3-Methylcrotonyl-CoA carboxylase deficiency (3-methylcrotonylglycinuria, methylcrotonyl-CoA carboxylase deficiency): clinical guidelines

List of Abbreviations

C3 — propionylcarnitine;

C5:1 — 3-methylcrotonylcarnitine;

C5OH — 3-hydroxyisovalerylcarnitine;

GC-MS — gas chromatography-mass spectrometry;

CoA — coenzyme A;

MCC — 3-methylcrotonyl-CoA carboxylase;

MCCD — 3-methylcrotonyl-CoA carboxylase deficiency;

TMS — tandem mass spectrometry.

Terms and Definitions

Metabolic crisis is a critical, life-threatening condition triggered by adverse factors that intensify cellular catabolism with the accumulation of toxic derivatives, presenting with acute encephalopathy, recurrent vomiting, and seizures.

Newborn screening — mass screening of newborns for the most common congenital and hereditary diseases in order to prevent severe forms of diseases before the development of clinical symptoms and to provide timely treatment.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

3-Methylcrotonyl-CoA carboxylase deficiency is a hereditary condition caused by biallelic pathogenic variants in the MCCC1 (MCCA) or MCCC2 (MCCB) genes, which encode the alpha and beta subunits, respectively, of the mitochondrial enzyme 3-methylcrotonyl-CoA carboxylase (MCC). MCC is one of the four biotin-dependent carboxylases that catalyzes the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA in leucine metabolism. A deficiency or lack of MCC enzyme activity leads to impaired leucine degradation and the accumulation of its toxic derivatives in the body [1, 2].

Synonyms: isolated 3-methylcrotonyl-CoA carboxylase deficiency, 3-methylcrotonylglycinuria.

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

3-Methylcrotonyl-CoA carboxylase deficiency (MCCD) is an autosomal recessive condition characterized by impaired leucine metabolism and caused by homozygous or compound heterozygous mutations in the MCCC1 (MCCA) or MCCC2 (MCCB), genes encoding the alpha and beta subunits of the mitochondrial enzyme 3-methylcrotonyl-CoA carboxylase (MCC). The disease was first described in 1970 in a 4.5-month-old girl who presented with feeding difficulties, muscular hypotonia, motor developmental delay, muscular atrophy, and high concentrations of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine in the urine [3]. Subsequently, many cases of asymptomatic disease course with concurrent biochemical and molecular genetic alterations were identified.

MCC belongs to the family of biotin-containing carboxylases. MCC consists of two heterosubunits, alpha and beta ($\alpha$ and $\beta$), which form an $\alpha$6$\beta$6 dodecamer with a molecular weight of 845 kDa [2]. The MCCC1 (MCCA) gene, encoding the biotin-containing alpha subunit of MCC, consists of 19 exons and is mapped to the long arm of chromosome 3 (3q25-q27); the MCCC2 gene, encoding the beta subunit of MCC, consists of 17 exons and is located on the long arm of chromosome 5 (5q12-q13) [1]. The alpha subunit contains a biotin carboxylase domain, a biotin carboxylase carrier protein domain covalently bound to biotin, and substrate binding sites (for bicarbonate and ATP). The beta subunit contains a carboxyltransferase domain and binds 3-methylcrotonyl-CoA [2, 4-6]. When MCC activity decreases, an impairment occurs at the fourth step of leucine catabolism: the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA fails to take place (Fig. 1). The activity of the mutant enzyme is not stimulated by biotin, which distinguishes MCCD from multiple carboxylase deficiency. As a result of decreased MCC activity, organic acids accumulate in the urine (3-hydroxyisovaleric acid and 3-methylcrotonylglycine) [2], and blood acylcarnitine concentrations increase (3-hydroxyisovalerylcarnitine, the ratio of 3-hydroxyisovalerylcarnitine to propionylcarnitine, and sometimes 3-methylcrotonylcarnitine) [7]. Exerting a toxic effect on tissues, primarily the central nervous system and the liver, patients develop hypoglycemia, hyperammonemia, free carnitine deficiency, developmental delay, and seizures [6].

Figure 1. L-leucine catabolism. When 3-methylcrotonyl-CoA carboxylase (MCC) activity is reduced, an impairment occurs at the fourth step of leucine catabolism (red line), and 3-methylcrotonyl-CoA is not carboxylated to 3-methylglutaconyl-CoA. As a result, the levels of 3-hydroxyisovaleric acid and 3-hydroxyisovalerylcarnitine in the urine increase. Deficiencies of all enzymes indicated in italics are known.

