Methylmalonic acidosis is a metabolic disorder in which the body does not break down certain proteins and fats properly. As a consequence, a substance called methylmalonyl CoA and other potentially toxic compounds accumulate in the body, leading to its gradual poisoning. If methylmalonic acidosis is not diagnosed in time, it can be fatal. What are the causes and symptoms of methylmalonic acidosis? What is the treatment?

Methylmalonic aciduria( MMA- Methylomalonic aciduria), or methylmalonic aciduria, is a rare inherited metabolic disorder in which the body it cannot break down certain proteins, lipids and cholesterol properly. As a consequence, a substance called methylmalonyl CoA and other potentially toxic compounds accumulate in the body, leading to its gradual poisoning, and if not treated - to death.

Methylmalonic acidosis, together with propionic, isovaleric and glutaric acidosis, belongs to the group of organic acidic acids. They are a group of rare congenital metabolic defects that mainly appear in infants or early childhood. Their symptoms resemble poisoning, worsen quickly and may lead to premature death or permanent organ dysfunction.

According to Genetics Home Reference data, the prevalence of methylmalonic acidosis is estimated at 1: 50,000 - 1: 100,000.

Methylmalonic acidosis - causes

The cause of methylmalonyl acidosis is a deficiency of an enzyme called methyl malonyl-CoA mutase (aka methyl malonyl mutase - MCM). This enzyme works with vitamin B12 (cobalamin) to break down several building blocks of protein (amino acids), certain lipids, and cholesterol.

This deficiency is caused by a mutation within the mutase gene - MUT, MMAA, MMAB, MMADHC or MCEE. In about 60 percent of cases, methylmalonic acidosis is caused by a mutation in the MUT gene. This gene contains instructions for the production of the methylmalonyl CoA mutase. The mutation changes the structure of the enzyme or reduces its amount, so that certain proteins and fats are not broken down properly. As a result, a substance called methylmalonyl CoA along with other potentially toxic substancescompounds build up in organs and tissues, causing symptoms of methylmalonic acidosis.

The disease is inherited in an autosomal recessive manner, i.e. in order for a child to become ill, they must receive one copy of the defective gene from each parent.

The cause of methylmalonic acidosis may also be a mutation in one of the steps in the synthesis of cobalamin (vitamin B12), which is needed by the methylmalonyl mutase in order to break down certain proteins and fats. A complicated set of disturbances in cobalamin metabolism lead to other forms of methylmalonic acidosis. Some of them are associated with hyperhomocysteinemia (a condition in which the concentration of homocysteine ​​- a protein metabolite containing sulfuric amino acids - is elevated).

Methylmalonic acidosis - symptoms

  • faster breathing ( tachypnoe)

Complications of methylmalonic acidosis may include intellectual disability, recurrent pancreatitis, osteoporosis, progressive renal failure.

  • vomiting and resulting dehydration
  • reduction of muscle tone (hypotonia)
  • feeding difficulties
  • excessive fatigue (lethargy)
  • liver enlargement
  • no weight gain or growth as expected
  • sleepiness
  • coma

Methylmalonic acidosis - diagnosis

In order to diagnose the disease, screening tests are performed, detected by tandem mass spectrometry (MS / MS), and the concentration of organic acids in the urine is assessed by GC / MS. The disease is indicated by an increased concentration of propionic and methylmalonic acid, neutropenia (decrease in the number of neutrophils below 1500 / μl, but not below 500 / μl - this is agranulocytosis), thrombocytopenia (thrombocytopenia - the number of platelets below 150 thousand / mm3), hyperammonaemia ( high levels of ammonia in the blood) and hypoglycaemia (or hypoglycaemia) - a condition in which the amount of glucose in the blood drops below 55 mg / dl, i.e. 3.0 mmol / l).

Molecular research is also needed: analysis of the MUT gene and other genes responsible for the disease.

Important

Methylmalonic acidosis in the Newborn Screening Program

Methylmalonic acidosis has been included in the Newborn Screening Program in Poland since December 2013. Neonatal screening involves the initial identification of any congenital disease before the onset of symptoms. These diseases, if not detected in the first month of life, lead to development disorders and often to severe intellectual disability, precluding independent functioning of the sick person.The only way to save these babies is early diagnosis, based on the analysis of newborns' blood collected on a special tissue paper.

Methylmalonic acidosis - treatment and diet

Treatment with huge doses of hydroxocobalamin (the active form of vitamin B12) can be used, but it is helpful in some cases of methylmalonic acidosis.

In the case of the form of methylmalonic acidosis not responding to vitamin B12, treatment includes the elimination of proteins from the diet (it requires excluding dairy products, meat, fish, seafood and eggs from the daily diet). In addition, when using an elimination diet, it is sometimes necessary to test for the supplementation of the missing amino acids based on the results of their concentration in the blood.

Category:

Genetic diseases