Isovaleric acidemia/aciduria: clinical guidelines

List of Abbreviations

IVA – isovaleric acidemia

BMI – body mass index

ABSt – acid-base status

TMS – tandem mass spectrometry

US – ultrasound examination

CNS – central nervous system

ECG – electrocardiography

EchoCG – echocardiography

Terms and Definitions

Metabolic crisis – a critical, life-threatening condition triggered by adverse factors that cause increased cellular catabolism with the production of toxic leucine derivatives, manifesting as acute encephalopathy, ataxia, vomiting, and tonic-clonic seizures.

Hemodialysis – a method of extracorporeal blood purification that removes toxic metabolic waste products from the body, corrects water and electrolyte balance disorders, where blood purification is performed through an artificial membrane using an artificial kidney machine.

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

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Isovaleric acidemia (aciduria) IVA – an inherited metabolic disorder from the group of organic acidemias caused by a mutation in the IVD gene encoding the enzyme isovaleryl-CoA dehydrogenase, leading to its deficiency or absence of activity and impaired leucine degradation [1].

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

Isovaleric acidemia is an autosomal recessive disorder caused by mutations in the gene for the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD), leading to its deficiency in the liver, kidneys, skeletal muscles, and fibroblasts. The localization of the IVD gene is 15q14-q15 [2, 3, 4]. More than 70 mutations of the IVD gene leading to the development of the disease have been described [3, 5, 6].

Enzyme deficiency leads to impaired synthesis of 3-methylcrotonyl-CoA from isovaleryl-CoA (leucine catabolism products), accumulation in tissues and biological fluids of organic acids derived from isovaleryl-CoA (isovaleric, 3-hydroxyisovaleric, 4-hydroxyisovaleric acids, isovalerylcarnitine (C5), isovalerylglycine, etc.), which exert a toxic effect mainly on the central nervous system (CNS), liver, and bone marrow, causing severe metabolic ketoacidosis, secondary hyperammonemia, hyperglycinemia, and hyper-/hypoglycemia. High renal excretion of isovalerylcarnitine results in secondary carnitine deficiency (the scheme of metabolic processes in isovaleric acidemia is presented in Appendix A3.2) [4].

In recent years, in a number of countries, following the inclusion of IVA in neonatal screening programs by tandem mass spectrometry (TMS), it has become possible to diagnose the asymptomatic form of IVA. The most common missense mutation, 932C>T (p.A282V), characteristic of the asymptomatic form, has been described. With this mutation, enzyme activity is partially preserved. However, its impact on clinical outcome and the need for treatment remain debatable [4, 5, 7].

1.3 Epidemiology of the Disease or Condition

The disease occurs in various populations. The incidence among newborns in European countries and the USA according to various data is 1:60,000 - 1:150,000 [8]. In the Russian Federation, the prevalence of the disease has not been determined.

1.4 Features of Coding the Disease or Condition

E71.1 - Other disorders of branched-chain amino acid metabolism.

1.5 Classification of the disease or condition

There are three clinical forms of the disease: acute neonatal form, occurring in 60-70% of patients, chronic intermittent, and asymptomatic [4, 7, 9].

1.6 Clinical presentation of the disease or condition

The clinical presentation of IVA varies in severity from an asymptomatic form to a life-threatening condition with the development of severe metabolic decompensation [7].

IVA can manifest in the neonatal period in the first two weeks of life or in late infancy, usually before one year of age. The neonatal form is characterized by a rapid, fulminant course accompanied by symptoms of CNS depression, vomiting, lethargy, rapid development of seizures, and coma against the background of ketoacidosis [4, 10]. In the chronic form, symptoms of psychomotor and physical developmental delay, seizures, renal dysfunction, gastrointestinal tract disorders (pancreatitis) [11,12,13], and pancytopenia/neutropenia/thrombocytopenia predominate [4].

In children diagnosed outside the neonatal period, relatively non-specific signs of the disease are noted: physical and psychomotor developmental delay, and mental retardation. Apart from the "sweaty feet" odor of isovaleric acid, which is absent unless metabolic decompensation is present, little helps to suggest this diagnosis in a patient. Patients with the chronic form of the disease are also at risk for episodes of metabolic acidosis and metabolic decompensation, usually due to intercurrent illnesses or other physiological stress, including fasting [15]. These acute conditions may be misdiagnosed as diabetic ketoacidosis due to hyperglycemia, acidosis, and the apparent presence of ketones in the blood and urine. The age of crises can vary; for example, an 18-year-old male with IVA developed acute nausea, vomiting, and altered mental status during training at a US Air Force camp [63]. Some patients develop acute pancreatitis, myeloproliferative syndrome, Fanconi syndrome, and cardiac arrhythmia [15]. Brain MRI reveals abnormalities in the globus pallidus area, and brain edema during a metabolic crisis [33].

Early signs of a metabolic crisis include lethargy, drowsiness or irritability, refusal to eat, vomiting, and gait disturbances. Respiratory disorders and tachycardia appear. Neurological disorders progress to stupor or coma, causing high mortality. The severity of the condition is mainly determined by pronounced metabolic ketoacidosis. Hypoglycemia (in about 50% of children), hyperammonemia, and dehydration are frequently noted.

Crises are usually triggered by adverse factors that cause increased cellular catabolism with the production of toxic leucine derivatives:

- intake of protein and leucine in amounts exceeding the patient's tolerance;

- malnutrition, low calorie intake;

- intercurrent respiratory or gastrointestinal infectious diseases;

- physical or psycho-emotional stress [5].

With adequate metabolic therapy, the prognosis is favorable; there are reports of successful pregnancies in women with IVA resulting in the birth of healthy children [64].

In the differential diagnosis in infants with the above-described symptoms (CNS depression, vomiting, seizures, refusal to eat), diagnoses such as sepsis, congenital infections, drug poisoning, diabetes mellitus, encephalitis, hypoxic nervous system injuries, and adrenal insufficiency should be considered.

Repeated vomiting and poor weight gain in infancy may be related to cow's milk protein allergy or other food allergies.

When pronounced metabolic disorders are detected, the diagnostic search narrows down to a number of inherited metabolic disorders, in particular other forms of organic acidemias (propionic, methylmalonic acidemias), inherited aminoacidopathies (phenylketonuria, maple syrup urine disease, homocystinuria, tyrosinemia), urea cycle disorders, fatty acid beta-oxidation defects, galactosemia, and others.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis of isovaleric acidemia (IVA) is based on pedigree analysis, medical history assessment, and clinical manifestations, and is confirmed by biochemical methods (comprehensive determination of amino acid and acylcarnitine concentrations in blood by tandem mass spectrometry, gas chromatography-mass spectrometry) and molecular genetic testing of the IVD gene.

