What is mma medical?

Disorder name: Methylmalonic Acidemia Acronym: MMA Download PDF

This fact sheet contains general information about MMA. Every child is different and some of these facts may not apply to your child specifically. Certain treatments may be recommended for some children but not others. All children with MMA should be followed by a metabolic doctor in addition to their primary care provider.

MMA stands for “methylmalonic acidemia.” It is one type of organic acid disorder.  People with MMA have problems breaking down and using certain amino acids and fatty acids from the food they eat.

In order for the body to use protein from the food we eat, it is broken down into smaller parts called amino acidsAmino acids are small molecules that make up proteins. There are over 100 different amino acids, but our body uses only 20 amino acids to make all of its proteins. Our genes determine the sequence of amino acids in a protein. This sequence determines what shape the protein takes, and what function that protein serves in the body.. Special enzymes then make changes to the amino acids so the body can use them. In the same way, fatFat is one of the three main nutrients in food (carbohydrates, fat, protein). Some foods that contain fat are butter, margarine, oils, nuts, meats, poultry, fish and some dairy products. Extra calories from food are stored as body fat. Stored body fat provides the body with a reserve supply of energy. from the food we eat is broken down by enzymes into fatty acids that the body can use for energy.

MMA occurs when one of these special enzymes is either missing or not working properly. Without this enzyme, certain amino acids and fatty acidsThese are the building blocks of fat. Fat from food is broken down by enzymes into fatty acids. These are changed by other enzymes and are used as energy or stored as body fat. Some types of fatty acids are: short-chain, medium-chain, long-chain, and very-long chain. cannot be used correctly. This causes glycineThis is one of 20 amino acids that make up protein. It has many functions, one of which is helping cells create energy for the body. It is made by the body and does not need to be eaten in the diet. It is also available as a supplement. People with isovaleric acidemia (IVA) are often given glycine to help prevent health problems., methylmalonic acidThis is a substance made when the body digests food containing protein and fat. Normally, it is quickly changed by the body into other substances. If the body is missing an enzyme needed to break down methylmalonic acid, it builds up in the blood and causes illness. Excess methylmalonic acid is found in the blood of people with methylmalonic acidemia., and other harmful substances to build up in the blood and urine and cause health problems.

There are a number of different types of MMA. Some types can be treated with vitamin B12This is a type of B vitamin. It is also called cobalamin. It helps in the breakdown and use of food for energy. It also helps to make red blood cells and keep the nervous system healthy. It is found in meat, dairy products, and eggs. It can also be given by injection to people who have low levels or who have certain metabolic disorders. injections. These types are called ‘vitamin B12 responsive.’ Two types of MMA that often can be treated with vitamin B12 are Cobalamin A (CblA) deficiency and Cobalamin B (CblB) deficiency.

There are other types of MMA which cannot be treated with vitamin B12. These types are called ‘vitamin B12 non-responsive.’ One of these is called ‘Mut 0.’ It is caused by the absence of an enzyme called methylmalonyl-CoA mutase (MCM). Another type of MMA that does not respond to vitamin B12 treatment is called ‘Mut –.‘  People with the ‘Mut–‘ type of MMA have too little of the MCM enzyme.

Another type of MMA, called ‘MMA with homocystinuria,’ is described in a separate fact sheet.  See the fact sheet MMA+HCU for more information about this condition.

IsoleucineThis is one of 20 amino acids that make up protein. It is not made by the body and must be eaten in the diet. It is found in all foods that contain protein., valineThis is one of 20 amino acids that make up protein. It is not made by the body and must be eaten in the diet. It is found in all foods that contain protein., methionineThis is one of 20 amino acids that make up protein. It is not made by the body and must be eaten in the diet. It is found in all foods that contain protein., and threonine are the four amino acids that cannot be used correctly by people with MMA. These amino acids are found in all foods that contain protein. Large amounts are found in meat, eggs, milk, and other dairy products. Smaller amounts are found in flour, cereal, and some vegetables and fruits.

Each child with MMA is likely to have somewhat different effects. Many babies with MMA start having symptoms in the first few days of life. Others begin to show symptoms sometime in infancy or childhood. Some people with MMA may never develop symptoms.

