Methylmalonic acidemia (MMA) is a rare metabolic disorder that results as a consequence of the accumulation of toxic levels of methylmalonic acid. This rare condition is associated with serious sequelae such as neurological manifestations and/or even organ failure.
The age of onset and clinical picture are correlated to the phenotype of the disease, which may occur in ages ranging from neonatal period through adulthood . The neonatal form can be fatal within the first month of life. Those with the infantile, or the B12 unresponsive, phenotype are normal at birth but soon develop symptoms with the first few weeks or early infancy. The intermediate B12 responsiveness form appears in infancy or early childhood. There is also an atypical phenotype that occurs in adults but is usually benign and is characterized by increased methylmalonic acid in the urine .
The clinical presentation of the majority of affected neonates and children manifests during an episode of metabolic decompensation  , which is characterized by emesis, dehydration, hypotonia, lethargy, respiratory distress, poor feeding, failure to thrive, and seizures. Patients with MMA may develop recurrent infections, which often precipitates the decompensation . Moreover, renal failure and end-stage liver failure are common in certain phenotypes.
During these acute episodes, neurological features such as seizures and progressive hyperammonemic encephalopathy may occur. Additionally, the metabolic crisis may result in strokes in the brainstem which are typified by dysarthria, dysphagia, dystonia, and choreoathetosis.
Remarkable findings on the physical exam may include hepatomegaly, lethargy, floppiness, dehydration, and failure to thrive. Additionally, they may display neurological signs and deficits suggestive of stroke.
Neonates and children presenting with clinical features suspicious for MMA should be evaluated thoroughly through a personal and family history. The clinician should ascertain specifics in the family history such as neonatal deaths, neurological disorders, consanguinity, and evidence of similar symptoms in siblings. Additionally, the clinician should perform a full physical exam and obtain the pertinent studies.
The investigation is typically comprehensive with a myriad of findings. In addition to a clinical picture suggestive of MMA and positive results for methylmalonic acid on urine organic acid screen, further testing will support the diagnosis. For example, the baseline studies in these patients will reveal anemia, neutropenia as well as thrombocytopenia on complete blood count (CBC), high anion gap metabolic acidosis on arterial blood gas, lactic acidosis, hyperammonemia, and ketonuria. Additionally, plasma glucose, electrolytes, renal functional tests, and amylase and lipase are also ordered.
Note that while levels of methylmalonic acid in the plasma and urine are elevated, B12, homocysteine, and methionine are normal. These combined findings will exclude differential diagnoses. Hence, all of these must be performed in all individuals suspected to have MMA.
In another context, asymptomatic neonates may have positive newborn screening for propionylcarnitine (C3). When this occurs, gas chromatography-mass spectrometry (GC-MS) will confirm the high levels of methylmalonic acid if they truly have the disease. There are also other biochemicals that may be positive.
Testing is also done through observation of the patient's response to administered vitamin B12. This is monitored by measurements of plasma methylmalonic acid, C3, and homocysteine and/or urine organic acid analyses. A successful response is indicated by a greater than 50% decrease in plasma concentration  .
Biochemical and genetic studies
The gold standard study in characterizing the subtype of MMA involves biochemical testing on skin fibroblasts using vitamin B12 in vitro. The responsiveness will allow for the distinction of which subtype is the culprit.
Genetic analysis can establish the diagnosis of MMA through detection of the specific phenotype. In vitamin B12 unresponsive patients, the clinician should assess for mutations in MUT and MMAB genes while vitamin B12 responsive individuals will be evaluated for defects in the MMAA gene. If these genes are not involved, then there is further testing other genes.
Many states and countries across the globe have implemented mass spectrometry in newborn screening, which has resulted in the detection of C3 and the diagnosis of MMA . Although the C3 marker lacks specificity, it may help identify affected newborns early .
Computed tomography (CT) and/or magnetic resonance imaging (MRI) of the brain will be performed if a stroke is suspected.