Neonatal and early-onset forms of IVA are diagnosed in the first year of life through selective screening performed in at-risk infants and upon the appearance of clinical symptoms [14].

2.1 Complaints and Anamnesis

When taking the medical history and assessing complaints, attention should be paid to the following symptoms and anamnestic events:

• positive family history (family history of a patient with IVA, cases of sudden unexplained death in early childhood)

• sudden deterioration against the background of complete health or acute respiratory viral infection (ARVI),

• feeding difficulties;

• frequent regurgitation/vomiting;

• depressed level of consciousness;

• lethargy, weakness, drowsiness;

• seizures;

• agitation, crying;

• increased sweating;

• muscle hypotonia/hypertonia;

• involuntary/involuntary movements;

• acute/chronic pancreatitis

• cardiac arrhythmia

• characteristic body odor of "cheese" or "sweaty feet"

• altered mental status

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;

• surgical interventions;

• physical or psychoemotional stress.

2.2 Physical Examination

Physical examination should focus on the following main clinical manifestations [4, 5, 9, 15, 16]:

neonatal period

• regurgitation/vomiting, food refusal;

• growth retardation;

• motor developmental delay;

• lethargy, drowsiness;

• depressed level of consciousness;

• muscle hypotonia/hypertonia;

• pyramidal signs (hyperactive deep tendon reflexes);

• extrapyramidal signs (various types of hyperkinesia, muscle dystonia);

• tremor;

• seizures;

• characteristic body odor of "cheese" or "sweaty feet"

children of early age

• episodic vomiting;

• psychomotor and speech developmental delay;

• changes in muscle tone (muscle hypotonia/hypertonia);

• periodic ataxia, tremor;

• seizures;

• characteristic body odor of "cheese" or "sweaty feet"

adults

• characteristic body odor of "cheese" or "sweaty feet"

• altered mental status

2.3 Laboratory Diagnostics

Comments: in IVA, an increase in blood concentration of isovalerylcarnitine (C5) is observed, with frequently elevated C5/C2 ratio and sometimes increased glycine levels [20].

Comments: IVA should be suspected and TMS considered in the following cases [14]:

• patients of any age from families with affected individuals (primarily siblings of the patient);

• infants in the first weeks and months of life who, after a period (sometimes very short, lasting several days) of satisfactory condition, develop vomiting, food refusal, lethargy, hypotonia, seizures, coma, metabolic acidosis, ketonuria;

• patients of any age with recurrent episodes of vomiting, lethargy, drowsiness, hypotonia, ketoacidosis;

• patients with altered mental status, psychomotor retardation, epilepsy, muscle tone abnormalities, cerebral hemorrhages, tubular dysfunction, acute pancreatitis.

Elevated concentrations of isovaleric acid, 3-hydroxyisovaleric acid, and isovalerylglycine are detected in the patients' urine. Additionally, 3-hydroxybutyric, 3-hydroxyisobutyric, and 2-methyl-3-hydroxybutyric acids, reflecting the state of ketosis, may be present in the urine.

Caution must be exercised when interpreting these indicators. In some cases, pivaloylcarnitine, a derivative of antibiotics and cosmetics (emollients) containing pivalic acid, can be misidentified as isovalerylcarnitine during blood sample TMS [5, 21, 22].

Elevated concentrations of organic acids in urine (isovaleric, 3-hydroxyisovaleric acids, isovalerylglycine, etc.) can also be determined by gas chromatography-mass spectrometry [3, 5, 23].

• In patients with abnormalities detected by tandem mass spectrometry characteristic of IVA, to confirm the diagnosis and provide genetic counseling, it is recommended to perform molecular genetic testing to identify mutations in the IVD gene (comprehensive panel for the diagnosis of organic acidurias) [4, 7, 20, 24, 25].

Recommendations Grade BEvidence Level 3Recommendation validity score B (level of evidence – 3)

Comments: standard molecular genetic methods are used to study the IVD gene responsible for the development of IVA.

DNA diagnostics is indicated for prenatal or preimplantation diagnosis as clinically indicated [26].

Comments: a characteristic feature of organic acidemias, including IVA, is high anion gap metabolic acidosis (≥16), hyperammonemia, hyperketonemia and ketonuria, and elevated plasma lactate.

Comment: the test is performed during dynamic follow-up; the frequency is determined individually.

2.4 Instrumental Diagnostics

Comments: Anesthesia and contrast enhancement are performed according to indications.

Comments: including video-EEG monitoring.

Comment: in metabolic disorders affecting the cardiovascular system, cardiomyopathy and cardiac arrhythmias may be observed.

2.5 Other Procedures

Comments:

All patients with IVA must undergo initial and follow-up consultations (examinations) by a pediatrician / general practitioner / family physician during diagnosis and follow-up to assess their general condition, administer therapy, and participate in prescribing and implementing treatment and rehabilitation measures.

All patients with IVA must undergo initial and follow-up consultations (examinations) by a neurologist and psychiatrist to assess the severity of central nervous system involvement and mental status, and to determine the management strategy for treatment and rehabilitation [3, 4, 5, 9, 15, 39].

All patients with IVA must undergo initial and follow-up consultations (examinations) by a dietician or medical geneticist to prescribe pathogenetic diet therapy, and subsequently as needed to adjust the diet therapy and monitor adherence [4, 9, 31, 39].

Patients with suspected IVA must undergo a consultation (examination) by a medical geneticist to establish a diagnosis; patients with a confirmed diagnosis of IVA and families with relatives affected by IVA must consult a geneticist for family planning [9, 27, 37].

If visual organ pathology is suspected or present in the patient, initial and follow-up examinations (consultations) by an ophthalmologist are performed [3, 9, 37].

If cardiovascular system pathology is suspected or present in the patient, initial and follow-up examinations (consultations) by a cardiologist/pediatric cardiologist are performed [40].

To plan an individualized rehabilitation program for psychological and pedagogical support for patients and their families, initial and follow-up examinations (testing, consultation) by a medical psychologist and a medical speech therapist (speech therapist-defectologist) are performed [9, 39].

If necessary, other specialists, such as an anesthesiologist-reanimatologist, participate in the diagnostic and treatment process.

