelic variants. Mutations in the C-terminal region (exons 3, 4, or 5) that cause a cblD variant 2 only phenotype (isolated methylmalonic aciduria) include c.57_64delCTCTTTAG, c.160C>T, and c.307_324dup.

Missense mutations in the N-terminal region (exons 6 and 8) that cause cblD variant 1 only phenotype (isolated homocystinuria) include c.776T>C, c.545C>A, c.746A>G and c.737A>G.

Truncating mutations in exons 5 and 8 and intron 7 that cause the classic cblD phenotype (combined homocystinuria and methylmalonic aciduria) include c.748C>T, c.419dupA, c.683C>G, and c.696+1_4delGTGA [Coelho et al 2008, Miousse et al 2009].

Normal gene product. The MMADHC protein product is predicted to have 296 amino acids with a calculated molecular mass of 32.8 kd. It shows homology to the putative ATPase component of a bacterial ABC transporter. There is an N-terminal mitochondrial leader sequence and a predicted B12 binding sequence [Coelho et al 2008]. The gene contains a second initiation codon, Met62 that leads to the reinitiation of translation resulting in the formation of a shorter functional cblD protein product that lacks the putative mitochondrial leader sequence but allows for normal methylcobalamin synthesis [Coelho et al 2008].

Abnormal gene product. There are no clearly identified common disease-causing variants. The mutations describe to date are either missense or truncating mutations (nonsense or frameshift).

References

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Suggested Reading

  1. Junyent M, Parnell LD, Lai CQ, Lee YC, Smith CE, Arnett DK, Tsai MY, Kabagambe EK, Straka RJ, Province M, An P, Borecki I, Ordovás JM. Novel variants at KCTD10, MVK, and MMAB genes interact with dietary carbohydrates to modulate HDL-cholesterol concentrations in the Genetics of Lipid Lowering Drugs and Diet Network Study. Am J Clin Nutr. 2009;90:686–94. [PMC free article: PMC2728650] [PubMed: 19605566]
  2. Paré G, Chasman DI, Parker AN, Zee RR, Mälarstig A, Seedorf U, Collins R, Watkins H, Hamsten A, Miletich JP, Ridker PM. Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study. Circ Cardiovasc Genet. 2009;2:142–50. [PMC free article: PMC2745176] [PubMed: 20031578]
  3. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM, Strait J, Duren WL, Maschio A, Busonero F, Mulas A, Albai G, Swift AJ, Morken MA, Narisu N, Bennett D, Parish S, Shen H, Galan P, Meneton P, Hercberg S, Zelenika D, Chen WM, Li Y, Scott LJ, Scheet PA, Sundvall J, Watanabe RM, Nagaraja R, Ebrahim S, Lawlor DA, Ben-Shlomo Y, Davey-Smith G, Shuldiner AR, Collins R, Bergman RN, Uda M, Tuomilehto J, Cao A, Collins FS, Lakatta E, Lathrop GM, Boehnke M, Schlessinger D, Mohlke KL, Abecasis GR. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008;40:161–9. [PubMed: 18193043]

Chapter Notes

Author Notes

Dr Manoli is a pediatrician and clinical and biochemical geneticist. She is a staff clinician at the Organic Acid Research Unit of the National Human Genome Research Institute, at the National Institutes of Health.

Dr Venditti is a pediatrician and clinical and biochemical geneticist. He is the director of the Organic Acid Disorder Research Unit at the National Human Genome Research Institute and an attending physician at the National Institutes of Health Clinical Center.

Revision History

  • 28 September 2010 (me) Comprehensive update posted live
  • 18 January 2007 (cd) Revision: testing for mutations in MMAA and MMAB clinically available
  • 16 August 2005 (me) Review posted to live Web site
  • 11 May 2004 (cpv) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview ‘Methylmalonic Acidemia’ is in the public domain in the United States of America.

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