Propionic acidemia / aciduria: clinical guidelines

List of Abbreviations

DNA — deoxyribonucleic acid

ABs — acid-base status

MRI — magnetic resonance imaging

MS/MS — tandem mass spectrometry

MLFP — specialized medical nutrition products

PA — propionic acidemia / aciduria

US — ultrasound

ALP — alkaline phosphatase

ECG — electrocardiography

EchoCG — echocardiography

EEG — electroencephalography

Terms and Definitions

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.

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.

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.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Propionic acidemia (aciduria) is a genetically heterogeneous disease with an autosomal recessive inheritance pattern, caused by propionyl-CoA carboxylase deficiency, leading to impaired metabolism of propionate, a number of amino acids (methionine, valine, threonine, isoleucine), as well as odd-chain fatty acids and cholesterol [1].

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

The cause of propionic acidemia is a deficiency of the enzyme propionyl-CoA carboxylase, arising due to pathogenic variants in the PCCA and PCCB genes. Propionyl-CoA, being an intermediate product of the catabolism of valine, isoleucine, threonine, methionine, odd-chain fatty acids, and cholesterol, and a product of anaerobic carbohydrate fermentation by gut bacteria, is converted into methylmalonyl-CoA with the participation of propionyl-CoA carboxylase (the ratio of these three propionyl-CoA production pathways is approximately 2:1:1, respectively). A decrease in enzyme activity leads to the accumulation of propionyl-CoA and associated metabolites: propionic acid, 3-hydroxypropionic acid, propionylcarnitine, propionylglycine, and 2-methylcitrate, which exert a toxic effect on the cells of multiple organs and tissues, especially the central nervous system and liver [2]–[4].

Propionyl-CoA carboxylase is a mitochondrial enzyme from the group of small acyl-CoA carboxylases, is a heterodoodecamer — consisting of 6 alpha and 6 beta subunits encoded by the PCCA (OMIM*232000) and PCCB (OMIM*232050) genes, respectively. Biotin is a cofactor of the enzyme [5], [6].

1.3 Epidemiology of the Disease or Condition

Propionic acidemia is a rare disease: according to available data, the incidence in Europe and North America is approximately 1 case per 300,000 newborns. In the Asia-Pacific region, the incidence of PA is estimated at 1 case per 345,000 newborns, with the highest rate in South Korea — according to published data for 2005, 4 cases per 79,179 (~ 1:20,000) newborns were recorded as part of neonatal screening. In the Middle East and North Africa, the incidence of PA is approximately 1 case per 24,000 newborns. The highest incidence rate of PA is recorded in Saudi Arabia — 1:12,000. In Russia, the incidence of propionic acidemia at the time of writing is unknown [7]–[9].

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

Depending on the degree of enzyme deficiency and other factors, PA can manifest at different ages — neonatal, infantile, and late forms are distinguished. Clinically, the infantile form is characterized by earlier manifestation and a severe undulating and crisis-prone course, especially during intercurrent infections and stress conditions [1], [10].

1.6 Clinical presentation of the disease or condition

Clinical symptoms of PA are nonspecific; the disease can manifest at any age, either with acutely arising symptoms or as an insidiously progressing chronic disease (Table 1) [11].

Table 1.

Propionic acidemia is diagnosed in 65% of cases in the neonatal period, often in the form of an episode of acute metabolic decompensation. The development of newborn screening makes it possible to identify PA almost immediately after birth; however, despite timely diagnosis and prevention, patients are at high risk of developing a metabolic crisis throughout their lives. The provoking factor is the intensification of catabolism: stress, physical activity, infectious diseases, surgical intervention, low-calorie food, as well as excessive consumption of protein food containing amino acids associated with PA [12]. The clinical picture of propionic acidemia is not specific. The severity of the crisis and the nature of the provoking event depend on the degree of propionyl-CoA carboxylase deficiency. The main symptoms are vomiting, dehydration, refusal to feed, weight loss, hypothermia, hypotonia, depressed consciousness up to a comatose state, and seizures. In the absence of timely therapy, multi-organ failure and a rapid deterioration of the patient's condition up to death develop. The chronic form and patients with late manifestation of the disease are also characterized by developmental delay, cardiac dysfunction, and in some cases renal dysfunction [12]–[14].

Against the background of damage to multiple organ systems due to the accumulation of toxic metabolites, the clinical picture of patients with PA is characterized by the development of a wide range of complications. The most frequent disorder is hepatomegaly, described in almost 80% of patients. Alanine aminotransferase activity is on average increased by 16% of normal, aspartate aminotransferase by 19%, and gamma-glutamyl transferase by 25% [15], [16]. About 50% of studied patients with propionic acidemia have cognitive impairments, and other neurological complications are also described: autism spectrum disorders, anxiety, episodes of acute psychosis [17]. Movement disorders can develop against the background of stroke-like episodes, often occurring in PA patients during acute metabolic decompensation or shortly after it (several cases unassociated with metabolic crisis are also described) [18], [19]. Seizure syndrome occurs, according to various estimates, in 25%–59% of cases, often as the first sign of the disease [20]. Cases of vision and hearing impairment are described: about 25% of patients are susceptible to optic neuropathy, and sensorineural hearing loss is less common [16], [21].

