Clinical characteristics.

For this GeneReview, 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 that result from the failure to isomerize (convert) methylmalonyl-coenzyme A (CoA) into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid. Isolated MMA 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, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Prior to the advent of newborn screening, common phenotypes included:

• Infantile/non-B₁₂-responsive form (mut⁰ enzymatic subtype, cblB), the most common phenotype, associated with infantile-onset lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds. Without appropriate treatment, the infantile/non-B₁₂-responsive phenotype could rapidly progress to coma due to hyperammonemic encephalopathy.
• Partially deficient or B₁₂-responsive phenotypes (mut^– enzymatic subtype, cblA, cblB [rare], cblD-MMA), in which symptoms occur in the first few months or years of life and are characterized by feeding problems, failure to thrive, hypotonia, and developmental delay marked by episodes of metabolic decompensation
• Methylmalonyl-CoA epimerase deficiency, in which findings range from complete absence of symptoms to severe metabolic acidosis. Affected individuals can also develop ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures.

In those individuals diagnosed by newborn screening and treated from an early age, there appears to be decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage. However, secondary complications may still occur and can include intellectual disability, tubulointerstitial nephritis with progressive impairment of renal function, "metabolic stroke" (bilateral lacunar infarction of the basal ganglia during acute metabolic decompensation), pancreatitis, growth failure, functional immune impairment, bone marrow failure, optic nerve atrophy, arrhythmias and/or cardiomyopathy (dilated or hypertrophic), liver steatosis/fibrosis/cancer, and renal cancer.

Diagnosis/testing.

The diagnosis of isolated MMA is established in a proband by identification of biallelic pathogenic variants in MCEE, MMAA, MMAB, MMADHC, or MMUT or (in some instances) by significantly reduced activity of one of the following enzymes: methylmalonyl-CoA mutase, methylmalonyl-CoA mutase enzyme cofactor 5'-deoxyadenosylcobalamin, or methylmalonyl-CoA epimerase. Because of its relatively high sensitivity, easier accessibility, and noninvasive nature, molecular genetic testing can obviate the need for enzymatic testing in most instances.

Management.

Treatment of manifestations / Prevention of primary manifestations: When isolated MMA is suspected during the diagnostic evaluation due to elevated propionylcarnitine (C3) on a newborn blood spot, metabolic treatment should be initiated immediately, while the suspected diagnosis is being confirmed. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach by experienced subspecialists from a specialized metabolic center. The main principles of treatment are to provide supplemental vitamin B₁₂ to those who are known to be vitamin B₁₂ responsive; restrict natural protein, particularly of propiogenic amino acid precursors, while maintaining a high-calorie diet; address feeding difficulties, recurrent vomiting, and growth failure; provide supplemental carnitine to those with carnitine deficiency; reduce propionate production from gut flora; and provide emergency treatment during episodes of acute decompensation with the goal of averting catabolism and minimizing central nervous system injury. In those with significant metabolic instability and/or renal failure, liver and/or renal transplantation may be considered.

Prevention of secondary complications: MedicAlert^® bracelets and up-to-date, easily accessed, detailed emergency treatment and presurgical protocols to facilitate care.

Surveillance: Regular evaluations by a metabolic specialist and metabolic dietician; screening laboratory testing, including plasma amino acids, plasma and urine MMA levels, serum acylcarnitine profile and free and total carnitine levels, blood chemistries, and complete blood count at least every six months to one year, or more frequently in infants or in those who are unstable or require frequent changes in dietary management; measurement of renal function at least annually or as clinically indicated; assessment for liver disease at least annually or as clinically indicated; assessment of developmental progress and for signs of movement disorder at each visit; ophthalmology evaluation to monitor for optic atrophy at least annually or as clinically indicated; audiology evaluation at least annually in childhood and adolescence or as clinically indicated.

