ORGANIC ACID DISORDER

Disorder name: Methylmalonic Acidemia with Homocystinuria
Acronym: There is no standard acronym for this condition.
For this fact sheet, we will use MMA+HCU
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• What is MMA+HCU?
• What causes MMA+HCU?
• If MMA+HCU is not treated, what problems occur?
• What is the treatment for MMA+HCU?
• What happens when MMA+HCU is treated?
• What causes the enzyme to be absent or not working correctly?
• How is MMA+HCU inherited?
• Is genetic testing available?
• What other testing is available?
• Can you test during a future pregnancy?
• Can other members of the family have MMA+HCU or be carriers?
• Can other family members be tested?
• How many people have MMA+HCU?
• Does MMA+HCU happen more often in a certain ethnic group?
• Does MMA+HCU go by any other names?
• Where can I find more information?

This fact sheet contains general information about methylmalonic acidemia with homocystinuria (MMA+HCU). 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+HCU should be followed by a metabolic doctor in addition to their primary care provider.

WHAT IS MMA+HCU?

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

Organic Acid DisordersThis is a group of rare inherited conditions. OA disorders are caused by one or more enzymes that do not work properly. People with these conditions cannot digest certain parts of protein from the food they eat. This causes harmful substances to build up in their blood and urine. This can cause serious effects on health, growth, and learning.: Organic acid disorders (OAs) are a group of rare inheritedAcquiring a trait from one’s parents. Most traits, such as eye color or hair color, are inherited from a parent through genes. conditions. They are caused by enzymes that do not work properly. A number of enzymesA molecule that helps chemical reactions take place. For example, enzymes in the stomach speed up the process of breaking down food. Each enzyme can participate in many chemical reactions without changing or being used up. are needed to process protein from the food we eat for use by the body. Problems with one or more of these enzymes can cause an organic acid disorder. People with organic acid disorders cannot break down proteinA molecule that makes up many parts of every cell in the body. Examples of proteins include hormones, enzymes, hair, and antibodies. Proteins are made up of 20 different types of individual units called amino acids. It is the order of these amino acids in a protein that determines what form and function a protein has. Each gene holds the instructions for making a single protein. properly. This causes harmful substances to build up in their blood and urine. These substances can affect health, growth, and learning. The symptoms and treatment vary between different organic acid disorders. They can also vary from person to person with the same organic acid disorder. See the fact sheets for each specific organic acid disorder. Organic acid disorders are inherited in an autosomal recessive manner and affect both males and females.

WHAT CAUSES MMA+HCU?

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 into 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. that the body can use for energy.

MMA+HCU occurs when one of these special enzymes is either missing or not working properly. The job of these enzymes is to change vitamin B12 (also called cobalamin) into a form that the body can use. When the body is not able to use 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. correctly, it causes homocystineThis is a type of amino acid made by the body. High levels can occur in people with homocystinuria or certain other metabolic disorders., 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. This can lead to serious health problems.

There are a number of different types of MMA+HCU. The most common type is called Cobalamin C deficiency (CblC). Rarer types include Cobalamin D deficiency (CblD) and Cobalamin F deficiency (CblF).

There are other types of MMA that occur without homocystinuria. These are described in a separate fact sheet – see MMA.

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+HCU. They 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.

IF MMA+HCU IS NOT TREATED, WHAT PROBLEMS OCCUR?

Each child with MMA+HCU is likely to have somewhat different effects:

• Most babies with CblC deficiency have shown symptoms within the first year, often by one month of age. A small number of children with CblC deficiency have not had symptoms until after 4 years of age. A small number of individuals have been reported to have developed their first symptoms in their teens or early twenties.
• Babies with CblF deficiency usually have their first symptoms shortly after birth.
• Children with CblD deficiency usually show initial symptoms later in childhood.

It is possible that a small number of people with this condition never develop symptoms.

