Maple syrup urine disease is a hereditary disease, which is based on a deficiency of dehydrogenases of branched chain ketoacids, as well as a violation of the metabolism of the amino acids leucine, isoleucine and valine. It is manifested by pathological weakness, quiet crying, vomiting, muscle twitching, a characteristic “maple” smell of urine, delayed psychomotor development. During a crisis, respiratory and circulatory disorders occur, loss of consciousness. Diagnostics includes analysis for amino acids and derivatives (blood, urine), molecular genetic testing and urine screening tests. For treatment, a diet with protein mixtures freed from branched-chain amino acids (BCAA) is used.
Synonyms of maple syrup urine disease are branched acid disease, branched chain ketonuria, short chain ketoaciduria, urine disease with the smell of maple syrup, maple syrup disease. The origin of synonymous names is connected with the history of the study of this pathology. At the beginning of 1954, the Austrian-American pediatric neurologist J. H. Menkes first described a disease in which patients had a specific smell of urine, similar to the smell of wood syrup and burnt sugar. Another, less common name is Menkes syndrome. The disease is classified as rare (orphan, “orphan”) pathologies. It is diagnosed with a frequency of 1 case per 120-300 thousand newborns.
The development of the disease is due to the presence of a pair of mutational genes encoding the production of branched alpha-keto acid dehydrogenase. If this enzyme is deficient, the process of catabolic breakdown of leucine, alloisoleucine, isoleucine, valine is disrupted. The structure of dehydrogenase is represented by four protein compounds: E3, E2, alpha subunit E1, beta subunit E1. Localization of genes responsible for the synthesis of components of enzyme complexes was revealed: the a-subunit of protein E1 is encoded by the BCKDHA gene on chromosome 19, the b-subunit E1 is the BCKDHB gene on chromosome 6, the E2 protein is the DBT gene on chromosome 1, the E3 protein is the DLD gene on chromosome 7. Hereditary transmission occurs autosomal recessive, the disease manifests itself in a child who has received a pair of mutant genes of the same localization. When a mutation is transmitted from only one parent, there are no symptoms, because the dominant gene provides the body with the necessary amount of enzyme.
The disease is based on the genetic insufficiency of ketoacid dehydrogenases having side chains. Branched-chain amino acids and their derivatives accumulate in body fluids: 2-ketoisocaproic, 2-keto-3-methylvaleric and 2-ketoisvaleric acids. Excess leucine and its metabolites have a neurotoxic effect. At the same time, there is a deficiency of other amino acids, such as alanine, glycine, glutamine, tyrosine, tryptophan. Their transport inside cells is disrupted, neurotransmitter transmission disorders are formed. Ketoacidosis develops, hypoglycemia against the background of a decrease in gluconeogenesis, hyponatremia, hyperammonemia, the processes of oxidative phosphorylation are inhibited.
In the form of maple syrup urine disease caused by the destruction of protein E3, the pathogenesis is more complex. This subunit is a component of several enzyme complexes that participate in the metabolism of pyruvate and the implementation of the Krebs cycle. As a result of the structural and functional defect of these complexes, the energy exchange of cells changes, lactic acidosis occurs.
At the initial stages of the study, maple syrup urine disease was described as a rapidly progressive disease that develops from the first days of life and inevitably leads to a fatal outcome. Later it was found that there are several types of pathology with different time of debut, course and prognosis. Currently, there are five forms of maple syrup urine disease:
- Acute. Also called classical. It manifests itself from birth, symptoms increase rapidly even with timely treatment. The activity of the enzyme is less than 2% of the norm.
- Intermediate. Often debuts in early and preschool childhood. It has a paroxysmal course, the leading symptom is ataxia. Seizures are provoked by acute diseases, stress, deviation from the diet. The enzyme performs its functions by 3-30%.
- Intermittent. Other names are intermittent, intermittent. It is usually diagnosed at the age of 5-24 months. Seizures occur acutely with convulsions, dehydration, ataxia. In the absence of emergency care, a coma occurs. The enzymatic activity ranges from 5 to 20%.
- Thiamine-dependent. Develops in the neonatal period. By the nature of the flow, it may resemble intermediate or intermittent forms. There are no signs of the disease in remission. The enzyme is active by 30-40%.
- E3 is scarce. It is determined in infants from 2 months of life. It is accompanied by lactic acidosis, violation of energy metabolism. It belongs to the group of mitochondrial pathologies.
In children with the classic form of the disease, symptoms appear in the first week of life. The beginning is always sharp. The debut of maple syrup urine disease is characterized by a sharp deterioration in the general condition of the newborn – the development of generalized seizures, pathological excitability, muscle hypertension, indomitable vomiting, dehydration. The child screams, refuses to eat. The state of excitement is replaced by pathological lethargy. Signs of central nervous system depression are detected, somnolence increases, and then coma. The surface of the skin is exfoliated, covered with erythema. The urine smells like maple syrup. The child is excessively vulnerable to infections, lags behind in mental and motor development. The disease ends with an early death, the main cause of which is cerebral edema.
In the intermittent form, seizures are accompanied by the appearance of cerebellar ataxia – the patient’s gait and coordination of movements are disrupted. There are no clinical symptoms between attacks. Intermediate maple syrup urine disease is more severe. Seizures do not have clear time boundaries, they increase and subside in waves. Children lag behind in development, suffer from ataxia, seizures and muscle hypotension, they learn walking, manipulative actions, and speech late. The symptoms of the thiamine-dependent form may be mild or moderate. As in the previous two variants, signs of gait and movement coordination disorders dominate, muscle tone is reduced, seizures are possible. In patients with the E3-dependent form, there is a progressive lag in motor and mental development, vomiting, muscle hypotension, respiratory disorders. Hypoglycemia with apathy, weakness, dizziness, increased drowsiness is periodically detected.