According to rough estimates, cardiomyopathy is observed in a quarter of PA cases, which can rapidly progress, leading to severe heart failure. In two large cohorts of PA patients, a prolonged QTc interval and arrhythmia were described in 22% and 33% of patients, leading in some cases to sudden cardiac arrest [16], [17]. A frequent disorder in PA is pancytopenia (especially neutropenia), occurring both during a metabolic crisis and in the chronic course of the disease [22].

Renal dysfunction is quite rarely noted in PA patients, but when present, it can lead to bone damage — osteoporosis, a risk factor for which is also chronic acidosis [23]. In 5%–10% of cases, chronic or acute pancreatitis is described as one of the complications of PA, developing regardless of the frequency and severity of acute metabolic decompensation episodes [12].

Metabolic crisis.

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

- recurrent episodes of vomiting (90% of cases);

- refusal to eat;

- depressed consciousness: from somnolence to coma.

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

Complications associated with metabolic crisis [2]:

- 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 PA patient in metabolic crisis must be addressed immediately, as the risk of stroke is higher in this patient population. CT or MRI of the brain is performed in the presence of any neurological signs indicating the possibility of stroke. Changes in the basal ganglia, especially in the globus pallidus, characterize the "metabolic stroke" of PA.

- renal failure in PA patients: progressive renal failure may occur due to tubulointerstitial nephropathy. Renal function should be monitored in any PA patient in metabolic crisis.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The criteria for establishing the diagnosis of propionic acidemia/aciduria include elevated levels of propionylglycine, tiglylglycine, methylcitrate, and 3-hydroxypropionic acid in the urine, elevated propionylcarnitine (C3) and/or C3/C2 ratio in dried blood spots, and the result of molecular genetic testing revealing pathogenic variants in the PCCA and PCCB genes in a homozygous or compound heterozygous state*.

*Note: In rare cases, the diagnosis can be confirmed based solely on biochemical alterations if causative genetic variants are not identified using standard genetic diagnostic methods. Variants subject to limitations of standard methods include large structural rearrangements, deep intronic variants, and changes in regulatory gene regions.

2.1 Complaints and Anamnesis

When taking the medical history and complaints, it is recommended to pay attention to the following complaints and historical events:

- family history burdened by metabolic disorders (a family history of a patient with PA, or cases of sudden unexpected death in infancy);

- sudden clinical deterioration against a background of apparent health or an acute respiratory viral infection (ARVI);

- feeding difficulties;

- frequent regurgitation/vomiting;

- lethargy, weakness, drowsiness;

- depressed level of consciousness;

- stroke-like episodes;

- seizures;

- anxiety and agitation, tearfulness;

- increased sweating (diaphoresis);

- muscle hypotonia / hypertonia;

- involuntary movements;

- acute/chronic renal failure.

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

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

neonatal period

- regurgitation/vomiting, feeding refusal;

- growth retardation;

- motor development delay;

- lethegy, drowsiness;

- depressed level of consciousness;

- muscle hypotonia / hypertonia;

- pyramidal signs (hyperreflexia);

- extrapyramidal movement 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);

- periodic 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 the concentration of amino acids and acylcarnitines are detected in dried blood spots: propionic acidemia presents with an elevated concentration of propionylcarnitine (C3), low levels of free carnitine (C0), and an increased C3/C0 and C3/C2 ratio. Blood levels of leucine, isoleucine, valine, and methionine in patients may remain within the normal range, which does not allow confirming or ruling out the disease based on amino acid analysis alone. Glycine levels are elevated in many patients; however, this is non-specific and is also observed in other inherited metabolic disorders.

Comments: characteristic findings in PA include elevated concentrations of propionic, 3-hydroxypropionic, methylmalonic, 3-hydroxy-n-valeric, and methylcitric acids.

Comments: in most cases, biallelic pathogenic variants are identified in the PCCA and PCCB genes, which serves as the basis for molecular genetic confirmation of the diagnosis. However, if only a single pathogenic allele is detected or no alterations are found in these genes, the diagnosis cannot be ruled out if clinical and biochemical data point to PA. Genetic alterations may include large rearrangements, deep intronic variants, or variants in untranslated regions that are difficult to detect using standard molecular genetic testing methods.

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 disorders. Brain computed tomography (CT) may also be performed. Brain CT/MRI in patients with PA may reveal 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 disorders, methylmalonic acidemia, and other conditions. General anesthesia is performed according to indications.