Early-onset MMA+HCU
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)
• seizuresThese are also called "convulsions" or "fits." During a seizure, a person loses consciousness and control of his or her muscles. It may also cause involuntary movements. Seizures can happen for many reasons. Some causes are metabolic disorders, a metabolic crisis, brain injury, and infection.
• small head and brain size, called microcephalyThis is a head size that is too small for a child’s age. It is usually caused by lack of brain growth. It can happen for many reasons. Many children with microcephaly have intellectual disabilities.
• water on the brain, called hydrocephalusThis is also sometimes called 'water on the brain.' It occurs when extra fluid builds up in the ventricles - the inner chambers of the brain. It is often caused by a block in one of the chambers of the brain that does not allow the fluid to drain. When fluid builds up, it causes the ventricles and the skull to expand. It can be present at birth or can happen later in life. If it is not treated, it can cause learning disabilities or intellectual disabilities.
• 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 acidosisThis happens when acidic substances build up in the blood. It can cause rapid breathing, confusion, and extreme sleepiness. If not treated, it may lead to shock, coma or death.
• protein or blood in the urine
• anemiaThis is a condition in which the blood has too few red blood cells or too little hemoglobin, the oxygen carrying molecule in the blood. People with anemia are often pale, tired, weak, dizzy and short of breath.
• low plateletsThis is a type of blood cell that helps to clot the blood. Platelets help prevent or control bleeding.
• low white blood cellsThe smallest living unit. Cells make up all organs and tissues in multi-cellular organisms, like humans. They can also live independently, as in bacteria and other microorganisms. At a minimum, a cell is surrounded by a membrane, contains DNA at some stage in its life, and is able to replicate itself into two equal parts.
• excessive clotting of the blood

If not treated, metabolic acidosis can cause:

• breathing problems
• seizures
• swelling of the brain
• strokeThis is when the blood or oxygen supply to part of the brain is stopped. It can be caused either by a blood clot or a leak in a blood vessel. A stroke may cause loss of speech and language and the ability to move certain body parts. If severe, it can cause death.
• comaThis is a sleep-like condition from which a person cannot be awakened. People in a coma are unconscious. A coma can be caused by many things. Two causes are untreated low blood sugar (hypoglycemia) and a metabolic crisis., sometimes leading to death

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

Later-onset MMA+HCU
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
• tremor
• 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

WHAT IS THE TREATMENT FOR MMA+HCU?

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+HCU to care for your child.

It is not known how effective treatment is in preventing the effects of MMA+HCU.  However, prompt and ongoing treatment may lessen the chance for intellectual disabilities, psychiatric disorders, and serious health problems.

Many children are given injections of vitamin B12. It is important to start treatment as soon as you know your child has MMA+HCU. Children may be placed on a low-protein diet and drink a special medical formula.

The following are treatments often recommended for children with MMA+HCU:

1.  Medication
Vitamin B12
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.

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.
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.

BetaineThis is a vitamin-like substance found in grains and other foods. It can also be bought in pill form. It is sometimes used as a treatment for homocystinuria. It can help lower the amount of homocystine in the blood. It may also help lessen the risk of blood clots in people with this condition.
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.

Hospital care
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 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 prevent the breakdown of protein and fat stored in the body.

Do not use any medication without checking with your doctor or metabolic specialist.

2. Low-protein diet and medical formula and foods
Low-protein diet
A food plan 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:

• milk and dairy products
• meat and poultry
• fish
• eggs
• 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 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. 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 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+HCU need to eat frequently to prevent 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.. 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 illnesses 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
• vomiting
• diarrhea
• infection or illness
• fever

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 an illness.  Ask your metabolic doctor if you should carry a special travel letter with medical instructions for your child’s care.

WHAT HAPPENS WHEN MMA+HCU IS TREATED?

Treatment may help some children but not others. Even with treatment, some babies and children may die. Others may have life-long learning problems or intellectual disabilities. Some children develop psychiatric disorders that are difficult to treat.

WHAT CAUSES THE ENZYME TO BE ABSENT OR NOT WORKING CORRECTLY?