MMA causes episodes of illness called metabolic crises. Some of the first symptoms of a metabolic crisisThis is a serious health condition caused by low blood sugar and the build-up of toxic substances in the blood. Symptoms of a metabolic crisis are poor appetite, nausea, vomiting, diarrhea, extreme sleepiness, irritable mood and behavior changes. If not treated, breathing problems, seizures, coma, and sometimes even death can occur.Metabolic crises happen more often in people with certain metabolic disorders (some fatty acid oxidation disorders, amino acid disorders, and organic acid disorders). They are often triggered by things like illness or infection, going without food for a long time, and, in some cases, heavy exercise. are:

Common blood and urine findings are:

If a metabolic crisis is not treated, a child with MMA can develop:

A metabolic crisis can be triggered by:

Between episodes of metabolic crisis, children with MMA may be healthy. However, some continue to have problems with health and development. Some children have long-term problems even if they have never had a metabolic crisis. These can include:

Without treatment, brain and nerve damage can occur. This can cause intellectual disabilities and problems with involuntary movements. Death is common in untreated babies and children.

A small number of people with MMA never have any symptoms.

Your baby’s primary doctor will work with a metabolic doctorThis is a doctor or medical geneticist who has special training in diagnosing and treating metabolic disorders. They often work in university hospitals or large medical centers. and a dietician familiar with MMA to care for your child.

Prompt treatment is needed to reduce the chance for intellectual disabilities and serious medical problems. Children with vitamin B12 responsive-MMA are given vitamin B12. In addition, most children need to be on a low-protein diet and drink a special medical formula. You should start the treatments as soon as you know your child has MMA.

The following are treatments often recommended for children with MMA:

1.  Medication The main treatment for vitamin B12 responsive-MMA is vitamin B12 injections in the form of hydroxocobalamin (OH-cbl) or cyanocobalamin (CN-cbl). Vitamin B12 injections can prevent symptoms in children with this type of MMA.

Over 90% of children with CblA deficiency respond to vitamin B12 injections. About 40% of children with CblB deficiency are helped by this treatment. Your doctors may need to treat your child with vitamin B12 for a short period of time to determine whether this treatment is useful.

Children with MMA may benefit by taking L-carnitineThis is a natural substance found in muscle cells. It helps the body make energy from the fat in food and the fat stored in the body. It also helps the cells get rid of harmful wastes made during the breakdown of fat. Carnitine supplements may be used as a treatment for some metabolic disorders.. 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.

Antibiotics taken by mouth can help lower the amount of methylmalonic acid made in the intestines. Your doctor will decide if your child needs antibiotics and, if so, what type.

Children who are having symptoms of a metabolic crisis should be treated in the hospital. During a metabolic crisis, your child may be given medications such as bicarbonateThis is a substance that lowers the amount of acid in the blood. It is sometimes used as part of the treatment for children with certain organic acid disorders. through an IVThis is a small tube placed into a vein, usually in the hand or arm. Medications and nutrients can be given through this tube directly into the blood. IV’s are often used in the hospital to give fluids, glucose and medication over a long period of time. to help reduce the acid levels in the blood. GlucoseThis is a type of sugar made from the carbohydrates in food. Glucose is found in the blood. It is the main source of energy for the body and brain. is given by IV to prevent the breakdown of protein and fat stored in the body.  Carglumic acid (Carbaglu®) may be given to manage high blood ammoniaThis is a waste product made when protein is broken down for the body to use. Ammonia is harmful to the body. It is usually changed to a harmless substance called “urea.” Urea is then removed from the body in the urine. People with urea cycle disorders cannot get rid of ammonia. If these conditions are not treated, ammonia can build up and cause serious health problems. levels.

Do not use any medication without checking with your doctor.

2.  Low-protein diet, medical formula and foods Low-protein diet A food plan low in the amino acids leucineThis is one of 20 amino acids that make up protein. It is not made by the body and must be eaten in the diet. It is found in all foods that contain protein., valine, methionine, and threonineThis is one of 20 amino acids that make up protein. It is not made by the body and must be eaten in the diet. It is found in all foods that contain protein. with limited amounts of protein is often recommended. Most food in the diet will be carbohydrates (bread, cereal, pasta, fruit, vegetables, etc.). CarbohydratesThis is one of the three types of nutrients in food (carbohydrates, fats, proteins). Sugars and starches are the most important types of carbohydrates. They are broken down by the body into glucose, the main source of energy for the body. Carbohydrates are found in foods such as: bread, cereal, pasta, grains, fruits and vegetables. Milk and dairy products, fruit drinks, sugar, candy, and sweet desserts also contain 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:

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 need a certain amount to grow properly.