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

3.1 Conservative Treatment

Therapy for IVA is aimed at preventing metabolic decompensation (metabolic crisis), reducing the formation of isovaleryl-CoA and the accumulation of toxic metabolites, while ensuring anabolic processes, normal growth, and nutritional status.

3.1.1 Diet Therapy

The main principles of specialized medical nutrition therapy include:

• restriction of protein from natural foods to reduce the intake of the amino acid leucine into the body to the required minimum. For infants in the first half of life, this restriction applies to breast milk, adapted infant formulas, or soy formulas; for children in the second half of life and older, it includes a ban on introducing high-protein complementary foods (meat, fish, cottage cheese, eggs, dairy products, legumes, etc.);

• mandatory compensation for protein deficiency through the use of specialized leucine-free amino acid mixtures that meet the child's age-specific requirements for essential nutrients and energy. At the onset of treatment and during metabolic crises for 24 to 48 hours (no longer!), use only a specialized leucine-free amino acid mixture;

• 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: Since the development of a metabolic crisis can lead to irreversible neurological damage, if IVA is suspected, biomaterial should be collected for biochemical testing, after which the patient should be switched to a low-protein feeding regimen (the minimum safe protein level is presented in Appendix A3.4, Tables 1–3), while ensuring an adequate calorie intake to prevent catabolism (the minimum daily caloric intake is presented in Appendix A3.4, Table 4). For infants in the first half of life, breastfeeding or feeding with low-protein infant formulas (1.2–1.3 g/100 ml of reconstituted product) is 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, whereas molecular genetic studies may take about 2–3 weeks. Therefore, it is essential that the child remains on a low-protein diet during this period.

Comments: 1 g of protein contains approximately 50–80 mg of leucine and is provided by low-protein foods (vegetables, fruits, specialized low-protein cereals, and starch-based products). The leucine conversion factor is presented in Appendix A3.5, Table No. 2. The physiological requirements for other amino acids and essential nutrients should be maintained to prevent their deficiency and support anabolism (Appendix A3.4) [9].

Protein required to achieve the recommended age-appropriate daily allowance must be supplied by leucine-free amino acid mixtures. The diet is calculated individually for each patient. Patients with recurrent symptoms and more frequent episodes of decompensation may require a stricter restriction of leucine intake. However, due to the specific role of leucine in stimulating protein synthesis, strict leucine restriction may lead to adverse effects such as loss of muscle mass, among others.

Protein intake should be evenly distributed throughout the day.

Appendix A3.7 presents a daily food assortment for preschool children with isovaleric acidemia.

• Following confirmed diagnosis, patients with IVA are recommended to compensate for protein deficiency using specialized leucine-free amino acid formulas to maintain nutritional status [31, 32, 39].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: in the first months of life, the sole source of natural protein is expressed breast milk or infant formula, with a protein content not exceeding 1.2–1.3 g/100 ml of reconstituted product. Expressed breast milk or formula is combined with the required amount of the specialized product diluted with boiled water or special infant drinking water, while the total feeding volume must correspond to the patient's age. The specialized product is added to each feeding.

The organization of diet therapy for children over one year of age has certain specifics. The total protein amount is calculated individually, taking into account the child's age and body weight in accordance with age-related nutritional requirements. Transitioning from the specialized amino acid formula for infants to a formula for older children is recommended to be gradual, over 1–2 weeks. The product is given in divided portions 3–4 times a day for younger children, and 2–3 times a day for older children. The fat content in the diet should be within at least 30–35% of the daily caloric intake. The main sources of fats are various vegetable oils and clarified butter. The carbohydrate component of the diet is compensated by vegetables, fruits, juices, sugar, and starch-containing products. The total amount of carbohydrates should provide 50–60% of the energy value of the daily diet.

The patient must be provided with an adequate fluid intake.

To avoid hypoglycemia, frequent small feedings are prescribed with an interval of no more than 2.5–3 hours during the day and no more than 4 hours at night.

The criteria for the effectiveness of diet therapy are positive dynamics of clinical symptoms, homeostasis parameters, and biochemical markers of metabolic disorders in blood and urine, specifically a decrease in blood leucine levels (normal range 50–160 µmol/L), a decrease in urinary 3-hydroxyisovaleric acid (normal <2 mmol per 1 mol of creatinine) and isovalerylglycine (normal <0.1 mmol per 1 mol of creatinine). Treatment efficacy should be monitored at least once every 6 months for children under one year of age, and at least once a year for older children [9].

Comments: physiological requirements for other amino acids and essential nutrients should be maintained to prevent their deficiency and support anabolism (Appendix A3.5) [9].

Specialized products currently registered in the Russian Federation and included in the List of Specialized Medical Nutrition Products for Disabled Children, in accordance with Order of the Government of the Russian Federation No. 3551-r dated December 11, 2023, are used

At the onset of treatment and during metabolic crises, for 24 to 48 hours (no more!), use only the specialized amino acid mixture (Appendix A3.6). Protein intake should be evenly distributed throughout the day.

Appendix A3.7 presents a daily food assortment for preschool children with isovaleric acidemia.

Comments: The main difference is the exclusion of high-protein complementary foods from the diet (meat, eggs, cottage cheese, fermented dairy products, etc.). Depending on the child's nutritional status and the functional state of their gastrointestinal tract, vegetable puree or commercially produced low-protein dairy-free porridges are chosen as the first complementary food.

3.1.2 Pharmacotherapy

Comments: To enhance the binding of leucine metabolites and eliminate carnitine deficiency, patients are prescribed high doses of #levocarnitine. Children of all ages receive #levocarnitine at a dosage of 100–200 mg/kg/day orally, in 2–4 doses, up to a maximum of 3 g/day [73]. Therapy is administered continuously. For adult patients, the dose of #levocarnitine is 20–100 mg/kg/day [27].

#Glycine** has the ability to form conjugates with isovaleric acid, producing isovalerylglycine. The recommended dose of #glycine** is 150–250 mg/kg per day orally. In older children, it can average 60 mg/kg of body weight over a prolonged period, preferably under the control of plasma glycine levels (target values 200–400 µmol)

For adult patients, the dose of #glycine** is 150–300 mg/kg/day, preferably under the control of plasma glycine levels (target values 200–400 µmol) [38]

Comment: intake of benzoic acid and its derivatives (food additive) and drugs of the ATC group N02BA - salicylic acid and its derivatives, which compete with isovaleryl-CoA for glycine conjugation, should be restricted.

Benzoic acid is found in many fruits and berries; therefore, increased consumption of these foods likely plays a role in the development of crises. Products containing benzoic acid (E210) and its derivatives (E209, E211-E219) as food additives (preservatives) should not be used [42, 43].