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: tests are performed depending on the clinical situation; an initial/follow-up consultation (examination, consultation) with an otolaryngologist-audiologist is required.

2.5 Other Procedures

2.5.1 Specialist Consultations and Monitoring

Comments: indicated initial and follow-up consultations (examinations) with a medical geneticist, ophthalmologist, neurologist, gastroenterologist, endocrinologist, cardiologist, pediatric cardiologist, nephrologist, pediatrician / general practitioner / family physician, physical therapist, and exercise therapy physician, as well as specialists in other fields for patients with PA who have functional impairments 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. Prescription, monitoring, and adjustment of diet therapy may also be carried out by a pediatrician, neonatologist, general practitioner, or medical geneticist experienced 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.

Medical speech therapy services:

• medical speech-language assessment for dysphagia;

• medical speech-language assessment for aphasia;

• medical speech-language assessment for dysarthria;

• medical speech-language procedure for dysphagia;

• medical speech-language procedure for aphasia;

• medical-logopedic procedure for dysarthria;

• medical-logopedic tonal-rhythmic procedure;

• medical-logopedic 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 in reducing the formation of toxic metabolites, preventing the development of ketoacidosis, hyperammonemia, toxic damage to the brain and internal organs while ensuring anabolic processes, normal growth, and nutritional status in children. The main components of complex treatment in patients are a low-protein diet and specialized products without pathogenetically significant amino acids, and #levocarnitine preparations. According to indications, antiepileptic drugs, symptomatic therapy, and correction of vitamin deficiency are prescribed.

3.1 Conservative Treatment

Medical Nutrition 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 PA 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 six 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 are performed within 3–7 days, while molecular genetic studies may take about 2–3 weeks. Therefore, it is necessary for the child to remain on a low-protein diet during this period.

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 six months of life, the restriction applies to breast milk or infant dairy or soy formulas; for infants in the second six months of life, a prohibition on introducing high-protein complementary foods (meat, fish, cottage cheese, eggs, dairy products, legumes, etc.); for patients older than one year, 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;

- restriction of the intake of fatty acids with an odd number of carbon atoms and cholesterol;

- avoidance of fasting and prevention of catabolic processes;

The total protein of the therapeutic diet is calculated based on the child's age-specific requirements (Appendix A3.2), as well as taking into account the patient's protein tolerance depending on the form and severity of the disease [28]:

- the natural 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 without methionine, threonine, valine, or 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 the daily food ration for preschool children with propionic acidemia.

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

3.1.2 Pharmacotherapy.

Comments: #levocarnitine is prescribed at a dosage of 100–200 mg/kg/day in 2–4 doses; the dose is adjusted depending on the clinical response and carnitine levels. Therapy is carried out almost continuously. During a metabolic crisis and acute hyperammonemia, the dose may be increased up to 300 mg/kg/day. However, the expert group suggests not exceeding the daily dose of #levocarnitine above 12 g for adults [24].

Comments: considering that about 25% of propionates are formed under the influence of the intestinal microbiota, an additional method of metabolic correction is antibacterial therapy aimed at suppressing the activity of pathogenic and opportunistic microorganisms. Courses of #metronidazole**^, are prescribed at a dose of 10–20 mg/kg/day for 10–14 days; after 3–4 weeks, the course is repeated if necessary, or, in case of intolerance to #metronidazole**, alternated with #metronidazole** at a 1-month interval — #amoxicillin** (50 mg/kg) or #Co-trimoxazole [Sulfamethoxazole + Trimethoprim]** (20 mg/kg) [23]–[25], [31]. Alternating medications is necessary to prevent the development of microflora resistance to antimicrobial therapy. To avoid the development of drug-resistant colonies, 1–2 weeks of therapy are recommended, alternating with a 2–3 week break or alternating every month. It may be useful to take probiotic supplements (avoiding those containing propionic acid-producing bacteria) to restore and balance the intestinal flora [24].

Comment: an elevated blood plasma ammonium level in newborns is considered to be greater than 150 µmol/L (>260 µg/dL), and in older children and adults, greater than 100 µmol/L (175 µg/dL) [40]. According to literature, the ammonium level requiring the prescription of carglumic acid ranges from 142 ± 46.495 µmol/L. The average dose of carglumic acid is 85 mg/kg/day (range 100–250 mg/kg). A significant decrease in blood plasma ammonium levels with long-term carglumic acid treatment and a reduction in the number of hyperammonemia episodes requiring hospitalization have been identified [31], [34], [35]..

Experience with carglumic acid exists in a number of clinics, but the number of patients undergoing this therapy is still limited; therefore, further studies are required to gather evidence on the efficacy of this drug [27], [31], [36].

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.

