Maple syrup urine disease: clinical guidelines

List of Abbreviations

MSUD - maple syrup urine disease

BBB - blood-brain barrier

ABSt – acid-base status

CK – creatine kinase

DNPH test – dinitrophenylhydrazine test

MRI – magnetic resonance imaging

LC-MS/MS – tandem mass spectrometry

CRP – C-reactive protein

US – ultrasound examination

CNS – central nervous system

BCAA - branched-chain amino acids (leucine, isoleucine, and valine)

BCKD - Branched-chain Alpha-keto Acid Dehydrogenase complex

Terms and Definitions

Hemodialysis is a method of extracorporeal blood purification that removes toxic metabolic products from the body, corrects water and electrolyte imbalances, and filters blood through an artificial membrane using an artificial kidney machine.

Metabolic crisis is a critical, life-threatening condition triggered by adverse factors that enhance cellular catabolism with the accumulation predominantly of leucine and other branched-chain amino acids, manifesting as acute encephalopathy, dystonia, seizures, vomiting episodes, and signs of cerebral edema.

Peritoneal dialysis is a method of extracorporeal blood purification that removes toxic metabolic products from the body, corrects water and electrolyte imbalances by exchanging special solutions in the abdominal cavity, with the patient's peritoneum acting as the membrane.

Krebs cycle (tricarboxylic acid cycle, citric acid cycle) is a complex cyclic enzymatic process in which pyruvic acid is oxidized in the body to form carbon dioxide, water, and energy in the form of ATP, holding a central position in the overall metabolism and energy system of living organisms.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Maple syrup urine disease (leucinosis) (MSUD) is an inherited amino acid disorder caused by a deficiency of branched-chain alpha-keto acid dehydrogenase, leading to impaired metabolism of the amino acids leucine, isoleucine, and valine. The disease is characterized by wide clinical polymorphism ranging from severe forms presenting as acute neonatal encephalopathy (the majority of cases) to mild forms manifesting in adolescence [3,4,6,10].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The disease is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKD) complex, which provides oxidative decarboxylation (the second stage of catabolism) of branched-chain amino acids: leucine, isoleucine, and valine (BCAAs). This multienzyme complex is associated with the inner mitochondrial membrane and consists of 3 catalytic components: E₁ (consisting of 2 separate subunits, E1α and E1β), E₂, and E₃, and is associated with 2 regulatory enzymes: BCKD phosphatase and BCKD kinase. The coenzyme for the E1α subunit is thiamine pyrophosphate. MSUD is caused by mutations in the genes encoding the E1, E2, and E3 components of BCKD: the BCKDHA gene (E1α subunit) is localized on the long arm of chromosome 19 (19q13.1-q13.2); the BCKDHB gene (E1β subunit) is on the short arm of chromosome 6 (6p22-p21); the DBT gene (E₂ protein) is on the short arm of chromosome 1 (1p31); the DLD gene (E₃ protein) is on the long arm of chromosome 7 (7q31-q32). The inheritance pattern of MSUD is autosomal recessive [3,6,10].

The pathogenesis of the disease is associated with impaired metabolism and accumulation in biological fluids of branched-chain amino acids and their derivatives: 2-oxoisocaproic, 2-hydroxyisocaproic, 2-oxo-3-methylvaleric, 2-oxoisovaleric, 2-hydroxyisovaleric, and 2-hydroxy-3-methylvaleric acids. The main neurotoxic effect is due to high levels of leucine and its metabolites. Hyperleucinemia inhibits the transport of tyrosine, tryptophan, and other essential amino acids across the blood-brain barrier (BBB) and thus limits the supply of substrates for the synthesis of catecholamines, serotonin, and brain protein, leading to neurotransmitter disorders. Ketoacidosis, osmotic dysregulation, hyponatremia, cerebral edema and atrophy, secondary hyperammonemia, gluconeogenesis deficiency and hypoglycemia, as well as mitochondrial respiratory chain and oxidative phosphorylation dysfunction, play a major role in pathogenesis.

In disease associated with an E₃ protein defect, the pathogenesis is more complex. This subunit serves as a component of several multienzyme complexes: branched-chain alpha-keto acid dehydrogenase, pyruvate dehydrogenase complex, and alpha-ketoglutarate dehydrogenase complex, which are involved in pyruvate metabolism and the functioning of the Krebs cycle. The consequence of a defect in these complexes is impaired cellular bioenergetics and lactic acidosis; therefore, this variant is usually classified as a mitochondrial disease [6,8,10].

A diagram of the metabolic disorders observed in MSUD is presented in Appendix A3.1.

1.3 Epidemiology of the Disease or Condition

The disease is panethnic. The incidence among newborns is 1:185,000 [16]

In some populations, it occurs with a higher frequency: the incidence among live births is 1:26,000 in Ashkenazi Jews, 1:52,500 in the Galician population in Spain, and 1:176 in Mennonites.

1.4 Features of Coding the Disease or Condition

E71.0 – Maple syrup urine disease.

1.5 Classification of the disease or condition

Several clinical and genetic forms of MSUD are distinguished depending on the age of onset, severity of clinical symptoms, and potential response to #thiamine** treatment:

• classic, or neonatal (most frequent);

• intermediate;

• intermittent;

• thiamine-responsive;

• caused by E₃ protein deficiency and accompanied by lactic acidosis.

1.6 Clinical presentation of the disease or condition

The classic form of the disease and the variant caused by E₃ protein deficiency typically debut in the neonatal period, whereas other forms may manifest at any age with decompensation during periods of increased catabolism or intercurrent infections. Clinical signs of the classic form of MSUD generally appear in the first week of life. Upon manifestation, this form is characterized by generalized seizures, hyperexcitability (high-pitched cry), feeding refusal, persistent vomiting, muscular hypertonia, and signs of dehydration. Excitation is replaced by lethargy, central nervous system depression, somnolence, coma, paradoxical respiration, and a weak pulse. Periods of muscular hypertonia alternate with marked hypotonia. Stereotypic movements such as "fencing" and "bicycle riding" are characteristic.

The disease runs a very severe course and frequently leads to death in early childhood (cerebral edema is the main cause of death).

In children over 1 year of age, psychomotor retardation, mental disability, epigastric pain, anorexia, vomiting, muscle weakness, altered level of consciousness, movement disorders, ataxia, psychiatric symptoms, erythematous rashes, frequent infectious diseases, and seizure disorders are observed. Episodes of metabolic decompensation can be triggered by fever, infection, physical exertion, trauma, or surgery [3,4,6,19,23].

The intermittent form of the disease is the second most frequent after the classic form and has a milder clinical picture. Patients develop age-appropriately until 1–2 years of age, when episodes of metabolic decompensation develop against the background of intercurrent illnesses and following a high-protein diet, accompanied by impaired consciousness (somnolence, lethargy, coma), ataxia, seizures, and a specific urine odor (sweet, caramel) [14,23].

The intermediate form of the disease is characterized by feeding difficulties, growth retardation, psychomotor retardation, intellectual disability, seizures, and other neurological disorders described in the classical form of the disease.

It is uncertain whether a completely thiamine-responsive form of the disease exists that does not require dietary therapy. These patients are believed to have a high residual BCKD enzyme activity ex vivo (up to 40% of normal) and a clinical course similar to the intermediate form. To date, no patient with "thiamine-responsive" MSUD has been treated with #thiamine** alone. Therapy involves a combination of #thiamine** (doses ranging from 10 to 1000 mg/day) with dietary branched-chain amino acid restriction [15, 16, 24, 38, 39].

