Other disorders of branched-chain amino acid metabolism (Methylmalonic acidemia / aciduria): clinical guidelines

List of Abbreviations

DNA — deoxyribonucleic acid

CT — computed tomography

ABs — acid-base status

MRI — magnetic resonance imaging

MS/MS — tandem mass spectrometry

SLF — specialized medical nutrition

MMA — methylmalonic acidemia / aciduria

US — ultrasound

ALP — alkaline phosphatase

ECG — electrocardiography

EchoCG — echocardiography

EEG — electroencephalography

Terms and Definitions

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

Metabolic crisis — a critical, life-threatening condition triggered by adverse factors that cause enhanced cellular catabolism with the accumulation of toxic metabolites, manifesting as acutely onset encephalopathy, vomiting, and seizures.

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

Neonatal screening is a medical diagnostic technology of universal, population-wide laboratory screening of all newborns for certain diseases, designed to ensure timely detection and initiation of treatment in affected children to prevent disability.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Methylmalonic acidemia (aciduria) is a genetically heterogeneous group of inherited organic acidurias associated with impaired metabolism of methylmalonic acid and cobalamin (vitamin B12), accompanied by disturbed metabolism of certain amino acids (isoleucine, valine, threonine, methionine), odd-chain fatty acids, and cholesterol.

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

The classical form of the disease is caused by methylmalonyl-CoA mutase deficiency resulting from pathogenic variants in the MUT gene. The gene is mapped to 6p21. The disease is characterized by complete (mut0) or partial (mut-) absence of enzyme activity. This form is generally resistant to vitamin B12 therapy.

Forms of MMA associated with impaired vitamin B12 metabolism have been described: methylmalonic acidemia due to cblA-type adenosylcobalamin metabolism disorder resulting from variants in the MMAA gene (4q31.1-q31.2); methylmalonic acidemia due to cblB-type adenosylcobalamin metabolism disorder resulting from pathogenic variants in the MMAB gene (12q24) — these forms are responsive to vitamin B12 therapy; and methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency resulting from pathogenic variants in the MCEE gene (2p13.3), in which plasma vitamin B12 concentrations are within the normal range. An extremely rare form of methylmalonic aciduria is associated with transcobalamin receptor deficiency and pathogenic variants in the CD320 gene, mapped to 19p13.2.

Methylmalonic aciduria with homocystinuria includes three disease forms: cblF, caused by variants in the LMBRD1 gene; cblD, caused by variants in the MMADHC gene; and cblC, caused by variants in the MMACHC gene.

The inheritance pattern of MMA for all genetic variants is autosomal recessive.

The pathogenesis of the disease is associated with the accumulation of methylmalonic and propionic acid derivatives due to a metabolic block at the conversion step of methylmalonyl-CoA to succinyl-CoA. Propionate precursors in the body include the amino acids isoleucine, valine, threonine, and methionine (50% of total propionates), odd-chain fatty acids, and cholesterol (25%); the remaining propionates are produced in the gut by the activity of the endogenous flora. The accumulation of organic acids (propionic, methylmalonic, methylcitric, etc.) leads to severe metabolic ketoacidosis, secondary hyperammonemia, hyperglycinemia, and hypoglycemia. Elevated blood levels and high renal excretion of propionylcarnitine lead to the depletion of carnitine stores and its secondary deficiency. The scheme of metabolic disturbances observed in methylmalonic acidemia is presented in Appendix A3.1.

States associated with dietary vitamin B12 deficiency are also distinguished, in which elevated methylmalonic acid in blood and urine, as well as propionylcarnitine in dried blood spots, may be observed. Furthermore, maternal vitamin B12 deficiency can lead to biochemical abnormalities in newborns and cause positive newborn screening results.

1.3 Epidemiology of the Disease or Condition

The disease occurs in various populations. The incidence among newborns in European countries is 1:48,000 to 1:61,000; half of the cases are B12-resistant forms. In the Russian Federation, the incidence of the disease based on expanded newborn screening results for 2023 was 1:95,000 live births.

1.4 Features of Coding the Disease or Condition

ICD-10: Class IV (endocrine, nutritional and metabolic diseases), E71.1 — other disorders of branched-chain amino acid metabolism.

ICD-11: 5C50.E0

OMIM: 251000

ORPHAcode: 27

1.5 Classification of the disease or condition

Isolated MMA and MMA combined with homocystinuria are distinguished. Isolated MMA is subdivided into B12-resistant (about ½ of cases) and B12-dependent forms of methylmalonic aciduria. The B12-resistant form is characterized by earlier manifestation and a severe, fluctuating, and crisis-prone course, especially during intercurrent infections and stressful conditions.

According to the age of onset of initial symptoms, neonatal, infantile, and late-onset forms are distinguished.

1.6 Clinical presentation of the disease or condition

Clinical symptoms of MMA are nonspecific, and the disease can manifest at any age, either with acutely emerging symptoms or as an insidiously progressing chronic disorder (Table 1).

Table 1.

The classic neonatal form of MMA typically begins in the first week of life with acute metabolic decompensation manifesting as uncontrollable vomiting, dehydration, failure to thrive, temperature instability, neurological disorders—muscle hypotonia/hypertonia, irritability, epileptic seizures, and progressive lethargy progressing to coma. Sometimes in the neonatal period, patients with partial cblA or cblB deficiency present with clinical symptoms of isolated renal tubular acidosis or the development of chronic kidney disease [6, 9].

Laboratory tests reveal severe metabolic acidosis, hyperketonemia, hyperammonemia, and occasionally transient abnormalities such as thrombocytopenia, neutropenia, and anemia.

Despite early diagnosis of MMA and timely initiation of pathogenetic treatment, a high risk of mortality during metabolic crisis in the neonatal period remains (about 40%) [1, 10].

In the infantile form, the disease manifests as metabolic crises triggered by high-protein intake, acute respiratory viral infections, intestinal infections, and other factors that activate catabolic processes. Early signs of a metabolic crisis include lethargy, drowsiness or irritability, refusal to eat, and vomiting. Neurological disorders progress to sopor or coma, which can be fatal. The severity of the condition is primarily determined by pronounced metabolic ketoacidosis, hyperammonemia, and, in some cases, hypoglycemia. According to literature, the majority of patients with MMA exhibit physical and psychomotor developmental delay; frequent manifestations of MMA include extrapyramidal symptoms (chorea, tremor, tics, ballism, etc.) and stroke-like episodes. Intellectual impairment is generally observed in severe forms of MMA. Retrospectively, severe neurological disorders and an IQ below 80 are shown to occur in 50% of patients with mut 0, and in 25% of those with cblA/cblB deficiency [1]. Epilepsy syndrome develops in 50% of children: tonic-clonic seizures, absence seizures, and myoclonus. Dilated or hypertrophic cardiomyopathy and cardiac rhythm disturbances, such as a prolonged QT interval, are observed in 20–30% of patients. Acute pancreatitis, optic atrophy, and erythematous dermatitis have also been described. Children frequently suffer from acute respiratory viral infections and intestinal infections [1].

Late (adolescent and adult) form.

Older patients develop microcephaly, intellectual disability, pharmacoresistant symptomatic epilepsy, spastic tetraparesis, and extrapyramidal disorders. Intracranial hemorrhages may occur [1]. In some patients, neurological disorders progress with age [7]. The literature describes patients with MMA in whom neurological symptoms emerged during adolescence as progressive lower limb hyperkinesia and facial myoclonus, without associated cognitive impairment. A number of patients experience progressive vision loss up to blindness. Some patients present with hepatomegaly in the setting of normal liver enzymes; adults may develop acute hemorrhagic pancreatitis, particularly in the B12-resistant form. There are reports of renal function impairment resembling renal tubular acidosis with elevated uric acid levels, frequently leading to urate dysmetabolic nephropathy and renal failure. Tubulointerstitial nephritis has also been described in patients with this condition. Fungal skin infection serves as a marker of metabolic decompensation; it is believed that high levels of methylmalonates and other intermediate metabolites affect hematopoietic cell maturation, including a reduction in T-cell production. Osteoporosis is seen in many patients and frequently leads to fractures of the femoral head and tibia.

