Co-written by Dave and Chris Gordon, parents (MMA) and MDDA National MMA link parents.
Co-written and edited by Dr Jim McGill, Director Metabolic Medicine, Royal Children's Hospital, Brisbane, Queensland, Australia.
There are several different enzyme deficiencies that can cause methylmalonic acidaemia (MMA) and these have a wide range of clinical presentations and prognosis. All forms are inherited as an autosomal-recessive trait (ie both parents must be carriers, leaving all children with a 25% or 1 in 4 chance of inheriting the disorder).
The most common form of methylmalonic acidemia results from a deficiency of the enzyme, methylmalonyl CoA mutase. Those individuals with no functional mutase are described as having the mut0 version of the disorder. Those who have an altered mutase function affecting its ability to work properly have mut-. In order to work properly, Methylmalonyl CoA mutase requires a helper or cofactor. That cofactor is adenosyl cobalamin (AdoCbl) which is a form of vitamin B12. Two further forms of the disorder result from abnormal AdoCbl synthesis which in turn, impairs the ability of mutase to work properly. They are usually referred to as MMA (cblA) and MMA (cblB).
There is another form of vitamin B12, methylcobalamin (MeCbl), which if deficient results in homocystinuria. If there are blocks early in the steps to convert vitamin B12 into its two active forms, then neither AdoCbl or MeCbl will be formed. This results in the individual having both MMA and homocystinuria. The blocks to this pathway are referred to as cblC, cblD and cblF Homocystinuria will be dealt with separately at the end of this section.
Babies with the severe forms of MMA usually present in the first week of life with poor feeding, rapid breathing due to acidosis, decreased conscious state which may progress to coma and are extremely sick. Children with milder forms of the disorder may present with failure to thrive, lethargy and recurrent vomiting attacks usually precipitated by viral infections or eating a lot of protein (meat). They are usually sicker than their brothers and sisters with colds and flus. Clinical presentations may also include respiratory distress, muscular hypotonia (floppy baby), coma or developmental delays.
Given the mild and non-specific nature of the symptoms in some forms of the disorder, some parents have reported difficulty in obtaining early diagnosis. Babies with mut0 tend to present earlier (first week in life) and the vast majority are picked up due to their clinical symptoms by the age of one month. Diagnosis for those with mut-, cblA and cblB usually occurs during the first year of life. Untreated, babies will accumulate large amounts of methylmalonic acid in their blood and urine.
Treatment involves limiting protein in the diet. Protein formulas minus methionine, threonine, valine and isoleucine may also be prescribed. Those with the cbl forms of the disorder should also respond well to supplementary vitamin B12 therapy (usually given as hydroxocobalamin injections) to correct that deficiency. Some individuals with cbl forms of MMA may be controlled with oral forms of vitamin B12.
Metronidazole and other medication have been shown to be helpful in reducing the levels of MMA by changing the flora of the gut and reducing the amount of MMA produced there.
L-carnitine is commonly prescribed to children and adults with MMA. Carnitine is a naturally occurring substance that is important in transporting toxic compounds out of mitochondria (the energy producing units in the cells) and cells. The carnitine combines with the toxic compound and carries it out of the body into the urine. As more and more toxin is removed, more and more carnitine is lost from the body into the urine so that eventually the body stores of carnitine are diminished. This is called a secondary carnitine deficiency. (A primary deficiency results when there is a problem making or transporting the carnitine). Carnitine deficiency can cause major physical problems and some carers have noted a detrimental effect in brain/cognitive functioning or behaviour when children are carnitine deprived.
Like most other forms of inborn errors of metabolism (IEMs), early detection is vital. States that use Tandem Mass Spectroscopy newborn screening will pick up cases of MMA shortly after birth. Like other IEM's, if the child is diagnosed early enough and managed appropriately, the chance of disability can be minimised. Disabilities which can occur include disorders of speech, mobility, movement and learning skills. In many cases, this can be avoided/averted and children can lead a relatively normal and productive lives. However, it should be remembered that for severe cases, even TMS screening may not detect the condition early enough and some may slip into a coma within a few days of birth. Conversely, there are some very mild forms of the disease and these children lead relatively normal lives with only moderate changes to the diet.
The main issues for families revolve around diet. Most children have a poor appetite possibly because a build up of acid occurs while the child eats, leading to a feeling of nausea. Some may require a gastrostomy to be tube fed. This is important to maintain a constant intake of protein and calories. For people with severe forms of MMA (typically mut0), organ failure may be another complication. Kidney damage does seem to affect older patients, sometimes requiring a transplant in their teens or later. Liver transplantation has been tried, with some success, to cure severe forms of the disease, however some patients have developed disabilities after the transplant, including kidney failure and brain changes. In some centres combined liver and kidney transplants have been successful. There may be some hope with new stem cell technology being tried around the world to gradually replace the liver with unaffected cells, but this is still in the experimental stage.
MMA with Homocystinuria - This condition has been somewhat more difficult to diagnose clinically. Most are diagnosed in the first year of life, but some people have been well into adulthood before being picked up. Clinical presentations are similar to MMA eg failure to thrive, lethargy and poor feeding. Developmental delay is common as is anaemia. Later presentations may involve more severe learning defects and renal failure.
Other forms of MMA
MMA can occur in babies and infants who are deficient in vitamin B12 for nutritional reasons rather than due to an enzyme deficiency. The most common cause of this is when the baby or infant is breast fed and the mother is vitamin B12 deficient either because she has a very restricted diet (such as a vegan) or has a condition called pernicious anaemia in which vitamin B12 is not absorbed normally. These infants and children usually also have homocystinuria.
More recently a group of children with MMA due to a deficiency of methylmalonyl semialdehyde has been recognised. These children usually do not get the severe episodes of acidosis.