The clinical presentation of the form of the disease caused by E₃-protein deficiency is similar to the intermediate form of maple syrup urine disease, with the exception of early-onset lactic acidosis. The disease has a broad phenotypic spectrum ranging from early neurological manifestation to isolated liver involvement manifesting in adulthood.

All children with maple syrup urine disease are characterized by an unusual aromatic urine odor, described as the smell of maple syrup or caramel.

Differential diagnosis should be performed with hypoglycemic conditions (e.g., hyperinsulinism), meningitis, encephalitis, hypoxic central nervous system injuries, intracranial hemorrhages, intrauterine infections, and inherited metabolic disorders presenting in the neonatal period: beta-ketothiolase deficiency, urea cycle disorders, nonketotic hyperglycinemia (glycine encephalopathy), other forms of aminoacidopathies and organic acidurias, mitochondrial diseases, and degenerative CNS disorders.

Screening newborns for the condition significantly reduces the risk of intellectual disability, mental disorders, and somatic abnormalities [8, 26].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The criteria for establishing MSUD include characteristic alterations in blood concentrations of the amino acids leucine, isoleucine, and valine, as well as the ratios of leucine+isoleucine/alanine, valine/phenylalanine, and leucine+isoleucine/phenylalanine in the blood, along with the identification of pathogenic variants in the corresponding genes in a homozygous or compound heterozygous state.

2.1 Complaints and Anamnesis

When taking the medical history and assessing complaints, it is recommended to pay attention to:

• family history of genetic disorders (presence of a family member with a confirmed diagnosis of MSUD, history of sudden infant death syndrome in the family)

• sudden clinical deterioration against the background of complete health or acute respiratory viral infection,

• feeding difficulties;

• frequent regurgitation;

• vomiting;

• depressed level of consciousness;

• lethargy, weakness, drowsiness;

• seizures;

• agitation, crying;

• increased sweating;

• muscle hypotonia/hypertonia;

• involuntary movements ("fencing" and "bicycling" posturing);

• sweetish odor of urine/body;

Disease onset in childhood may be associated with the following factors:

• high protein intake;

• prolonged fasting, unjustified dietary restrictions, low caloric intake;

• intercurrent respiratory or gastrointestinal infections;

• physical or psychoemotional stress.

2.2 Physical Examination

A patient with suspected MSUD should undergo a physical examination, paying attention to physical and mental development, skin turgor, muscle tone, and an unusual maple syrup-like odor of the urine and skin.

During the physical examination, attention must be paid to the main physical manifestations:

neonatal period

• lethargy, drowsiness;

• altered mental status (stupor, coma);

• seizures;

• vomiting, refusal to eat;

• apnea;

• weight loss, growth retardation;

• motor developmental delay;

• muscular hypotonia;

• pyramidal signs (hyperreflexia, pathological plantar reflexes);

• tremor;

• involuntary movements ("fencing" and "bicycling" posturing);

• clinical signs of sepsis.

Young children

• episodic vomiting;

• psychomotor and speech developmental delay;

• alterations in muscle tone;

• periodic ataxia, tremor;

• seizures;

• stroke-like episodes.

Detailed physical examination findings are described in the "Clinical Presentation" section.

2.3 Laboratory Diagnostics

Comments: in patients with MSUD during a metabolic crisis, metabolic ketoacidosis, hyponatremia, hypoglycemia, and hyperammonemia are observed, which carry the risk of cerebral edema and require intensive correction of the identified abnormalities. Testing in acute conditions must be performed urgently.

Comment: performed during follow-up monitoring; frequency is determined individually.

Comment: performed during follow-up monitoring; frequency is determined individually.

Comment: performed during follow-up monitoring; frequency is determined individually.

Comment: in MSUD, blood concentrations of the amino acids leucine, isoleucine, and valine are elevated, as well as the ratios of leucine+isoleucine/alanine, valine/phenylalanine, and leucine+isoleucine/phenylalanine; urine shows increased excretion of organic acids—2-oxoisocaproic, 2-hydroxyisocaproic, 2-oxo-3-methylvaleric, 2-oxoisovaleric, 2-hydroxyisovaleric, and 2-hydroxy-3-methylvaleric acids. Potential fluctuations in plasma amino acid concentrations are presented in Appendix A3.6. Performed during follow-up monitoring; frequency is determined individually.

Comment: analysis of the coding and adjacent intronic regions of the BCKDHA, BCKDHB, DBT, and DLD genes by massively parallel sequencing (exome analysis or targeted panels) is required. Mutations in the BCKDHB gene are the most common (~60% of all cases); testing may begin with this gene using Sanger sequencing. Mutations in the DLD gene lead to a specific form of the disease that is considered a mitochondrial disorder. When MSUD is suspected, given the risk of developing a life-threatening condition, treatment should be initiated before the molecular genetic cause is identified. If molecular genetic testing methods are used to confirm the diagnosis, the patient's parents should be screened for carrier status of the identified mutations, and the results should be subsequently used for prenatal diagnosis in informative MSUD families [1, 3, 4, 5].

2.4 Instrumental Diagnostics

Comments: Anesthesia as indicated. Patients with MSUD may exhibit both diffuse and localized brain tissue edema. Localized edema in patients with MSUD primarily affects the cerebellar white matter, brainstem, globus pallidus, internal capsule, and thalamus [11, 12]. Performed during follow-up monitoring; necessity and frequency are determined individually.

Comment: echographic signs of cerebral edema are detected: diffuse increase in the echogenicity of the cerebral parenchyma, decreased differentiation of sulci and gyri, slit-like cerebrospinal fluid spaces. Performed during dynamic monitoring; the need and frequency are determined individually.

Comments: including video-EEG monitoring. Performed during dynamic monitoring; the need and frequency are determined individually.

Comment: performed during follow-up monitoring; frequency is determined individually.

Comment: performed during follow-up monitoring; frequency is determined individually.

Comment: performed during follow-up monitoring; frequency is determined individually.

2.5 Other Procedures

Specialist consultations may be provided to patients at various stages of medical care, including during the disease diagnosis period.

Comments: initial and follow-up consultations are indicated by a geneticist, ophthalmologist, neurologist, gastroenterologist, nutritionist, endocrinologist, cardiologist, pediatric cardiologist, nephrologist, pediatrician, general practitioner/family physician, psychiatrist, medical psychologist, as well as doctors of other specialties for patients with impaired functions of the respective organs and systems.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The treatment strategy consists of reducing the production of toxic metabolites, primarily leucine, as well as isoleucine and valine, preventing the development of ketoacidosis, damage to the nervous system and internal organs, while ensuring anabolic processes, normal growth, and nutritional status of children.

3.1 Conservative Treatment

3.1.1 General principles of conservative treatment

Comments: since the development of a metabolic crisis can lead to irreversible neurological damage, when MSUD is suspected, biomaterial should be collected for biochemical testing, and the patient should then be switched to a low-protein diet (the minimum safe protein level is presented in Appendix A3.2) while ensuring an adequate calorie intake. For infants in the first half of life, breast milk or low-protein infant formulas (1.2–1.3 g/100 ml of reconstituted product) are used; for children over 6 months of age, high-protein foods (meat, cottage cheese, fish) are excluded from the diet. Biochemical tests are performed within 3–7 days, while molecular genetic studies may take about 2–3 weeks. Therefore, it is necessary for the child to remain on a low-protein diet during this period [1, 2, 8].

