Methylmalonic Acidaemia (MMA)

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What is methylmalonic acidaemia?

Methylmalonic acidaemia is a genetically inherited disease in which the body is unable to process certain amino acids and fats correctly. This leads to the accumulation of a molecule called methylmalonyl-CoA and other by-products in the blood, which poison the body and brain. Methylmalonyl-CoA is a form of methylmalonic acid. Methylmalonic acidaemia (-aemia = in the blood) is also known as methylmalonic aciduria (-uria = in the urine) since high levels of methylmalonyl-CoA are also excreted in the urine. The disease shows many similarities to propionic acidaemia.

There are several variants of methylmalonic acidaemia, which range in severity from mild to life threatening. Seizures and progressive brain damage are common. Stroke, due to abnormal blood flow to the brain, and coma are two other serious complications. Untreated, the prognosis is poor.

The main amino acids involved are isoleucine, valine, threonine and methionine. Amino acids are the building blocks of proteins. After eating proteins, the body ‘metabolises’ or breaks them down into amino acids. Animal proteins include dairy products, meat, eggs and fish. Proteins are also found in plants including soy, legumes, grains and nuts. The body uses the amino acids to make its own proteins essential for life – for example enzymes; structural proteins in muscles, hair, skin, cells and cartilage; proteins that generate movement in muscles; or those involved in cell functioning or immune responses. In periods of fasting or illness, the body often switches to use its own proteins, and stored fats, to generate energy. Isoleucine, valine, threonine and methionine are essential amino acids meaning that the body cannot make them. Therefore, these amino acids come from ingested protein or from the breakdown of previously ingested and stored proteins.

How common is methylmalonic acidaemia?

Methylmalonic acidaemia is estimated to occur in 1 in 25,000 to 48,000 individuals globally. The condition affects both sexes equally.

What causes methylmalonic acidaemia?

Most commonly, methylmalonic acidaemia arises from a genetic mutation that limits the quantity or functioning of an enzyme called ‘methylmalonyl-CoA mutase’. This enzyme is involved in the metabolism of certain amino acids and fats. Alternatively, the mutation may be in genes that code for cobalamin (vitamin B12), which is a metabolic co-factor or ‘helper’ for methylmalonyl-CoA mutase. Individuals with the co-factor deficiency have a better prognosis than those in whom the methylmalonyl-CoA mutase is missing or reduced in activity.

Methylmalonic acidaemia is a recessively inherited genetic disorder, meaning that a child would only have the condition if both parents ‘carry’ the genetic mutation. Genes are arranged in structures called chromosomes that contain two strings or ‘alleles’. Offspring inherit one allele from their father and one from their mother. Carrying one copy of the mutated gene does not affect health, but when two mutated copies come together, the linked enzyme is deficient either in quantity or effect and the disease is expressed. For each and every pregnancy, there is a 1 in 4 chance of two carriers of the genetic mutation having a child with the disease. 

What are the symptoms and signs of methylmalonic acidaemia?

Although various forms of methylmalonic acidaemia exist, each with a specific profile of symptoms, they share the feature of intermittent metabolic attacks or ‘crises’. The crises are triggered by infections, fever and periods without food, and are due to the body breaking down stored proteins and fats and releasing the toxic substances into the blood. During attacks, metabolic acidosis occurs where the blood and tissues become abnormally acidic due to pronounced accumulation of metabolic products. Keto acids also build up in the blood and tissues causing ketoacidosis, and spill over to the urine. Keto acids are metabolic by-products created when the body resorts to using its own protein and fat stores for energy.

The most severe form of methylmalonic acidaemia is seen in very young infants. Although healthy at birth, within the first 1 to 2 weeks of life infants show poor feeding, extreme tiredness, vomiting, floppiness, weak muscle tone and signs of brain damage. Metabolic acidosis and ketoacidosis are severe and high blood levels of ammonia, a waste product of protein breakdown, and the amino acid glycine can be detected. Infants with this form rarely survive.

Less severe forms of methylmalonic acidaemia appear slightly later in infancy or in early childhood. In addition to feeding problems, vomiting, extreme tiredness and failure to thrive, individuals may suffer seizures and stroke; the latter potentially causing permanent movement disorder. There may be noticeable developmental delay, learning difficulties or intellectual impairment. The liver and spleen may be enlarged and kidney disease can develop. The immune system is often impaired, making the children susceptible to infections. In some individuals, there may be reduced vision and damage to the lining at the back of the eye.

How is methylmalonic acidaemia diagnosed?

Several tests are used to arrive at a diagnosis and to assess the severity of methylmalonic acidaemia. In some countries, newborn screening programmes help detect the condition early.

Blood and urine tests showing high levels of methylmalonic acid are the main diagnostic indicator. Other non-specific tests include detecting signs of ketoacidosis and metabolic acidosis and high levels of ammonia and glycine in the blood. Enzyme analysis and genetic testing are also useful to establish the form of methylmalonic acidaemia. Computed tomography (CT) and magnetic resonance imaging (MRI) can help evaluate brain damage.

How is methylmalonic acidaemia treated?

Treatment of methylmalonic acidaemia involves dietary modification to restrict the intake of isoleucine, valine, threonine and methionine. The diet needs to be continued indefinitely and must be initiated only after consultation with a dietician.

As with any restrictive diet, it is important to ensure optimal nutrition for growth and development. While natural protein intake is limited, a formula free of isoleucine, valine, threonine and methionine is prescribed. A range of such formulas is available, designed specifically to meet the nutritional needs of children at different ages. These specially formulated powders contain a balanced mix of essential and non-essential amino acids, vitamins, minerals and carbohydrates to avoid malnutrition of other amino acids and to sustain normal growth in children. Several low-protein food products are also available.

During periods of illness, fasting and infection, aggressive treatment is initiated to prevent the body breaking down its own energy stores. This comprises limiting protein intake, giving glucose and additional fluids, increasing carnitine supplementation plus, in some cases, using dialysis to reduce ammonia levels and correct metabolic acidosis.

Vitamin B12 supplementation helps to improve metabolic control and reduce the risk of complications in those with a deficiency in this co-factor. Supplementation with carnitine (an enzyme involved in fatty acid metabolism) helps to neutralise the toxic metabolic by-products. Antibiotics may help to lower the amount of methylmalonic acid produced within the body. Kidney and/or liver transplantation may also be necessary for some.

Sufferers are advised to avoid long periods of fasting. For example, by eating a snack at bedtime, the period of overnight fasting can be reduced.

Methylmalonic acidaemia is typically a serious condition, with potentially devastating consequences. Early and appropriate intervention helps to reduce the risk of complications. However, even with treatment some individuals develop permanent learning difficulties, kidney failure and movement disorders.