There are descriptions of healthy children born to mothers with MMA, proving the absence of teratogenic effects of methylmalonic acid.

Metabolic crisis

A serious complication of this disease is a metabolic crisis, which most frequently develops during acute intercurrent infections. Early clinical symptoms of a metabolic crisis include:

- repeated vomiting in 90% of cases;

- refusal to eat;

- depressed level of consciousness ranging from lethargy to coma.

The severity of the condition is primarily determined by pronounced metabolic ketoacidosis, hyperammonemia, and, in some cases, hypoglycemia.

Complications associated with metabolic crisis [14]:

- acute pancreatitis: serum amylase and lipase levels must be checked if there are any symptoms suggesting acute pancreatitis. These include vomiting, abdominal pain, and refusal to eat.

- stroke (especially involving the basal ganglia): any neurological deterioration in a patient with MMA experiencing a metabolic crisis must be addressed immediately, as the risk of stroke is higher in this patient population. Brain CT or MRI is performed in the presence of any neurological signs suggesting a stroke. Changes in the basal ganglia, particularly the globus pallidus, characterize MMA 'metabolic stroke'.

- renal failure: in patients with MMA, progressive renal failure may occur due to tubulointerstitial nephropathy. Renal function should be monitored in any patient with MMA during a metabolic crisis.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis of methylmalonic aciduria is based on pedigree analysis, medical history evaluation, and clinical manifestations.

The criteria for establishing the diagnosis of methylmalonic acidemia/aciduria are elevated levels of tiglylglycine, methylcitrate, 3-hydroxypropionic and methylmalonic acids in urine, elevated propionylcarnitine (C3) and/or C3/C2 ratio on dried blood spots, and molecular genetic test results demonstrating pathogenic variants in the MMUT, MMAA, MAB, MCEE, CD320, LMBRD, MMADHC, or MMACHC genes in a homozygous or compound heterozygous state. In some cases, the diagnosis can be confirmed based solely on biochemical changes if pathogenic variants are not identified using standard analysis methods. Such variants include large deletions, insertions, deep intronic variants, and alterations in gene regulatory regions.

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 (presence of a family member with MMA, cases of sudden unexplained death in infancy)

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

- feeding difficulties;

- frequent regurgitation/vomiting;

- lethargy, weakness, drowsiness;

- depressed level of consciousness;

- stroke-like episodes;

- seizures;

- agitated behavior, tearfulness;

- increased sweating;

- muscle hypotonia/muscle hypertonus;

- involuntary movements;

- acute/chronic renal failure.

The onset of clinical manifestations in childhood may be associated with the following factors:

- consumption of high-protein foods

- prolonged fasting, unjustified dietary restrictions, low caloric intake,

- intercurrent respiratory or gastrointestinal infections;

- vaccination^*;

- surgical interventions;

- physical or psychoemotional stress.

^* Infectious diseases are significantly more dangerous for patients with MMA than vaccination. Immunization is strictly indicated for patients with MMA; however, before vaccination, it should be ensured that the patient is in a compensated state and free of acute illnesses (see section 5.2). Patients in a decompensated state or undiagnosed patients represent a risk group for developing a metabolic crisis triggered by any factor [31, 54].

2.2 Physical Examination

During the physical examination, attention should be paid to the following main clinical manifestations:

Neonatal period

- regurgitation/vomiting, refusal to eat;

- growth retardation;

- motor developmental delay;

- lethargy, drowsiness;

- depressed level of consciousness;

- muscle hypotonia/muscle hypertonus;

- pyramidal signs (hyperreflexia);

- extrapyramidal disorders (various types of hyperkinesia, muscle dystonia);

- tremor;

- seizures;

children of early age

- episodic vomiting;

- delayed psychomotor and speech development;

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

- intermittent ataxia, tremor;

- seizures;

- stroke-like episodes;

- cardiomyopathy;

- cardiac arrhythmias,

- acute pancreatitis;

adults

- epileptic seizures;

- intellectual disability of varying severity;

- microcephaly;

- vision loss up to blindness;

- hepatomegaly;

- chronic kidney disease;

- osteoporosis;

- spontaneous fractures.

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

2.3 Laboratory Diagnostics

Please note that, in accordance with the requirements for developing clinical guidelines, each recommendation statement must be accompanied by its recommendation grade and evidence level based on the grading systems for the levels of evidence certainty (LEC) and recommendation credibility levels (RCL). For many statements, the RCL and LEC will be low due to the lack of high-design clinical studies addressing them. Despite this, they are essential elements of patient evaluation for establishing a diagnosis and selecting treatment strategies.

Comments: changes in amino acid and acylcarnitine concentrations are detected in dried blood spots: methylmalonic aciduria presents with an elevated propionylcarnitine (C3) concentration, low free carnitine (C0) levels, and an increased C3/C0 and C3/C2 ratio. In some cases, methylmalonylcarnitine (C4) may also be elevated. Blood levels of leucine, isoleucine, valine, and methionine in patients may remain within the normal range, which precludes confirming or excluding the disease based on amino acid analysis alone. Glycine levels are elevated in many patients; however, this is not specific and is observed in other inherited metabolic disorders.

During mass neonatal screening, if the C3 level exceeds 6.8 µmol/L or the C3/C2 ratio exceeds 0.22, the child is urgently recalled for a consultation with a geneticist. The geneticist assesses the child's clinical condition and decides whether there are indications for emergency hospitalization in an intensive care unit or neonatal pathology unit.

Comments: changes in amino acid and acylcarnitine concentrations are detected in dried blood spots: methylmalonic aciduria presents with an elevated propionylcarnitine (C3) concentration, low free carnitine (C0) levels, and an increased C3/C0 and C3/C2 ratio. In some cases, methylmalonylcarnitine (C4) may also be elevated. Blood levels of leucine, isoleucine, valine, and methionine in patients may remain within the normal range, which precludes confirming or excluding the disease based on amino acid analysis alone. Glycine levels are elevated in many patients; however, this is not specific and is observed in other inherited metabolic disorders.

During mass neonatal screening, if the C3 level exceeds 6.8 µmol/L or the C3/C2 ratio exceeds 0.22, the child is urgently recalled for a consultation with a geneticist. The geneticist assesses the child's clinical condition and decides whether there are indications for emergency hospitalization in an intensive care unit or neonatal pathology unit.

Comments: characteristic findings in MMA include elevated concentrations of methylmalonic, 3-hydroxypropionic, and methylcitric acids.

Comments: characteristic findings in MMA include elevated concentrations of methylmalonic, 3-hydroxypropionic, and methylcitric acids.

Comments: an elevated concentration of total homocysteine is characteristic of certain forms of MMA, which implies a specific therapeutic approach [11].

Comments: performed during initial diagnosis and follow-up monitoring, especially in patients with impaired renal function. Neutropenia may be detected.

Comments: laboratory precursors of a metabolic crisis include a tendency toward metabolic acidosis with base deficit, decreased free carnitine levels, elevated blood propionylcarnitine levels, and increased renal excretion of organic acids.

2.4 Instrumental Diagnostics

Comments: these studies are also performed for differential diagnosis with other hereditary diseases. Brain computed tomography (CT) may be performed. Brain CT/MRI in patients with MMA reveals cortico-subcortical atrophy, ventricular enlargement, delayed myelination, and increased signal intensity in the basal ganglia. It should be noted that these abnormalities are not highly specific and can be observed in mitochondrial diseases, propionic aciduria, and other disorders. General anesthesia is performed as indicated.

Comments: these tests are also necessary during a metabolic crisis. If necessary and indicated, Holter monitoring of heart rhythm and/or 24-hour ambulatory blood pressure monitoring should be performed (in accordance with the relevant clinical guidelines for cardiac arrhythmias and/or arterial hypertension).

Comments: intervals between visits should be determined individually, taking into account age, disease severity, metabolic stability, and adherence to diet therapy.

