Methylmalonic acidemia (MMA) is an inherited disorder where the body is unable to properly process certain protein and fats (lipids). The effects usually occur in early infancy, and can range from mild symptoms to life threatening. Infants who are affected can exhibit the following symptoms: vomiting, dehydration, weak muscle tone (hypotonia), developmental delay, excessive tiredness (lethargy), an enlarged liver (hepatomegaly), and failure to gain weight and grow at the expected rate (failure to thrive). Complications that can be long term can include feeding problems, intellectual disability, chronic kidney disease, and inflammation of the pancreas (pancreatitis). This disorder can lead to coma or death without treatment.
The NCBI offers the following information regarding Isolated Methylmalonic Aciduria:
“Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress.
- In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life.
- In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age.
- An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake.
- Atypical and “benign”/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate.
Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; “metabolic stroke” (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.”¹
Why Get Tested?
To help detect early and/or mild vitamin B12 deficiency; to help diagnose methylmalonic acidemia, a rare inherited metabolic disorder. If you have a low vitamin B12 level and/or have symptoms of B12 deficiency such as numbness, tingling in the hands or feet, trouble walking, swelling of body tissues, or yellowing of the skin or eyes or as part of newborn screening.
How is MMA tested?
A blood sample dram from a vein in your arm or for a newborn, a heelstick; sometimes a random or 24 hour urine sample.
Do I need to prepare for the test?
You may be instructed to fast (overnight) before sample collection for this test. Urine samples should be collected on the second urination of the day (discard the first sample in the morning).
What is Being Tested?
The level of MMA in the blood and urine. The measurement of elevated amounts of methylmalonic acid in the blood or urine serves as a sensitive and early indicator of vitamin B12 deficiency. MMA is a substance produced in trace amounts and is necessary for human metabolism and energy production.
Is This New?
The relationship between MMA and B12 has been known for 40 years, but the use of MMA testing is not widespread nor is there agreement on its clinical utility. Previously, vitamin B12 levels were measure in the blood , however since a relatively large amount of the B12 found in the blood is bound to proteins, and is not biologically active, some medical professionals believe an MMA test is more accurate measure of bioavailable B12 than the standard B12 blood test. Others believe that MMA and homocysteine levels (which are elevated when either B12 or folate is deficient) are valuable in detecting early onset and mild cases of B12 deficiency.
Testing newborns for high levels of MMA may help diagnose methylmalonic acidemia, a rare metabolic disorder that occurs in about 1 in 25,000 to 100,000 people. Screening for this disorder is now part of mandatory programs in all 50 states in the US. Babies with this disease are unable to convert methylmalonyl CoA to succinyl CoA. These babies appear normal at birth, but as they consume protein, they begin to show symptoms described above. For more, see the newborn screening article.
When is it ordered?
MMA is usually ordered, sometimes along with a homocysteine test, when a vitamin B12 test results are in the lower portion of normal or in the low range, especially when presenting with symptoms of B12 deficiency.
What are the symptoms?
- Fatigue, muscle weakness
- Loss of appetite
- Pale skin
- Rapid heart rate, irregular heartbeats
- Shortness of breath
- Sore tongue and mouth
- Tingling, numbness, and/or burning in the feet, hands, arms, and legs (with B12 deficiency)
- Confusion or forgetfulness
MMA is also ordered for asymptomatic adults who have a higher likelihood of having vitamin B12 deficiency, such as the elderly, or for those taking certain drugs, like Metformin, for a long time. An MMA test also may be ordered as a follow-up to an elevated homocysteine level if the two tests are not ordered together.
MMA testing may be ordered when a health practitioner suspects that an acutely ill infant may have inherited methylmalonic acidemia.²
“Methylmalonic Acidemias can usually be diagnosed before birth (prenatally) by measuring the concentration of methylmalonic acid in amniotic fluid or activity of the deficient enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS]). During amniocentesis, a sample of fluid surrounding the developing fetus is removed and analyzed. CVS involves the removal and examination of tissue from a portion of the placenta. The disorder can be identified at birth through expanded newborn screening with tandem mass spectrometry.” ³
MMA + HCU (Methylmalonic Acidemia with Homocystinuria
In babies who have symptoms, common findings are:
- poor appetite
- poor growth
- extreme sleepiness or lack of energy
- low muscle tone (floppy muscles and joints)
- small head and brain size, called microcephaly
- water on the brain, called hydrocephalus
- other brain abnormalities
- delays in learning or intellectual disabilities
- vision problems
- heart problems
- kidney problems
- skin rashes
Lab findings can include:
- high levels of homocysteine and methylmalonic acid in the blood and urine
- high levels of acidic substances in the blood, called metabolic acidosis
- protein or blood in the urine
- low platelets
- low white blood cells
- excess clotting of the blood
If not treated, metabolic acidosis can cause:
Metabolic acidosis and other symptoms can be triggered by:
- eating large amounts of protein
- illness or infection
- going too long without food
- stressful events such as surgery
Children who do not have symptoms until later in childhood often have some or all of the following symptoms:
- sudden loss of mental skills
- forgetfulness and confusion
- episodes of psychosis or delirium
- behavior problems
- numbness or weakness in the limbs
- unsteady gait
- slurred speech
- blood clots
- anemia, low platelets, and/or low white blood cells
- vision problems
- kidney problems
Your baby’s primary doctor will work with a metabolic doctor and a dietician familiar with MMA+HCU to care for your child.
