Introduction

Methylmalonic Acidemia (MMA) is a genetic condition where individuals cannotmetabolise fats and proteins normally. This leads to an abnormal accumulation of organic acids.¹ The Central Nervous System (CNS) is especially sensitive to MMA which is why injuries in the CNS can lead to delays in the child’s development and therefore impact the quality of many factors of their life like socialising and education.² Additionally, the child’s growth can be affected as diet will have to be restricted but in a way that will balance both: preventing a metabolic MMA crisis and ensuring sufficient nutrients are being received by the body for development.

What is methylmalonic acidemia?

MMA is an autosomal recessive disease, meaning an infant will inherit MMA if they receive an affected gene from each parent. This genetic variant is what is responsible for the unusual metabolism of proteins and fats, resulting in an accumulation of toxic metabolites and acids. Despite MMA’s low incidence, its high mortality rate increases the urgency to screen for the disease in newborns.² 

The pathway that goes wrong

To understand what is occurring in MMA, it is important to first understand the normal mechanism of this metabolism pathway in someone unaffected by the condition.

• Firstly, the substrates are odd-chain fatty acids, cholesterol and certain amino acids (Valine, Methionine, Isoleucine and Threonine). 
• These substrates are converted into propionyl CoA, then D-methylmalonyl CoA, and then L-methylmalonyl CoA.
• The L-methylmalonyl CoA can be converted into succinyl CoA, using the enzyme methylmalonyl CoA mutase (MCM) and the cofactor adenosylcobalamin (which is formed from vitamin B12).
• Succinyl CoA can join the Krebs cycle to be used in ATP synthesis during aerobic respiration; therefore, this pathway provides energy for processes in the body.³

However, this pathway is interrupted in MMA. This can be down to two possible factors: 

1. The individual has a deficiency in MCM (the genetically inherited form of MMA). 
2. The individual has a deficiency in vitamin B12 (they have ‘vitamin B12-responsive MMA’). 

The genetically inherited form is as a result of the individual inheriting mutated forms of the MMUT gene(a gene responsible for the synthesis of MCM). Therefore, if this gene is mutated, MCM will not be able to function normally resulting in abnormal break down of the amino acids, fatty acid chains and cholesterol.¹ This leads to increases in methylmalonic acid and other organic acids or metabolites, which consequently disrupts cells, mitochondria and biochemical processes.

In vitamin B12-responsive MMA, less adenosylcobalamin is present due to the lack of vitamin B12. Since this is a cofactor of MCM, it is required for the enzyme to function so when insufficient, the enzyme’s activity decreases.³ Both forms of MMA result in decreased production of succinyl CoA but increased concentrations of acid and intermediate metabolites, which leads to the symptoms of the condition.

Symptoms

The abnormally increased levels of metabolites and acids leads to dysfunction in the mitochondria due to electron transport chain disruption and alterations in enzyme behaviour caused by pH fluctuations. This mitochondrial dysfunction, in addition to decreased concentrations of succinyl CoA in the Krebs cycle, explains the lethargy in MMA.² Many infants with MMA often feel drowsy easily so require more snacks throughout the day than others their age.⁴ Other organs can also be affected by acid accumulation, and muscles will be impacted too with some children presenting with hypotonia.²

The main system affected by MMA is the CNS and this is because the acid build up can cause changes in the composition and function of the myelin sheath that surrounds neurons. The odd chain fatty acids that build up integrate within membranes of the neuron's myelin sheath – altering membrane composition. This disrupts the transmission of electrical impulses and therefore communication within the nervous system. 

Furthermore, changes in pH can lead to increased neuronal apoptosis and changes in biochemical processes (usually as a result of disruption to enzyme activity). The myelination of neurons is a process requiring high amounts of ATP, therefore the decreased succinyl CoA in the Krebs cycle and mitochondrial dysfunction means there is insufficient energy for the synthesis of neurons.⁵ 

All of these forms of disruption to CNS can be seen in symptoms like seizures, epilepsy, intellectual disability, encephalopathy, cognitive decline, ataxia, and developmental delays.