Comments: electroencephalography with video monitoring is also performed.

Comments: studies are performed depending on the clinical situation.

2.5 Other Procedures

2.5.1 Specialist Consultations and Monitoring

Comments: indicated are initial and follow-up consultations with a geneticist, ophthalmologist, neurologist, gastroenterologist, endocrinologist / pediatric endocrinologist, cardiologist, pediatric cardiologist, nephrologist, pediatrician / general practitioner / family physician, physical therapy physician, exercise therapy physician, as well as physicians of other specialties for patients with MMA who have impaired functions of the corresponding organs and systems.

Comments: intervals between visits should be determined individually, taking into account age, disease severity, metabolic stability, and adherence to diet therapy. The prescription, monitoring, and adjustment of diet therapy can be carried out by a dietitian, as well as a pediatrician / neonatologist / general practitioner / geneticist with experience in the treatment and diet therapy of inherited metabolic disorders

Comments: the onset of mental disorders is associated with toxic metabolites (psychoses, bipolar disorder, etc.); adjustment of diet therapy helps resolve symptoms of mental impairment. Intervals between visits should be determined individually, taking into account age, disease severity, metabolic stability, and adherence to diet therapy.

Comments: development of an individual program of defectological rehabilitation, development of an individual program of speech therapy rehabilitation. Patients need testing using approved methods to determine intellectual development. Psychological support for patients may require a course of sessions, depending on the individual characteristics of the patient and family.

Speech therapy services:

Medical and speech-language examination in dysphagia

Medical and speech-language examination in aphasia

Medical and speech-language examination in dysarthria

Medical and speech-language procedure in dysphagia

Medical and speech-language procedure in aphasia

Medical and speech-language procedure in dysarthria

Medical and speech-language tonal-rhythmic procedure

Medical and speech-language procedure using interactive information technologies

2.5.2 Differential Diagnosis

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

The treatment strategy for patients consists of reducing the formation of toxic metabolites, preventing the development of ketoacidosis, hyperammonemia, and toxic damage to brain tissues and internal organs while ensuring anabolic processes, normal growth, and nutritional status in children. The main components of complex treatment for patients are a low-protein diet and specialized products free of pathogenetically significant amino acids, and #levocarnitine preparations. Therapy is supplemented by the administration of vitamins (B group) (#cyanocobalamin**) and dietary supplements (hydroxocobalamin) [11, 17]. Antiepileptic drugs, symptomatic therapy, and correction of vitamin deficiency are prescribed as indicated.

3.1 Conservative Treatment

3.1.1 Diet Therapy

Comments: it is desirable that specialists have experience in the treatment and prescription of diet therapy for patients with inherited metabolic disorders; for the purpose of prescribing and monitoring the effectiveness of diet therapy, a consultation with a pediatrician / neonatologist / general practitioner is also possible, preferably with experience in the treatment and diet therapy of inherited metabolic disorders. Examples of diet calculations are given in Appendix A3.4.

Comments: an initial and follow-up consultation with a pediatrician and/or initial and follow-up consultation with a geneticist and/or initial and follow-up consultation with a neonatologist and/or initial and follow-up consultation with a dietitian is required. In the 1st year of life, monitoring the effectiveness of diet therapy is performed up to once a month, then up to once every 3 months, and after 3 years with a frequency of up to once every 6 months. Fluid intake must be monitored.

Comments: since the development of a metabolic crisis can lead to irreversible nervous system damage, if MMA is suspected, biomaterial should be collected for biochemical testing and the patient should then be switched to a low-protein diet. For infants in the first 6 months of life, breastfeeding or feeding with low-protein infant formulas (1.2–1.3 g/100 ml of reconstituted product). For children older than 6 months — exclusion of high-protein foods (meat, cottage cheese, fish) from the diet. Biochemical tests take 3–7 days, while 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: after confirmation of the diagnosis, dietary management tactics are based on the following principles:

- restriction of dietary intake of isoleucine, valine, threonine, and methionine to the minimum requirement; for infants in the first 6 months of life, this restriction applies to breast milk, infant formulas, or soy formulas; for infants in the second 6 months of life, a ban on introducing high-protein complementary foods (meat, fish, cottage cheese, eggs, dairy products, legumes, etc.); for patients over one year of age, strict restrictions on the use of high-protein foods

- ensuring physiological requirements for other amino acids and essential nutrients to prevent deficiencies and maintain anabolism;

- limiting the intake of odd-chain fatty acids and cholesterol;

- avoidance of fasting and prevention of catabolic processes;

Total protein in the therapeutic diet is calculated based on the child's age-specific requirements (Appendix A3.2), taking into account the patient's protein tolerance depending on the form and severity of the disease [4]:

- the natural food protein quota is prescribed taking into account the minimum requirement for pathogenetically significant amino acids — methionine, threonine, valine, isoleucine (Appendix A3.3);

- specialized amino acid-based products free of methionine, threonine, valine, and isoleucine are used to compensate for protein deficiency (Appendix A3.3, A3.4).

Consistent reference materials on the chemical composition of foods should be used (data may vary across different manuals) to prevent calculation errors.

- Appendix A3.5 presents a daily food allowance for preschool children with methylmalonic acidemia, as well as a table of restricted and permitted foods.

Comments: vegetable oils containing polyunsaturated fatty acids (rapeseed, linseed, olive, sunflower, etc.) are preferred as a fat source

3.1.2 Pharmacotherapy.

Comment: for this purpose, a short course (8–10 days) of #cyanocobalamin** at a dose of 1 mg/day is prescribed, monitored by methylmalonic acid excretion (measured in urine samples collected every other day for 8–10 days). A reduction of 50% or more from baseline levels indicates a B₁₂-responsive form of the disease. Patients with an established B₁₂-responsive form of MMA are prescribed long-term treatment with #cyanocobalamin**, with the dose selected individually based on clinical and biochemical parameters [1], for example, 30 mg every 2 or 4 weeks [29]. The use of active vitamin forms (registered in the Russian Federation as dietary supplements) — hydroxocobalamin (1–14 mg/week i.m.) is more effective [30].

Even in the case of the B₁₂-responsive form, patients are additionally prescribed dietary treatment with a moderate restriction of natural food protein, monitored by blood propionylcarnitine levels and methylmalonic acid excretion.

Comments: #levocarnitine is prescribed at 100–200 mg/kg/day divided into 2–4 doses; the dose is adjusted based on the clinical response and carnitine levels. Therapy is administered almost continuously. During a metabolic crisis and acute hyperammonemia, the dose may be increased to 300 mg/kg/day. However, the expert group suggests not exceeding a daily dose of #levocarnitine above 12 g for adults [1].

Comment: an elevated plasma ammonium level is considered to be greater than 150 µmol/L (>260 µg/dL) in newborns, and greater than 100 µmol/L (175 µg/dL) in older children and adults [40]. According to literature data, the ammonium level requiring the prescription of carglumic acid ranges from 142 ± 46.495 µmol/L. Carglumic acid is prescribed at a dosage of 100–250 mg/kg. A significant decrease in plasma ammonium levels with long-term carglumic acid treatment and a reduction in the number of hyperammonemic episodes requiring hospitalization have been demonstrated [41, 42, 43].

Experience with carglumic acid exists in a number of medical institutions, but the number of patients receiving this therapy is still limited, so further studies are required to gather evidence on the efficacy of this drug [44, 45].

3.1.3 Management of Patients During a Metabolic Crisis

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

Treatment measures are aimed at halting the formation and accumulation of toxic organic compounds and eliminating them from the body. Treatment tactics for children during a crisis include dietary management, elimination of accumulating organic acids, correction of metabolic acidosis, hyperammonemia, and water-electrolyte disturbances, energy support, and reduction of catabolism intensity [1, 2, 4].

Comments: if any factor capable of triggering a metabolic crisis is present, the initiation of infusion therapy must be considered.

Factors capable of triggering a metabolic crisis.