Comments: The main principles of specialized diet therapy include:

• strict restriction of natural food protein in order to reduce the intake of the amino acids leucine, isoleucine, and valine in the body to the required minimum. For infants in the first half of life, the restriction applies to breast milk, adapted infant formulas, or soy formulas; for children in the second half of life and older, high-protein foods (meat, fish, cottage cheese, eggs, dairy products, legumes, etc.) are prohibited as complementary foods;

• mandatory compensation for protein deficiency through the use of specialized amino acid-based formulas free of leucine, isoleucine, and valine, corresponding to the child's age-specific nutritional and energy needs. At the start of treatment and during metabolic crises, use only the specialized amino acid formula for 24–48 hours (no longer!) [15];

• ensuring sufficient energy value of the diet to support anabolic processes and prevent the activation of catabolism;

• providing the patient with an adequate amount of fluid;

• frequent feedings without prolonged intervals to avoid fasting, especially in infants and young children;

• educating parents on the rules for organizing diet therapy during the interictal period and during the threat of a metabolic crisis.

Comments:

• the protein quota from natural foods is prescribed taking into account the minimum requirement for pathogenetically significant amino acids—leucine, valine, and isoleucine (Appendix A3.2)—and considering the leucine content in natural foods (1 g of natural protein contains 50 to 80 mg of leucine), and is provided through low-protein foods (vegetables, fruits, specialized low-protein cereals, and starch-based products). The leucine conversion factor is presented in Appendix A3.3;

• to compensate for protein deficiency, specialized amino acid-based products free of leucine, isoleucine, and valine (Appendix A3.3) and individual amino acid supplements of valine and isoleucine are used;

An approximate daily food set for a preschool child is given in Appendix A3.3.

Comments: If a sharp decrease in plasma isoleucine and valine is observed, complications in the form of severe enteropathic acrodermatitis and megaloblastic anemia may develop. The approximate dose of isoleucine and/or valine is 30–95 mg per day (in two divided doses) to maintain their serum levels at no less than 200–400 µmol/L [15, 24].

Comments: Therapy includes a combination of oral #thiamine tablets (doses from 10 to 1000 mg/day) with dietary branched-chain amino acid (BCAA) restriction. The initial dose of #thiamine is 50–200 mg/day, which the patient receives for 1 month with an evaluation of plasma BCAAs and/or tolerance to dietary BCAAs. In case of sensitivity to #thiamine, its administration should be continued against the background of restricting BCAA-containing foods in the diet. [15, 38]

Comments: #levocarnitine is prescribed for a long period (3–6 months).

#Levocarnitine is usually prescribed at a rate of 50 mg/kg/day (in 2–3 daily doses) [1, 4, 8, 10, 34]. However, this dosage was calculated in early studies involving a limited number of treated patients. Currently, there are no clear data on the optimal dose of #levocarnitine in patients with MSUD. Given the expected negative impact of a restrictive diet, the requirement for #levocarnitine may be higher [40].

3.1.2 Treatment during a metabolic crisis

Treatment must be initiated immediately if there is a threat of or in the event of a metabolic crisis.

Therapeutic measures are aimed at stopping the production and accumulation of toxic organic compounds and excreting them from the body. Treatment tactics for patients during a crisis include adjusting diet therapy, eliminating accumulating organic acids, correcting metabolic acidosis, hyperammonemia, and water-electrolyte disturbances, providing nutritional support, and reducing the intensity of catabolic processes.

Comments: Treatment of a metabolic crisis must be initiated immediately upon the appearance of symptoms. Metabolic crises leading to critical, life-threatening conditions in maple syrup urine disease are characterized by acute-onset encephalopathy accompanied by seizures, recurrent vomiting, and signs of cerebral edema. The condition of children deteriorates rapidly, potentially progressing to coma. Hypoglycemia, hyponatremia, and signs of metabolic acidosis may occur. The triggering unfavorable factors that cause the development of a metabolic crisis in patients with MSUD include:

• intake of protein, leucine, isoleucine, and valine in amounts exceeding the tolerance of the sick child's body;

• malnutrition, low caloric intake;

• intercurrent respiratory or gastrointestinal infectious diseases and other factors precipitating catabolism;

The severity of the condition is mainly due to severe metabolic ketoacidosis, hyponatremia, and the risk of cerebral edema.

Comments: in the presence of regurgitation, vomiting, or refusal to eat, feeding should be performed via a nasogastric tube or gastrostomy. Follow a frequent, fractional feeding schedule with intervals of 2–3 hours between feedings.

Comments: proteins are introduced based on ¼ of the required daily volume on the first day, ½ on days 2–3, ¾ on days 3–4, and subsequently in full volume. For infants in the first six months of life, the source of natural protein is breast milk/infant formula; for infants in the second half of life, it also includes low-protein complementary foods; for children over one year of age, it includes low-protein natural foods (cereals, vegetables, fruits, vegetable oils) and specialized starch-based products.

In the presence of regurgitation, vomiting, or refusal to eat, feeding should be administered via a nasogastric tube or gastrostomy (gastrostomy placement). Follow a frequent, fractional feeding schedule with intervals of 2–3 hours between feedings. The daily protein equivalent level must not be lower than the safe level, while ensuring high-calorie nutrition (Appendix A3.2) to reduce the production of toxic metabolites.

Comments: according to some data, maintaining high blood levels of isoleucine and valine produces a beneficial effect by competing with leucine for cellular transport. The dosage of isoleucine and/or valine is 80–120 mg per day (in two divided doses) [24].

Comments the calculation is based on an energy value of 1 g of carbohydrates = 4 kcal; 1 g of maltodextrin is equivalent to 1 g of carbohydrates [1, 2, 3].

Comments: Intravenous administration of 10% dextrose** solution calculated as follows: newborns and children under 3 years old 10-12 mg/kg/min, from 3 to 10 years old 8-10 mg/kg/min, older than 10 years old 5-8 mg/kg/min. To ensure adequate caloric intake and prevent excessive hydration and hemodilution, lipids (fat emulsions for parenteral nutrition) may be administered up to 2 g/kg/day (0.4 ml/kg/hour of a 20% solution). If the patient develops significant hyperglycemia (e.g., blood glucose level greater than 250 mg/dL) with glucosuria and signs of metabolic decompensation, the initiation of an infusion of #soluble insulin (human genetically engineered)** should be considered instead of reducing the dextrose** infusion rate, to promote an anabolic state. The initial dose for the infusion of #soluble insulin (human genetically engineered)** is 0.01 IU/kg/min. The level of #soluble insulin (human genetically engineered)** should be titrated to maintain blood glucose levels between 100 and 150 mg/dL.

Comments: administered intravenously at a dose of 0.15 mg/kg every 6–8 hours.

Comments: Sodium bicarbonate** solutions are used to correct metabolic ketoacidosis. Sodium bicarbonate** is used as an 8.4% and 4.2% solution for convenience in recalculating to mmol NaHCO3. Its dosage (mmol) is determined by the formula: (-BE) x body weight (kg) x 0.3. In addition, patients are recommended to consume alkaline drinks – a baking soda solution at the rate of ½-1 teaspoon per 200 ml of water, and alkaline mineral waters.

Depending on the severity of the condition, blood acid-base balance, blood sodium, and potassium levels must be monitored every 6-12 hours.

In case of decompensated metabolic acidosis refractory to medical therapy, extracorporeal methods of homeostasis correction (e.g., hemodialysis, peritoneal dialysis, continuous venovenous hemodiafiltration) are performed [45, 46, 47, 48].