With life-compatible forms of maple syrup urine disease, the main complication is a lag in mental and physical development. The severity of violations varies: sometimes patients are capable of self-care, lead an autonomous lifestyle, attend school, in other cases they need constant care, have difficulty mastering simple motor skills and speech. The lack of medical care for patients with acute maple syrup urine disease and crises leads to severe complications – brain edema, acute kidney and liver failure. These conditions become the cause of death of patients.
All children with a burdened family history are subject to examination for maple syrup urine disease, especially if the diagnosis was confirmed in older brothers and sisters, as well as if the newborn showed characteristic symptoms after a period of satisfactory condition: refusal to eat, vomiting, convulsions, pathological agitation or lethargy, ataxia, coma, acidosis. Diagnostics is carried out by specialists in various fields: pediatricians, neurologists, geneticists. At the initial stage, the study of the anamnesis and complaints of parents, a general examination of the child with the determination of muscle tone and weight, assessment of motor activity is carried out. In order to confirm the diagnosis, exclude hypoxic lesions of the central nervous system, intracerebral hemorrhages, acute infections and hereditary metabolic pathologies, laboratory tests are prescribed:
- Amino acid blood test. An increase in the level of BCAA in the blood and urine is detected. A highly specific marker of the disease is an increase in the content of alloisoleucine in blood plasma, the indicator is in the range from 72 to 220 mmol / l. The concentration of isoleucine is 200-12,000 mmol/l, leucine – 500-5,000 mmol/l, valine – 500-1, 800 mmol/l.
- Analysis of amino acids, ketoacids of urine. An increase in the indicators of amino acids in the urine is detected. The number of branched ketoacids increased (in mmol/mmol of creatinine): the concentration of 2hydroxy-3-methylvaleric acid – 60-400, 2hydroxy-isocaproic – 3-80, 2hydroxy-isovalerian – 850-3600, 2keto-3methylvalerian – 500-2500, 2-keto-isocaproic – 400-4 400, 2-keto-isovalerian – 300-800.
- Specific tests. For the express diagnosis of an increase in the level of amino acid metabolites, a reaction with 2,4-dinitrophenylhydrazine and a Pheling test are carried out. Biomaterial – a portion of a single urine. With maple syrup urine disease, both tests give a sharply positive result. Since the methods have low sensitivity and specificity, their use is advisable only within the framework of screening.
- Molecular genetic analysis. Confirmation of the primary defect is necessary for prenatal and preimplantation diagnosis, while examination of newborns is not mandatory. Patients have homozygous and compound-heterozygous mutations in the genes BCKDHA, BCKDHB, DBT and DLD (types 1A, 1B, 2 and 3, respectively).
Maple syrup urine disease treatment
Therapeutic tactics are focused on suppressing the production of toxic BCAA metabolites, stimulating the processes of anabolism, reducing the rate of ketoacidosis, preventing brain edema and damage to internal organs. Therapeutic measures for all patients are carried out as planned, with the development of an acute crisis – in an emergency. Planned procedures include:
- A special diet. The nutrition system is developed for each child, but is based on general principles. Protein food is replaced by protein hydrolysates that do not contain valine, isoleucine, leucine. The source of fats is corn oil, the source of carbohydrates is dextrinmaltose. Additionally, minerals and vitamins are introduced into the diet. The energy value of nutrition is controlled, which allows to support the processes of anabolism.
- Cofactor therapy. Upon confirmation of the diagnosis of maple syrup urine disease and before establishing its form, trial therapy with thiamine is carried out. If the treatment carried out for two weeks normalizes the concentration of amino acids with a branched side chain, a conclusion is made about the thiamine-dependent form of the disease. Thiamine intake is continued in the minimum effective dosage.
- Levocarnitine therapy. An auxiliary method of etiotropic therapy is the use of levocarnitine. The drug enhances the binding of amino acid metabolites, reducing the level of their free forms. Treatment is prescribed for a period of 3 to 6 months.
- Symptomatic therapy. In addition to the main therapy, patients are shown medications that relieve the symptoms of the disease. The selection of drugs is made individually, taking into account the peculiarities of the clinical picture. B vitamins, anticonvulsants, antiemetics, nootropics are used.
Metabolic crisis requires immediate hospitalization and intensive therapy. Patients are completely transferred to nutrition from a mixture of amino acids. When refusing food or frequent vomiting, a probe, a gastrostomy is used. High calorie nutrition is provided by the introduction of glucose and maltodextrin solutions. Toxic metabolic products are removed by peritoneal dialysis and hemodialysis. With cerebral edema, a hypertonic saline solution and diuretics are administered.
Prognosis and prevention
The classical (acute) form of maple syrup urine disease is characterized by a severe progressive course. Her prognosis is unfavorable, effective therapy has not been developed, and the risk of death remains high. In other variants of the disease, strict adherence to a diet and the appointment of drug therapy can improve the quality of life of patients, reduce the lag in general development, improve social adaptation. Prevention consists in conducting prenatal diagnostics – determining the amino acid composition of the amniotic fluid, molecular genetic examination of the material obtained during chorionic biopsy with the identification of mutations of the corresponding genes.