- dietary intake of proteins and fats exceeding the tolerance of the sick child's body;

- malnutrition, low caloric intake;

- intercurrent respiratory or gastrointestinal infectious diseases and other factors provoking catabolism;

- fever;

- anesthesia, surgical interventions.

Comments: in case of regurgitation, vomiting, refusal to eat – feeding via a nasogastric tube or gastrostomy (gastrostomy placement) [1]. Observe a frequent and fractional feeding regimen and avoid prolonged fasting.

Comments: the energy value of food and administered fluid is increased by using 5-10% dextrose**, glucose polymer solutions (maltodextrin) in addition to the amino acid-based formula; the calculation is based on the caloric value of 1 g of carbohydrates = 4 kcal, 1 g of maltodextrin is equated to 1 g of carbohydrates. Parenteral administration of carbohydrates (5-10% dextrose**), as well as lipids up to 1 g/kg/day, is possible; Table 2. Safe protein intake level and energy requirement in children of various ages with methylmalonic acidemia during a metabolic crisis¹

¹ - adapted from Matthias R Baumgartner et al. 2014 [1].

Comments: The source of natural protein for infants in the first six months of life 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 old, it includes low-protein natural foods (cereals, vegetables, fruits, vegetable oils) and specialized starch-based low-protein products [1].

Comments:

The amount of dextrose** solution should be determined in accordance with the total daily fluid intake appropriate for age.

Table 1. Fluid and dextrose** solution volume during the development of a metabolic crisis

Comments: #levocarnitine is administered as a bolus of at least 100 mg/kg of body weight, followed by a maintenance dose of 100 mg/kg/day. To increase efficacy, intravenous or intramuscular administration is preferred to maintain free carnitine levels in the blood above normal values. This ensures the detoxification function of carnitine, improving the binding and elimination of toxic propionic derivatives from the body. High doses may cause side effects such as nausea and an unpleasant odor (urine, breath, sweat). These phenomena resolve after dose reduction. During a metabolic crisis and acute hyperammonemia, the dose may be increased up to 300 mg/kg/day. However, the daily dose of #levocarnitine should not exceed 12 g in adult patients [1].

Comments: intravenous administration of dextrose** solution at the following rates: newborns and children under 1 year – 8-10 mg/kg/min, 1 to 3 years – 7-8 mg/kg/min, 4 to 6 years – 6-7 mg/kg/min, 7 to 12 years – 5-6 mg/kg/min, over 12 years – 4-5 mg/kg/min, adults – 3-4 mg/kg/min. If blood glucose drops below 2.5 mmol/L, an intravenous bolus injection of 10%-25% dextrose** at 2-3 ml/kg is required, followed by continuous intravenous infusion of 10% dextrose** at a rate of 7-9 mg/kg/min until blood glucose levels normalize. Administration of dextrose** not only replenishes tissue energy deficits, but also suppresses lipolysis and reduces the production of toxic fatty acid derivatives.

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

Solutions for intravenous infusion containing 10% dextrose** (or more) should be used even with normal blood glucose levels. If the patient develops significant hyperglycemia with glucosuria and signs of metabolic decompensation, the initiation of a drug from the group "short-acting insulins and analogues for injection" should be considered instead of reducing the dextrose** infusion rate, to promote an anabolic state. The level of the drug from the group "short-acting insulins and analogues for injection" should be titrated to maintain blood glucose at 5.5 - 8.3 mmol/L (100-150 mg/dL).

It should be noted that infusion of a more concentrated dextrose** solution (15-25%) at a lower infusion rate via a central catheter may be required if cardiac function is insufficient. In addition, caution should be exercised when discontinuing the intravenous infusion — the rate must be reduced slowly to avoid rebound hypoglycemia [28].

Comments: sodium bicarbonate** is used as an 8.4% and 4.2% solution for convenience in recalculating to mmol of sodium bicarbonate** (NaHCO₃). Its dosage (in mmol) for the 4.2% solution is determined by the formula: (-BE) × body weight (kg) × 0.3 [35].

In addition, patients require alkaline drinks — a soda solution at the rate of ½–1 teaspoon per 200 ml of water, and alkaline mineral waters. In cases of decompensated metabolic acidosis refractory to medical therapy, methods of extracorporeal correction of homeostasis are performed (e.g., continuous venovenous hemodiafiltration) (see section 3.3) [36]. Depending on the severity of the condition, blood acid-base balance parameters (study of blood buffer substances, hydrogen ion concentration [pH] level), blood sodium, potassium, and ionized calcium levels, as well as lactate (blood lactic acid level), ammonia, and blood glucose levels should be monitored on average every 6–12 hours to control the treatment.

Comments: Sodium benzoate (dietary supplement) is prescribed at a rate starting from 250 mg/kg per day (maximum up to 500 mg/kg/day; if body weight exceeds 20 kg, up to 5.5 g/m²/day). Blood ammonium levels must be monitored every 6–12 hours. Mandatory monitoring of blood sodium and potassium levels must be performed at least once every 2 hours. According to international guidelines for the treatment of hyperammonemia, intravenous administration of ammonia-scavenging agents is indicated, but currently these drugs are not registered in the Russian Federation.

Some sensitive patients with chronic hyperammonemia may also receive oral sodium benzoate therapy, with careful monitoring of amino acid and electrolyte levels. This protocol is not a standardized practice, but may be employed by a physician based on personal experience [46; 47].

Comment: N-carbamylglutamate allosterically activates carbamoyl phosphate synthetase I in the urea cycle, leading to a decrease in ammonium levels. The dosage selection of N-carbamylglutamate, which is available as an oral preparation, varies in the literature. In studies, the minimum effective dose was 12.5 mg/kg/day, and the maximum dose was 250 mg/kg (range 100–250 mg/kg) without any side effects. In persistent hyperammonemia, the prescription of sodium benzoate either as monotherapy or in combination with carglumic acid is possible [39].

3.2. Surgical treatment

Comments: indications for liver transplantation or combined liver and kidney transplantation are currently not strictly defined; however, severe metabolic decompensation and the inefficacy of ongoing metabolic therapy are most commonly cited in global practice. At the same time, MMA is the most common indication for liver transplantation in pediatric patients among inherited metabolic disorders. Liver transplantation has been recognized as a method of enzyme replacement therapy. Combined liver and kidney transplantation is generally performed in the presence of progressive renal function impairment and the development of chronic renal failure [22, 25-27].

Comments: infusion therapy in cases requiring prolonged fasting, using dextrose** solutions and solutions affecting the water-electrolyte balance, is administered at a rate of 8–10 mg/kg/min for infants in their first year of life, 6–7 mg/kg/min for children aged 1 to 10 years, 5–6 mg/kg/min for children over 10 years old, and 4–5 mg/kg/min for adults. A table outlining management tactics can be found in Appendix A3.7 [1].

Comment: as needed, replacement of the gastrostomy tube, gastrostomy closure, and care of the nasogastric tube are performed.

3.3 Other Treatment

Comments: peritoneal dialysis or hemodialysis are performed to achieve a more efficient elimination of toxic metabolites.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

Since January 1, 2023, expanded newborn screening has been carried out in the Russian Federation for the early diagnosis of a number of hereditary diseases, including methylmalonic aciduria.

5.1 Prevention

Comments: considering the autosomal recessive inheritance pattern of MMA, the risk of having a child with MMA is 25% for each pregnancy. To perform prenatal and preimplantation diagnostics, the married couple must first undergo testing for heterozygous carriage of pathogenic/likely pathogenic variants in the MUT, MMAA, MAB, MCEE, CD320, LMBRD, MMADHC, and MMACHC genes by contacting specialized diagnostic laboratories and medical centers. Prenatal diagnostics is performed using molecular genetic methods by examining DNA extracted from chorionic villus biopsy samples and/or amniotic fluid cells and/or fetal blood.

Comments: vaccination should be carried out against influenza and rotavirus infection among others, and with other vaccines if necessary, strictly adhering to the age restrictions of immunobiological preparations alongside rigorous compliance with dietary and therapeutic prescriptions. It is advisable to conduct vaccination under the supervision of specialists experienced in working with patients with metabolic disorders. In the post-vaccination period, vaccinated individuals should be closely monitored with repeated measurement of body temperature, which is necessary for the prompt prescription of antipyretic therapy if a fever >38.0°C is diagnosed.