It is not known how effective treatment is in preventing effects of MMA+HCU. However, prompt and ongoing treatment may lessen the chance for intellectual disabilities, psychiatric disorders, and serious health problems.
Most children need to be on a low-protein diet and drink a special medical formula. Many children are given injections of vitamin B12. It is important to start treatment as soon as you know your child has MMA+HCU.
The following are treatments often recommended for children with MMA+HCU:
1. Low-protein diet, medical foods and medical formula
A food plan low in the amino acids leucine, valine, methionine, and threonine with limited amounts of protein is often recommended. Most food in the diet will be carbohydrates (bread, cereal, pasta, fruit, vegetables, etc.). Carbohydrates give the body many types of sugar that can be used as energy. Eating a diet high in carbohydrates and low in protein and fat can help prevent metabolic crises.
Foods high in protein that may need to be avoided or limited include:
- milk and dairy products
- meat and poultry
- dried beans and legumes
- nuts and peanut butter
Many vegetables and fruits have only small amounts of protein and can be eaten in carefully measured amounts. Do not remove all protein from the diet. Children with MMA+HCU need a certain amount to grow properly.
Your dietician can create a food plan that contains the right amount of protein, nutrients, and energy to keep your child healthy. Your child will need to be on a special food plan throughout life.
Medical formula and foods
In addition to a low-protein diet, your child may be given a special formula. This formula contains the correct amount of protein and nutrients needed for normal growth and development. Your metabolic doctor and dietician will tell you whether your child needs formula, what type is best, and how much to use.
There are also medical foods such as special low-protein flours, pastas, and rice that are made especially for people with organic acid disorders. Your dietician will tell you how to use these foods as part of your child’s diet.
Some states offer help with payment or require private insurance to pay for the formula and other special medical foods.
Babies and children with MMA+HCU may be given vitamin B12 injections in the form of hydroxocobalamin (OH-cbl). This treatment seems to lessen the symptoms in some children but not others. Your doctor may need to treat your child with OH-cbl for a short period of time to determine whether this treatment is useful.
Some children with MMA+HCU may benefit by taking L-carnitine. This is a safe and natural substance that helps the body make energy. It also helps get rid of harmful wastes. Your doctor will decide whether or not your child needs L-carnitine. Unless you are advised otherwise, use only L-carnitine prescribed by your doctor.
Betaine is a vitamin-like substance found in grains and other foods. It can also be bought in pill form as a supplement. Betaine helps lower the amount of homocysteine in the blood. It may lessen the risk of blood clots. Your metabolic specialist will decide whether your child needs betaine. He or she will need to write a prescription.
Children with extreme sleepiness or lack of energy and those who are ill may need to be treated in the hospital. If your child has metabolic acidosis, he or she may be given medications such as bicarbonate by IV to help reduce the acid levels in the blood. Glucose is given by IV to prevent the breakdown of body stores of protein and fat.
Do not use any medication without checking with your doctor or metabolic specialist.
3. Avoid going a long time without food
Infants and young children with MMA+HCU need to eat frequently to prevent a metabolic crisis. Your metabolic doctor will tell you how often your child needs to be fed. In general, it is often suggested that infants be fed every four to six hours. Some babies need to eat even more frequently than this. It is important that infants be fed during the night. They may need to be woken up to eat if they do not wake up on their own. Your metabolic doctor and dietician will give you an appropriate feeding plan for your infant. Your doctor will also give you a ‘sick day’ plan, tailored to your child’s needs, for you to follow during illnesses or other times when your child will not eat.
Your metabolic doctor will continue to advise you on how often your child should eat as he or she gets older.
4. Regular blood and urine tests
Your child will likely need regular blood and urine tests to measure the level of amino acids and other substances. Your child’s diet and medication may need to be adjusted based on the results of these tests.
5. Call your doctor at the start of any illness
In children with MMA+HCU, even minor illness could lead to serious health problems. In order to prevent problems, call your doctor right away when your child has any of the following:
- loss of appetite
- infection or illness
When ill, your child needs extra fluids and carbohydrates to prevent more serious health problems. During an illness, you should restrict protein and give your child starchy foods and fluids.
Children with MMA+HCU may need to be treated in the hospital during illness. Ask your metabolic doctor if you should carry a special travel letter with medical instructions for your child’s care.
¹ Isolated Methylmalonic Acidemia, (Isolated Methylmalonic Aciduria), Irini Manoli, MD, PhD, Jennifer L Sloan, PhD, and Charles P Venditti, MD, PhD., Initial Posting: August 16, 2005; Last Revision: December 1, 2016.