Since the patients are at risk for severe complications such as stroke and coma, the treatment must be initiated early and promptly while the workup is being performed. They should be stabilized, protein intake should be terminated, and intravenous glucose must be administered along with volume and electrolyte replacement.
As part of the crucial inpatient management, these individuals are placed on a protein-restricted diet with nutritional supplementation of 1) L-carnitine, which metabolizes long-chain fatty acids and helps promote the excretion of acyl-CoA metabolites that result from low protein diets and 2) vitamin B12 (cobalamin) which is a cofactor in the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA.
As dietary modifications are being implemented, the patient is assessed clinically and quantitatively through measurement of methylmalonic acid in the urine. Typically, vitamin B12 responsive patients will experience better outcomes in comparison to those who are vitamin B12 unresponsive  .
The overall nutrition needs to be carefully managed. Moreover, ill infants may require total parenteral nutrition (TPN). Additionally, plasma amino acids, electrolytes, and urine output should be monitored frequently.
Infections and other coexisting complications will be treated appropriately.
Prevention of recurrent episodes
Patients should adhere to a diet low in protein in order to prevent further episodes of metabolic crises and to avoid the development of organ damage . The clinical team will provide the parents and/or caretakers with education on the correct diet for the child. Additionally, nutritionists and other specialists are available to help guide families through this process.
The outcomes associated with MMA have improved with better management in neonatal and long-term contexts when comparing pre and post- 1990. In recent decades, less than 20% died in infancy or prior to the age of 10 , although the surviving patients exhibited poor nutrition as well as growth retardation. Furthermore, approximately 40% demonstrated neurological deficits. However, 40% showed a developmental improvement . The same study also observed a better quality of life in the few that have received organ transplantation (liver and/or kidney). Overall, the investigation suggested that long-term metabolic and nutritional strategies are paramount in children with MMA .
Another study reported that patients with the mut0 subtype had a 100% mortality rate (at a median age of 1.6 years) in the 1970s. However, in the 1990s, this rate was 20% and the related median age was 2.2 years . The report also noted that mortality was greatest in the mut0 subtype (50% at the median age of 2), followed by cblB (50% at the median age of 2.9), mut– (40% at the median age of 4.5), and cblA enzymatic subtype (rare) .
There are two types of this autosomal recessive disorder. The vitamin B12 responsive form occurs secondary to impaired synthesis of AdoCbl, which is a cofactor for the conversion of methylmalonyl-CoA to succinyl-CoA. Mutations occur in one of three proteins that is involved in the production of AdoCbl: MMAA, MMAB and MMADHC. These are associated with distinct subtypes: MMA cblA, MMA cblB, and MMA cblD    .
The vitamin B12 unresponsive type results from a genetic mutation in the mitochondrial enzyme methylmalonyl-CoA mutase (MUT) itself. The deficiency of the activity of MUT can be complete (mut0) or partial (mut-)    . Moreover, the mut0 apoenzyme has no activity while the mut- subtype exhibits low to moderate activity    .
In North America, the prevalence of MMA is 1 in 48,000 to 1 in 61,000 live births . It is more common in China with a prevalence of 1 in 26,000 . The prevalence of isolated cases of MMA overall is thought to be 1 in 50,000 newborns .
There is no gender preference. Additionally, the disease may occur more frequently in populations with increased consanguinity.
MMA is caused by an insufficiency of L- methylmalonyl-CoA mutase activity or an abnormality in the synthesis of AdoCbl. Specifically, methylmalonyl-CoA mutase plays a role in the catabolism of isoleucine, valine, methionine, threonine, thymine, as well as cholesterol, and certain fatty acids . Therefore, low activity of this enzyme will result in the build up of methylmalonic acid in tissues such as the brain, which produces neurological complications and damage to the globus pallidus .
