Introduction
Methylmalonic acidemia (MMA) is a term used to describe a collection of hereditary diseases in which the body has difficulty correctly metabolizing specific proteins and fats (lipids). For example, methymalonyl-coenzyme A cannot be changed or "metabolized" by people with this condition. Methylmalonic acid builds in the body as a result. In addition, methylmalonic acid can accumulate in the body due to vitamin B12 insufficiency conditions that are not inherited, such as vitamin B12 deficiency.
What Are the Causes of Methylmalonic Acidemia?
Several gene mutations (or errors) can result in methylmalonic acidemia. Two categories of people with methylmalonic acidemia exist:
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Those who have methylmalonic acid elevations and isolated MMA.
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Patients who have combination defects and elevated homocysteine levels.
The MMAA, MMAB, and MUT genes have mutations (or errors) that lead to isolated methylmalonic acidemia. MUTgene mutations exist in almost 50 % of individuals with isolated methylmalonic acidemia. A phase in the degradation of various amino acids (the building blocks of proteins), specific lipids, and cholesterol are carried out by an enzyme called methyl malonyl CoA mutase that is produced as a result of instructions from this gene. These compounds cannot be adequately broken down because of mutations in the MUT gene, which change the structure or lower the amount of the enzyme. As a result, substances like methyl malonyl-CoA and other possibly hazardous substances might build up, leading to the symptoms and signs of methylmalonic acidemia.
What Are the Different Types of Methylmalonic Aciduria?
There are typically two categories for patients with methylmalonic acidemia who have mutations in the MUT gene. Patients are labeled ‘mut0’ when MUT gene mutations result in no enzyme activity. Patients are referred to be ‘mut’ when mutations in the MUT gene alter the structure of methyl malonyl CoA mutase but do not entirely stop its activity. Although it is unclear how exactly to separate these two categories, most people would concur that patients with mutations would exhibit measurable enzyme activity that rises when excess vitamin B12 is supplied to the cells. Moreover, persons categorized as ‘mut’ may have a clinically milder variant of the illness. They might experience fewer hospitalizations, for instance.
Isolated Methylmalonic Acidemia - At least three more genes can develop mutations that result in isolated methylmalonic acidemia. Mutations in the MMAA gene cause the cobalamin A (cblA) form of methylmalonic acidemia. Mutations in the MMAB gene lead to the cobalamin B (cblB) form of methylmalonic acidemia. These ailments are comparable to those experienced by people with mut0 methylmalonic acidemia. But when vitamin B12 is added to the diet, most people with cblA and cblB see clinical and metabolic improvements (hydroxocobalamin). The precise roles of the MMAA and MMAB enzymes within the body remain unknown. These enzymes may aid in synthesizing adenosylcobalamin, a vitamin B12 form necessary for the normal operation of the methyl malonyl CoA mutase enzyme. Methylmalonic acidemia can result from mutations that alter any of these enzymes (MMAA, MMAB), which can reduce their activity.
Combination Abnormalities - Homocysteine and methylmalonic acid levels are higher in patients with combination abnormalities. They include deficits in cobalamins C (cblC), D (cblD), and F (cblF). The most prevalent of the combined diseases is CblC deficiency. In this condition, there is an alteration in the MMACHC gene. Patients with this condition have higher levels of homocysteine and methylmalonic acid in their bodily fluids and may experience neurological and visual issues. The genes MMADHC and LMBRD1 have recently been found to be the causes of the more uncommon diseases CblD and CblF. However, methylmalonic acidemia may also result from other genes yet to be discovered alone or in conjunction with homocysteinemia.
What Is the Inheritance Pattern of Methylmalonic Acidemia?
Methylmalonic acidemia is passed down through the autosomal recessive gene. Both copies of the MUT, MMAA, MMAB, MMACHC, MMADHC, and LMBRD1 genes are altered or mutated in a person with methylmalonic acidemia. Most frequently, a person inherits one altered gene copy from their mother and another from their father. As a result, each affected child's parents have two copies of the affected gene—one changed and one unaltered. When parents have one mutated gene copy but do not exhibit the disorder's symptoms, they are called ‘carriers’. There is an equal impact on boys and girls. In addition, people from various races and ethnic backgrounds can develop this set of ailments.
What Are the Symptoms of Methylmalonic Aciduria?
At birth, infants could seem healthy, but after they consume more protein, the issue may manifest as symptoms. Seizures and strokes may result from the condition. These signs include:
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More severe brain illness (progressive encephalopathy).
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Delays in development.
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Failing to thrive.
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Lethargy.
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Vomiting.
How Is Methylmalonic Aciduria Diagnosed?
The following tests could be used to identify this condition:
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A nitrate test.
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A blood gas.
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Thorough blood count.
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The brain's MRI (magnetic resonance imaging) or CT (computed tomography)scan.
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Amounts of electrolytes.
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Genetic analysis.
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Blood test for methylmalonic acid.
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Test for plasma amino acids.
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Amniocentesis or chorionic villus sampling (CVS) - The prevalence of methylmalonic acid in amniotic fluid or the activity of the defective enzyme in fluid or tissue samples taken from the fetus or uterus during pregnancy may usually be used to detect methylmalonic acidemias before birth (prenatally) (amniocentesis or chorionic villus sampling). A sample of the fluid encircling the growing fetus is taken during amniocentesis and examined. CVS includes removing tissue from a section of the placenta and examining it. The condition can be detected at birth using tandem mass spectrometry and comprehensive newborn screening.
Based on a thorough clinical evaluation, a thorough patient and family history, and various specialized testing, the disease is typically identified or confirmed in most affected infants' first few weeks of life. To establish the insufficient activity of the defective enzyme, laboratory investigations (assays) are often carried out on particular white blood cells (leukocytes) or cultivated skin cells (fibroblasts). Additional laboratory tests may reveal elevated levels of glycine in the blood and urine (hyperglycinemia and hyperglycinuria), high levels of ammonia in the blood (hyperammonemia), excessive levels of acids, and increased accumulations of ketone bodies in bodily tissues and fluids (ketoacidosis), and decreased levels of circulating platelets and white blood cells (thrombocytopenia and neutropenia).
How Is Methylmalonic Acidemia Managed?
A low-protein, high-calorie diet, certain medicines, antibiotics, and organ transplantation are the main treatments for methylmalonic acidemia in some circumstances. The medication regimen comprises cobalamin (Vitamin B12) injections, carnitine, and antibiotics. As isoleucine, threonine, methionine, and valine can all cause an affected patient to produce methylmalonic acid, the diet is protein-restricted to prevent this from happening. To ensure they are getting adequate protein for growth, most patients also need to take a formula containing some amino acids but leaving out others. Therefore, each patient needs a customized diet and medication schedule.
Conclusion:
Infants who experience this disease's initial round of symptoms may not survive. Despite the possibility of normal cognitive growth, those who survive frequently struggle with nervous system development.