Comments: When blood ammonium levels exceed 200 µmol/L, agents that promote ammonium elimination are prescribed, such as sodium benzoate (dietary supplement) at a rate of 250 mg/kg/day (maximum up to 500 mg/kg/day; if body weight exceeds 20 kg, up to 5.5 g/m²/day). Depending on the severity of the condition, blood ammonia levels must be monitored every 6-12 hours.

3.2 Surgical Treatment

Comment: UCD belongs to inherited metabolic disorders that can be corrected by liver transplantation. Liver transplantation prevents catastrophic brain damage that can occur during metabolic intoxication and stops the progression of neurocognitive impairment, but it does not correct pre-existing cognitive deficits [8]. The risks of surgery and immunosuppression did not differ from those for other pediatric transplant recipients [27]. For patients who have successfully undergone liver transplantation, it is recommended to expand the diet and provide assistance in transitioning to an expanded diet with monitoring of anthropometric parameters and nutritional status [1, 3].

3.3 Other Treatment

3.4 Elective surgery, anesthesia.

Comment: infusion therapy in cases requiring prolonged fasting: dextrose** solutions are administered at the rate of 10–12 mg/kg/min for newborns and children under 3 years, 8–10 mg/kg/min for children aged 3 to 10 years, and 5–8 mg/kg/min for those over 10 years of age.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

5.1. Prevention

Since January 1, 2023, expanded neonatal screening has been carried out in the Russian Federation for the early diagnosis of a number of hereditary diseases, including maple syrup urine disease.

Comment: The genetic risk of having another child with MSUD in the family is 25%.

Comments: Vaccination should preferably be carried out by specialists experienced in working with patients with metabolic disorders, or under their supervision. In the post-vaccination period, vaccinated individuals should be closely monitored with repeated body temperature measurements, which is necessary for the immediate administration of antipyretic therapy if a fever >38.0°C is diagnosed (paracetamol** or ibuprofen**).

5.2 Dispensary monitoring

Comments: The frequency of tests is determined by the child's condition. Typically, these tests are performed in patients with MSUD at the following intervals: every 6 months for patients under 6 years of age, and every 6–12 months for patients over 6 years of age. However, during infectious illnesses or when a metabolic crisis threatens, they should be performed at least once every 7–10 days.

Comments: The frequency of tests is determined by the child's condition. Typically, these tests are performed in patients with MSUD at the following intervals: every 6 months for patients under 6 years of age, and every 6–12 months for patients over 6 years of age. However, during infectious illnesses or when a metabolic crisis threatens, they should be performed at least once every 7–10 days.

Comments: The frequency of tests is determined by the child's condition. Typically, these tests are performed in patients with MSUD at the following intervals: every 6 months for patients under 6 years of age, and every 6–12 months for patients over 6 years of age. However, during infectious illnesses or when a metabolic crisis threatens, they should be performed at least once every 7–10 days.

Comment: The frequency of testing is determined by the patient's condition (on average, monthly), but during infectious diseases or when a metabolic crisis is threatened, it should be done daily until parameters stabilize.

Comments: The frequency of testing is determined by the child's condition (on average, once every 3 months), but during infectious illnesses or when a metabolic crisis threatens, at least once every 7–10 days.

Amino acid levels should be close to age-specific reference values. Blood levels of leucine, isoleucine, and valine should be maintained slightly above normal parameters. A leucine level of 75–200 µmol/L (in children under 5 years) and 75–300 µmol/L (in children over 5 years) is considered optimal; during recovery from a metabolic crisis, this leucine level serves as an indication to start reintroducing natural protein. The optimal valine and isoleucine level is 200 to 400 µmol/L [15, 24].

Free L-carnitine in the blood should be maintained at the upper limit of normal: 40–60 µmol/L. A downward trend in blood pH, base deficit, decreased free carnitine, glucose, rising levels of leucine, isoleucine, valine, and the leucine/alanine (or leucine/tyrosine) ratio, as well as increased urinary excretion of keto acid metabolites, serve as harbingers of a ketoacidotic crisis.

Comments: including video-EEG monitoring. In the absence of seizures – at least once a year; in the presence of epileptic seizures – as clinically indicated.

Comments: Frequency in the absence of abnormalities is at least once a year; in the presence of liver pathology, as clinically indicated.

Comments: If findings are normal, frequency should be at least once a year; if pathology is present, as clinically indicated.

Comments: Dietary therapy adjustments are carried out by geneticists or dietitians at a frequency of once a month during the 1st year of life, then once every 3 months and as indicated up to 3 years of age; once every 6 months after 3 years of age.

Monitoring of actual nutrition (dietary chemical composition) to prevent deficiency states is performed in children during the intensive care period daily, in infants in their first year of life at least once every 7–10 days, and in patients over 1 year of age once every 1–3 months.

A decrease in hemoglobin, iron, total protein, albumin, and amino acids indicates inadequate nutritional support.

6. Organization of Medical Care

6.1 Indications for hospital admission

Indications for planned hospitalization in a medical organization:

1. provision of diagnosis and treatment requiring prolonged (day or round-the-clock) medical observation and monitoring of clinical and laboratory parameters;

2. the need for various types of expert evaluations or examinations in a medical organization when they cannot be performed on an outpatient basis (including issuing a conclusion of a federal concilium / medical commission).

Indications for emergency hospitalization in a medical organization:

1. acute life-threatening conditions and complications threatening development, including a metabolic crisis requiring emergency treatment, including intensive care, as well as round-the-clock medical monitoring and special diagnostic and therapeutic procedures.

6.2 Indications for patient discharge from a medical organization

1. absence of a life-threatening condition and risk of complications requiring emergency treatment upon completion of diagnostic measures.

2. stabilization of the patient's condition and main clinical and laboratory parameters of the pathological process, no need for prolonged medical supervision (day or inpatient care);

3. the diagnostic and treatment plan has been completed, and recommendations for further follow-up and management have been provided;

4. need to transfer the patient to another medical facility or social care institution.

After discharge from the hospital, the patient must undergo outpatient follow-up care provided by a pediatrician, neurologist, and geneticist; patients with symptomatic epilepsy require follow-up by a neurologist experienced in managing patients with epilepsy. Consultations with other specialists are scheduled based on indications.

Principles of organizing medical care for patients with MSUD

Establishing a diagnosis of MSUD raises many questions for the patient's relatives and for specialists working with such patients. Numerous problems arise during the detection and progression of the disease, which require efficient organization of the care process with the participation of a multidisciplinary team of specialists and adherence to the basic principles and approaches to its delivery.

These principles must be observed at any stage of medical care delivery, both at the time of diagnosis and at any stage of patient follow-up.

1) The patient and their representatives must receive complete information about the disease, its course, pathogenesis, prognosis, complications, and potential treatment methods.

2) A diagnosis of MSUD implies the provision of primary, specialized, and palliative care at all stages of the disease.

3) Upon establishing a diagnosis of MSUD, the family should be referred to a specialist experienced in working with MSUD patients, possessing up-to-date information on the disease course and the possibility of participating in clinical trials (of new drugs and/or medical devices). It is also important to inform families about existing public organizations operating for this patient group.

4) Monitoring of a patient with MSUD must involve a multidisciplinary team of specialists consisting of: a pediatrician/general practitioner, geneticist, nutritionist, neurologist, medical psychologist, endocrinologist, psychiatrist, cardiologist, physical therapist, and gastroenterologist. Other specialists should be involved as specific problems arise.