Comments: To avoid triggering epileptic seizures, drugs of the ATC group N06BX "Other psychostimulants and nootropics" should be used with caution.

3.2 Management 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 eliminating them from the body. Treatment tactics for children during a crisis include adjusting diet therapy, eliminating accumulating organic acids, correcting metabolic acidosis, hyperammonemia, and water-electrolyte imbalances, providing nutritional support, and reducing the intensity of catabolic processes [45].

3.2.1 Diet therapy during a metabolic crisis:

Comments: factors capable of triggering a metabolic crisis:

• dietary protein intake exceeding the patient's metabolic tolerance;

• malnutrition, low caloric intake;

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

• surgical interventions.

Comments: in the presence of regurgitation, vomiting, or refusal to eat, feeding should be administered via a nasogastric tube or gastrostomy (gastrostomy placement) [31]. Follow a frequent and fractional feeding schedule with intervals of 2–3 hours between feedings.

Comments: the energy value of food and administered fluid is increased by using dextrose** solutions and glucose polymer solutions (maltodextrin) (registered as a food additive) in addition to the amino acid-based formula; calculations are based on an energy value of 1 g of carbohydrates = 4 kcal, with 1 g of maltodextrin being equivalent to 1 g of carbohydrates.

Comments: proteins are introduced starting at 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 or infant formula; for infants in the second half of life, low-protein complementary foods are also used; for children over one year of age, low-protein natural foods (cereals, vegetables, fruits, vegetable oils) and specialized low-protein starch-based products are used;

3.2.2 Pharmacotherapy during a metabolic crisis:

Comments: during a metabolic crisis, the dose is generally increased 2-fold, most frequently up to 200 mg/kg/day. Intravenous administration of the drug is preferred. This may result in blood free carnitine levels rising above normal values, which is considered a favorable factor and does not constitute grounds for interrupting therapy.

Comments: during a metabolic crisis, the dose is generally increased 2-fold, most frequently up to 200 mg/kg/day.

High doses of glycine prevent/reduce the accumulation of isovaleric acid in the blood upon leucine intake, as well as the duration and severity of symptoms during intercurrent illnesses.

A dose-dependent increase in isovalerylglycine excretion was observed in patients; in at least one report, increasing the glycine dose from 300 to 600 mg/kg/day of body weight led to a decrease in isovalerylglycine excretion, presumably due to the inhibition of glycine N-acylase by glycine [60].

When using the specified dose of #glycine**, an elevation of its blood levels is also not a reason to discontinue the drug. The dose should be reduced if adverse effects occur, such as lethargy and ataxia caused by excessive glycine accumulation and decreased isovalerylglycine excretion due to the inhibition of glycine N-acylase.

Comments: to correct metabolic acidosis, Sodium bicarbonate** solutions (ATC code – B05XA), #Potassium chloride+Sodium bicarbonate+Sodium chloride are used. Sodium bicarbonate** is used as an 8.4% and 4.2% solution for convenience of conversion to mmol of NaHCO3. Its dosage (mmol) is determined by the formula: (-BE) x body weight (kg) x 0.3. In addition, patients are recommended to drink alkaline fluids – a baking soda solution at a ratio of ½-1 teaspoon per 200 ml of water, and alkaline mineral waters.

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

Comments: Compound sodium lactate solution [potassium chloride+calcium chloride+sodium chloride+sodium lactate]** or sodium chloride** 0.9% at a rate of 10 ml/kg (maximum up to 500 ml) [71] may be used, with periodic reassessment of the condition.

Comments: Intravenous administration of a 10% dextrose** solution (along with standard electrolyte solutions) at the following rates: newborns and children under 2 years, 8 mg/kg/min (5 ml/kg/h); children 2 to 4 years, 7 mg/kg/min (4.2 ml/kg/h); children 4–14 years, 6 mg/kg/min (3.5 ml/kg/h); patients over 14 years, 4 mg/kg/min (2.5 ml/kg/h) [71]. If blood glucose drops below 2.5 mmol/L, an intravenous bolus injection of at least 10% dextrose** at 2–3 ml/kg is required, followed by a continuous intravenous drip of 10% dextrose**.

To ensure adequate caloric intake and prevent excessive hydration and hemodilution, it is possible to administer parenteral nutrition solutions - lipids (lipid emulsions for parenteral nutrition**) up to 2 g/kg/day (0.4 ml/kg/h (2 g/kg/day) of a 20% solution for children 0–24 months; 0.3 ml/kg/h (1.5 g/kg/day) for children aged 2 years and older, and adults)

Emergency intravenous therapy should be initiated as early as possible in more severe conditions characterized by high fever, repeated vomiting, or severe gastroenteritis.

Intravenous infusion solutions containing 10% dextrose** (or higher) should be used even with normal blood glucose levels. If the patient develops significant hyperglycemia (e.g., blood glucose greater than 250 mg/dL) with glucosuria and signs of metabolic decompensation, the initiation of an insulin infusion (#soluble insulin (human genetically engineered)**) should be considered instead of reducing the dextrose infusion rate, to promote an anabolic state. The starting dose for #soluble insulin (human genetically engineered)** infusion is 0.01 IU/kg/min [45]. Insulin levels should be titrated to maintain blood glucose between 100 and 150 mg/dL.

It should be noted that an infusion of a more concentrated dextrose** solution (15–25%) at a lower infusion rate via a central catheter may be required in case of insufficient cardiac function. In addition, caution should be exercised when discontinuing intravenous infusion – the rate must be reduced slowly to avoid reactive hypoglycemia.

Comments:

drugs that promote ammonium elimination:

carglumic acid orally or via a nasogastric tube as a single dose of 100 mg/kg of body weight, followed by a gradual dose increase to up to 250 mg/kg/day (on average, 50 mg/kg every 6 hours) [71].

or, if carglumic acid cannot be used:

sodium benzoate (currently registered as a dietary supplement), orally at a rate of 250 mg/kg/day (maximum up to 6 g over 2 hours, then 250 mg/kg/24 hours (max. 12 g/24 hours)) [45, 69, 70, 71].

Depending on the severity of the condition, monitor blood ammonia levels every 6–12 hours.

Comments: during complex treatment, the levels of 3-hydroxyisovaleric acid and isovalerylglycine in urine are determined. The frequency of tests depends on the child's condition, but during infectious diseases and metabolic crises, amino acids and carnitines must be measured at least once every 7–10 days, and acid-base balance daily until parameters stabilize. Blood amino acid levels during treatment should be close to age-specific reference values. Glycine levels may be moderately elevated.