Therapeutic measures are aimed at stopping the formation and accumulation of toxic organic compounds and excreting them from the body. Treatment tactics for children during a crisis include dietary adjustment, elimination of accumulating organic acids, correction of metabolic acidosis, hyperammonemia, and water-electrolyte disturbances, energy support, and reduction of catabolic processes [24], [28], [37].

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

Factors that can trigger 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 promoting catabolism;

- elevated body temperature;

- anesthesia, surgical interventions.

Comments: in the presence of regurgitation, vomiting, or food refusal – feeding via a nasogastric tube or gastrostomy (gastrostomy placement) [24]. Observe a regimen of frequent, small feedings 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; calculations are 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 (B05BA - Solutions for parenteral nutrition) up to 1 g/kg/day is possible.

Table 2. Safe level of protein intake and energy requirement in children of various ages with propionic acidemia during a metabolic crisis*

*- adapted from Matthias R Baumgartner et al. 2014 [24].

Comments: #levocarnitine is prescribed 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 of the drug is preferred to maintain blood free carnitine levels above normal values. This ensures the detoxification function of carnitine and improves the binding and excretion of toxic propionic derivatives from the body. When using high doses, side effects such as nausea and an unpleasant odor (urine, breath, sweat) may occur. These symptoms resolve after reducing the dose. During a metabolic crisis and acute hyperammonemia, the dose may be increased up to 300 mg/kg/day. However, it is not recommended to exceed the daily dose of #levocarnitine above 12 g for adult patients [24].

Comments: intravenous administration of a dextrose** solution at the following rates: newborns and children under 1 year old, 8–10 mg/kg/min; aged 1 to 3 years, 7–8 mg/kg/min; aged 4 to 6 years, 6–7 mg/kg/min; aged 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 blood glucose drops below 2.5 mmol/L, an intravenous bolus injection of at least 10% dextrose** at a dose of 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 compensates for 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 higher) should be used even when blood glucose levels are normal. If the patient develops significant hyperglycemia with glucosuria and signs of metabolic decompensation, the initiation of an infusion of soluble [human recombinant] insulin** should be considered instead of reducing the dextrose** infusion rate, to promote an anabolic state. The initial dose for soluble [human recombinant] insulin** infusion is 0.01–0.05–0.1 IU/kg/h. Insulin levels should be titrated to maintain blood glucose between 100 and 150 mg/dL [57].

It should be noted that infusion of a more concentrated dextrose** solution (15–20%) at a lower infusion rate via a central venous catheter may be required in case of impaired cardiac function [57]. In addition, caution should be exercised when stopping the intravenous infusion — the rate must be tapered slowly to avoid reactive hypoglycemia [41].

Comments: sodium bicarbonate** is used as an 8.4% and 4.2% solution for convenience in converting to mmol of $NaHCO_3$. Its dosage (mmol) is determined by the formula: $(-BE) \times \text{body weight (kg)} \times 0.3$. In addition, patients are recommended to consume alkaline drinks—a soda solution at a rate of $\frac{1}{2}$ to 1 teaspoon per 200 mL of water, and alkaline mineral waters. Depending on the severity of the condition, blood acid-base status, sodium, and potassium levels should be monitored every 6–12 hours. Patients experiencing a metabolic crisis due to PA need to have blood lactate (blood lactic acid level test), ammonia, and glucose levels, as well as blood acid-base status (blood buffer substances test, blood hydrogen ions (pH) level test) monitored to evaluate treatment efficacy.

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 used by a physician based on personal experience [24], [47].

Comment: N-carbamylglutamate allosterically activates carbamoyl phosphate synthetase I in the urea cycle, leading to a decrease in ammonium levels. The dosing regimen for N-carbamylglutamate, which is available as an oral formulation, 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). In persistent hyperammonemia, sodium benzoate may be prescribed either as monotherapy or in combination with carglumic acid. Carglumic acid can be considered an effective and safe treatment for chronic hyperammonemia in patients with propionic aciduria [27].

Comment: in patients with propionic aciduria during a metabolic crisis, carglumic acid is prescribed at a dose of 70 to 250 mg/kg/day to resolve the condition [58].

3.2 Surgical treatment.

Comments: performed in accordance with guidelines for liver and kidney transplantation. Indications for liver transplantation or combined liver and kidney transplantation are currently not strictly defined; however, in global practice, the most common ones are severe metabolic decompensation and the ineffectiveness of ongoing metabolic therapy. At the same time, PA is the most frequent indication for liver transplantation in pediatric patients among inherited metabolic disorders. Liver transplantation has been recognized as a form of enzyme replacement therapy. Combined liver and kidney transplantation is generally performed in cases of progressive impairment of renal function and the development of chronic kidney disease [49], [50].