The geneticist provides primary follow-up care for patients with MSUD. The duties of the geneticist include examining and establishing the diagnosis, informing the family about the disease, drawing up a multidisciplinary follow-up plan, monitoring the patient, assessing the dynamics and degree of disease progression during regular examinations, and prescribing supportive therapy. When MSUD patients reach childbearing age, the geneticist develops a preconception preparation plan to prevent maternal MSUD and tests the partner for heterozygous carrier status. When drawing up the multidisciplinary follow-up plan, the geneticist determines the frequency of consultations with other specialists of the multidisciplinary team according to the patient's current condition. At each examination, the geneticist reassesses the patient's current condition and accordingly adjusts the multidisciplinary follow-up plan. In their recommendations, the geneticist indicates the necessary medications, diet therapy, etc., in accordance with the patient's identified needs.

7. Additional Information

The prognosis for the patient's condition and level of mental development depends on the clinical form and associated severity of the enzyme defect; the timing and adequacy of specialized treatment; and the effectiveness of intensive therapy for ketoacidotic crises leading to cerebral edema and severe central nervous system damage. The prognosis for life is relatively favorable with early diagnosis and rigorous metabolic control.

Criteria for Evaluating the Quality of Medical Care

Criteria for evaluating the quality of primary health care

Criteria for evaluating the quality of specialized medical care

References

Appendix A1. Working Group Composition

Anisimova I.V. – Candidate of Medical Sciences, Head of the Department of Medical Care Organization – Medical Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

Baydakova G.V. – Candidate of Biological Sciences, Head of the "Metabolom" Shared Research Facility, Leading Research Fellow, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Russian Society of Medical Geneticists

Baranov A.A. – Academician of the RAS, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pedians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the Central Clinical Hospital of the RAS, Professor of the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chief Freelancer Pediatrician of the Ministry of Health of Russia.

Borovik T.E. – Professor, Doctor of Medical Sciences, Head of the Laboratory of Nutrition for Healthy and Sick Children, National Medical Research Center for Children's Health of the Ministry of Health of Russia, Member of the Association of Medical Geneticists (AMG)

Bushuyeva T.V. – Doctor of Medical Sciences, Leading Research Fellow of the Laboratory of Nutrition for Healthy and Sick Children, National Medical Research Center for Children's Health of the Ministry of Health of Russia, Member of the Association of Medical Geneticists (AMG)

Vashakmadze N.D. – Doctor of Medical Sciences, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health of the Central Clinical Hospital of the RAS, Professor of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia

Vishneva E.A. – Doctor of Medical Sciences, Deputy Head for Scientific Work at the Research Institute of Pediatrics and Child Health of the Central Clinical Hospital of the Ministry of Science and Higher Education, Associate Professor of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Member of the Union of Pedians of Russia

Grebenkin D.I. – Medical Geneticist at the Department of Medical Genetics, Medical Genetic Center, National Medical Research Center for Children's Health of the Ministry of Health of Russia, Member of the Association of Medical Geneticists (AMG)

Globa O.V. – Candidate of Medical Sciences, Neurologist-Epileptologist, Pediatrician, Leading Research Fellow of the Department of Psychoneurology and Psychosomatic Pathology, National Medical Research Center for Children's Health of the Ministry of Health of Russia, Member of the Association of Medical Geneticists (AMG).

Davydova Yu.I. – Medical Geneticist at the Department of Medical Genetics, Medical Genetic Center, National Medical Research Center for Children's Health of the Ministry of Health of Russia, Member of the Association of Medical Geneticists (AMG)

Degtyareva A.V. – Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Professor of the Department of Neonatology, Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Member of the Russian Society of Neonatologists

Zhurkova N.V. – PhD in Medical Sciences, Leading Researcher, Department of Orphan Diseases and Prevention of Disabling Conditions, Medical Geneticist at the Research Institute of Pediatrics and Child Health of the Central Clinical Hospital of the Russian Academy of Sciences, Member of the Association of Medical Geneticists (AMG), Member of the Union of Pediatricians of Russia.

Zarubina V.V. – Medical Geneticist, Medical Genetics Department, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department

Zakharova E.Yu. – MD, PhD, Head of the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics, Member of the Russian Society of Medical Genetics, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

Zvonkova N.G. – PhD in Medicine, Senior Researcher at the Laboratory of Nutrition for Healthy and Sick Children, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists (AMG).

Zubkov V.V. – MD, PhD, Director of the Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Member of the Russian Society of Neonatologists.

Kondakova O.B. – PhD in Medical Sciences, Medical Geneticist, Head of the Medical Genetics Department, Medical Genetics Center, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists (AMG)

Kuzenkova L.M. – Professor, MD, PhD, Head of the Center for Pediatric Psychoneurology, Head of the Department of Psychoneurology and Psychosomatic Pathology, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists (AMG).

Kutsev S.I. – Academician of the Russian Academy of Sciences, Professor, MD, PhD, Director of the Research Centre for Medical Genetics, President of the Association of Medical Geneticists (AMG).

Lyalina A.A. – Medical Geneticist, Medical Genetics Department, Medical Genetics Center, National Medical Research Center for Children's Health, Member of the Association of Medical Geneticists (AMG)

Mikhailova S.V. – MD, PhD, Head of Department, Russian Children's Clinical Hospital of the Ministry of Health of the Russian Federation

Nazarenko L.P. – Professor, MD, PhD, Deputy Director for Research and Clinical Work, Head of the Laboratory of Hereditary Pathology, Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Member of the Association of Medical Geneticists (AMG).

Namazova-Baranova L.S. – Academician of the Russian Academy of Sciences, Professor, MD, PhD, President of the Union of Pediatricians of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health of the Central Clinical Hospital of the Russian Academy of Sciences, Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief freelance pediatric specialist in preventive medicine of the Russian Ministry of Health.

Nikolaeva E.A. – MD, PhD, Chief Researcher, Department of Clinical Genetics, Veltischev Research and Clinical Institute of Pediatrics, Professor of the Department of Innovative Pediatrics and Pediatric Surgery, Institute of Continuing Education and Professional Development, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Russian Society of Medical Genetics, Member of the Association of Medical Geneticists

Pak L.A. – MD, PhD, Deputy Director for Clinical and Organizational Work, Highest Category Neurologist, Chief Researcher, Research Institute of Childhood of the Ministry of Health of Moscow Region

Pashkova I.E. – PhD in Medical Sciences, Head of the Pediatric Department, National Medical Research Center of Transplantology and Artificial Organs named after Academician V.I. Shumakov of the Ministry of Health of the Russian Federation

Pushkov A.A. – PhD in Biological Sciences, Leading Researcher, Laboratory of Medical Genomics, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists

Repina S.A. — PhD in Medicine, Medical Geneticist at the Research Centre for Medical Genetics (Bochkov Research Centre), Member of the Russian Society of Medical Geneticists, Member of the Association of Medical Geneticists

Savostyanov K.V. — Doctor of Biological Sciences, Head of the Medical Genetic Centre, Head of the Laboratory of Medical Genomics at the National Medical Research Centre for Children's Health of the Russian Ministry of Health, Professor at the Department of Pediatrics and Public Health at the National Medical Research Centre for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists

Sviridova V.V. — Medical Geneticist at the Department of Medical Care Organization, Academician N.P. Bochkov Research Centre for Medical Genetics, Junior Researcher at the Mutagenesis Laboratory, Academician N.P. Bochkov Research Centre for Medical Genetics

Selimzyanova L.R. — PhD in Medicine, Leading Researcher at the Research Institute of Pediatrics and Children's Health Stewardship of the Central Clinical Hospital of the Russian Academy of Sciences under the Ministry of Science and Higher Education of the Russian Federation, Associate Professor at the Department of Pediatrics and Pediatric Rheumatology at the Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, at the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

Subbotin D.M. — Medical Geneticist at the Research Centre for Medical Genetics (Bochkov Research Centre), Member of the Association of Medical Geneticists.