5.2 Dispensary monitoring

Comments: a comprehensive complete blood count should be monitored at least once a year. Blood levels of methionine, threonine, valine, and isoleucine as a result of treatment should be close to age-related reference values. It is especially important to ensure normal serum levels of branched-chain amino acids. Thus, insufficient protein intake and isoleucine deficiency cause severe acrodermatitis and serve as an indication for additional supplementation of L-isoleucine in the diet at a dose of 50-100 mg/day (foods containing isoleucine at a dosage of 50-100 mg per day) depending on the degree of deficiency. Blood glycine levels may be moderately elevated.

Comments: The frequency of tests depends on the patient's condition. Quantitative determination of amino acids in the blood (comprehensive determination of amino acid and acylcarnitine concentrations in the blood, comprehensive determination of amino acid and acylcarnitine concentrations in the blood by tandem mass spectrometry) — in a stable condition — every 3–6 months. During infectious diseases and metabolic crises, the determination of amino acids and carnitines in the blood (comprehensive determination of amino acid and acylcarnitine concentrations in the blood, comprehensive determination of amino acid and acylcarnitine concentrations in the blood by tandem mass spectrometry) is carried out at least once every 7–10 days, and acid-base balance (blood hydrogen ion (pH) level testing, blood buffer substance testing) — daily until parameters stabilize.

Comments: tests are performed annually

Comments: the test is performed annually.

Comments: the test is performed at least once every 6 months.

Comments: creatinine clearance (glomerular filtration rate) should be calculated by a formula based on serum creatinine and height variable using the "bedside" Schwartz formula (2009) and the Schwartz-Lyon formula (2012). Upon reaching stage 3-4 chronic kidney disease, further treatment of the patient should be discussed with the involvement of a pediatric surgeon (specializing in transplantology) (see clinical guidelines "Chronic kidney disease" (pediatric age group)).

Comments: monitoring of actual nutrition (chemical composition of the diet) to prevent deficiency states is carried out in children in the ICU period — daily, in infants in the first year of life — at least once every 7–10 days, in patients older than 1 year — once every 1–3 months.

Comments: if necessary, when there are indications for the study — Holter ECG monitoring and/or 24-hour ambulatory blood pressure monitoring (according to the relevant clinical guidelines for cardiac arrhythmias and/or arterial hypertension).

Comments: the frequency of examinations is determined individually.

Comments: these studies are also performed for differential diagnosis with other hereditary diseases. Brain computed tomography (CT) may be performed. Brain CT/MRI in patients with MMA reveals cortico-subcortical atrophy, ventricular enlargement, delayed myelination, and increased signal intensity in the basal ganglia. It should be noted that these abnormalities are not highly specific and can be observed in mitochondrial diseases, propionic aciduria, and other disorders. General anesthesia is performed as indicated.

Comments: electroencephalography with video monitoring is also performed.

Comments: studies are performed depending on the clinical situation.

Comments: if necessary, it is possible to perform ophthalmoscopy, visometry, refractometry, computer perimetry, ophthalmotonometry, color vision testing, electrophysiological testing (recording of visual evoked potentials of the cerebral cortex), fundus biomicrophotography using a fundus camera, fundus biomicroscopy, optical examination of the optic nerve head and nerve fiber layer using a computer analyzer, etc.). Intervals between visits should be determined individually, taking into account age, severity of the disease, metabolic stability, and adherence to dietary therapy.

Comments: intervals between visits should be determined individually, taking into account age, severity of the disease, metabolic stability, and adherence to dietary therapy, but at least once a year.

Comments: patients are monitored, including after discharge from the hospital, by a pediatrician, general practitioner, family physician, geneticist, neurologist, nutritionist, trauma surgeon/orthopedist, endocrinologist/pediatric endocrinologist, cardiologist/pediatric cardiologist, ophthalmologist, otolaryngologist-audiologist, dentist/pediatric dentist, gastroenterologist, allergist-immunologist, hematologist/pediatric hematologist, nephrologist, pediatric surgeon (specializing in transplantology), psychiatrist/pediatric psychiatrist, rehabilitation specialist, medical psychologist, speech-language pathologist-defectologist, and others.

Annually, patients with MMA must undergo an advanced health check-up (dispensary evaluation) and necessary rehabilitation measures (Appendix A3.6).

Parents must be trained in the rules of organizing therapy during the interictal period and during the threat of a metabolic crisis. The child must always carry an information card indicating emergency measures during the onset of a metabolic crisis (Appendix A3.8).

6. Organization of Medical Care

When providing medical care to patients with MMA, it is necessary to use a multidisciplinary approach, which is necessitated both by the severity of the condition and the involvement of various organs and systems.

Patients with MMA may be provided with any type, condition, and form of medical care provided for by the legislation of the Russian Federation, as appropriate.

Management of patients with MMA is preferably carried out in specialized centers. Hospital-substituting technologies should be used whenever possible.

Monitoring and hospitalization of patients in a multidisciplinary medical organization must be provided.

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 urgent/emergency hospitalization to 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 the risk of complications requiring emergency treatment upon completion of diagnostic procedures.

2. Stabilization of the condition and basic clinical and laboratory parameters of the pathological process, absence of the need for prolonged medical observation (day or round-the-clock stay);

3. The patient's examination and treatment plan has been completed, and recommendations for further monitoring and treatment have been given.

4. The need to transfer the patient to another medical organization or social welfare institution.

6.2 Principles of organizing medical care for patients with MMA

Making a diagnosis of MMA raises many questions for the patient's relatives and for specialists working with such patients. Numerous problems arising upon the detection and progression of the disease require the organization of the medical care process with the participation of a multidisciplinary team of specialists.

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 therapy methods.

2) A diagnosis of MMA implies the possibility of providing primary, specialized, and palliative care at all stages of the disease.

3) Upon diagnosing MMA, it is recommended to refer the family to specialists with experience working with MMA patients who possess up-to-date information on the disease course and the possibility of participating in clinical trials (of new drugs and/or medical devices). In case of remoteness, consultation can be carried out using telemedicine technologies.

4) It is also important to inform families about existing public organizations working with this patient group.

5) A multidisciplinary team of specialists must be involved in monitoring the MMA patient, consisting of: a pediatrician, general practitioner, family physician, geneticist, neurologist, nutritionist, trauma surgeon/orthopedist, endocrinologist/pediatric endocrinologist, cardiologist/pediatric cardiologist, ophthalmologist, otolaryngologist-audiologist, dentist/pediatric dentist, gastroenterologist, allergist-immunologist, hematologist/pediatric hematologist, psychiatrist, rehabilitation specialist, medical psychologist, speech-language pathologist-defectologist, and others. Other specialists should be involved as specific problems arise.

Comments: the duties of a geneticist include examination and diagnosis making, informing the family about the disease, drawing up a multidisciplinary monitoring plan, patient observation, assessing the dynamics and degree of disease progression during regular examinations, prescribing pathogenetic treatment, monitoring its effectiveness and safety, and genetic counseling of the family when planning childbearing in order to prevent the birth of a child with the disease, taking into account the burdened medical history.

7. Additional Information

The prognosis of the patient's condition and mental development level depends on the severity of the disease, the presence of stroke-like episodes, the involvement of internal organs in the pathological process (kidneys, heart, pancreas), as well as the timing of the initiation of specialized therapy and the quality of treatment capable of preventing episodes of metabolic decompensation.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Inga V. Anisimova — PhD in Medical Sciences, Head of the Department of Medical Care Organization, Medical Geneticist at the Research Centre for Medical Genetics (Bochkov Research Centre), Member of the Association of Medical Geneticists

Baguaeva Madlena Enverovna — MD, PhD, Senior Research Fellow of the Department of Pediatric Gastroenterology, Hepatology and Dietetics, Clinic of the Federal Research Center of Nutrition, Biotechnology and Food Safety

Galina V. Baidakova — PhD in Biological Sciences, Leading Researcher at the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics (Bochkov Research Centre), Member of the Russian Society of Medical Geneticists.