Slower growth will also be noticed in some individuals with MMA due to feeding difficulties. The restricted diet necessary for these children may mean they aren’t absorbing sufficient protein necessary for growth. 

Growth and development

The difficulty that individuals with MMA face in metabolising certain amino acids and lipids can result in reduced growth during expected growth stages in childhood. This is because growth depends greatly on cell division (mitosis) and this is a biochemical process which requires sufficient ATP and protein.⁸ These two components tend to be in reduced quantities in those with MMA, leading to difficulty in organ and limb development. Furthermore, the body’s reduced ability to utilise specific proteins and lipids will mean there is a risk of certain nutrients being deficient, resulting in malnutrition which can reduce the synthesis of certain growth factors.⁹

The accumulation of toxic metabolites can increase oxidative stress, resulting in damaged neurones and this can contribute to delays in brain development and function. During oxidative stress, neuronal apoptosis will be induced and this can lead to cognitive and developmental delays.¹⁰ Further to this, the brain requires most of its energy to be delivered from mitochondria but since MMA results in mitochondrial dysfunction, this can contribute to impairments in the brain’s functioning and development. The abnormal metabolism of amino acids will impact neurotransmitter synthesis which can further weaken the function of the nervous system and contribute to symptoms like cognitive impairment.

Vitamin B12 is also said to have a key role in the development of the brain as research has shown that deficiencies in the vitamin in utero have been linked to impaired psychomotor function and growth. It is also known that the vitamin is necessary for the production of neurotransmitters and the myelination of neurons, which reinforces its importance in aiding cognitive development.¹¹

Intervention

Diagnosis

At birth, a blood spot can be taken from the baby and analysed to look for any evidence of high levels of methymalonic acid, acylcarnitines and methylcitric acid. In order to confirm the diagnosis, further blood, urine, and skin testing may be completed and MRI scans can show alterations in the brain’s structure suggestive of MMA. Additionally, some families may want genetic testing, looking for variants in the MMUT gene which can aid in the confirmation of the diagnosis.¹

Treatment

For individuals with vitamin B12-responsive MMA, they can be given vitamin B12 supplements to help overcome the deficiency and enhance MCM activity.⁶ Individuals with MCM deficiency may need special diets. These will involve foods that are low in certain proteins and fats, using special formulas, and eating regular meals to prevent drowsiness.¹ Some may be prescribed with L-carnitine which is a medication that can prevent the build-up of toxic compounds within the body.⁶

Dieticians will be advising families as to what special diets to give their children as it is important to consider the use of special metabolic formulas, volumes of breast milk to be fed daily, and limits on food with high protein content. This needs to be carefully planned and executed to ensure the child receives vital nutrients for growth and development whilst also ensuring the listed amino acids are avoided as best as possible.

The low protein diet will encourage avoiding foods like fish, eggs, meat, and nuts. It will mostly consist of carbohydrates as these not only help in preventing a metabolic crisis but also provide high supplies of energy. Parents can be encouraged to cook using medical foods like low-protein flour, pasta or rice. 

Regular monitoring using blood and urine tests is an important way of identifying whether improvements in the care plan are necessary. Ketone levels will be analysed as large concentrations in the urine indicate the beginning of a metabolic crisis. Blood tests will monitor amino acid levels.

An early intervention increases the likelihood of improving a child’s quality of life. However, some may continue to face life-long intellectual disabilities. Families should be given the appropriate care to ensure their child receives full educational support in their school.⁷

Summary

Although MMA is a condition that only affects a small proportion of our population, its symptoms can significantly reduce a patient’s quality of life. However, genetic testing and newborn screening can be good ways to detect the condition in  children early on. With the help ofdoctors, dieticians, physiotherapists, and support from schools, a child with MMA can grow to live a better life. The importance of following advice from dieticians is highlighted by studies showing that children with MMA who have controlled diets can grow equally as well as children without the condition.¹²