A decrease in hemoglobin, iron, total protein, albumin, and amino acid levels indicates inadequate nutritional support. Decreased free carnitine and glucose levels, a tendency toward lower blood pH, base deficit, and rising levels of isovalerylcarnitine in the blood, urinary excretion of 3-hydroxyisovaleric acid, isovalerylglycine, and 3-hydroxybutyric acid are unfavorable laboratory signs indicating the onset of a metabolic crisis.

Comments: monitoring of actual nutrition (chemical composition of the diet) to prevent deficiency states is performed in patients during a metabolic crisis – daily, in infants in the first year of life – at least once a month, and in patients older than 1 year – once every 3 months.

3.3 Other Treatment

Comments: The decision is made collectively by a medical board of specialist physicians.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comment: Parents/legal guardians/patients must be informed about the nature and severity of the disease and the consequences of non-compliance with medical prescriptions. Parents/legal guardians/patients must always carry an instruction sheet outlining emergency measures during the threat and development of a metabolic crisis.

5. Prevention and Dispensary Observation

5.1 Prevention

Neonatal screening is carried out in the Russian Federation.

Comment: The recurrence risk of having a child with IVA in a 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

Upon discharge from the hospital (for early-onset or neonatal forms presenting as a metabolic crisis), the child must undergo outpatient follow-up care by a pediatrician, neurologist, medical geneticist, and nutritionist. Patients with symptomatic epilepsy require monitoring by a neurologist. Consultations with other specialists are scheduled according to indications.

Comments: The frequency of analyses is determined by the child's condition. Typically, these tests are performed in patients with IVA at a frequency of: every 6 months for patients under 6 years old, and every 6–12 months for patients older than 6 years. However, during infectious diseases or when threatened with a metabolic crisis, testing must be done at least once every 7–10 days; the frequency of follow-up testing depends on age: more frequently in children under 1 year of age (monthly) and in early/preschool-aged children.

Comments: Blood isovalerylcarnitine levels and urinary excretion of organic acids (isovaleric acid, 3-hydroxyisovaleric acid, 4-hydroxyisovaleric acid, isovalerylglycine) are assessed based on individual indications depending on the clinical situation [31].

The frequency of testing is determined by the child's condition (on average, once a year).

Comment: tests are performed during follow-up monitoring; the frequency is determined individually, on average once every 6–12 months, and daily during a metabolic crisis.

• For patients with IVA, it is recommended to perform a complete blood count (CBC) with differential for comprehensive diagnosis of pancytopenia/neutropenia/thrombocytopenia [4, 26, 29].

Recommendations Grade CEvidence Level 4Recommendation validity score C (level of evidence – 4)

Comment: the test is performed at diagnosis and during follow-up monitoring; the frequency is determined individually, on average once every 12 months.

Comments: The frequency of analyses is determined by the child's condition. Typically, these studies are performed in patients with IVA with the following frequency: every 6 months for patients under 6 years of age, every 6–12 months for patients over 6 years of age. However, during infectious diseases or at risk of a metabolic crisis, at least once every 7–10 days.

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

• In the presence of clinical signs/complaints characteristic of cardiovascular system involvement, patients with IVA may be recommended electrocardiography (ECG) and echocardiography (EchoCG) to rule out/confirm cardiovascular pathology [36].

Recommendations Grade CEvidence Level 3Recommendation validity score C (level of evidence – 3)

Comment: in case of metabolic disorders involving the cardiovascular system, cardiomyopathy and cardiac arrhythmias may be observed. On average once a year.

• In patients with IVA, in the presence of clinical signs/complaints characteristic of pancreatic involvement, a comprehensive ultrasound examination of the abdominal cavity may be recommended to rule out/confirm pancreatic involvement [11, 12, 13].

Recommendations Grade CEvidence Level 4Recommendation validity score C (level of evidence – 4)

Comment: On average once a year.

• As clinically indicated (in the presence of clinical signs of optic atrophy / complaints of visual impairment), patients with IVA are recommended ophthalmoscopy to rule out / confirm / dynamically monitor optic atrophy [3, 37, 65].

Recommendations Grade CEvidence Level 4Recommendation validity score C (level of evidence – 4)

Comments:

All patients with IVA undergo initial and follow-up examinations (evaluations) by a pediatrician, general practitioner (family physician), or neonatologist during dynamic observation to assess the general condition, administer therapy, and participate in prescribing and implementing therapeutic and rehabilitation measures.

All patients with IVA undergo initial and follow-up examinations (evaluations, consultations) by a neurologist to clarify the severity of central nervous system involvement and determine the tactics of therapeutic and rehabilitation measures [3, 4, 5, 9, 15, 39].

All patients with IVA undergo initial and follow-up examinations (evaluations, consultations) by a nutritionist or geneticist to prescribe pathogenetic diet therapy and subsequently, if necessary, to adjust diet therapy and monitor compliance. On average, 1 time/month in the 1st year of life, then 1 time/3 months and as clinically indicated up to 3 years of age; 1 time every 6 months after 3 years of age [4, 9, 31, 39].

Patients with an established diagnosis of IVA undergo examinations (evaluations, consultations) by a geneticist — for families with relatives having IVA and for patients with IVA — for reproductive planning [9, 27, 37].

If visual organ pathology is suspected or present in the patient, initial and follow-up examinations (consultations) by an ophthalmologist are performed [3, 9, 37].

If cardiovascular system pathology is suspected or present in the patient, initial and follow-up examinations (consultations) by a cardiologist/pediatric cardiologist are performed [40].

To plan an individual rehabilitation program for psychological and pedagogical support, patients and their families undergo initial and follow-up evaluations (testing, consultations) by a medical psychologist and a speech and language pathologist (defectologist) [9, 39].

If necessary, other specialists participate in the diagnostic and treatment process, including an anesthesiologist-resuscitologist, gastroenterologist, and psychiatrist.

6. Organization of Medical Care

Neonatal and early-onset forms of IVA are diagnosed in the first year of life through selective screening performed in at-risk infants and upon the appearance of clinical symptoms [14].

Children with IVA are frequently admitted to the early childhood pathology department, infectious diseases department, or intensive care unit in a state of metabolic crisis developed against the background of metabolic acidosis, cerebral edema, and hypoglycemia.