Alexander A. Baranov — Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health; Chief freelance pediatric specialist of the Russian Ministry of Health

Tatyana E. Borovik — Doctor of Medical Sciences, Professor, 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, Member of the Scientific and Educational Society "Children's Health Association".

Tatyana V. Bushuyeva — Doctor of Medical Sciences, Chief 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, Member of the Scientific and Educational Society "Children's Health Association".

Nato D. Vashakmadze — Doctor of Medical Sciences, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, 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.

Elena A. Vishnyova — Doctor of Medical Sciences, Professor of the RAS, Deputy Head for Research at the Research Institute of Pediatrics and Child Health, 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

Oksana V. Globa — PhD in Medical Sciences, Neurologist at the National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists.

Anna V. Degtyareva — Doctor of Medical Sciences, Professor, Highest Category Physician, Head of the Pediatrics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatalogy

Natalia V. Zhurkova — PhD in Medical Sciences, Leading Researcher at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Member of the Union of Pediatrists of Russia, Member of the Association of Medical Geneticists (AMG)

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

Ekaterina Yu. Zakharova — Doctor of Medical Sciences, Head of the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics (Bochkov Research Centre), Member of the Russian Society of Medical Geneticists, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

Nina A. Krasnoshchekova — Head of the Department of Hereditary Metabolic Disorders, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department

Tatyana N. Kekeeva — Head of the Medical Genetic Department, Medical Geneticist at the Morozov Children's City Clinical Hospital of the Moscow Healthcare Department

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

Lyudmila M. Kuzenkova — Doctor of Medical Sciences, 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.

Sergey I. Kutsev — Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Director of the Research Centre for Medical Genetics (Bochkov Research Centre), President of the Association of Medical Geneticists (AMG).

Alla E. Lavrova — Doctor of Medical Sciences, Director of the Institute of Pediatrics, Head of Pediatric Department No. 2, University Clinic of the Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation, Excellence in Healthcare awardee

Tea V. Margieva — PhD in Medical Sciences, Chief Specialist at the Methodological Center for Accreditation of Specialists, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health, Nephrologist, Member of the Union of Pediatrists of Russia

Svetlana V. Mikhailova — Doctor of Medical Sciences, Head of Department at the Russian Children's Clinical Hospital of the Ministry of Health of the Russian Federation.

Lyudmila P. Nazarenko — Professor, Doctor of Medical Sciences, 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).

Leyla S. Namazova-Baranova — Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Union of Pediatrists of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health, 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

Ekaterina A. Nikolaeva — Doctor of Medical Sciences, Head of the Department of Clinical Genetics, Veltischev Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University, Member of the Russian Society of Medical Geneticists, Member of the Association of Medical Geneticists

Natalia L. Pechatnikova — Medical Geneticist at the Department of Hereditary Metabolic Disorders, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department, Neurologist

Alexander A. Pushkov — PhD in Medical Sciences, Leading Researcher at the Laboratory of Molecular Genetics and Medical Genomics, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists.

Svetlana A. Repina — PhD in Medical Sciences, 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.

Kirill V. Savostyanov — Doctor of Biological Sciences, Head of the Center for Fundamental Research in Pediatrics, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists.

Liliya R. Selimzyanova — PhD in Medical Sciences, Head of Department at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health; Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Pulmonologist, Member of the Union of Pediatrists of Russia

Olga Ya. Smirnova — Medical Geneticist, Senior Researcher at the Department of Standardization and Study of Evidence-Based Medicine Foundations, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Member of the Union of Pediatrists of Russia, Member of the Association of Medical Geneticists

Tatyana V. Strokova — Doctor of Medical Sciences, Professor of the RAS, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietology, Clinic of the Federal Research Centre of Nutrition and Biotechnology

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

Natella V. Sukhanova — Researcher (Laboratory of Genetic Epidemiology), Ophthalmologist (Consultative Department) at the Research Centre for Medical Genetics (Bochkov Research Centre), Ophthalmologist, Member of the Association of Pediatric Ophthalmologists of the Russian Federation, Member of the Union of Pediatrists of Russia

Rustem F. Tepayev — Doctor of Medical Sciences, Head of the Anesthesiology and Intensive Care Service, Bashlyeva Children's City Clinical Hospital of the Moscow Healthcare Department; Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health

Andrey P. Fisenko — Doctor of Medical Sciences, Professor, Honored Doctor of the Russian Federation, Director of the National Medical Research Center for Children's Health of the Russian Ministry of Health, Chairman of the Scientific and Educational Society "Children's Health Association"

Representatives of patient advocacy organizations:

Raisa Panfilova — Representative of the methylmalonic aciduria patient community

Stanislav V. Nikitin — Representative of the methylmalonic aciduria patient community

Marina V. Nikitina — Representative of the methylmalonic aciduria patient community

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

Appendix A2. Methodology for Developing Clinical Guidelines

These guidelines are intended for use by medical organizations and institutions of federal, territorial, and municipal healthcare management systems, compulsory and voluntary medical insurance systems, and other medical organizations of various legal forms engaged in the provision of medical care.

These guidelines establish the types, scope, and quality indicators of medical care for patients with methylmalonic acidemia.

The clinical guidelines are based on a literature review of Medline (PubMed version), Embase (Dialog version), Cochrane Library databases, Orphanet, and OMIM, as well as international clinical guidelines for the diagnosis, treatment, and management of patients with metabolic diseases.

Internet data presented on international and national websites of rare disease societies and public organizations were used.

The evaluation of the recommendation grading and the level of evidence for the use of medical technologies was carried out in accordance with the standardized scale presented in Tables 1–3.

Target audience for these clinical guidelines:

• Pediatricians;

• general practitioners (family doctors);

• general practitioners (internal medicine);

• medical geneticists;

• dietitians;

• gastroenterologists;

• allergists-immunologists;

• endocrinologists/pediatric endocrinologists;

• neurologists;

• psychiatrists;

• cardiologists/pediatric cardiologists;

• dentists/pediatric dentists;

• anesthesiologists-intensivists;

• neonatologists;

• nephrologists;

• urologists/pediatric urologists-andrologists;

• laboratory geneticists;

• medical psychologists;

• medical school 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, rehabilitation interventions)

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

Procedure for updating clinical guidelines.

The mechanism for updating the 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 regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to the previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

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 dated April 16, 2012, No. 366n, "On approval of the Procedure for Pediatric Care Delivery"

3. Order of the Ministry of Health of the Russian Federation dated April 21, 2022, No. 274n, "On approval of the Procedure for Medical Care Delivery to Patients with Congenital and/or Hereditary Diseases"

4. 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"

5. 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"

6. Order of the Government of the Russian Federation dated December 31, 2018, No. 3053-r, "On approval of the lists of medical devices implantable into the human body during the provision of medical care within the framework of the state guarantee program for free medical care to citizens and dispensed by prescription for medical devices upon the provision of a set of social services"

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

8. Order of the Ministry of Health of the Russian Federation dated May 2, 2023, No. 205n, "On approval of the nomenclature of positions of medical workers and pharmaceutical workers"

9. 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."

10. 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 'The Fundamentals of Healthcare Protection in the Russian Federation' regarding Clinical Guidelines."

11. 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".