Researchers investigating the neurological symptoms found in MMA patients have reported that this metabolite inhibits key enzymes such as pyruvate carboxylase, which is required for energy metabolism pathways in the brain . Other studies found that methylmalonic acid impairs the mitochondrial utilization of ketone bodies in the brain . Further in vivo studies have demonstrated antagonistic effects of methylmalonic acid on the respiratory chain complex mechanisms, which ultimately leads to a deficiency in energy for the brain . These conclusions, as well as plenty of others, may explain the neurological outcomes that occur in individuals with this metabolic disorder.
Genetic counseling and testing are available for family members who are at risk of being carriers. Additionally, prenatal testing for high-risk patients may be offered if the pathogenic variants in the family have been identified. Prenatal diagnosis may be obtained by using cultured fetal cells retrieved through chorionic villus sampling or amniocentesis. Enzymatic and metabolite analysis of the sample will determine the diagnosis of the fetus.
Methylmalonic acidemia (MMA) is a rare autosomal recessive disorder that develops from an inborn error in the metabolism of vitamin B12. This type of organic acidemia emerges from either genetic mutations that cause a deficiency in the activity of mitochondrial enzyme methylmalonyl-CoA mutase or an impairment in the synthesis of adenosylcobalamin (AdoCbl). As a result, there are two forms of MMA which are classified as vitamin B12 unresponsive or vitamin B12 responsive.
The clinical presentation typically manifests during the neonatal period or early childhood. Typical episodic features include vomiting, dehydration, lethargy, failure to thrive, hypotonia, seizures, and even coma. Long-term complications such a metabolic stroke and renal failure may occur.
The assessment of neonates and children suspected to have MMA and newborns with positive screening includes a detailed personal and family history. Additionally affected individuals warrant a physical exam and a thorough workup that includes the demonstration of elevated plasma and urine levels of methylmalonic acid and hallmark findings such as high anion gap metabolic acidosis, increased lactate, hyperammonemia, and ketonuria. Further studies include the patient's response to vitamin B12 treatment, as well as biochemical and genetic testing.
The treatment requires stabilization, infusion of glucose, withdrawal of protein intake, and the initiation of a low protein diet with vitamin B12 and carnitine supplementation. In certain cases, liver and/or kidney transplantation may be attempted to relieve or prevent the disease from developing.
Overall, the therapeutic principles consist of improving the child's nutritional status and tailoring the diet according to the disease, which have resulted in better outcomes over the past decades. Hence, the long-term management should include goals that focus on implementing a diet that maintains a metabolic balance.
What is Methylmalonic Acidemia (MMA)?
MMA is composed of a group of genetic disorders that affect the breakdown of certain proteins and fats. Therefore, methylmalonic acid builds up in the blood and tissues such as the brain. This occurs due to errors in the metabolism.
What are the causes of MMA?
This disorder is caused by inherited genetic mutations. Specifically, it is inherited in an autosomal recessive pattern. This means that the affected individual inherits a bad copy of the gene from each parent. In other words, the patient must receive two bad copies in order to develop MMA.
What are the signs and symptoms of MMA?
The signs and symptoms usually develop in patients while they are young infants or children. These features include:
These symptoms can worsen if the child gets an infection, starves, or eats too much protein.
How is it diagnosed?
Infants and children with the above signs and symptoms or with specific findings on newborn screening biochemical tests will raise suspicion for this disorder. The clinician will obtain a thorough history of the patient and the family. Additionally, s/he will perform a physical exam and order very important blood tests such as:
How is it treated?
Since patients usually present in a state of critical illness, they are immediately hospitalized and stabilized. They are treated with:
There is no cure but the symptoms can be controlled by adhering to a strict diet. In fact, long-term management of diet and nutrition is necessary in order to prevent further episodes from recurring.
Can it be prevented?
Since this disease is inherited, it cannot be prevented.
Genetic counseling and testing are offered to family members at risk for being a carrier of the disease. Prenatal testing may be offered in high-risk pregnancies.
What is the prognosis?
The prognosis has improved over the past few decades. This is due to the implementation of a diet that is low in protein as well as other specific modifications tailored to the child's disease.