Fedoseenko M.V. — PhD in Medicine, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Deviations and Chronic Diseases, Leading Researcher, Pediatrician at the Research Institute of Pediatrics and Children's Health Stewardship of the Central Clinical Hospital of the Russian Academy of Sciences under the Ministry of Science and Higher Education of the Russian Federation, Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, at the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

Fisenko A.P. — Doctor of Medical Sciences, Professor, Honored Doctor of the Russian Federation, Director of the National Medical Research Centre for Children's Health of the Russian Ministry of Health

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• pediatricians;

• general practitioners (family doctors);

• medical geneticists;

• dietitians;

• neurologists;

• medical psychologists;

• defectologists

• medical students, residents, postgraduate students.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Ministry of Health of the Russian Federation No. 274n dated April 21, 2022, "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases"

2. Order of the Ministry of Health and Social Development of the Russian Federation dated April 16, 2012, No. 366n, "On approval of the Procedure for Pediatric Care Delivery"

3. Decree of the Government of the Russian Federation dated April 9, 2015, No. 333, "On approval of the Rules for the Formation of the List of Specialized Medical Nutrition Products for Disabled Children"

4. Drug information: https://grls.rosminzdrav.ru

5. International Statistical Classification of Diseases and Related Health Problems (ICD-10);

6. Order of the Russian Ministry of Health No. 205n dated May 2, 2023, "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers"

7. Federal Law No. 489-FZ dated December 25, 2018 «On Amendments to Article 40 of the Federal Law «On Compulsory Medical Insurance in the Russian Federation» and the Federal Law «On the Fundamentals of Protecting Citizens' Health in the Russian Federation» Regarding Clinical Guidelines».

8. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for the Development and Revision of Clinical Guidelines, Their Template Form, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

9. Order of the Russian Ministry of Health No. 804n dated October 13, 2017 «On Approval of the Nomenclature of Medical Services».

10. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019, "On Classifications and Criteria Used in Carrying out Medical and Social Expertise of Citizens by Federal State Institutions of Medical and Social Expertise";

11. Order of the Ministry of Health and Social Development of the Russian Federation No. 494 dated August 9, 2005, "On the Procedure for Using Medicinal Products in Patients for Life-Saving Indications"

12. Information Letter of the Russian Ministry of Health on the possibility of procuring a medicinal product by trade name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu);

13. Directive of the Government of the Russian Federation No. 3551-r dated December 11, 2023, "On Approval of the List of Specialized Medical Nutrition Products for Disabled Children"

Main regulatory legal acts governing the provision of palliative medical care

1. Federal Law No. 18-FZ of March 6, 2019, "On Amendments to the Federal Law 'The Fundamentals of Health Protection of Citizens in the Russian Federation' Regarding the Provision of Palliative Medical Care."

2. Order of the Russian Ministry of Health No. 345n and the Ministry of Labor of Russia No. 372n of May 31, 2019, "On Approval of the Regulations on the Organization of Palliative Medical Care, Including the Procedure for Interaction Between Medical Organizations, Social Service Organizations, and Public Associations and Other Non-Profit Organizations Operating in the Field of Health Protection."

3. Order of the Russian Ministry of Health No. 348n of May 31, 2019, "On Approval of the List of Medical Devices Intended to Support the Functions of Human Organs and Systems Provided for Home Use."

4. Order of the Russian Ministry of Health No. 505n dated July 10, 2019, "On approval of the Procedure for the transfer by a medical organization to a patient (their legal representative) of medical devices intended to maintain the functions of human organs and body systems for home use in the provision of palliative medical care."

Sample diagnosis formulation

• Maple syrup urine disease. Thiamine-responsive form.

Appendix A3.1 Diagram of metabolic processes leading to the development of maple syrup urine disease

Note: the number "1" indicates the metabolic block.

Appendix A3.2 Reference values for physiological requirements of essential nutrients and energy in healthy children

Table 1 – Recommended daily intake for maple syrup urine disease

(PB.Acosta: Nutrition Management of Patients with inherited Metabolic Disorders, Jones & Barlett Publishers, 2010)

• Men and women outside of pregnancy and lactation

Table 2 Minimum safe protein level according to FAO/WHO/UNU 2007 by age.

Table No. 3

Recommended daily nutrient intake for MSUD patients in acute and asymptomatic periods (summary data) [37].

Table 4 Average daily norms of physiological energy requirements for children

according to FAO/WHO/UNU 2001 (WHO Technical Report Series 17-24 Oct 2001)

Appendix A3.3 Dietary calculation, chemical composition, and energy value for children with maple syrup urine disease

Table 1 Specialized amino acid-based products free of leucine, isoleucine, and valine¹.

¹ - all products are registered in the territory of the Russian Federation.

• the leucine content in natural foods varies. It is recommended to use a single reference source for the chemical composition of foods, as data may differ between different reference books;

• to facilitate calculations of leucine in foods, it is advisable to use standard tables containing data on the amount of food corresponding to 50 mg of leucine (Table 4).

Table 2 - Estimated amount of certain foods corresponding to 50 mg of leucine

Appendix A3.4 Diet calculation. Examples

Example No. 1:

Age 3 months, body weight 5.9 kg.

Serum leucine level 1700 µmol/L

1. Protein requirement: 2.5 g/kg of body weight = 2.5 × 5.9 = 14.75 g

Leucine: 40–100 mg/kg of body weight, but since the serum leucine level is elevated, a lower leucine intake should be established – 40 mg/kg of body weight = 40 × 5.9 = 236 mg.

energy requirement at least 95 kcal/kg.

2. Stage 1: the required leucine intake is 236 mg/day; breast milk or infant formula contains approximately 1.2 g of protein per 100 ml, which corresponds to 124.8 mg of leucine (1 g of dairy protein contains 104 mg of leucine). The daily volume of breast milk or infant formula will be equal to:

124.8 mg - 100 ml

236 mg - x ml

X = 236 × 100 / 124.8 = 190 (189.1) ml of breast milk or infant formula.

3. Stage 2: the total daily protein intake is 14.75 g, accordingly the protein volume in 190 ml of breast milk or infant formula will be:

1.2 g - 100 ml

X g - 190 ml

X = 1.2 × 190 / 100 = 2.28 g

Accordingly, from the specialized infant formula for dietary management of infants from 0 to 12 months as a primary food source and as a supplemental food for children up to 3 years, "MSUD Anamix Infant" (for maple syrup urine disease) ****, the child must receive 14.75 g - 2.28 g = 12.47 g of protein (protein equivalent).

4. Stage 3: if the specialized infant formula for dietary management of infants from 0 to 12 months as a primary food source and as a supplemental food for children up to 3 years, "MSUD Anamix Infant" (for maple syrup urine disease) **** at standard dilution contains 2 g of protein equivalent per 100 ml, then its required volume is:

2 g - 100 ml

12.47 g - x ml

X = 12.47 × 100 / 2 = 623.5 ml of the specialized infant formula for dietary management of infants from 0 to 12 months as a primary food source and as a supplemental food for children up to 3 years, "MSUD Anamix Infant" (for maple syrup urine disease) ****

Table 1

Chemical composition of the diet of a 3-month-old child with leucinosis:

5. The obtained amount of breast milk and formula should be evenly distributed into 6 feedings. To meet the child's energy requirements, it is possible to use #dextrose (10 g = 100 ml of a 10% solution = 40 kcal) for diluting the specialized formula or to add maltodextrin (10 g per day = 40 kcal) to the ready-to-feed formula, evenly distributing it between feedings. With 6 feedings per day, approximately 1.5 g of maltodextrin per feeding * - depending on plasma amino acid concentrations (PAAs), correction of isoleucine and valine concentrations is possible.