The duration of hospitalization depends on the speed of diagnosis verification, correction of metabolic disorders through intensive therapy, and initiation of pathogenetic diet therapy, as well as the timing of positive dynamics from the central nervous system and other organs, the rate of recovery of blood glucose and acid-base balance parameters. Response to treatment is observed within 5–7 days. Hospital stay averages 21 days.

Indications for scheduled 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 conditions that may develop severe complications requiring emergency treatment, including intensive care, as well as 24-hour medical supervision and special diagnostic and therapeutic procedures.

Indications for discharging a patient from a medical organization:

1. absence of a threat to the patient's life and risk of complications requiring emergency treatment upon completion of diagnostic procedures.

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. completion of the patient's diagnostic and treatment plan, with recommendations provided for further follow-up and management.

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

7. Additional Information

The prognosis for the patient's condition and level of mental development depends on the severity of the disease and the timing of specialized therapy initiation. With early diagnosis (before 5 weeks of age), about 85% of patients show no intellectual impairment or neurological disorders at an older age, compared to about 45% with late diagnosis.

The prognosis for life is relatively favorable with early diagnosis and strict metabolic control.

Criteria for Evaluating the Quality of Medical Care

Table 1. Criteria for assessing the quality of primary health care in adults and children with isovaleric acidemia/aciduria

References

Appendix A1. Working Group Composition

1. Anisimova I.V. — PhD in Medicine, Head of the Department of Medical Care Organization, Medical Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

2. Baydakova G.V. — PhD in Biology, Head of the "Metabolom" Shared Research Facility, Leading Research Fellow at the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Russian Society of Medical Genetics.

3. Baranov A.A. — Academician of the RAS, Professor, DSc in Medicine; Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the Clinical Research Center №2, Petrovsky National Research Centre of Surgery, Professor at 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 freelance pediatric specialist of the Russian Ministry of Health.

4. Borovik T.E. — Professor, DSc in Medicine, Head of 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).

5. Bushueva T.V. — DSc in Medicine, Leading Research Fellow 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).

6. Vashakmadze N.D. — DSc in Medicine, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health of the Clinical Research Center №2, Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

7. Vishnyova E.A. — DSc in Medicine, Deputy Head for Research at the Research Institute of Pediatrics and Child Health of the Clinical Research Center №2, Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatrists of Russia.

8. Globa O.V. — PhD in Medicine, Neurologist-Epileptologist, Pediatrician, Leading Research Fellow at 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).

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

10. Zhurkova N.V. — PhD in Medicine, Leading Research Fellow at the Research Institute of Pediatrics and Child Health of the Clinical Research Center №2, Petrovsky National Research Centre of Surgery, Member of the Union of Pediatrists of Russia, Member of the Association of Medical Geneticists (AMG).

11. Zarubina V.V. — Medical Geneticist at the Medical Genetic Department of the Morozov Children's City Clinical Hospital, Moscow Healthcare Department.

12. Zakharova E.Yu. — DSc in Medicine, Head of the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Russian Society of Medical Genetics, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

13. Zvonkova N.G. — PhD in Medicine, Senior Research Fellow 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).

14. Karaseva M.S. — Pediatrician, Research Fellow at the Research Institute of Pediatrics and Child Health of the Clinical Research Center №2, Petrovsky National Research Centre of Surgery.

15. Kretov V.V. — Critical Care Physician at the Department of Anesthesiology and Intensive Care, National Medical Research Center for Children's Health of the Russian Ministry of Health.

16. Kuzenkova L.M. — DSc in Medicine, 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.

17. Kutsev S.I. — Academician of the RAS, DSc in Medicine, Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, President of the Association of Medical Geneticists (AMG).

18. Mikhaylova S.V. — DSc in Medicine, Head of Department at the Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University.

19. Nazarenko L.P. — Professor, DSc in Medicine, 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 RAS, Member of the Association of Medical Geneticists (AMG).

20. Namazova-Baranova L.S. — Academician of the RAS, Professor, DSc in Medicine, President of the Union of Pediatrists of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health of the Clinical Research Center №2, Petrovsky National Research Centre of Surgery, 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.

21. Nikolaeva E.A. — DSc in Medicine, Head of the Department of Clinical Genetics, Academician Yu.E. Veltischev Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University, Member of the Russian Society of Medical Genetics, Member of the Association of Medical Geneticists.

22. Pushkov A.A. — PhD in Biology, Leading Research Fellow at the 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.

23. Repina S.A. — PhD in Medicine, Medical Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Russian Society of Medical Genetics, Member of the Association of Medical Geneticists.

24. Savostyanov K.V. — DSc in Biology, Head of the Medical Genetic Center, Head of the Laboratory of Medical Genomics, National Medical Research Center for Children's Health of the Russian Ministry of Health, Professor at the Department of Pediatrics and Public Health, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists.

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

26. Selimzyanova L.R. — PhD in Medicine, Leading Research Fellow at the Research Institute of Pediatrics and Child Health of the Clinical Research Center №2, Petrovsky National Research Centre of Surgery, Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatrists of Russia.

27. Smirnova O.Ya. – Medical Geneticist, Senior Research Fellow at the Department of Standardization and Study of Evidence-Based Medicine Foundations, Research Institute of Pediatrics and Child Health of the Clinical Research Center №2, Petrovsky National Research Centre of Surgery, Member of the Union of Pediatrists of Russia, Member of the Association of Medical Geneticists.

28. Strokova T.V. — DSc in Medicine, Professor of the RAS, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietology, Clinic of the Federal Research Centre of Nutrition and Biotechnology

29. Subbotin D.M. — Medical Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

30. Tepayev R.F. — DSc in Medicine, Head of the Anesthesiology and Intensive Care Unit, National Medical Research Center for Children's Health of the Russian Ministry of Health.

31. Fisenko A.P. — DSc in Medicine, Professor, Honored Doctor of the Russian Federation, Director of the National Medical Research Center 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;

• neonatologists;

• general practitioners (internal medicine);

• general practitioners (family doctors);

• medical geneticists;

• dietitians;

• neurologists;

• anesthesiologists-intensivists;

• ophthalmologists;

• gastroenterologists;

• cardiologists;

• pediatric cardiologists;

• medical psychologists;

• medical speech therapists (defectologist-speech therapists);

• medical students, residents, postgraduate students.