Agents/circumstances to avoid: Fasting, stress, increased dietary protein, supplementation with the individual propiogenic amino acids valine and isoleucine, nephrotoxic medications or agents, and agents that prolong QTc in the EKG.

Evaluation of relatives at risk: For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, measure serum methylmalonic acid, urine organic acids, plasma acylcarnitine profile, plasma amino acids, and serum B₁₂; test for the familial isolated methylmalonic acidemia-causing pathogenic variants if biochemistry is abnormal.

Pregnancy management for an affected mother: Monitor for complications including acute decompensation or hyperammonemia, deterioration of renal function, and obstetric complications including preeclampsia and preterm delivery.

Pregnancy management for an unaffected mother with an affected fetus: Oral and intramuscular vitamin B₁₂ has been administered to women pregnant with a fetus with vitamin B₁₂-responsive MMA, resulting in decreased maternal MMA urine output; however, further study of this treatment is needed.

Genetic counseling.

All forms of isolated MMA are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an isolated MMA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the isolated MMA-causing pathogenic variants have been identified in an affected family member, molecular genetic carrier testing and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Scenario 1: Abnormal Newborn Screening (NBS) Result

Newborn screening test. NBS for isolated methylmalonic acidemia is primarily based on quantification of the analyte propionylcarnitine (C3) on dried blood spots.

Elevated C3 values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see also the ACMG ACT Sheet).

• In the US, individual state NBS programs determine cutoffs based on analytic and other considerations, under the guidance of the CDC Newborn Screening Quality Assurance Program (NSQAP) and Association of Public Health Laboratories (APHL) [McHugh et al 2011, Held et al 2022].
• Since propionylcarnitine is one of the analytes most frequently responsible for false positive results, ratios including C3/C2, C3/C0, C3/C16, C3/glycine, or C3/methionine 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 [Gavrilov et al 2020].
• Additional biomarkers such as C16:1OH (3-hydroxypalmitoleolyl-carnitine) or, more accurately, C17 (heptadecanoylcarnitine) have been suggested to improve the sensitivity of the first-tier newborn screening test [McHugh et al 2011, Malvagia et al 2015].
• Amino acid analysis of the dried blood spot will show normal methionine and elevated C3/methionine ratio.
• Precision newborn screening and avoidance of false positive results can be further improved with the utilization of the Collaborative Laboratory Integrated Reports software [Gavrilov et al 2020].

The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this is a true positive NBS result and to establish the diagnosis of isolated MMA definitively (see Management):

• Prompt evaluation for prevention or treatment of possible hyperammonemia and metabolic ketoacidosis
• Daily intramuscular vitamin B₁₂ administration (Hydroxocobalamin is preferred over cyanocobalamin, especially in individuals with cobalamin C deficiency.)
• Initiation of a low-protein diet
• Carnitine supplementation

Testing to consider after a positive NBS. A positive C3 screening result is followed by testing for methylmalonic acid, 2-methylcitrate, and total homocysteine in the dried blood spot to differentiate isolated MMA from propionic acidemia and defects resulting in combined methylmalonic acidemia and homocystinuria [Turgeon et al 2010, Weiss et al 2020, Pajares et al 2021].

Follow-up biochemical testing after an abnormal NBS typically demonstrates:

• Elevated plasma methylmalonic acid (MMA) level
• Elevated levels of urine MMA and the presence of 3-hydroxypropionate, 2-methylcitrate, and tiglylglycine on urine organic acids
• Elevated concentrations of glycine and possibly alanine with normal methionine on plasma amino acids
• Elevated plasma concentration of propionylcarnitine (C3) and variable elevations in C4-dicarboxylic or methylmalonic/succinylcarnitine (C4DC) on plasma acylcarnitine profile
• Elevated plasma ammonia, metabolic ketoacidosis, pancytopenia, lactic acidosis, hypoglycemia (in some cases)
• Normal serum B₁₂ and plasma homocysteine

Note: (1) Although plasma and/or urine methylmalonic acid concentration can be precisely quantitated (see Table 1), this is generally not needed immediately for diagnostic purposes. (2) If MMA is confirmed, further biochemical testing of plasma homocysteine and serum vitamin B₁₂ (in both the newborn and the mother) helps further differentiate the cause of MMA (see Figure 2, left two columns).