Comments: infusion therapy with dextrose** solutions and solutions affecting water-electrolyte balance in cases requiring prolonged fasting is administered at a rate of 8–10 mg/kg/min for infants under one year of age, 6–7 mg/kg/min for children from one year to 10 years of age, 5–6 mg/kg/min for children over 10 years of age, and 4–5 mg/kg/min for adults. For a table detailing management tactics, see Appendix A3.7 [24].

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 is performed to achieve more efficient elimination of toxic metabolites.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

5.1 Prevention.

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

Comments: Considering the autosomal recessive inheritance pattern of PA, for each pregnancy of a carrier couple with pathogenic variants in associated genes, the risk of having a child with PA is 25%. To perform prenatal and preimplantation diagnostics, the couple must first undergo testing for heterozygous carriage of pathogenic variants in the PCCA and PCCB 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.

Comments: vaccination should also be carried out against influenza and rotavirus infection, adhering to age restrictions for immunobiological preparations alongside strict compliance with dietary and therapeutic prescriptions. Vaccination should preferably be performed under the supervision of specialists experienced in managing patients with metabolic disorders. During the post-vaccination period, close monitoring of vaccinated individuals is required, including repeated body temperature measurements, which is necessary for the prompt initiation of antipyretic therapy if a fever >38.0°C is detected.

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 testing depends on the patient's condition. Quantitative determination of blood amino acids (comprehensive determination of amino acid and acylcarnitine concentrations in blood, comprehensive determination of amino acid and acylcarnitine concentrations in blood by tandem mass spectrometry) – in a stable condition – every 3–6 months. During periods of infectious diseases or metabolic crises, the determination of blood amino acids and carnitines (comprehensive determination of amino acid and acylcarnitine concentrations in blood, comprehensive determination of amino acid and acylcarnitine concentrations in blood by tandem mass spectrometry) is performed at least once every 7–10 days, and acid-base balance (assessment of blood hydrogen ions (pH), assessment of blood buffer substances) – daily until parameters stabilize.

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: if necessary and indicated, Holter electrocardiographic monitoring and/or ambulatory blood pressure monitoring should be performed (in accordance with relevant clinical guidelines for cardiac arrhythmias and/or arterial hypertension).

Comments: the frequency of examinations is determined individually.

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 inpatient facility, by a pediatrician, general practitioner, family physician, geneticist, neurologist, nutritionist, orthopedic traumatologist, endocrinologist/pediatric endocrinologist, cardiologist/pediatric cardiologist, ophthalmologist, otolaryngologist-audiologist, dentist/pediatric dentist, gastroenterologist, allergist-immunologist, hematologist/pediatric hematologist, nephrologist, pediatric surgeon (specialized in transplantology), psychiatrist, rehabilitation specialist, medical psychologist, speech and language therapist-defecologist, and others.

Patients with PA must undergo comprehensive medical check-ups (dispensary evaluation) annually and receive necessary rehabilitation measures (Appendix A3.6).

Parents must be educated on how to organize therapy during the interictal period and when there is a risk of a metabolic crisis. The child must always carry an information card outlining emergency measures to be taken at the onset of a metabolic crisis (Appendix A3.8).

6. Organization of Medical Care

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 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 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. Need to transfer the patient to another medical institution or social security institution.

6.2 Principles of organizing medical care for patients with PA

Establishing a diagnosis of propionic acidemia raises many questions for the patient's relatives and for the specialists working with such patients. The numerous problems that arise upon the detection and progression of the disease require organizing the medical care process with the participation of a multidisciplinary team of specialists.

These principles must be observed at any stage of medical care, 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 propionic acidemia implies the provision of primary, specialized, and palliative care at all stages of the disease;

3. upon establishing a diagnosis of propionic acidemia, it is recommended to refer the family to specialists with experience in managing patients with propionic acidemia, who possess up-to-date information on the disease course and the possibility of participating in clinical trials (of new medications and/or medical devices). If distance is a factor, consultations may be conducted using telemedicine technologies;

4. it is also important to inform families about existing public organizations operating for this group of patients;

5. a multidisciplinary team of specialists must be involved in the follow-up of a patient with propionic acidemia, consisting of: a pediatrician, general practitioner/family physician, geneticist, neurologist, dietitian, 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 therapist/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 level of mental development depends on the severity of the disease, the presence of stroke-like episodes, the involvement of internal organs in the pathological process (heart, pancreas, kidneys), as well as the timing of specialized therapy initiation and the quality of treatment capable of preventing episodes of metabolic decompensation.