Your dieticianThis is a person with special training in food and nutrition. A registered dietician (RD) has met the necessary educational requirements and has passed a national examination. If your child has a metabolic disorder, it is important for you to work with a registered dietician. They help create healthy food plans for people with metabolic disorders or other special needs. can create a food plan that contains the right amount of protein, nutrients, and energy to keep your child healthy. It is likely 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 medical formula. This formula contains the correct amount of protein and nutrients your child needs for normal growth and development. Your metabolic doctor and dietician will tell you what type of formula 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 for this formula and special foods, and others require private insurance to pay for the formula and other special medical foods.

3.  Avoid going a long time without food Infants and young children with MMA 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

TrackingThe process of testing a disease for a person who does not appear to have the disease (non-symptomatic or asymptomatic). The goal of tracking is to find the disease in its earliest stages. of ketonesThese are substances made when the body breaks down fat (fatty acids) for energy. In people with certain metabolic disorders or diabetes, ketones can build up in the blood and spill over into the urine. If ketones build up in the blood, they can cause acidosis which can lead to serious health problems.

Periodic urine tests to check the level of ketones can be done at home or at the doctor’s office. Ketones are substances formed when body fat is broken down for energy. This happens after going without food for long periods of time, during illnesses, and during periods of heavy exercise. Too many ketones in the urine may signal the start of a metabolic crisis.

Blood tests

Your child will have regular blood tests to measure the level of amino acids. Urine tests may also be done. 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 For children with MMA, even minor illnesses could lead to a metabolic crisis. To prevent serious health problems, call your doctor right away when your child has any of the following:

When ill, your child needs extra fluids and carbohydrates in order to prevent a metabolic crisis. During an illness, you should restrict protein and give your child starchy foods and fluids. Children with MMA may need to be treated in the hospital during illnesses to avoid serious health problems.  Ask your metabolic doctor if you should carry a special travel letter with medical instructions for your child’s care.

6.  Organ transplantation Some children with MMA are given liver or kidney transplants, or both. This may reduce some of the symptoms. However, transplant surgery has serious risks and may or may not be right for your child. Talk with your doctor or metabolic specialist if you have questions about the risks and benefits of transplantation.

Babies and children who have prompt and ongoing treatment may be able to live healthy lives with normal growth and development. In general, the earlier treatment is started, the better the outcome.

Children who respond to vitamin B12 treatment tend to do very well as long as treatment is continued. Children who are not treated until after they have symptoms may have lasting health and learning problems.

Even with treatment, some children develop life-long learning problems or intellectual disabilities. In addition, despite treatment, seizures, involuntary movement disorders, and kidney failure have occurred in some children.

Genes tell the body how to make enzymes. MMA is caused by changes in one of five sets of genesA segment of DNA that contains the instructions to make a specific protein (or part of a protein). Genes are contained on chromosomes. Chromosomes, and the genes on those chromosomes, are passed on from parent to child. Errors in the DNA that make up a gene are called variants and can lead to diseases. – MMUT, MMAA, MMAB, MMADHC, and MCEE. Each of these genes provides the instructions for a specific enzyme. Everyone has two copies of each of these five genes. People with MMA have changes (variantsA variant is a change or alteration in a person’s DNA sequence. Variants can happen in genes and affect how the gene functions. There are different types of variants – they can be non-problem causing (benign), disease-causing (pathogenic) or of unknown significance. The term variants is now used in place of the term mutation.) in both copies of one of these five genes. Because of the variants in their genes, one of their enzymes either does not work properly or is not made at all.

MMA is inherited in an autosomal recessive manner. It affects both boys and girls equally.

Everyone has two copies of the genes that make the MMA enzymes. In children with MMA, both copies of these genes do not work correctly. These children inherit one non-working gene for MMA from each parent.