Figure 2.

An algorithm of conditions to be considered in the differential diagnosis of elevated serum or urine methylmalonic acid detected either during the follow up of an increased propionylcarnitine (C3) on newborn screening or following a positive urine organic (more...)

If follow-up biochemical testing supports the likelihood of isolated methylmalonic acidemia, additional testing is required to establish the diagnosis (see Establishing the Diagnosis).

Establishing the Diagnosis

The diagnosis of isolated MMA is established in a proband by identification of biallelic pathogenic variants in one of the genes listed in Table 2 on molecular genetic testing or – in some instances – by significantly reduced activity of the enzymes listed below and in Table 1. Because of its relatively high sensitivity, easier accessibility, and noninvasive nature, molecular genetic testing can obviate the need for enzymatic testing, and is thus increasingly the preferred confirmatory test for isolated MMA.

Isolated MMA is caused by any ONE of the following:

• Complete (mut⁰ enzymatic subtype) or partial (mut^–) deficiency of the enzyme methylmalonyl-CoA mutase, encoded by MMUT
• Diminished synthesis of the methylmalonyl-CoA mutase enzyme cofactor 5'-deoxyadenosylcobalamin, associated with cblA, cblB, or cblD-MMA complementation groups caused by biallelic pathogenic variants in MMAA, MMAB, or MMADHC, respectively
• Deficient activity of methylmalonyl-coenzyme A epimerase encoded by MCEE

Molecular genetic testing (see Table 2) can be used to establish the diagnosis of isolated MMA by identifying biallelic pathogenic variants in one of the genes listed in Table 2 and confirming carrier status in the parents.

Clinical Description

The phenotypes of isolated methylmalonic acidemia (MMA) described below that are associated with the enzymatic subtypes mut⁰, mut^–, cblA, cblB, and cblD-MMA share clinical presentations and a natural history characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress [Zwickler et al 2012]. Each such decompensation can be life threatening. Table 3 reviews the phenotypes, causative genes, enzymatic subtypes, and clinical correlations that will be discussed further in this section.

Genotype-Phenotype Correlations

Precise genotype-phenotype correlations are difficult to determine since most affected individuals are compound heterozygotes and many pathogenic variants are not recurrent in the population.

MMAB

• c.556C>T (p.Arg186Trp). This is the most common pathogenic variant, present in 29%-33% of alleles from European and North American cohorts [Lerner-Ellis et al 2006, Forny et al 2022].
  Individuals homozygous for this pathogenic variant typically present in the neonatal period and are not responsive to hydroxocobalamin treatment.
• c.700C>T (p.Gln234Ter). Individuals with at least one c.700C>T (p.Gln234Ter) pathogenic variant generally have more variable, often later age of presentation/diagnosis (range: 2 days – 6.5 years) and some affected individuals demonstrate a biochemical response to hydroxocobalamin therapy [Forny et al 2022]. This variant is located in the last exon and may avoid nonsense-mediated decay, resulting in a partially functional protein.

MMADHC. Truncating pathogenic variants in the N-terminal region (exons 3, 4) cause isolated methylmalonic aciduria due to a defect in adenosylcobalamin synthesis; pathogenic variants elsewhere in this gene cause the other two biochemical phenotypes (see Genetically Related Disorders).

MMUT. The phenomenon of interallelic complementation makes prediction of genotype/phenotype/enzyme activity difficult because some individuals who have two pathogenic variants can have a mut^– enzymatic subtype in the compound state but a mut⁰ enzymatic subtype in the homozygous state [Acquaviva et al 2005].

