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

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

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.

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].

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.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in MUT, MMAA, MMAB, and MCEE.

Mutations in MMADHC are also associated with CblD (methylmalonic acidemia/aciduria and hyperhomocysteinemia/homocystinuria) and CblD variant 1 (hyperhomocysteinemia/homocystinuria), which are discussed in Disorders of Intracellular Cobalamin Metabolism.

Natural History

The phenotypes of isolated methylmalonic acidemia described below that are associated with the genetic variants mut⁰ enzymatic subtype, mut^–enzymatic 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 mut^–enzymatic 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 Arg727X 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.

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 D_12.5. 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 Propimex^TM. A protein-free formula, such as Prophree^TM, 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 't 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.

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.

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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]

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.