Table 3. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 4. Scale for assessing levels of evidence (LE) for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 5. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based data regarding 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

Appendix A3.1 Documents and resources used in the preparation of clinical guidelines

1. Order of the Ministry of Health and Social Development of the Russian Federation No. 185 dated March 22, 2006 "On mass screening of newborns for hereditary diseases",

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

3. Order of the Russian Ministry of Health No. 274n dated April 21, 2022 "On approval of the Procedure for providing medical care to patients with congenital and (or) hereditary diseases"

4. State Register of Medicinal Products: https://grls.rosminzdrav.ru

5. Order of the Ministry of Health of the Russian Federation No. 1183n dated December 20, 2012 "On approval of the nomenclature of positions of medical and pharmaceutical workers".

6. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

7. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines."

8. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 "On approval of the nomenclature of medical services".

9. Order of the Ministry of Health of the Russian Federation No. 1094n dated November 24, 2021 "On approval of the Procedure for prescribing medicinal products, prescription forms for medicinal products, the Procedure for issuing said forms, their accounting and storage, forms of prescriptions containing appointments of narcotic drugs or psychotropic substances, the Procedure for their manufacture, distribution, registration, accounting and storage, as well as the Rules for issuing prescription forms, including in the form of electronic documents"

10. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017 "On approval of criteria for assessing the quality of medical care"

11. List of specialized medical nutrition products for disabled children for 2024, approved by Order of the Government of the Russian Federation No. 3551-r dated December 11, 2023. Order No. 500 dated June 14, 2016 "On organizing selective screening"

Appendix A3.2 Scheme of metabolic processes in isovaleric acidemia

Fig. 1 Scheme of the metabolic process in isovaleric acidemia. The metabolic block is highlighted in black.

Appendix A3.3 Indications for selective screening for inherited metabolic disorders by tandem mass spectrometry

Children under 18 years of age are referred for selective screening for inherited metabolic disorders upon identification of one of the main criteria (symptoms) or two or more additional criteria (symptoms) [14]:

Main criteria (symptoms):

1. Sudden deterioration of the child's clinical condition after a period of normal development (days, weeks, month):

• Acute metabolic encephalopathy,

• Lethargy (coma),

• Seizures resistant to antiepileptic therapy.

2. Hepatomegaly (hepatosplenomegaly)

3. Metabolic acidosis

4. Multiple fractures

5. Infant mortality in the family from diseases with similar symptoms.

Additional criteria (symptoms):

1. Cardiomyopathy

2. Hypoglycemia

3. Thrombocytopenia

4. Elevation of liver enzymes (ALT, AST) more than 1.5 times the upper limit of normal

5. Elevation of creatine phosphokinase (CPK) more than 2 times the upper limit of normal

6. Decrease in alkaline phosphatase (ALP) below the age norm

7. Metabolic alkalosis

8. Elevation of ketone bodies in blood and/or urine

9. Abnormal odor of urine, body, earwax, any unusual odor

10. Hair growth disorder, alopecia

11. Treatment-resistant seizures

12. Bone and joint anomalies (joint stiffness, chest deformity, rickets-like changes)

13. Hernias (umbilical, inguinoscrotal)

14. Frequent regurgitation, vomiting

15. Dystonia, hyperkinesia.

Appendix A3.4 Norms of physiological requirements for basic nutrients and energy for healthy children

Table 6. Average daily requirements for basic nutrients and energy for infants in the first year of life (per kg of body weight) [9]

Table 7. Norms of physiological requirements for basic nutrients and energy for healthy children over one year of age¹

¹ - for children with isovaleric acidemia older than one year, protein intake compared to that indicated in the table is reduced by 10-25% depending on the form of the disease, severity of the condition, and nutritional status of the child.

Table 8. Minimum safe protein level according to FAO/WHO/UNU 2007 by age

Table 9. Average daily physiological energy requirements for children according to FAO/WHO/UNU 2001 (WHO Technical Report Series 17-24okt 2001)

Appendix A3.5 Leucine and glycine requirements in patients with isovaleric acidemia by age

Table 10. Minimum requirement for leucine, glycine, and carnitine in patients with isovaleric acidemia by age¹ [9]

¹Dietary therapy in inherited amino acid metabolism disorders. Guidelines. Moscow 2013, 97 p.

Table 11. Leucine conversion factor

The calculation of the daily protein intake for infants is based on the protein intake standards for healthy children. For patients older than 1 year, the safe level of protein intake and the patient's tolerance to dietary protein should be used as a guide (see Appendix A3.4)

Appendix A3.6 Specialized amino acid-based products without leucine1

Table 12. Specialized dietary products

¹-products registered within the territory of the Customs Union member states.

Appendix A3.7 Sample daily diet for patients with isovaleric acidemia

Table 13. Approximate daily food set, its chemical composition and energy value for preschool children with isovaleric acidemia

The low-protein diet for adult patients consists of grains, specialized low-protein products, fruits and vegetables, a wide range of vegetable oils, and sweets.

At the same time, it is permitted to freely (without special calculations) consume fresh, frozen, or canned fruits and vegetables with a protein content of less than 1 g per 100 g. When including fruits or vegetables with a protein content of more than 1 g / 100 g in the diet, the amount of protein in them must be accounted for.

Appendix A3.8. Explanation of footnotes

** – the drug is included in the list of vital and essential drugs (Order 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", Order 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 medical device implanted into the human body when providing medical care within the framework of the state guarantees program for free medical care to citizens;

**** - 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 2024, approved by Order of the Government of the Russian Federation No. 3551-r dated December 11, 2023).

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What is isovaleric acidemia (aciduria)?

Isovaleric acidemia (aciduria) is an inherited amino acid metabolism disorder. It is caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD), which leads to the accumulation of isovaleryl-CoA derivatives.

How does isovaleric aciduria manifest?

Isovaleric aciduria can manifest at various ages, from infancy to childhood. In this disease, toxic substances accumulate, which affect the cells of the nervous system, pancreas, and heart muscle. The child may exhibit symptoms resembling poisoning (intoxication) such as frequent regurgitation, vomiting, refusal to eat, muscle weakness, lethargy, seizures, and increased drowsiness. Especially during periods of metabolic decompensation, a specific body and earwax odor resembling cheese or sweat is characteristic.

The most life-threatening conditions, leading in the absence of treatment to irreversible consequences up to death, are "metabolic crises". During these periods, the concentration of organic acids in the blood and ammonia increases, the acid-base balance of the blood changes, and energy metabolism is disrupted.

Crises are usually triggered by adverse factors such as diet violations, neglect of medical prescriptions, viral and bacterial infections, stressful situations, injuries, surgical procedures, and emotional and physical exertion.

The precursors of a crisis are a decrease in emotional tone, lethargy, drowsiness; then the child refuses to eat, vomiting may occur, body temperature may rise, especially at the onset of an infectious disease, and seizures are possible.