• Persons with two truncating pathogenic variants usually have the mut⁰ enzymatic subtype.
• Most of the pathogenic variants identified in the N-terminal domain have been associated with mut⁰ enzymatic subtype of methylmalonic acidemia [Acquaviva et al 2005, Forny et al 2016]
• The mut^– enzymatic subtype is known to be associated mostly, but not exclusively, with pathogenic variants in the adenosylcobalamin-binding C-terminal domain of the MMUT protein.
• The mut^– enzymatic subtype pathogenic variant usually plays a dominant role when in compound heterozygous state with a mut⁰ enzymatic subtype pathogenic variant, given a OH-Cbl response in the in vitro assay [Lempp et al 2007, Forny et al 2016].
• A linker domain spanning residues 482-585 separates the N-terminal, or substrate (methylmalonyl-CoA) binding domain from the C-terminal cobalamin-binding domain. This linker region is less conserved and has a lower frequency of pathogenic variants [Forny et al 2016].

Prevalence

Several studies have estimated the birth prevalence of isolated methylmalonic acidemia. Urine screening for isolated methylmalonic acidemia in Quebec identified "symptomatic methylmalonic aciduria" in approximately 1:80,000 newborns screened [Sniderman et al 1999].

The aggregate incidence from different newborn screening (NBS) programs in the US is reported as 1:159,614 [Therrell et al 2014, Chapman et al 2018]. A meta-analysis [Almási et al 2019] confirmed that the detection rate of MMA and isolated MMA in North America, Europe and Asia-Pacific regions was <1:100,000, while rates in the Middle East, North Africa, and Japan were higher [Shigematsu et al 2002].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with isolated MMA, the evaluations summarized Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Guidelines developed by professionals across 12 European countries and the US based on rigorous literature evaluation and expert group meetings outline the current management recommendations and areas for further research. See Baumgartner et al [2014] (full text) and Forny et al [2021] (full text).

Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma), often occurring in the setting of intercurrent illness and/or inadequate caloric intake, should be managed symptomatically and with generous caloric support in a hospital setting, with aggressive treatment and supportive care. Immediate consultation with a metabolic/biochemical geneticist is essential. Individuals with MMA can deteriorate rapidly and consultations with neurology, nephrology, and ICU teams are often required during crises (see Table 10).

Transition from pediatric to adult-centered multidisciplinary care settings. As MMA is a lifelong disorder with varying implications according to age, smooth transition of care from the pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Standardized procedures for transitional care do not exist for isolated MMA due to the absence of multidisciplinary outpatient departments.

• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with isolated methylmalonic acidemia together with pediatric or adult metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized and there is limited availability of clinics for adults with IEMs, continuous supervision by a center with expertise in metabolic diseases with sufficient resources is essential.

Prevention of Primary Manifestations

See also Table 7, which outlines dietary therapies that can help to prevent a metabolic crisis.

Large case series of affected individuals undergoing elective liver or combined liver/kidney transplantation (as opposed to isolated kidney transplantation) have detailed the indications, peri-operative complications, surgical and anesthesia approaches, anti-rejection regimens, and long-term outcomes in people with MMA undergoing these procedures. Inclusion of enzymatic and genotype information in case series of transplanted individuals allows for better comparisons of the outcomes and genotype-phenotype associations that could inform decisions about the indication and timing of transplantation in individual cases.

Liver transplantation is increasingly offered to younger affected individuals with significant metabolic instability, often in infancy, as a measure to prevent neurologic damage from recurrent metabolic crises associated with hyperammonemia. Referral to centers with experience in managing people with organic acidemias and continued monitoring and dietary therapy are essential for all MMA transplant recipients.

