Methylmalonic acidaemia (MMA): symptoms, diagnosis and management

The body breaks proteins down into amino acids using enzymes and then breaks the amino acids into smaller parts. Metabolic Support UK explains that in MMA the body lacks an enzyme called methylmalonyl-CoA mutase, so it cannot break down four amino acids, and a chemical called methylmalonic acid builds up in the blood and urine. That build-up can damage the brain and kidneys and other organs and may delay development, such as walking and talking.

MedlinePlus Genetics describes MMA as a group of inherited disorders that prevent the body from breaking down proteins and fats properly, with effects that usually appear in early infancy and range from mild to life-threatening. It lists variants in several genes (MMUT, MMAA, MMAB, MMADHC and MCEE) as causes, with about 60 percent of people having variants in MMUT. The long-term effects depend on which gene is altered and how severe the variant is. Three of the genes (MMAA, MMAB and MMADHC) make proteins that help produce and regulate vitamin B12, which the enzyme needs in order to work.

MMA belongs to a wider family called the organic acidaemias or organic acid disorders. The UK National Screening Committee describes these as a group of rare, inherited disorders in which the body cannot break down certain types of amino acids and fats, causing a build-up of harmful compounds that can damage vital organs such as the brain, heart and liver, with variable age of onset and severity.

Metabolic Support UK lists the early signs in babies as poor feeding, vomiting, dehydration, being floppy, being excessively sleepy, rapid breathing and seizures. MedlinePlus Genetics adds weak muscle tone, developmental delays, an enlarged liver and faltering weight. Long-term complications it lists include feeding problems, intellectual disability, movement problems, chronic kidney disease and inflammation of the pancreas.

The most important concept for families is metabolic crisis. When the body does not get enough food energy, for instance during illness or after going without food for too long, it breaks down its own protein, and toxic chemicals including ammonia can build up. Metabolic Support UK says this is usually triggered by childhood illnesses such as vomiting and diarrhoea or by fasting for too long, that the effects quickly become life-threatening if untreated, and that avoiding a crisis is essential.

• Poor feeding, vomiting and signs of dehydration, especially during illness.

• Unusual sleepiness, floppiness or difficulty waking.

• Rapid breathing.

• Seizures.

• Symptoms that continue despite the emergency regimen, or any time you are worried: Metabolic Support UK says to go immediately to hospital.

Metabolic Support UK says MMA is diagnosed by measuring high levels of methylmalonic acid and other chemicals in the blood and urine, and it can also be diagnosed by looking at enzyme levels and at the body's genes.

Newborn screening is a common question. The UK National Screening Committee page says that, based on its last review in March 2016, screening is not currently recommended for the organic acid disorders methylmalonic acidaemia and propionic acidaemia. It gives reasons including that the quality of evidence is not high enough to know whether screening is of long-term benefit, and that it is unclear how to treat babies detected at screening who show no signs of being ill. The same page notes the next review was estimated for 2021 to 2022, so families may wish to check the current position with their metabolic team.

MMA is inherited in an autosomal recessive pattern, which MedlinePlus Genetics explains means both copies of the gene must have a variant to cause the disorder. The parents each carry one copy but typically do not show symptoms. Metabolic Support UK adds that there is nothing that could have been done to prevent a baby having MMA, and gives the 1 in 4, 1 in 2 and 1 in 4 chances of an affected child, a carrier or an unaffected non-carrier in each pregnancy when both parents are carriers.

Metabolic Support UK explains the balance: enough protein for growth, but not too much, because toxic chemicals are then made. The management it lists is a protein-restricted diet, ensuring a sufficient energy supply, a generous fluid intake, regular feeding and carnitine medication, with other medicines if needed. Tube feeding may be needed to give regular feeds and so meet energy, nutrient and fluid needs and reduce the production of abnormal chemicals.

MMA is monitored with frequent blood tests, height and weight checks and developmental checks, and diet and medicines are adjusted according to age, weight and blood chemical levels. Its practical advice includes keeping a good supply of dietary products and medicines that are in date, having emergency feed products and a written emergency plan, and keeping supplies of medicines to control fever, which are given as normally recommended.

During any childhood illness an emergency regimen is given. Metabolic Support UK sets out the steps as: stop all protein in food and drink, start the emergency regimen, which is made up of glucose polymer, continue medication as prescribed, always take the full amount of emergency feeds as prescribed, and go immediately to hospital if symptoms continue or you are worried. It stresses that emergency feeds must be started promptly and that there should be no delays.

The written plan matters because other staff may not know the condition. Metabolic Support UK says always to have emergency feed products and a written emergency plan to hand, and to update the metabolic team regularly. In a real emergency such as a seizure, difficulty waking or breathing difficulty, call 999.

MedlinePlus Genetics says that without treatment the disorder can lead to coma and death in some cases, and that the long-term effects depend on the gene and variant, with the mut 0 form the most severe and having the poorest outcomes. Metabolic Support UK describes MMA as a serious inherited metabolic disorder that can lead to severe problems, which is why close specialist follow-up and strict attention to illness plans are the main safeguards.

Metabolic Support UK says MMA is monitored with frequent blood tests and checks of growth and development, which implies ongoing contact with a specialist metabolic team. Support organisations such as Metabolic Support UK exist for families and adults living with inherited metabolic conditions.

Metabolic Support UK says dietary products and medicines for MMA are prescribed and obtained through a pharmacy or home delivery, and that families should keep a written emergency plan and keep the metabolic team updated. In practice care is led by a specialist metabolic team and shared with the local hospital and GP, so a written plan is important.

Some families seek a second opinion or genetic counselling privately, and a private provider may not have the same access to specialist metabolic dietary products and monitoring, so it is worth asking what would be provided. Whatever route is used, ask which team is responsible for the emergency plan and how to reach them out of hours.