Example No. 2:

Age 4 months, body weight 6.5 kg.

Serum leucine level 1800 µmol/L

1. Protein requirement: 2.5 g/kg = 2.5 × 6 = 15 g

Leucine: 40–100 mg/kg of weight, but since the serum leucine level is elevated, a lower leucine intake should be set – 40 mg/kg = 40 × 6 = 240 mg.

Energy requirement: at least 85 kcal/kg.

2. Stage 1: required leucine intake 240 mg/day; breast milk or infant formula contains approximately 1.2 g of protein per 100 mL, which corresponds to 124.8 mg of leucine (1 g of dairy protein contains 104 mg of leucine). The daily volume of breast milk or infant formula will be equal to:

124.8 mg - 100 ml

240 mg - x mL

X = 236 × 100 / 124.8 = 192 mL of breast milk or infant formula.

3. Stage 2: daily total protein intake is 15 g; accordingly, the amount of protein in 192 mL of breast milk or infant formula will be:

1.2 g - 100 ml

X g - 192 mL

X = 1.2 × 190 / 100 = 2.3 g

Accordingly, from the specialized infant formula for children of the first year of life from 0 to 12 months as the main diet and as an additional diet for children up to 3 years "MSUD Anamix Infant" (for maple syrup urine disease)****, the child must receive 15 g – 2.3 g = 12.7 g of protein (protein equivalent).

4. Stage 3: if the specialized therapeutic formula at standard dilution contains 1.8 g of protein equivalent per 100 mL, then its required volume is:

1.8 g - 100 mL

12.7 g - x mL

X = 12.7 × 100 / 1.8 = 705 mL of specialized dry product for dietary therapeutic nutrition of infants of the first year of life suffering from maple syrup urine disease, "Nutrigen 14-leu, -ile, -val"****

Table 2.

Chemical composition of the diet of a 4-month-old child with leucinosis:

Correction of the caloric value of the diet is not required.

Example No. 3.

Child 3 years old, body weight 14 kg

1. Leucine tolerance – 40 mg/kg, which corresponds to 560 mg of leucine per day.

   Daily protein intake allowance 1.5 g/kg – 21 g.

2. On average, 1 gram of natural protein contains 70 mg of leucine.

   560 / 70 = 8 g of natural protein.

3. Accordingly, the amount of protein equivalent in the specialized formula: 21 – 8 = 13 g.

4. Caloric value of the daily diet 80 × 14 = 1120 kcal.

5. To calculate the daily diet and the amount of natural products, you can use Table 2 of Appendix A3.3 (provided as an example) and similar tables with data on the leucine content in foods.

Appendix A3.5 Recommended plasma amino acid levels

Appendix A3.6 Range of branched-chain amino acid concentrations in blood plasma of apparently healthy children and pediatric patients with MSUD

Range of branched-chain amino acid concentrations in blood plasma of apparently healthy children and pediatric patients with MSUD

Appendix A3.7 Legend for notes

…^** – the drug is included in the list of vital and essential drugs (Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 "On Approval of the List of Vital and Essential Drugs for 2020, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for Medical Care", Decree of the Government of the Russian Federation No. 3073-r dated November 23, 2020)

# - off-label use – outside the indications registered in the drug instructions, carried out by decision of the medical commission, with the permission of the Local Ethics Committee of the medical organization (if any), subject to the signed informed consent of the parents (legal representative) and the patient over 15 years of age;

**** - a specialized medical nutrition product included in the list of specialized medical nutrition products for disabled children (List of specialized medical nutrition products for disabled children for 2021, approved by the Order of the Government of the Russian Federation of December 7, 2020.

Appendix B. Physician Action Algorithms

Neonatal screening algorithm for maple syrup urine disease

Appendix B1. Algorithm of physician actions for MSUD during a metabolic crisis

Appendix C. Patient Information

What is maple syrup urine disease or leucinosis?

Maple syrup urine disease or leucinosis is a rare hereditary disease involving impaired protein breakdown processes. Proteins are an essential component of nutrition. They are necessary for the growth and repair of cells in our bodies. For the body to use dietary protein, it must be broken down into smaller parts – amino acids. Then, thanks to specialized enzymes, these amino acids are used to perform specific functions. In patients with maple syrup urine disease the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme does not work, which prevents the body from breaking down the amino acids leucine, isoleucine, and valine. As a result, these amino acids and their derivatives (organic acids) accumulate in the body, exerting a toxic effect. High levels of certain organic acids can cause an unusual sweet odor in urine and sweat, hence the name of this disease – maple syrup urine disease.

The enzyme impairment may be associated with changes in one of the genes, BCKDHA, BCKDHB, DBT, or DLD.

How does maple syrup urine disease manifest?

The main symptoms of the disease in infants are a sharp deterioration in general condition a few days (usually 7–14 days) after the start of feeding with breast milk or formula, lethargy or hyperexcitability, vomiting, and refusal to feed. Seizures, impaired consciousness, coma, bluish skin discoloration (cyanosis), and breathing disorders (apnea) are also possible. In children older than one year, psychomotor delay, intellectual disability, erythematous skin rashes, frequent infections, and seizure disorders are observed.

How is maple syrup urine disease diagnosed?

Based on clinical symptoms, a physician may suspect the diagnosis and refer the patient for laboratory testing. Tandem mass spectrometry is used to determine the levels of compounds such as carnitine, acylcarnitines, and amino acids in the blood, and gas chromatography-mass spectrometry is used to determine urine organic acid levels. In maple syrup urine disease, elevated blood concentrations of leucine, isoleucine, and valine are observed. Increased concentrations of 2-oxoisocaproic, 2-hydroxyisocaproic, 2-oxo-3-methylvaleric, 2-oxoisovaleric, 2-hydroxyisovaleric, and 2-hydroxy-3-methylvaleric acids are detected in the urine. Patients with biochemical changes characteristic of maple syrup urine disease undergo molecular genetic testing to confirm the diagnosis by identifying mutations in the BCKDHA, BCKDHB, DBT, or DLD genes. Targeted gene panels are usually used for this purpose.

How is maple syrup urine disease treated?

The main principle of therapy for maple syrup urine disease is to reduce the intake of the amino acids leucine, isoleucine, and valine into the body to prevent the damaging effects of these substances. To achieve this, natural protein in the diet is restricted, and high-protein foods such as meat, fish, eggs, dairy products, legumes, etc., are excluded. Protein deficiency is compensated for by using specialized amino acid-based formulas free of leucine, isoleucine, and valine, which meet the child's age-specific nutritional and energy requirements.

In the absence of appropriate therapy, the patient's condition may deteriorate sharply, leading to a metabolic crisis and irreversible consequences up to death. A metabolic crisis can also be triggered by adverse factors such as dietary non-compliance, failure to follow medical prescriptions, viral and bacterial infections, stressful situations, trauma and surgical interventions, emotional and physical stress, or it may occur against a background of complete well-being. Precursors of a crisis include decreased emotional tone, lethargy, drowsiness, refusal to eat, possible vomiting, and a rise in temperature, especially at the onset of an infectious disease.

