Methylmalonic acidemia is a genetic disease that occurs when the metabolism of branched chain amino acids is disrupted. Pathology has an autosomal recessive type of inheritance. Clinical manifestations include eating disorders, delayed psychomotor development, neurological complications. With an unfavorable course, methylmalone crises occur. For diagnostics, biochemical blood and urine tests, genetic tests, methods of instrumental visualization of brain structures are performed. Treatment includes lifelong diet therapy, medications that allow you to adjust your metabolism.
For the first time, the symptoms of methylmalonic acidemia were described in 1967 by the doctor V.G. Oberholzer, and the genetic mutations underlying the disorders were identified in 1975. The prevalence of pathology in the world is, according to various data, from 1:48000 to 1:61000. Significant sexual or ethnic differences in the structure of the patients have not been established. In modern genetics, there are two forms of methylmalonic acidemia: B12-dependent and B12-resistant, which occur with the same frequency.
In the classical form, there is a partial or complete mutation of the methymalonyl-CoA mutase (MUT) gene at the 6p21 locus on the short arm of the 6th chromosome. Also, typical disorders of amino acid metabolism occur with a defect in the genes of adenosylcobalamin (MMAA, MMAB), methylmalonyl-CoA epimerase (MCEE), a defect in the transcobalamin receptor. In such cases, loci 4q31.1-q31.2, 12q24, 2p13.3, 19p13.2 are respectively damaged.
Methylmalonic acidemia is inherited by autosomal recessive type: if both clinically healthy parents have a gene defect, the risk of having a sick child is 25%. If the father or mother has symptoms of the disease, the probability of its manifestation in the child increases to 50%.
In the mechanism of development of methylmalonic acidemia, the main role is played by a violation of the cleavage of the amino acids valine, threonine, isoleucine and methionine, as well as the pathology of cholesterol metabolism, fatty acids with an odd number of carbon atoms in the molecule. These substances are the precursors of about 50% of the propionates formed in the body.
The accumulation of toxic compounds occurs with a deficiency of the enzymes propionyl-CoA carboxylase and methylmalonyl-CoA mutase, which normally convert propionyl-CoA to succinyl-CoA substrate of the Krebs cycle. Increased renal excretion of propionylcarnitine is associated with secondary carnitine deficiency. As a result, the patient increases metabolic ketoacidosis, hyperammonemia, hyperglycinemia, hypoglycemia.
In the neonatal form, the clinical picture of the hereditary variant of acidemia is formed in the first 2-4 weeks of a child’s life, and in the infant form — at the age of 1-3 months. The main symptoms include repeated vomiting attacks, sluggish sucking and complete refusal to eat, pathological lethargy and drowsiness of the child. A few weeks later, parents notice that the baby is not gaining weight or even losing weight.
Neurological disorders are manifested by hypotension, hyperreflexia, the appearance of pathological reflexes. Convulsions occasionally occur, in severe cases, a comatose state is possible. Methylmalonic acidemia is characterized by frequent respiratory and gastrointestinal infections, and at an older age there is a delay in psychomotor development. Half of patients face optic nerve atrophy, 30% of patients suffer from cardiomyopathy.
Methylmalonic acidemia refers to severe diseases. With untimely diagnosis and late initiation of treatment, mortality is up to 40% in the first year of patients’ life. Due to prolonged toxic damage to the central nervous system, mental retardation, spastic tetraparesis, resistant symptomatic epilepsy are often detected, cases of intracranial hemorrhages are also described. Tubulointerstitial nephritis, erythematous dermatitis often occur.
The most dangerous consequence of the disease is considered to be a methylmalone crisis, which develops when a diet is not followed, against the background of intercurrent infections, physical or psychoemotional overloads. It is accompanied by severe acidosis, encephalopathy, massive intoxication of the body with propionic derivatives. In the absence of timely medical care, there is a high probability of death.
Clinical signs of methylmalonic acidemia are nonspecific, similar to other severe conditions of the infancy period. A thorough study of the family history helps in making the correct diagnosis. To verify violations of amino acid metabolism, the child is assigned a laboratory and instrumental examination, which includes:
- Tandem mass spectrometry. High-precision analysis is used to determine the elevated level of propionylcarnitine in the blood, to detect excessive excretion of methylmalonic acid, 3-hydroxypropionic acid and propionylglycine in the urine.
- Genetic testing. To confirm methylmalonic acidemia, a molecular genetic study is performed, with the help of which pathognomonic mutations MUT, MMAA, MCEE are detected. According to the indications, the tests are supplemented by a study of the culture of cutaneous fibroblasts.
- Neuroimaging. CT or MRI of the brain are necessary to establish the cause of neuropsychiatric disorders. According to the results of the study, cortical atrophy, dilation of the cerebral ventricles, delay of myelination processes are diagnosed.
- Additional diagnostics. In case of symptoms of somatic complications of methylmalonic acidemia, chest radiography, electrocardiography, echocardiography are recommended. Abdominal ultrasound, ultrasound of the kidneys and bladder is also performed.
Etiotropic therapy of methylmalonic acidemia has not yet been developed. Treatment begins with diet therapy: restriction of protein products in the diet or feeding with special mixtures (in infancy), reduction of the mass fraction of fats. For the correction of protein metabolism, ready-made amino acid formulations that do not contain isoleucine, valine, threonine are recommended. Medications are also prescribed:
- Vitamin B12. In the B12-dependent form of aciduria, it gives a good result, helps to reduce the number of toxic metabolites in the blood. Active forms of the substance are used: hydroxycobalamin, methylcobalamin, cobamamide.
- Carnitine. Levocarnitine in large doses binds the toxic propionic radical, enhances its excretion from the body with urine, normalizes the energy balance.
- Antibiotic therapy. Considering that 25% of propionates are synthesized in the intestine with the participation of pathogenic bacteria, intestinal antiseptics and antibiotics in age doses are used for special indications.
With a methylmalone crisis, emergency medical care is required. In the period of deterioration, diet therapy continues, supplemented with increased dosages of levocarnitine, glycine. Correction of the caloric content of the diet is carried out with carbohydrate solutions. To eliminate metabolic acidosis, alkalizing solutions with sodium bicarbonate are introduced.
Prognosis and prevention
With lifelong adherence to a diet, regular dispensary supervision, timely relief of crises, the prognosis is favorable. However, due to the complexity of diagnosis, neglect of medical recommendations, fatal cases of the disease are not uncommon. Prevention consists in prenatal diagnosis of methylmalonic acidemia, medical and genetic counseling of families with burdened heredity.