Criteria for Evaluating the Quality of Medical Care

Criteria for evaluating the quality of primary health care

Criteria for evaluating the quality of specialized medical care

References

Appendix A1. Working Group Composition

Anisimova Inga Vadimovna — PhD in Medical Sciences, Head of the Medical Care Organization Department, Geneticist, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Association of Medical Geneticists

Bagaeva Madlena Enverovna — PhD in Medical Sciences, Senior Researcher, Department of Pediatric Gastroenterology, Hepatology, and Dietology, Clinic of the Federal Research Centre of Nutrition and Biotechnology

Baydakova Galina Viktorovna — PhD in Biological Sciences, Head of the 'Metabolom' Shared Research Facility, Leading Researcher, Laboratory of Hereditary Metabolic Diseases, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists

Baranov Aleksandr Aleksandrovich — Academician of the RAS, Professor, MD; Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery, Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Chief freelance specialist pediatrician of the Russian Ministry of Health

Borovik Tatyana Eduardovna — MD, 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

Bushueva Tatyana Vladimirovna — MD, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists

Vashakmadze Nato Dzhemberovna — MD, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Children's 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

Vishneva Elena Aleksandrovna — MD, Deputy Head for Scientific Work at the Research Institute of Pediatrics and Children's 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

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

Degtyareva Anna Vladimirovna — MD, Professor, Highest Category Physician, Head of the Department of Pediatrics, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatalogy

Zhurkova Natalya Vyacheslavovna — PhD in Medical Sciences, Leading Researcher, Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery, Member of the Union of Pediatrists of Russia, Member of the Association of Medical Geneticists (AMG)

Zarubina Vera Vladimirovna — Geneticist, Medical Genetics Department, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department

Zakharova Ekaterina Yuryevna — MD, Head of the Laboratory of Hereditary Metabolic Diseases, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

Kekeeva Tatyana Nikolaevna — Head of the Medical Genetics Department, Geneticist, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department

Kretov Vladimir Vladimirovich — Critical Care Physician, Reanimation and Intensive Care Unit, National Medical Research Center for Children's Health of the Russian Ministry of Health.

Kuzenkova Lyudmila Mikhailovna — MD, 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

Kutsev Sergey Ivanovich — Academician of the RAS, MD, Director of the Academician N.P. Bochkov Research Centre for Medical Genetics, President of the Association of Medical Geneticists

Lavrova Alla Evgenyevna — MD, 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 Public Health

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

Mikhailova Svetlana Vitalievna — MD, Head of Department, Russian Children's Clinical Hospital of the Ministry of Health of the Russian Federation

Lyudmila P. Nazarenko — Professor, MD, Deputy Director for Research and Clinical Work, Head of the Laboratory of Hereditary Pathology at the Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, member of the Association of Medical Geneticists.

Namazova-Baranova Leyla Seymurovna — Academician of the RAS, Professor, MD, President of the Union of Pediatrists of Russia; Past-President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Children's 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 — MD, DSc, Chief Researcher, Department of Clinical Genetics, Veltischev Research and Clinical Institute of Pediatrics; Professor, Department of Innovative Pediatrics and Pediatric Surgery, Institute of Continuing Education and Professional Development, Pirogov Russian National Research Medical University of the Russian Ministry of Health; member of the Russian Society of Medical Geneticists, member of the Association of Medical Geneticists

Natalia L. Pechatnikova — Neurologist, Head of Department, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department

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

Svetlana A. Repina — PhD in Medical Sciences, Medical Geneticist, Bochkov Research Centre for Medical Genetics, member of the Russian Society of Medical Geneticists, member of the Association of Medical Geneticists

Kirill V. Savostyanov — MD, DSc, Head of the Medical Genetics Center, Head of the Laboratory of Medical Genomics, National Medical Research Center for Children's Health of the Russian Ministry of Health; Professor, 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

Liliya R. Selimzyanova — PhD in Medical Sciences, Leading Researcher, Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery; Associate Professor, Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Associate Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, member of the Union of Pediatricians of Russia

Olga Ya. Smirnova — Medical Geneticist, Senior Researcher, Department of Standardization and Study of Evidence-Based Medicine Fundamentals, Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery, member of the Union of Pediatricians of Russia, member of the Association of Medical Geneticists

Tatiana V. Strokova — MD, DSc, Professor of the RAS, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietetics, Clinic of the Federal Research Centre of Nutrition and Biotechnology

Dmitry M. Subbotin — Medical Geneticist, Bochkov Research Centre for Medical Genetics, member of the Association of Medical Geneticists.

Natella V. Sukhanova — Head of the Aniridia Center, Researcher, Research Institute of Pediatrics and Children's Health, Central Clinical Hospital of the Russian Academy of Sciences; Ophthalmologist, member of the Association of Pediatric Ophthalmologists of the Russian Federation, member of the Union of Pediatricians of Russia

Rustem F. Tepaev — MD, DSc, Head of the Anesthesiology and Intensive Care Unit, Bashlyaeva Children's City Clinical Hospital of the Moscow Healthcare Department; Professor, Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University)

Andrey P. Fisenko — MD, DSc, Professor, Honored Doctor of the Russian Federation, Director of the National Medical Research Center for Children's Health of the Russian Ministry of Health

Representatives of public patient organizations:

Raisa Panfilova — Representative of the methylmalonic and propionic aciduria patient community

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

Marina V. Nikitina — Representative of the methylmalonic and propionic 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 propionic 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 Newborn Screening 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 No. 274n dated April 21, 2022, "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases."