Antioxidants. One individual with isolated MMA who was documented to be glutathione deficient after a severe metabolic crisis responded to ascorbate therapy [Treacy et al 1996]. Several studies document increased oxidative stress, glutathione depletion, and specific respiratory chain complex deficiencies in persons with the mut⁰ enzymatic subtype of MMA [Atkuri et al 2009, Chandler et al 2009, de Keyzer et al 2009, Manoli et al 2013], suggesting a potential benefit of treatment with antioxidants or other mitochondria-targeted therapies in these individuals.

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]. Thiamine can help with severe lactic acidosis by overcoming pyruvate dehydrogenase inhibition during the treatment of acute metabolic crises (see Table 10). Whether chronic administration of CoQ10, vitamin E, or N-acetylcysteine could prevent long-term complications requires further study [Haijes et al 2019b].

Base replacement. Individuals with MMUT methylmalonic academia (subtype mut⁰ or mut^-) have renal tubular dysfunction and low-grade chronic acidosis that can accelerate the progression of their chronic kidney disease. Sodium bicarbonate or citrate (Bicitra^®) replacement aiming for a serum bicarbonate concentration of 22-24 µmol/L, is recommended per standard guidelines for management of chronic kidney disease in children [KDOQI Work Group 2009, Brown et al 2020]. Bicitra has the additional benefit of offering citrate for TCA cycle anaplerosis and was studied in propionic acidemia [Longo et al 2017]. Polycitra contains potassium, which should be monitored closely due to the risk of developing hyperkalemia in individuals with kidney disease.

Prevention of Secondary Complications

One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also Tables 9 and 10). Adherence to a low-protein diet and frequent monitoring by the primary metabolic clinic (see Table 13), as well as continued care by other specialists (nephrologist, neurologist, gastroenterologist, cardiologist, and others), is necessary throughout life.

Surveillance

During the first year of life, infants may need to be evaluated as frequently as every week and continued at intervals determined by the frequency of metabolic crises/admissions, growth patterns, and dietary needs. Attention to transition periods (e.g., after the first two years, in adolescence) with other stressors in the family are necessary for modification of dietary prescription.

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the following are recommended. See Table 13.

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
• Supplementation with the individual propiogenic amino acids valine and isoleucine, as they directly increase the toxic metabolite load in patients with disordered propionate oxidation [Nyhan et al 1973, Hauser et al 2011, Manoli et al 2016b]
• Nephrotoxic medications or agents (e.g. ibuprofen)
• Agents that prolong QTc in the EKG

Evaluation of Relatives at Risk

Evaluation of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of isolated methylmalonic acidemia.

For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, measure serum methylmalonic acid, urine organic acids, plasma acylcarnitine profile, plasma amino acids, and serum B₁₂; and test for the familial isolated methylmalonic acidemia-causing pathogenic variants if biochemistry is abnormal.

Prenatal diagnosis of at-risk sibs may allow for prompt treatment of affected newborns at the time of delivery or prenatal administration of vitamin B₁₂ in responsive subtypes, especially cblA.

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

Pregnancy Management

Affected mother

• In pregnancies of affected women with MMA, complications observed included acute decompensation or hyperammonemia, deterioration of renal function, and obstetric complications including preeclampsia, preterm delivery, and cæsarean section [Raval et al 2015].
• Despite high maternal MMA levels, fetal growth and development have been reported to be normal, suggesting negligible teratogenic effects to the fetus from exposure to high methylmalonic acid levels in utero, though long-term follow up with age-appropriate neurocognitive testing is limited [Wasserstein et al 1999, Deodato et al 2002].
• Pregnancies in transplant recipients are rare and further studies on the health of the offspring are needed [Marcellino et al 2021].