Parents of children with MMA rarely have the disorder. Instead, each parent has a single non-working gene for MMA. They are called carriersA person who has one copy of a gene mutation for a particular autosomal recessive disorder (remember genes come in pairs). Carriers are not affected by the disorder. However, they can pass on the gene variant to their children. Children who inherit two such gene variants will be affected by the disorder. The term variants is now used in place of the term mutation.. Carriers do not have MMA because their other gene is working correctly.

When both parents are carriers, there is a 25% chance in each pregnancy for the child to have MMA. There is a 50% chance for the child to be a carrier, just like the parents. And, there is a 25% chance for the child to have two working genes.

GeneticRelating to (or due to) genes and heredity or the field of studying genes and heredity. counseling is available to families who have children with MMA. Genetic counselors can answer your questions about how MMA is inherited, choices during future pregnancies, and how to test other family members. Ask your doctor about a referral to a genetic counselorThese are health care providers who have special training in genetic conditions. They help families understand genetic disorders and how they are passed down. Genetic counselors offer information and support to people who have genetic conditions in their families or are concerned that they may have a child with an inherited disorder..

Genetic testing is available for MMA. Genetic testing, also called DNA testing, looks for changes (variants) in the pair of genes that cause MMA. Talk with your genetic counselor or metabolic doctor if you have questions about DNADeoxyribonucleic acid (DNA) is a molecule found in the chromosomes that carries genetic information. DNA is composed of four units (called bases) that are designated A, T, G, and C. The sequence of the bases spell out instructions for making all of the proteins needed by an organism. A gene is a section of DNA that holds the instructions for a specific protein. A change in one or more of the DNA bases making up a gene is called a mutation. Some mutations change the protein instructions and can lead to particular health problems or disorders. Each parent passes half of their chromosomes, and thus half of their DNA instructions, onto their children. It is these instructions that cause certain traits, such as eye or hair color, to be inherited. testing.

DNA testing is not necessary to diagnose your child. However, if available, it can be helpful for carrier testing or prenatal diagnosis, discussed below.

Special tests on blood, urine, or skin samples can be done to help confirm MMA.  Talk to your metabolic doctor or genetic counselor if you have questions about testing for MMA.

If both gene changes have been found in your child with MMA, DNA testing can be done during future pregnancies. The sample needed for this test is obtained by either CVS or amniocentesisThis is a test done during pregnancy. A needle is used to remove a small sample of fluid from the sac around the fetus. The sample can be used to test for certain genetic disorders in the fetus. Amniocentesis to test for genetic conditions is usually done between 13 and 20 weeks of pregnancy..

If DNA testing would not be helpful, MMA can also be detected by an enzyme test using cells from the fetus. The sample needed for this test is obtained by amniocentesis.

Parents may either choose to have testing during pregnancy or wait until birth to have the baby tested. Parents may also choose to use assisted reproductive techniques to decrease the chance that their future children would have MMA. A genetic counselor can talk to you about your choices and answer questions about prenatal testing or testing your baby after birth.

Having MMA If they are healthy and growing normally, older brothers and sisters of a baby with MMA are unlikely to have the condition. However, finding out if other children in the family have this condition is important because early treatment can prevent serious health problems. Ask your metabolic doctor whether your other children should be tested to see if they also have MMA.

MMA carriers Brothers and sisters who do not have MMA still have a chance to be carriers like their parents. Except in special cases, carrier testing should only be done on people over 18 years of age.

If you are a parent of a child with MMA, your brothers and sisters have a 50% chance to be an MMA carrier. It is important for other family members to be told that they could be carriers. There is a small chance they are also at risk to have children with MMA.

All states provide newborn screening for MMA. However, when both parents are MMA carriers, newborn screeningA screening test that looks for different disorders using a small sample of blood taken from a newborn’s heel. A positive or abnormal newborn screening result means that there are slight differences that were found in the baby’s blood, and further testing is needed to figure out if the baby has a metabolic disorder. results are not sufficient to rule out the condition in a newborn baby. In this case, special diagnostic testing should be done in addition to newborn screeningThe process of testing for disease in a person who does not show signs of having the disease (nonsymptomatic or asymptomatic person). The goal of screening is to catch the disease in its early stages..

Diagnostic testing Brothers and sisters of a child with MMA can have special tests on blood, urine, or skin samples to see if they also have MMA. Talk to your doctor or genetic counselor if you have questions about testing for MMA.