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

13. Order of the Ministry of Labor and Social Protection of the Russian Federation dated August 27, 2019, No. 585n, "On classifications and criteria used in medical and social evaluation of citizens by federal state institutions of medical and social evaluation"

14. Order of the Ministry of Health and Social Development of the Russian Federation dated August 9, 2005, No. 494, "On the procedure for the use of medicinal products in patients for vital indications"

15. List of specialized medical nutrition products for disabled children for 2024, Order of the Government of the Russian Federation dated December 11, 2023, No. 3551-r

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

Main regulatory legal acts governing the provision of palliative medical care

1. Federal Law No. 18-FZ dated March 6, 2019, "On amendments to the Federal Law 'The Fundamentals of Healthcare Protection in the Russian Federation' regarding the provision of palliative care"

2. Order of the Ministry of Health of Russia No. 345n and Ministry of Labor of Russia No. 372n dated May 31, 2019, "On approval of the regulation on the organization of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations, other non-profit organizations operating in the field of health protection"

3. Order of the Ministry of Health of Russia No. 348n dated May 31, 2019, "On approval of the list of medical devices intended to support human body organs and systems, provided for home use"

4. Order of the Ministry of Health of Russia No. 505n dated July 10, 2019, "On approval of the Procedure for the Transfer of Medical Devices Intended to Support Human Body Organs and Systems from a Medical Organization to a Patient (their legal representative) for Home Use in the Provision of Palliative Medical Care"

Appendix A3.1. Diagram of metabolic processes in methylmalonic acidemia.

Metabolic blocks are highlighted in light blue (1-propionic, 2-methylmalonic acidemia), and pathological metabolites are highlighted with a double border.

Appendix A3.2. Physiological requirements for basic nutrients and energy in healthy children.

Table 1. Minimum safe protein level according to FAO/WHO/UNU 2007 by age (safe protein intake levels, age-adjusted mean + 2 SD) [1].

Table 2. Recommended macronutrient requirements in patients with PA and MMA [37].

Comments:

1. the recommended amount of natural protein is 60-100% of the RDA (Recommended Dietary Allowance) and AI (Adequate Intake).

2. protein requirement is calculated individually for each patient based on protein tolerance, anthropometric parameters, and laboratory test results.

3. if natural protein tolerance is less than 100% of AI/RDA, it is recommended to add amino acid-based specialized medical nutrition products free of methionine, threonine, valine, and isoleucine to ensure a minimum of 100-120% of AI/RDA.

4. the recommended energy value of the diet is 80-120% of DRI EER (Estimated Energy Requirement) calculated for the ideal body weight.

Table No. 3 Average daily physiological energy requirements for children according to FAO/WHO/UNU 2001 (WHO Technical Report Series 17-24 Oct 2001)

Appendix A3.3. Methionine, threonine, valine, and isoleucine requirements in patients with methylmalonic acidemia by age.

Table 1 Approximate requirement for methionine, threonine, valine, and isoleucine in patients with methylmalonic aciduria by age.

Table 2 Specialized amino acid-based products free of methionine, threonine, valine, and isoleucine (per 100 g of dry powder).

Appendix A3.4. Examples of diet calculations for patients upon initiation of dietary therapy.

I Example of diet calculation for a 1-month-old female infant. Weight 4000 g. Breastfeeding + amino acid-based specialized medical nutrition product free of methionine, threonine, valine, and isoleucine "MMA/PA Anamix Infant" or specialized medical nutrition product "Nutrigen 14 -tre, -met, -val, -ile"

1) calculating the basic protein requirement:

- Total protein 1.82 g/kg/day = 1.82 x 4 = 7.28 g*

- Natural protein 1.2 g/kg/day = 1.2 x 4 = 4.8 g

2) Calculating the amount of breast milk:

100 ml contains 1.2 g of protein

X - 4.8 g, hence X = 4.8 x 100 / 1.2 = 400 ml

3) Calculating the amount of protein the child should receive from the amino acid-based specialized medical nutrition product free of methionine, threonine, valine, and isoleucine: 7.28 - 4.8 = 2.48 g of protein

4) Calculating the amount of specialized medical nutrition product the child should receive:

A) Calculate the amount of formula if 100 g of dry formula contains 13.1 g of protein (protein equivalent).

100 g – 13.1 g of protein

X – 2.48 g, hence X = 2.48 × 100 / 13.1 = 18.9 g (19 g) of dry formula.

B) Calculate the amount of formula if 100 g of dry formula contains 14 g of protein (protein equivalent)

100 g – 14 g of protein

X – 2.48 g, hence X = 2.48 × 100 / 14 = 17.7 g (18 g) of dry formula.

Given that in infants it is advisable to use amino acid-based formula (AAF) at every feeding, with an interval of at least 3 hours between feedings, we distribute it across 8 feeds: 19 : 8 = 2.4 g (2.3 g) × 8 times a day.

C) Reconstituting the dry formula:

If 5 g of dry formula is diluted in 30 ml – dilute 2.4 g (2.3 g) in 15 ml of water.

4) Calculate the volume and number of feedings.

If the infant is fed 8 times a day, this results in:

50 ml of breast milk + 2.5 g of AAF reconstituted in 15 ml of water

5) Check the energetic value of the diet:

100 ml of breast milk contains 70 kcal, therefore 400 ml contains 280 kcal

100 g of dry formula (AAF) contains 469 kcal, therefore 19 g contains 89 kcal

280 + 89 = 369 kcal = 91 kcal/kg

5) Replenish the caloric deficit**, target energetic value of the diet is 107 kcal/kg:

A) Calculate the demand for additional calories:

107 - 91 = 16 kcal

B) Calculate the amount of 10% dextrose:

10 ml of 10% dextrose contains 4 kcal

X – 14 kcal, hence X = 16 × 10 / 4 = 40 ml of 10% dextrose per day, divided into 8 feedings, yielding 5 ml of 10% dextrose per feeding.

*Protein requirements are calculated individually for each patient depending on protein tolerance, anthropometric parameters, and laboratory test results. In a stable condition without hyperammonemia, total protein may be increased via AAF devoid of methionine, threonine, valine, and isoleucine.

**In case of caloric deficit and the impossibility of adding a greater amount of AAF devoid of methionine, threonine, valine, and isoleucine (e.g., in hyperammonemia), dextrose solutions, maltodextrin, and protein-free milk substitutes are used to achieve the optimal energetic value of the diet.

II Example of calculating nutrition for a 3-year-old child, body weight 15 kg, using amino acid-based formula devoid of methionine, threonine, valine, and isoleucine «Nutrigen 40

-tre, -met, -val, -ile». The calculation is performed in accordance with the principles outlined above. The ratio of proteins : fats : carbohydrates from the total energetic value of the diet should aim for 10:30:60.

1) Calculate the baseline protein requirement:

- Total protein: 1.26 g/kg/day = 1.26 × 15 = 18.9 g*

2) Calculate natural protein:

0.85 g/kg/day = 0.85 × 15 = 12.75 g

3) Calculate the amount of AAF devoid of methionine, threonine, valine, and isoleucine (if 100 g of dry formula contains 40 g of protein).

A) Calculate how much protein the child should receive from AAF: 18.9 - 12.75 = 6.15 g of protein

B) Calculate the amount of formula:

100 g – 40 g of protein

X – 6.15 g, hence X = 6.15 × 100 / 40 = 15 g of dry formula.

4) Calculate the energetic value of the diet:

66–99 kcal/kg/day = 990–1485 kcal/day.

Based on these calculations, the following meal plan can be proposed:

*In a stable condition, without hyperammonemia, total protein may be increased via AAF devoid of methionine, threonine, valine, and isoleucine.

Appendix A3.5. Sample daily food basket, its chemical composition and energetic value for preschool children with methylmalonic acidemia.

Permitted and restricted foods in MMA ("food traffic light")

Appendix A3.6. Metabolic control, monitoring of dietary treatment, nutritional status, and potential long-term complications of the disease

Appendix A3.7. Pre- and postoperative management tactics for patients.

Appendix A3.8. Patient guide for metabolic disorders.

PATIENT PASSPORT WITH A METABOLIC DISORDER

Full Name ____________________________________

Date of Birth____________________________

Diagnosis: _______________________ (ICD-10)

CHI Policy: _____________________

DEPARTMENT / ATTENDING PHYSICIAN CONTACT INFORMATION: _____________

RUSSIAN MINISTRY OF HEALTH CLINICAL GUIDELINES

https://cr.minzdrav.gov.ru

EMERGENCY AND URGENT CARE

The patient is at high risk of developing a metabolic crisis

Emergency hospitalization is required if symptoms of a metabolic crisis are present

SYMPTOMS OF A METABOLIC CRISIS: prolonged refusal to eat, nausea, vomiting, altered mental status, seizures.