Unaffected mother with an affected fetus. Oral and intramuscular vitamin B₁₂ has been administered to women pregnant with a fetus with vitamin B₁₂-responsive MMA, resulting in decreased maternal MMA urine output [Ampola et al 1975, van der Meer et al 1990]. These observations notwithstanding, maternal vitamin B₁₂ supplementation for isolated MMA needs further study.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

13-C-propionate breath test. A stable isotope 13-C-propionate breath test has been developed as a surrogate biomarker of disease severity and was shown to correlate with in vitro 14-C-propionate incorporation, isolated MMA subtype, and several disease-related manifestations (rate of progression of chronic renal disease, growth parameters, and cognitive outcomes). Moreover, it showed a response to B₁₂ supplementation or solid organ transplantation [Manoli et al 2021]. It can be used in specialized centers to help prognosticate disease severity and select affected individuals with very low oxidation rates for referral to transplantation or clinical trials testing novel genomic therapies.

Increased understanding of the underlying pathophysiology and the generation of disease-specific animal or cellular models has allowed the development of several novel therapies for isolated MMA [Chandler & Venditti 2019, Luciani et al 2020, Dimitrov et al 2021, Head et al 2022]. The effect of each of these therapeutic approaches on the long-term clinical outcomes of MMA remains to be elucidated.

• Liver-targeted genomic therapies including systemic canonic recombinant adeno-associated virus (rAAV) gene therapy [Chandler & Venditti 2008, Carrillo-Carrasco et al 2010, Chandler & Venditti 2010, Chandler & Venditti 2012, Sénac et al 2012, Chandler et al 2021], systemic mRNA replacement [An et al 2017], and genome editing into the albumin locus [Chandler et al 2021] have shown significant promise in animal models and are reaching Phase I/II clinical trials as promising alternatives to liver transplantation.
• Studies using primary hepatocytes from individuals with methylmalonic and propionic acidemia have found that administration of the small molecule 2,2-dimethylbutanoic acid (HST5040) leads to a dose dependent reduction in levels of methylmalonyl-CoA and other serum metabolites. This small molecule is being tested in clinical trials [Armstrong et al 2021].
• Investigational therapies intended to increase CoA levels by allosterically modulating pantothenate kinases, key enzymes in the CoA biosynthesis pathway, have been shown to increase free CoA and alleviate mitochondrial dysfunction in mouse models of propionic academia (PA) [Subramanian et al 2021] and are being tested in clinical trials for MMA and PA.
• Carefully designed clinical studies are required to evaluate the efficacy of antioxidant regimens in people with MMA.

Review the following for more information on current clinical trials on isolated MMA:

clinicaltrials.gov/ct2/show/NCT04581785

clinicaltrials.gov/ct2/show/NCT04732429

clinicaltrials.gov/ct2/show/NCT04899310

clinicaltrials.gov/ct2/show/NCT04836494

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

All forms of isolated methylmalonic acidemia (MMA) – including complete or partial deficiency of the enzyme methylmalonyl-CoA mutase; defect in transport or synthesis of the methylmalonyl-CoA mutase cofactor, 5'deoxyadenosyl-cobalamin; and deficiency of the enzyme methylmalonyl-CoA epimerase – are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an MMUT, MMAA, MMAB, MCEE, or MMADHC pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an isolated MMA-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy has been reported (MMUT [id(6)pat] and MMAA [segmental upd(4)mat] [Abramowicz et al 1994, Chen et al 2020].)
• Heterozygotes (carriers) of a pathogenic variant in an isolated MMA-related gene (i.e., MMUT, MMAA, MMAB, MCEE, or MMADHC) have normal metabolite concentrations.

Sibs of a proband

• If both parents are known to be heterozygous for an isolated MMA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) of a pathogenic variant in an isolated MMA-causing gene (i.e., MMUT, MMAA, MMAB, MCEE, or MMADHC) have normal metabolite concentrations.

Offspring of a proband. Unless an affected individual's reproductive partner also has isolated MMA or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an isolated MMA-related gene.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an isolated MMA-causing pathogenic variant.

Carrier Detection

• Carrier testing for at-risk relatives requires prior identification of the isolated MMA-causing pathogenic variants in the family.
• MMUT is included in the recommended gene list for carrier screening (Tier II) and may be included on expanded carrier screening panels [Gregg et al 2021].