Carrier testing If the gene changes have been identified in your child with MMA, carrier testing can be done for other family members. If you have questions about carrier testing, ask your genetic counselor or metabolic doctor.

About one in 80,000 babies in the United States is born with MMA.

MMA occurs in all ethnic groups around the world. It does not occur more often in any specific race, ethnic group, geographical area, or country.

There are a number of different types of MMA. The vitamin B12 non-responsive types are sometimes also called:

The vitamin B12 responsive types are sometimes also called:

Another type of MMA has additional symptoms of a separate condition called homocystinuria.  See the fact sheet MMA+HCU for more information about this type of MMA.

Organic Acidemia Association http://www.oaanews.org

Metabolic Support UK https://www.metabolicsupportuk.org

MedlinePlus https://medlineplus.gov/genetics/condition/methylmalonic-acidemia/

Baby’s First Test http://www.babysfirsttest.org

Methylmalonic acidemia, also called methylmalonic aciduria,[note 1] is an autosomal recessive[1] metabolic disorder that disrupts normal amino acid metabolism.[2] It is a classical type of organic acidemia.[3] The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.[4]

Methylmalonic acidemia stems from several genotypes,[5] all forms of the disorder usually diagnosed in the early neonatal period, presenting progressive encephalopathy, and secondary hyperammonemia. The disorder can result in death if undiagnosed or left untreated. It is estimated that this disorder has a frequency of 1 in 48,000 births, though the high mortality rate in diagnosed cases make exact determination difficult.[4] Methylmalonic acidemias are found with an equal frequency across ethnic boundaries.[6]

Depending on the affected gene(s), this disorder may present symptoms that range from mild to life-threatening.

The inherited forms of methylmalonic acidemia cause defects in the metabolic pathway where methylmalonyl-coenzyme A (CoA) is converted into succinyl-CoA by the enzyme methylmalonyl-CoA mutase.[9]

Vitamin B12 is also needed for the conversion of methylmalonyl-CoA to succinyl-CoA. Mutations leading to defects in vitamin B12 metabolism or in its transport frequently result in the development of methylmalonic acidemia.[citation needed]

This disorder has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene—one from each parent—must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.[citation needed]

Though not always grouped together with the inherited versions, a severe nutritional deficiency of vitamin B12 can also result in syndrome with identical symptoms and treatments as the genetic methylmalonic acidemias.[10] Methylmalonyl-CoA requires vitamin B12 to form succinyl-CoA. When the amount of B12 is insufficient for the conversion of cofactor methylmalonyl-CoA into succinyl-CoA, the buildup of unused methylmalonyl-CoA eventually leads to methylmalonic acidemia. This diagnosis is often used as an indicator of vitamin B12 deficiency in serum.[11]

In methylmalonic acidemia, the body is unable to break down the amino acids methionine, threonine, isoleucine and valine; as a result methylmalonic acid builds up in the blood and tissues. Those afflicted with this disorder are either lacking functional copies or adequate levels of one or more of the following enzymes: methylmalonyl-CoA mutase, methylmalonyl-CoA epimerase, or those involved in adenosylcobalamin synthesis.[7][8]

It is estimated that as many as 60% of cases are the result of a mutated MUT gene which encodes the protein methylmalonyl-CoA mutase. This enzyme is responsible for the digestion of potentially toxic derivatives of the breakdown of the above-mentioned amino acids and fats, primarily cholesterol,[8] particularly this enzyme converts methylmalonyl-CoA into succinyl-CoA.[12] Without this enzyme, the body has no means to neutralize or remove methylmalonic acid and related compounds. The action of this enzyme can also be crippled by mutations in the MMAA, MMAB, and MMADHC genes, each of which encodes a protein required for normal functioning of methylmalonyl-CoA mutase.[8]

Mutations in the MCEE gene, which encodes the methylmalonyl-CoA epimerase protein, also referred to as methylmalonyl racemase, will cause a much more mild form of the disorder than the related methylmalonyl-CoA mutase variant. Like the mutase, the epimerase also functions in breaking down the same substances, but to a significantly lesser extent than the mutase does.[8] The phenotypic differences caused by a deficiency of the epimerase as opposed to the mutase are so mild that there is debate within the medical community as to whether or not this genetic deficiency can be considered a disorder or clinical syndrome.[13]