Emergency treatment is very important since there is a high risk of neurological complications.

How is isovaleric aciduria inherited?

Isovaleric aciduria 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, transmit two affected genes to the child. Most families with a child having this disease have not previously encountered such a problem. The recurrence risk of having a child with IVA in a family that already has children with this condition is 25% for each pregnancy.

Brothers and sisters of a child with IVA may also have this disease, even if they had no symptoms at the time of family screening. In this case, diagnostics must be performed to start therapy as early as possible and avoid complications. They can also be carriers, like their parents. As for 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 disease.

All families with [this condition] must undergo genetic counseling and receive complete information from a geneticist about 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 consultations operate in every region.

For the purpose of prenatal and preimplantation diagnostics, the couple must first undergo screening for carrier status of mutations in the IVD gene by contacting specialized diagnostic laboratories and medical centers. Prenatal diagnostics is carried out using molecular genetic methods by examining DNA extracted from chorionic villus sampling and/or amniotic fluid cells and/or fetal blood.

How is the diagnosis of isovaleric aciduria established?

Based on clinical symptoms, the doctor 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, while gas chromatography-mass spectrometry determines the level of urinary organic acids. In isovaleric aciduria, an increased blood concentration of isovalerylcarnitine (C5) is observed, often with an elevated C5/C2 ratio and sometimes glycine levels. In the urine, increased concentrations of isovaleric acid, 3-hydroxyisovaleric acid, and isovalerylglycine are detected. Patients with biochemical changes characteristic of isovaleric aciduria undergo molecular genetic testing to confirm the diagnosis by identifying a mutation in the IVD gene. Targeted gene panels are usually used for this purpose.

How are patients with isovaleric aciduria treated?

The main methods of treating isovaleric aciduria are diet therapy and the prescription of special medications that reduce the impact of toxic metabolites on the body and facilitate their excretion in the urine. Diet therapy consists of restricting the intake of protein and those amino acids whose metabolism is impaired. Specialized therapeutic formulas have been developed for feeding children of various ages. In isovaleric aciduria, patients must follow a diet consisting of low-leucine foods. The doctor will create a meal plan containing the required amount of protein, nutrients, and energy. This meal plan must be followed throughout life. A medical geneticist and a nutritionist will help calculate the diet, properly introduce complementary foods, and teach the basic rules of diet therapy.

Glycine and levocarnitine are also prescribed for isovaleric acidemia. Glycine is an amino acid that helps the body rid itself of isovaleric acid. This can help prevent metabolic crises.

Levocarnitine is a safe and natural substance that helps cells produce energy. It also helps the body get rid of isovaleric acid and other harmful substances.

Do not take any medications or supplements without consulting your doctor. It is extremely important to follow all medical recommendations to minimize the risk of developing metabolic crises.

How are patients treated during a metabolic crisis?

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

At home, at the very first signs of illness, especially when the child has a reduced appetite (e.g., 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 first signs of an approaching illness (paleness, drowsiness, irritability, loss of appetite, fever, headache, aches and generalized pain, cough, sore throat, or earache), as a precaution, the child should be given a drink of the solution once. 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 mild drowsiness, they can be given a glucose polymer solution orally in frequent, small portions (Table 14). 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 drinks sold in supermarkets, but the carbohydrate concentrations in such drinks are lower. Purchased drinks should be used with caution. Low-calorie and sugar-free drinks contain very few or no carbohydrates and therefore should not be used.

Upon the appearance of the first signs of a metabolic crisis, without waiting for the doctor to arrive, protein intake should be stopped (for 24, maximum 48 hours)!, the dose of oral #levocarnitine should be increased to 200 mg/kg/day, and the dose of glycine should be doubled.

Table 14. Volume of maltodextrin during the development of a metabolic crisis https://webgate.ec.europa.eu/chafea_pdb/assets/files/pdb/20101201/20101201d09-00_lft_gb_ps.pdf

Then, the child's clinical condition should be regularly assessed over the course of 1–2 hours.

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 is required for patients with isovaleric aciduria?

A multidisciplinary approach involving various specialists is necessary for the monitoring and treatment of patients with isovaleric aciduria to ensure comprehensive therapy and its timely adjustment when necessary. Regular examinations are required for patients with isovaleric aciduria. Table 15 provides an indicative list and frequency of examinations, but in each case, you should coordinate the examination plan with your attending physician.

Table 15. Frequency of examinations in isovaleric aciduria

How do patients receive treatment in the Russian Federation?

Isovaleric aciduria is a rare inherited metabolic disorder and is included in the list of rare (orphan) diseases, the treatment of which is funded from the regional budget. Following diagnosis, the patient must be enrolled in the regional segment of the registry for life-threatening rare (orphan) diseases in order to ensure continued provision of necessary medical nutrition and medications. Different specialists are responsible for managing the registry in different regions, but most often these are medical geneticists; therefore, after establishing a diagnosis, it is essential to contact the 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, dietary relapses must be prevented under any circumstances, and attention should be paid to rehabilitation and scheduled check-ups. All family members must know that the child requires a special diet, and close relatives should master the skills of dietary calculation.

Parents of a patient with isovaleric aciduria, and subsequently the patient themselves, must be trained in the rules for organizing therapy during the interictal period and during periods at risk 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.

Appendix B2. Example of an "emergency information card"

Emergency Card

Caution! The patient is at risk of 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;

- feeding difficulties, frequent regurgitation, vomiting;

- excessive sweating;

- changes in muscle tone.

- specific "cheesy" or "sweaty feet" body odor.

2. Indications for hospitalization:

- signs of decompensation;

- recurrent 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 intake to 120% of the normal requirement using specialized leucine-free amino acid-based formulas.

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

3.4. Ensure frequent small feeds throughout the 24-hour period.

3.5. If the patient is at home, increase carbohydrate intake to meet caloric needs using a dextrose** or maltodextrin solution (if unavailable — sweet compote, kissel).

Table 16. Correlation between child age and enteral dextrose dose in suspected metabolic crisis

[24]

The total volume is divided into 12 feeds 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 dextrose administration until the condition stabilizes, monitored by blood glucose, acid-base balance, and blood levels of leucine, valine, and isoleucine.

Upon resolution of metabolic decompensation symptoms and a decrease in leucine levels, reintroduce natural protein-containing foods: ¼ of the required daily volume on the first day, ½ on days 2–3, ¾ on days 3–4, and full volume thereafter.

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

Not recommended