At the first symptoms of a metabolic crisis, the patient must be hospitalized urgently, and home therapy should be started immediately before the ambulance arrives.

The patient must always carry a handout outlining emergency measures during the onset of a metabolic crisis.

How is maple syrup urine disease inherited?

Maple syrup urine disease is inherited in an autosomal recessive manner. This means that the disease manifests only if both parents are carriers of the disease and, although they are not ill themselves, pass two affected genes to the child. Most families with a child affected by this disorder have not encountered such a problem before. The risk of having another affected child in a family that already has affected children is 25% for each pregnancy.

Siblings of an affected child may also be affected, even if they had no symptoms at the time of family screening. In this case, diagnostics must be performed as early as possible to initiate treatment and prevent complications. They can also be carriers, just like their parents. Regarding other family members, it is important to inform them that they may be carriers. This means they also have a risk of having a child with this condition.

All families with this disease must undergo medical genetic counseling and receive complete information from a geneticist regarding the risk of recurrence of this disease in the family, and discuss all issues related to the inheritance of the disease with a specialist. In Russia, medical genetic clinics operate in every region.

To conduct prenatal and preimplantation genetic diagnosis, the married couple must first undergo screening for carrier mutations in one of the genes responsible for this disorder: BCKDHA, BCKDHB, DBT, or DLD, by contacting specialized diagnostic laboratories and medical centers. Prenatal diagnosis is performed using molecular genetic methods by analyzing DNA extracted from a chorionic villus biopsy and/or amniotic fluid cells and/or fetal blood.

Do not take any medications or supplements without consulting your doctor. It is extremely crucial to follow all medical recommendations to prevent the development of metabolic crises as much as possible.

How are patients treated during a metabolic crisis?

Protein intake should be temporarily stopped (for 24–48 hours). Completely eliminating protein is impossible because the body requires protein intake, and if insufficient amounts are supplied, catabolic processes are activated.

At home, at the very first signs of illness, especially when the child has a reduced appetite (for example, during a cold, flu-like symptoms, viral infections, any illnesses accompanied by a temperature >37 °C, tonsillitis, gastroenteritis), therapy to prevent the development of a crisis should be initiated. If parents are unsure whether the child is showing the early signs of an approaching illness (paleness, drowsiness, irritability, loss of appetite, fever, headache, body aches and general pain, cough, sore throat, or earache), the child should be given a solution to drink once as a precautionary measure. The earliest signs are usually minor behavioral changes that are easily noticed by parents. If the child is relatively healthy and has no vomiting, only weakness and slight drowsiness, they can be given a glucose polymer solution orally in frequent, small portions (Table 1). The exact recipe/concentration of the glucose polymer recommended for each child varies; you should consult your attending physician to find out what is right for your child. Some children dislike the taste of the glucose polymer and prefer store-bought beverages, but the carbohydrate concentrations in such drinks are lower. Purchased beverages should be used with caution. Low-calorie and sugar-free drinks contain very little or no carbohydrates and therefore should not be used.

If the child has persistent vomiting and does not improve, parents should immediately go to the hospital for an evaluation.

Ambulance paramedics must be provided with a discharge summary containing the doctor's conclusion and recommendations for therapy during a metabolic crisis.

Parents should bring all information about the solutions used to the hospital, and preferably the solutions themselves.

What monitoring should be performed for patients with maple syrup urine disease?

A multidisciplinary approach involving specialists from various fields is necessary for the monitoring and treatment of patients with maple syrup urine disease to ensure comprehensive therapy and its timely correction when necessary. Regular examinations are required for patients with maple syrup urine disease. Table 1 shows an approximate list and frequency of examinations, but in each case, you must coordinate the examination plan with your attending physician.

Table 1 Frequency of examinations in maple syrup urine disease

How do patients receive treatment in the Russian Federation?

Maple syrup urine disease is one of the rare inherited metabolic disorders and is included in the list of rare (orphan) diseases funded by the regional budget. After diagnosis establishment, the patient must be included in the regional segment of the registry for life-threatening rare (orphan) diseases to ensure future provision of necessary medical nutrition and medications. Different specialists are responsible for maintaining the registry in different regions, but most often they are medical geneticists; therefore, after establishing the diagnosis, you must consult a regional medical geneticist.

How can family and loved ones help?

Do not forget — the success of treatment also depends on the family. Recommendations must be followed, "lapses" in diet therapy must not be allowed under any circumstances, and attention should be paid to rehabilitation and scheduled examinations. All family members must know that the child needs a special diet, and close relatives must master the skills of diet calculation.

Parents of a patient with maple syrup urine disease, and subsequently the patient themselves, must be trained in the rules for organizing therapy during the intercritical period and during the threat of a metabolic crisis.

The child must always carry an emergency information card detailing the urgent measures to be taken during the onset of a metabolic crisis.

The prognosis depends on the form of the disease and therapy. With timely initiation of treatment, the prognosis is generally favorable. The patient must follow the diet throughout their life.

Appendix B1. Example of an "emergency card"

Emergency memo

Attention! The patient is at risk for developing an acute metabolic crisis associated with an inherited disorder

1. Signs of decompensation:

- depressed consciousness;

- lethargy, weakness, drowsiness;

- onset or worsening of seizures;

- restless behavior, tearfulness;

- sweetish odor of urine/body;

- changes in muscle tone.

2. Indications for hospitalization:

- signs of decompensation;

- repeated vomiting, diarrhea;

- infections with high fever;

- dehydration.

3. Action plan:

If a metabolic crisis is suspected:

3.1. Increase daily caloric intake by 25–50%.

3.2. Increase protein by 120% of the normal baseline using specialized amino acid-based formulas free of leucine.

3.3. Restrict leucine intake by 50% or eliminate it completely for 24–48 hours, depending on symptom severity.

3.4. Ensure frequent small feedings over a 24-hour period.

3.5. When the patient is at home, increase carbohydrate intake to meet caloric needs using a #dextrose or maltodextrin solution (if unavailable – sweet compote, fruit Kissel)

Table No. 1 Correspondence between the child's age and the dose of enteral #dextrose for suspected metabolic crisis.

[24] 

* The total volume is divided into 12 doses and administered every 2 hours.

3.6. If oral feeding is impossible or cannot be maintained, place a nasogastric tube.

3.7. Upon hospital admission, initiate continuous infusion of 10% dextrose** solution at the following rates: newborns and children under 3 years — 10–12 mg/kg/min, children aged 3 to 10 years — 8–10 mg/kg/min, over 10 years — 5–8 mg/kg/min.

3.8 Laboratory monitoring:

- Acid-base balance, electrolytes, ammonia

- Complete blood count

- Urinalysis for ketone bodies

- Blood biochemistry (CK, ALT, AST, glucose, total and direct bilirubin, urea, creatinine, GGT, ALP, total protein, albumin, CRP, potassium, sodium, calcium, chloride)

- Amino acid and acylcarnitine profile

4. Post-emergency patient management:

Continue administering dextrose** until the condition stabilizes, monitored by blood glucose, acid-base balance, and blood levels of leucine, valine, and isoleucine.

Upon relief of metabolic decompensation symptoms and reduction of leucine levels to 200 µmol/L in children under 5 years and 300 µmol/L in children over 5 years, reintroduce natural protein foods at ¼ of the required daily volume on the first day, ½ on the 2nd–3rd day, ¾ on the 3rd–4th day, and then in full volume.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.