Genes tell the body how to make enzymes. The different types of MMA+HCU are caused by problems with different enzymes and by changes, called 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 their corresponding 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.. For example, Cobalamin C deficiency is caused by variants in the MMACHC gene. Everyone has two copies of the MMACHC gene. People with Cobalamin C deficiency have variants in both copies of their MMACHC genes. Because of the variants in their MMACHC genes, the MMACHC enzyme either does not work properly or is not made at all. Other types of MMA+HCU are caused by variants in other genes.

HOW IS MMA+HCU INHERITED?

MMA+HCU 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+HCU enzymes. In children with MMA+HCU, both copies of these genes do not work correctly. These children inherit one non-working gene for MMA+HCU from each parent.

Parents of children with MMA+HCU rarely have the disorder. Instead, each parent has a single non-working gene for MMA+HCU. 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+HCU 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+HCU. 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+HCU. Genetic counselors can answer your questions about how MMA+HCU 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..

IS GENETIC TESTING AVAILABLE?

Genetic testing for MMA+HCU is available. Genetic testing, also called DNA testing, looks for variants in the pair of genes that cause MMA+HCU. 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.

WHAT OTHER TESTING IS AVAILABLE?

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

CAN YOU TEST DURING A FUTURE PREGNANCY?

If both genetic variants have been found in your child with MMA+HCU, 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+HCU can be detected by an enzyme test using cells from the fetus. The sample needed for this test is obtained by CVS or 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+HCU. A genetic counselor can talk to you about your choices and answer questions about prenatal testing or testing your baby after birth.

CAN OTHER MEMBERS OF THE FAMILY HAVE MMA+HCU OR BE CARRIERS?

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

MMA+HCU carriers
Brothers and sisters who do not have MMA+HCU 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+HCU, your brothers and sisters have a 50% chance to be a 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+HCU.

All states offer newborn screening for MMA+HCU. However, when both parents are MMA+HCU 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..

CAN OTHER FAMILY MEMBERS BE TESTED?

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

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

HOW MANY PEOPLE HAVE MMA+HCU?

The most common type called methylmalonic acidemia with homocystinuria, cblC type (Cobalamin C deficiency) is estimated to affect 1 in 50,000 – 100,000 newborns worldwide.

DOES MMA+HCU HAPPEN MORE OFTEN IN A CERTAIN ETHNIC GROUP?

MMA+HCU does not occur more often in any specific race, ethnic group, geographical area, or country.

DOES MMA+HCU GO BY ANY OTHER NAMES?

MMA+HCU is also sometimes called:

• Combined deficiency of methylmalonyl CoA mutase and homocystinuria
• Methyltetrahydrofolate methyltransferase deficiency
• Vitamin B12 metabolic defect, Type 2
• Methylmalonic acidemia and homocystinuria
• Cbl C deficiency
• Cbl D deficiency
• Cbl F deficiency

WHERE CAN I FIND MORE INFORMATION?

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

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

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

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

DOCUMENT INFO:

Created by:	www.newbornscreening.info
Reviewed by:	HI, CA, OR, and WA metabolic specialists
Review date:	September 31, 2007 May 1, 2011 August 29, 2013 May 29, 2020 March 5, 2023
Update on:	March 5, 2023

 

DISCLAIMER:

THIS INFORMATION DOES NOT PROVIDE MEDICAL ADVICE. All content (“Content”), including text, graphics, images and information are for general informational purposes only. You are encouraged to confer with your doctor or other health care professional with regard to information contained on this information sheet. After reading this information sheet, you are encouraged to review the information carefully with your doctor or other healthcare provider. The Content is not intended to be a substitute for professional medical advice, diagnosis or treatment. NEVER DISREGARD PROFESSIONAL MEDICAL ADVICE, OR DELAY IN SEEKING IT, BECAUSE OF SOMETHING YOU HAVE READ ON THIS INFORMATION SHEET. This project is supported by a grant from the MaternalHaving to do with the mother. and Child Health Bureau, Health Resources and Service Administration, Genetic Services Branch, MCH Project #:UH7MC30774-01-00 http://mchb.hrsa.gov