Also known as vitamin B12, this form of cobalamin is a required cofactor of methylmalonyl-CoA mutase. Even with a functional version of the enzyme at physiologically normal levels, if B12 cannot be converted to this active form, the mutase will be unable to function.[8]

Though there are not distinct stages of the disease, methylmalonic acidemia is a progressive condition; the symptoms of this disorder are compounded as the concentration of methylmalonic acid increases. If the triggering proteins and fats are not removed from the diet, this buildup can lead to irreparable kidney or liver damage and eventually death.[4]

One of, if not the most common form of organic acidemia,[14] methylmalonic acidemia is not apparent at birth as symptoms usually do not present themselves until proteins are added to the infant's diet.[4] Because of this, symptoms typically manifest anytime within the first year of life.[14] Due to the severity and rapidity in which this disorder can cause complications when left undiagnosed, screening for methylmalonic acidemia is often included in the newborn screening exam.[4][15]

Because of the inability to properly break down amino acids completely, the byproduct of protein digestion, the compound methylmalonic acid, is found in a disproportionate concentration in the blood and urine of those afflicted. These abnormal levels are used as the main diagnostic criteria for diagnosing the disorder. This disorder is typically determined through the use of a urine analysis or blood panel.[14] The presence of methylmalonic acidemia can also be suspected through the use of a CT or MRI scan or ammonia test, however these tests are by no means specific and require clinical and metabolic/correlation.[4] Elevated levels of ammonia, glycine, and ketone bodies may also be present in the blood and urine.[7]

Methylmalonic acidemia has varying diagnoses, treatment requirements and prognoses, which are determined by the specific genetic mutation causing the inherited form of the disorder.[5] The following are the known genotypes responsible for methylmalonic acidemia:

The mut type can further be divided into mut0 and mut- subtypes, with mut0 characterized by a complete lack of methylmalonyl-CoA mutase and more severe symptoms and mut- characterized by a decreased amount of mutase activity.[6]

Mut-, cblB, and cblA versions of methylmalonic acidemia have been found to be cobalamin responsive. Mut0 is a nonresponsive variant.[6]

Treatment for all forms of this condition primarily relies on a low-protein diet, and depending on what variant of the disorder the individual suffers from, various dietary supplements. All variants respond to the levo isomer of carnitine as the improper breakdown of the affected substances results in sufferers developing a carnitine deficiency. The carnitine also assists in the removal of acyl-CoA, buildup of which is common in low-protein diets by converting it into acyl-carnitine which can be excreted in urine. Some forms of methylmalonyl acidemia are responsive to cobalamin although cyanocobalamin supplements could prove detrimental to some forms. [18] If the individual proves responsive to both cobalamin and carnitine supplements, then it may be possible for them to ingest substances that include small amounts of the problematic amino acids isoleucine, threonine, methionine, and valine without causing an attack.[4]

A more extreme treatment includes kidney or liver transplant from a donor without the condition. The foreign organs will produce a functional version of the defective enzymes and digest the methylmalonic acid, however all of the disadvantages of organ transplantation are of course applicable in this situation.[4] There is evidence to suggest that the central nervous system may metabolize methylmalonyl-CoA in a system isolated from the rest of the body. If this is the case, transplantation may not reverse the neurological effects of methylmalonic acid previous to the transplant or prevent further damage to the brain by continued build up.[19][12]

The prognosis will vary depending on the severity of the condition and the individual's response to treatment. Prognosis is typically better for those with cobalamin-responsive variants and not promising in those suffering from noncobalamin-responsive variants.[12] Milder variants have a higher frequency of appearance in the population than the more severe ones.[14] Even with dietary modification and continued medical care, it may not be possible to prevent neurological damage in those with a nonresponsive acidemia.[12] Without proper treatment or diagnosis, it is not uncommon for the first acidemic attack to be fatal.[4]

Despite these challenges, since it was first identified in 1967, treatment and understanding of the condition has improved to the point where it is not unheard of for even those with unresponsive forms of methylmalonic acidemia to be able to reach adulthood and even carry and deliver children safely.[19]