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

5. Decree of the Government of the Russian Federation No. 3053-r dated December 31, 2018, "On Approval of Lists of Medical Devices Implantable into the Human Body When Providing Medical Care Within the Framework of the State Guarantee Program of Free Medical Care to Citizens and Dispensed by Prescription for Medical Devices Upon Provision of a Set of Social Services."

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

7. 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."

8. 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."

9. 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".

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

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

12. Order of the Ministry of Health and Social Development of the Russian Federation "On the Procedure for the Use of Medicinal Products in Patients on Vital Indications" No. 494 dated August 9, 2005.

13. Information Letter of the Russian Ministry of Health on the possibility of procuring a medicinal product by its trade name.

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

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 Protecting Citizens' Health in the Russian Federation' Regarding the Provision of Palliative Medical Care."

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

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

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

5. Order of the Ministry of Health of the Russian Federation No. 831 dated October 3, 2019, "On Approval of the Departmental Target Program 'Development of the Palliative Medical Care Delivery System'".

Appendix A3.1. Scheme of metabolic processes in propionic 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. Recommended macronutrient intake 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 requirements are calculated individually for each patient depending 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 methionine-, threonine-, valine-, and isoleucine-free amino acid-based medical nutrition to provide 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 target weight.

Table No. 2. Average daily physiological energy requirements for children according to FAO/WHO/UNU 2001 (WHO Technical Report Series, Oct 17–24, 2001)

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

Table 1. Estimated methionine, threonine, valine, and isoleucine requirements in patients with propionic acidemia 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 feeding calculation for a 1-month-old female infant. Weight: 4000 g. Breastfeeding + methionine-, threonine-, valine-, and isoleucine-free amino acid-based specialized medical nutrition "MMA/PA Anamix Infant"

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) Calculate the amount of methionine-, threonine-, valine-, and isoleucine-free amino acid-based specialized medical nutrition the infant should receive (given that 100 g of dry powder contains 13.1 g of protein/protein equivalent).

A) Calculate the amount of protein the infant should receive from specialized medical nutrition: 7.28 - 4.8 = 2.48 g of protein

B) Calculate the amount of formula:

100 g – 13.1 g of protein

X — 2.48 g, hence X = 2.48 × 100 / 13.1 = 18.9 g (20 g) of dry powder.

Given that in infants specialized medical nutrition should preferably be given at every feeding, and the interval between feedings is at least 3 hours, divide into 8 feeds: 20 : 8 = 2.5 g × 8 times a day.

C) Reconstituting the dry formula:

If 5 g of dry powder is diluted in 30 ml, then 2.5 g is diluted 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 specialized medical nutrition diluted 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 powder (specialized medical nutrition) contains 469 kcal, therefore 20 g contains 93.8 kcal

280 + 93.8 = 373.8 kcal = 93 kcal/kg

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

A) Calculate the demand for additional calories:

107 - 93 = 14 kcal

B) Calculate the amount of 10% dextrose (10 grams of dextrose per 100 ml of solution):

10 ml of 10% dextrose (1 g of dextrose) contains 4 kcal

X = 14 kcal, hence X = 14 x 10 / 4 = 35 ml of 10% dextrose per day, divided into 8 feedings, which gives 4–5 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 a methionine-, threonine-, valine-, and isoleucine-free amino acid-based specialized medical nutrition product “Nutragen 40

-tre, -met, -val, -ile». The calculation is carried out in accordance with the principles given above. The ratio of proteins:fats:carbohydrates to the total energy 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 x 15 = 12.75

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. Approximate daily food product set, its chemical composition, and energy value for preschool children with propionic acidemia.

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

adapted from Matthias R. Baumgartner et al. 2014.

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/recomend/694_1 

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, parenteral solutions)

• Prolonged fasting

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

• Drug therapy: Valproic acid preparations**

NOT RECOMMENDED:

High doses of glucocorticoids

URGENT DIAGNOSTICS:

determination of blood electrolytes (blood potassium, sodium, chloride tests, total blood serum magnesium test), glucose, urea, creatinine, lactic acid blood tests, blood amylase activity determination, acid-base balance and blood gas test, blood buffer substance test.

URGENT THERAPY:

• Emergency intravenous dextrose administration**: 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, older than 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 at least 10% dextrose** at 2–3 ml/kg is required, followed by a transition to continuous intravenous infusion of 10% dextrose** at a rate of 7–9 mg/kg/min until blood glucose normalizes. Add insulin if necessary.