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 testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the isolated MMA-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Biochemical testing. Both amniotic fluid measurements for methylmalonic acid and cellular biochemical assays (¹⁴C propionate incorporation and complementation assays) on cultured fetal cells obtained by amniocentesis or chorionic villus sampling have been used for prenatal testing [Morel et al 2005]. However, due to the limited availability and longer turnaround time for cellular biochemical assays, the preferred method for prenatal diagnosis is molecular genetic testing.

Molecular Pathogenesis

Isolated MMA results from the failure to isomerize (convert) methylmalonyl-CoA into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid (Figure 1). Several different enzyme deficiencies affecting these metabolic steps can cause isolated MMA (Figure 2), including the methylmalonyl-CoA mutase itself and those providing the adenosylcobalamin as a cofactor. MMAA encodes a GTPase critical for the mitochondrial assembly of adenosylcobalamin (AdoCbl) to the methylmalonyl-CoA enzyme [Froese et al 2010]. MMAB encodes an ATP:cob(I)alamin adenosyltransferase (ATR) that transfers 5′-deoxyadenosyl from ATP to Cbl forming AdoCbl and delivers it to the methylmalonyl-CoA enzyme. MMUT encodes methylmalonyl-CoA mutase, a mitochondrial enzyme that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, which requires AdoCbl as coenzyme. MMADHC encodes a protein necessary in the early metabolic pathway of AdoCbl formation.

Aberrant post-translational modifications (methylmalonylation) have inhibitory effects on critical enzymes in the urea cycle and glycine cleavage pathways, causing the secondary disease manifestations such as hyperammonemia and hyperglycinemia in MMA [Head et al 2022].

Plasma fibroblast growth factor 21 (FGF21) has been characterized as a marker of hepatic mitochondrial dysfunction in MMA murine models and was shown to correlate with disease severity and long-term complications in different patient cohorts [Manoli et al 2018, Molema et al 2018, Manoli et al 2021].

Mechanism of disease causation. Loss of function

Notable variants by gene. See Table 4 for a list of specific pathogenic MMUT variants, that when in a homozygous state, lead to a specific predicted enzymatic phenotype. Further notable pathogenic variants by gene are listed in Table 15.

Author Notes

Dr Manoli is a pediatrician and clinical and biochemical geneticist. She is a clinician associate investigator and senior staff clinician in the Organic Acid Research Section of the National Human Genome Research Institute, and an attending physician at the National Institutes of Health Clinical Center.

Dr Sloan is a genetic counselor, molecular geneticist, and cytogeneticist. She is a staff scientist in the Organic Acid Research Section of the National Human Genome Research Institute.

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

Websites:

www.genome.gov/staff/Charles-P-Venditti-MD-PhD

www.genome.gov/about-nhgri/Division-of-Intramural-Research/Metabolic-Medicine-Branch

Acknowledgments

The authors are supported by the Intramural Research Program of the National Human Genome Research Institute, Bethesda, MD. They have a longitudinal natural history protocol on methylmalonic acidemias and cobalamin disorders at the NIH (Study URL: clinicaltrials.gov/ct2/show/NCT00078078) and a focused interest on translational research in these disorders. Further details and contact information are provided at the group's website: www.genome.gov/Current-NHGRI-Clinical-Studies/Methylmalonic-Acidemia-MMA.

The authors wish to acknowledge the non-profit organizations "Angels for Alyssa," "A Cure for Clark," and the Organic Acidemia Association (OAA), all founded by families and friends of patients with MMA, for their ongoing dedication and support of MMA research.

Revision History

• 8 September 2022 (ma) Comprehensive update posted live
• 1 December 2016 (cpv) Revision: Molecular Genetics: MMAB and MMUT
• 7 January 2016 (me) Comprehensive update posted live
• 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 live
• 11 May 2004 (cpv) Original submission

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

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