MMA was first characterized by Oberholzer et al.[20] in 1967.[19]

That MMA can have disastrous effects on the nervous system has been long reported; however, the mechanism by which this occurs has never been determined. Published on June 15, 2015, research performed on the effects of methylmalonic acid on neurons isolated from fetal rats in an in vitro setting using a control group of neurons treated with an alternate acid of similar pH. These tests have suggested that methylmalonic acid causes decreases in cellular size and increase in the rate of cellular apoptosis in a concentration dependent manner with more extreme effects being seen at higher concentrations. Furthermore, micro-array analysis of these treated neurons have also suggested that on an epigenetic-level methylmalonic acid alters the transcription rate of 564 genes, notably including those involved in the apoptosis, p53, and MAPK signaling pathways.[21]

As the conversion of methylmalonyl-CoA to succinyl-CoA takes place inside the mitochondria, mitochondrial dysfunction as a result of diminished electron transport chain function has long been suspected as a feature in MMA. Recent[when?] research has found that in rat models mitochondria of rats affected by the disorder grow to unusual size, dubbed megamitochondria. These megamitochondria also appear to have deformed internal structures and a loss in electron richness in their internal matrix. These megamitochondria also showed signs of decreased respiratory chain function, particularly in respiratory complex IV which only functioned at about 50% efficiency. Similar changes were identified in the mitochondria of a liver sample removed during transplant from a 5-year-old boy suffering from MMA.[22]

Recent[when?] case studies in several patients presenting nonresponsive mut0 MMA with a specific mutation designated p.P86L have suggest the possibility of further subdivision in mut type MMA might exist. Though currently unclear if this is due to the specific mutation or early detection and treatment, despite complete nonresponse to cobalamin supplements, these individuals appeared to develop a largely benign and near completely asymptomatic version of MMA. Despite consistently showing elevated methylmalonic acid in the blood and urine, these individuals appeared for the large part developmentally normal.[23]

Methylmalonic acidemia (MMA) is a rare, genetic disorder of the liver. People with this condition are unable to produce an enzyme that is needed to break down and use certain proteins and fats found in food.

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This metabolic dysfunction leads to a buildup of methylmalonic acid in the body. Methylmalonic acidemia can cause coma and other serious symptoms if not correctly diagnosed and treated.

This article explains the symptoms of methylmalonic acidemia and how it is passed down within families. It also discusses how MMA is diagnosed and treated, along with some of the long-term impacts.

Methylmalonic acidemia is a complex disease that can cause a variety of different symptoms. The intensity of these symptoms varies based on the exact genetic mutation causing the disease.

In the most severe cases, symptoms begin almost immediately at birth. In others, they might not appear until later infancy, childhood, or even adulthood.

Many of the symptoms of methylmalonic acidemia get worse in particular situations. These periods of more dangerous illness may be triggered by fasting, fever, vomiting, infection, surgery, stress, or by failing to follow the recommended treatments.

Called “decompensation” of the illness, this may lead to life-threatening symptoms. For example, an infant undergoing a decompensation might experience:

This can happen with even with the best medical interventions. Infants are particularly at risk.

Methylmalonic acidemia can lead to serious long-term health conditions as well, including:

Additional symptoms and conditions are possible as well. But it’s important to note that not everyone with MMA will have them all, or experience them at all times. For example, someone with a mild form of methylmalonic acidemia might first experience kidney disease symptoms in adulthood.

Methylmalonic acidemia belongs in a group of disorders known as inborn errors of metabolism.

Metabolism refers to how the body converts nutrients in food into energy. Inborn errors of metabolism are caused by different genetic defects that lead to problems with metabolism.

Methylmalonic acidemia also belongs to a smaller subset of these diseases, termed organic acidurias. These genetic diseases result from difficulties metabolizing certain types of amino acids, the building blocks of proteins. It results in unhealthy levels of products otherwise normally present in the body.

Defects in different enzymes lead to different types of organic aciduria. For example, propionic acidemia is another rare disease in this class. Other rare diseases in this group may have some similar symptoms.

More specifically, methylmalonic acidemia can be caused by a defect in one of several different genes. Due to the defect in the gene, the resulting proteins don’t work as well as they should. These defects cause problems with the functioning of a specific protein enzyme, called methylmalonyl-CoA mutase.