CONTRAINDICATIONS:

• Administration of protein solutions (Amino acids for parenteral nutrition)

• Prolonged fasting

• EXCLUDE meat, fish, dairy, legume, soy, and nut products.

• Pharmacotherapy: Valproic acid preparations

NOT RECOMMENDED:

High doses of glucocorticoids

URGENT DIAGNOSTICS:

determination of blood electrolytes, glucose, urea, creatinine, amylase, acid-base balance (bicarbonates, lactate, buffer bases), ammonium.

URGENT THERAPY:

• Emergency intravenous administration of dextrose**: neonates and children under 1 year 8-10 mg/kg/min, from 1 to 3 years 7-8 mg/kg/min, from 4 to 6 years 6-7 mg/kg/min, from 7 to 12 years 5-6 mg/kg/min, older than 12 years 4-5 mg/kg/min, adults — 3-4 mg/kg/min. If glucose drops below 2.5 mmol/L — bolus administration of 10%-25% dextrose at 2-3 ml/kg, followed by continuous infusion of 10% dextrose at a rate of 7-9 mg/kg/min until blood glucose normalizes. If necessary, add a drug from the "short-acting insulins and their analogues for injection (e.g., #insulin aspart**, #soluble insulin [human recombinant] **) subgroup at a dose of 0.01-0.05-0.1 IU/kg/h.

• #Levocarnitine 100-200 mg/kg per day until condition normalizes. During a crisis and acute hyperammonemia, the dose can be increased to 300 mg/kg/day (12g maximum).

• Diet. Within 24-48 hours (no more), switch exclusively to an amino acid formula without isoleucine, methionine, threonine, and valine while maintaining daily caloric intake.

• surgical intervention/anesthesia - infusion therapy in cases requiring prolonged fasting, dextrose** solutions (calculated as 8-10 mg/kg/min for infants in the first year of life, 6-7 mg/kg/min for children from 1 to 10 years, 5-6 mg/kg/min for children over 10 years) and solutions affecting water-electrolyte balance (potassium chloride + sodium acetate + sodium chloride**).

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What is methylmalonic acidemia/aciduria?

Methylmalonic aciduria (acidemia) is a group of inherited disorders of methylmalonic acid or cobalamin (vitamin B12) metabolism. There are 7 known forms of MMA, all associated with enzyme deficiencies required for the proper metabolism of amino acids: methionine, threonine, valine, isoleucine.

How common is methylmalonic acidemia?

MMA is a rare disease. The incidence of early, severe MMA averages 1 in 50,000 live births.

What are the symptoms of methylmalonic aciduria?

MMA can manifest at various ages, from infancy to childhood. In this disorder, toxic substances accumulate and affect the cells of the nervous system, pancreas, and myocardium. The child may exhibit symptoms resembling poisoning (intoxication) — frequent regurgitation, vomiting, refusal to eat, muscle weakness, lethargy, seizures, increased drowsiness.

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 typically triggered by factors such as viral and bacterial infections, stressful situations, trauma and surgical interventions, emotional and physical exertion, and certain medications.

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

How is methylmalonic aciduria inherited?

All forms of MMA are inherited in an autosomal recessive manner. This means the disease manifests only if both parents are carriers and, although unaffected themselves, pass on two mutated genes to the child. Most families with an affected child have no prior history of the condition. The recurrence risk for a subsequent child in a family with affected children is 25% for each pregnancy. Pathogenic variants in 1 of 7 different genes can cause this disease. It is extremely crucial to determine the genetic form of the disease, as treatment tactics and prognosis depend on it.

Siblings of an affected child may be ill even if they were asymptomatic at the time of family screening. In this case, diagnostics must be performed to initiate therapy as early as possible and avoid complications. They may 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 are also at risk of having a child with this condition.

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

For prenatal and preimplantation genetic diagnosis, the couple must first be screened for carrier status of pathogenic/likely pathogenic variants in the MUT, MMAA, MAB, MCEE, CD320, LMBRD, MMADHC, MMACHC, genes by contacting specialized diagnostic laboratories and medical centers. Prenatal diagnosis is performed using molecular genetic methods by analyzing DNA extracted from chorionic villus sampling and/or amniotic fluid cells and/or fetal blood.

How is methylmalonic aciduria diagnosed?

Based on clinical symptoms, the physician may suspect the diagnosis and refer the patient for laboratory testing. Tandem mass spectrometry is used to determine blood levels of compounds such as carnitine, acylcarnitines, and amino acids; gas chromatography-mass spectrometry is used to measure urine organic acids. MMA is characterized by elevated propionylcarnitine (C3), low free carnitine (C0), elevated C3/C0 and C3/C2 ratios in the blood, and increased concentrations of methylmalonic, 3-hydroxypropionic, and methylcitric acids in the urine. Certain forms of MMA also present with elevated blood homocysteine. Patients with biochemical changes characteristic of MMA undergo molecular genetic testing to confirm the diagnosis by identifying pathogenic variants in MMA-associated genes. This is typically done using targeted gene panels.

How are patients with methylmalonic aciduria treated?

The primary treatments for MMA are diet therapy and specific medications that reduce the impact of toxic metabolites on the body and facilitate their excretion in urine. Diet therapy involves restricting protein intake and specific amino acids whose metabolism is impaired. Specialized medical formulas have been developed for feeding children of different ages. A geneticist and dietitian will help calculate the diet, correctly introduce complementary foods, and teach the basic rules of diet therapy. It is crucial to follow all medical recommendations to minimize the risk of metabolic crises.

How are patients treated during a metabolic crisis?

Protein intake should be temporarily discontinued (for 24-48 hours). Completely eliminating protein is impossible because the body requires protein, and if intake is insufficient, catabolic processes will be 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 first signs of an approaching illness (paleness, drowsiness, irritability, loss of appetite, fever, headache, body aches and general pain, cough, sore throat or earache), as a precaution, the child should be given a glucose solution to drink once (Table 1). The earliest signs are usually minor behavioral changes that are easily noticed by parents. If the child is relatively healthy and has no vomiting, but only weakness and mild drowsiness, you can give them 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 check with your attending physician to find out what is right for your child. Some children dislike the taste of the glucose polymer and prefer commercially available supermarket drinks, but the carbohydrate concentrations in such drinks are lower. Purchased drinks should be used with caution. Low-calorie and sugar-free drinks contain very little or no carbohydrates and therefore should not be used.

With the onset of the first signs of a metabolic crisis, without waiting for the doctor to arrive, the dose of oral levocarnitine should be increased to 200 mg/kg/day [46].

Table 1. Fluid volume during the development of a metabolic crisis.

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 should be performed for patients?

A multidisciplinary approach involving specialists from various profiles is necessary for the monitoring and management of patients with MMA to ensure comprehensive therapy and timely adjustment when necessary. Regular examinations are required for patients with MMA. The table provides an approximate list and frequency of examinations, but in each case, you must coordinate the examination plan with your attending physician.

Table 2. Approximate list and frequency of consultations and examinations in patients with MMA

How do patients receive treatment in the Russian Federation?

MMA is among the rare hereditary metabolic disorders and is included in the list of rare (orphan) diseases, the treatment of which is funded by the regional budget. After diagnosis establishment, the patient must be included in the regional segment of the register for life-threatening rare (orphan) diseases in order to ensure subsequent provision with the necessary therapeutic nutrition and medications. Different specialists are responsible for maintaining the register in different regions, but most often these are medical geneticists; therefore, after establishing a diagnosis, it is essential to 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, dietary relapses 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.

The parents of a patient with MMA, and subsequently the patient themselves, must be trained in the rules of organizing therapy during the intercritical period and during the threat of a metabolic crisis.

The child must always carry an information card indicating emergency measures during the onset of a metabolic crisis (Appendix A3.8).

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

Not applicable.