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

• Diet. Within 24–48 hours (no more), switch exclusively to feeding with an amino acid formula free from isoleucine, methionine, threonine, and valine while maintaining daily caloric intake.

• surgery/anesthesia - infusion therapy in cases requiring a prolonged fasting period; dextrose solutions and solutions affecting water-electrolyte balance are administered at 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 old, 5–6 mg/kg/min for children older than 10 years.

Appendix B. Physician Action Algorithms

Neonatal screening algorithm for propionic and methylmalonic aciduria.

Appendix C. Patient Information

What is propionic acidemia/aciduria?

Propionic acidemia / aciduria (PA) is a rare hereditary metabolic disorder belonging to the group of organic acidemias. PA is associated with a dysfunction of the enzyme required for the proper metabolism of certain amino acids: methionine, threonine, valine, isoleucine, as well as cholesterol and fatty acids.

How common is propionic acidemia?

PA is an orphan (rare) disease. The incidence among newborns in European countries and the USA is 1:350,000. There are no data on the prevalence of PA in Russia [53].

How does propionic aciduria manifest?

PA can manifest at various ages — from infancy to childhood. In this disease, toxic substances accumulate and affect the cells of the nervous system, pancreas, and heart muscle. 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 usually triggered by factors such as viral and bacterial infections, stressful situations, injuries, surgical procedures, emotional and physical exertion, and the use of certain medications. Emergency treatment is crucial due to the high risk of neurological complications.

How is propionic acidemia inherited?

PA 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 suffering from this disorder have not encountered similar problems before. The risk of having another sick child in a family that already has affected children is 25% for each pregnancy. Mutations in one of 2 genes (PCCA or PCCB) can lead to this disease.

Siblings of an affected child may be ill even if they showed no symptoms 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. If carrier status is confirmed, they also have a risk of having a child with this condition.

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

For prenatal and preimplantation diagnostics, the couple must first undergo screening for mutations in the PCCA and PCCB genes by contacting specialized diagnostic laboratories and medical centers. Prenatal diagnostics are performed using molecular genetic methods by analyzing DNA isolated from a chorionic villus biopsy and/or amniotic fluid cells and/or fetal blood.

How is propionic acidemia 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 the blood levels of compounds such as carnitine, acylcarnitines, and amino acids, while gas chromatography-mass spectrometry is used to determine urine organic acid levels. PA is characterized by elevated propionylcarnitine (C3), low free carnitine (C0), an increased C3/C0 and C3/C2 ratio in the blood, and elevated urinary concentrations of propionic, 3-hydroxypropionic, methylmalonic, 3-hydroxy-n-valeric, and methylcitric acids. Patients with biochemical changes characteristic of PA undergo molecular genetic testing to identify mutations in PA-related genes to confirm the diagnosis. Targeted genetic panels are typically used for this purpose.

How are patients with propionic acidemia treated?

The main methods of treatment for PA are diet therapy and the administration of special medications, which 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 created for feeding children of various ages. A geneticist and a nutritionist will help calculate the diet, properly introduce complementary foods, and teach the basic rules of diet therapy. It is extremely important to follow all medical recommendations to avoid the development of metabolic crises as much as possible.

How are patients treated during a metabolic crisis?

Protein intake should be temporarily discontinued (for 24–48 hours). It is impossible to completely eliminate protein, as the body requires protein intake, and if insufficient protein is supplied, catabolic processes are activated.

At home, at the first signs of illness, especially when the child has a reduced appetite (for example, during a cold, flu-like symptoms, viral infections, any illnesses associated with 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 early 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 single dose of glucose solution (Table 1) [24]. 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, they can be given a glucose polymer solution orally in frequent, fractional portions (Table 1) [24]. 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 glucose polymer and prefer beverages sold in supermarkets, but the carbohydrate concentrations in such drinks are lower. Purchased drinks must be used with caution. Low-calorie and sugar-free drinks contain very few 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.

Table 1. Fluid volume during 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 to the observation and treatment of PA patients by specialists in various fields is necessary to ensure comprehensive therapy and its timely correction when necessary. Regular examinations are required for patients with PA. The table provides an approximate list and frequency of examinations, but in each case, you must coordinate the examination plan with your attending physician.

How do patients receive treatment in the Russian Federation?

PA is one of 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 registry for life-threatening rare (orphan) diseases in order to ensure further provision of the necessary therapeutic nutrition and medications. Different specialists are responsible for maintaining the registry in different regions, but most often these are geneticists; therefore, after establishing the diagnosis, it is imperative to contact the regional geneticist.

How can family and loved ones help?

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

Parents of a PA patient, and subsequently the patient themselves, must be trained in the rules for 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).

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

Not applicable.