In more than 60% of cases, the cause is:

Methylmalonic acidemia is an autosomal recessive genetic condition. This means that a person has to inherit an affected gene from both of their parents to get the disease.

If a couple has had one child born with methylmalonic acidemia, there is a 25% chance that their next child would also have the condition. It’s also important to test existing siblings for the disease since not all people with MMA display symptoms right away.

Early diagnosis and management may then help prevent long-term complications from the disease. Talking with a genetic counselor can be very helpful for many families. This can give you a sense of the risks in your situation. Prenatal testing may also be an option.

The standard newborn screening tests sometimes provide the diagnosis of methylmalonic acidemia. However, not all places test for this specific disease. Also, infants might first experience symptoms before the results of these screening tests are available.

Diagnosis of methylmalonic acidemia requires a thorough medical history and exam. Laboratory testing is critical as well. It’s important that diagnosis happens as quickly as possible since affected individuals are often very ill. Also, untreated decompensations can worsen the long-term complications of MMA (for example, causing permanent brain damage).

Many different types of medical problems can lead to neurological and other symptoms such as those seen in decompensated methylmalonic acidemia. It can be a challenge to rule out these other possible diagnoses and narrow down on the specific cause. Since MMA is a rare condition, a medical specialist may be needed to help diagnose the disease.

In people with MMA, these levels should be higher than usual. However, there are also some other different inborn errors of metabolism that can cause methylmalonic acid to build up as a result of different genetic problems.

Blood tests that may be helpful in diagnosing methylmalonic acidemia include:

Additional genetic tests can help finalize the diagnosis and can also identify the specific genetic mutation involved. In some cases, this may affect treatment options.

The treatment for methylmalonic acidemia depends on a person's history with the disorder and their specific symptoms. These options vary according to whether the needed treatment is immediate because of an emergency context, or if they're meant for long-term care.

Periods of decompensations from methylmalonic acidemia are medical emergencies. Without support in this time, individuals may die. These periods might happen before an initial diagnosis or at other times of stress or illness. Intensive support in a hospital setting is necessary.

Some interventions that might be needed during an emergency include:

Dietary management is an important part of treatment for methylmalonic acidemia. A dietary specialist who is experienced in rare metabolic diseases can help guide nutritional support.

However, limiting protein too severely has its own negative health impacts. That’s why it’s helpful to work with a professional. A feeding tube is also sometimes helpful to help ensure proper nutrition, especially during decompensations.

L-carnitine (a supplement) and Neomycin (an antibiotic) can potentially enhance the removal of some of the toxic metabolic byproducts from the body.

Injections of vitamin B12 (hydroxocobalamin) are a very helpful treatment for people with specific genetic subtypes of MMA, but not for all subtypes.

Other long-term medications might also be needed to treat complications. For example, someone might need to take a bisphosphonate drug to help treat osteoporosis related to methylmalonic acidemia.

Liver transplant is also an option for some people with MMA. It doesn’t cure the disease, but it can help a person experience less frequent and less severe decompensations. Kidney transplant might also be needed for people with severe kidney disease.

Preventing decompensations is also an important part of treatment. People with methylmalonic acidemia should not fast or increase their intake of protein because this might trigger a decompensation.

If an individual with MMA is ill, such as from a virus, it’s important that they decrease protein intake and receive additional fluids with sugar. This can help prevent a decompensation.

Affected individuals need to be closely monitored whenever they are exposed to stressors that might trigger a decompensation. That way, treatment can begin promptly if necessary.

People with methylmalonic acidemia also need regular monitoring for long-term complications of the condition. For example, this should include regular eye exams and tests of kidney function.

Ideally, people with MMA should see a specialist with experience in rare genetic diseases. Treatment and monitoring will require a range of medical professionals working together as a team.

Researchers are also investigating potential new treatments for methylmalonic acidemia, such as gene therapy and antioxidant treatments. These treatments have not received the same rigorous study as treatments already approved by the Food and Drug Administration.

Ask your healthcare provider if you are interested in participating in a clinical trial. Or, check out the United States database for clinical trials.

A diagnosis of methylmalonic acidemia can be challenging for many families. Fortunately, both diagnosis and treatment have improved in recent years.