According to ClinVar data, there are currently at least 126 pathogenic variants of the MCCC1 gene and 78 pathogenic variants of the MCCC2 gene associated with decreased enzyme activity and elevated metabolite concentrations in blood and/or urine.

The disease is genetically and phenotypically heterogeneous. Currently, no correlations have been established between the genotype and the clinical picture of MCCD [7], as known pathogenic variants have not been exclusively associated with either a mild/asymptomatic form or a more severe form of MCCD [1, 4, 8, 9]. Differences in phenotype between type 1 MCCD caused by mutations in the MCCC1 gene and type 2 MCCD caused by mutations in the MCCC2 gene have not been established either [10], and the degree of phenotypic severity varies among patients [9]. It has been demonstrated that even a complete absence of MCC enzyme activity far from always leads to clinical symptoms [1, 4]. It is hypothesized that the MCCD phenotype is influenced not only by the genotypes of the MCCC1 and MCCC2 loci, but also by other modifier genes and environmental factors [11-13].

The high level of 3-hydroxyisovaleric acid in biological fluids is explained by the hydration of 3-methylcrotonyl-CoA to 3-hydroxyisovaleryl-CoA by the action of crotonase followed by the hydrolysis of CoA esters, while the high concentration of 3-methylcrotonylglycine is a consequence of the conjugation of 3-methylcrotonyl-CoA with glycine [14]. An increase in the concentration of acyl-CoA thioesters leads not only to the accumulation of acyl-CoA derivatives in biological fluids and to metabolic acidosis, but also to their binding to carnitine and excretion from the body, since acylcarnitines (3-hydroxyisovalerylcarnitine) are not reabsorbed in the renal tubules. A decrease in free carnitine levels impairs the transport of fatty acids across the mitochondrial membrane and the generation of energy for metabolic processes [15]. Fasting, infections, and immunization stimulate catabolic processes, contribute to an increase in the concentration of amino acids, including leucine, and exacerbate the severity of processes along the molecular pathogenetic chain.

1.3 Epidemiology of the Disease or Condition

MCCD is one of the most frequent disorders within the group of organic acidurias detected using tandem mass spectrometry in neonatal screening programs in Europe, North America, and Australia. The prevalence of the disease varies across different populations: from 1:2,615 in Germany to 1:68,333 in China [16-23]. In the Russian Federation, the prevalence of the disease has not been determined.

1.4 Features of Coding the Disease or Condition

According to ICD-10, MCCD belongs to Class IV: Endocrine, nutritional and metabolic diseases.

ICD-10: E71.1 — Other disorders of branched-chain amino-acid metabolism.

ICD-11: 5C50.E0 — Classical organic acidurias.

OMIM: 210200 (type 1 MCCD), 210210 (type 2 MCCD).

ORPHA code: 6

1.5 Classification of the disease or condition

A distinction is made between type 1 MCCD caused by mutations in the MCCC1 gene and type 2 MCCD caused by mutations in the MCCC2 gene. No differences in phenotype have been established between type 1 and type 2 MCCD [10].

1.6 Clinical presentation of the disease or condition

Patients with MCCD have a variable clinical phenotype, with the vast majority of patients being asymptomatic, while a small subgroup exhibits clinical symptoms, usually associated with triggering external factors. Many newborns currently diagnosed through expanded screening programs remain asymptomatic, indicating a very low clinical penetrance of the disease [37]. Isolated patients may experience an acute metabolic crisis, usually between 2 and 33 months of age following a minor infection, fasting, or the introduction of a protein-rich diet. In such rare cases, MCCD manifests as a Reye-like syndrome triggered by an infectious disease, vaccination, fasting, or the introduction of a high-protein diet. The main symptoms are refusal to eat, vomiting, irritability, muscular hypotonia, altered mental status, lethargy, apnea, opisthotonos, hyperkinetic disorders, encephalopathy, epileptic seizures of the infantile spasm type, or convulsions against the background of metabolic ketoacidosis and hypoglycemia, sometimes combined with hyperammonemia [6, 16, 24-27]. Between episodes of metabolic crisis, patients are often asymptomatic. Between episodes of metabolic crisis, patients typically have no symptoms.

In some patients, weakness and fatigue are described during adolescence and adulthood, but the association of these symptoms with MCCD is not always precisely established.

Despite its low penetrance, MCCD can in extremely rare cases lead to a severe clinical phenotype resembling classical organic aciduria. However, neither the genotype nor the biochemical phenotype can help in predicting the clinical course.

In rare cases, patients with MCCD experience episodes of acute cerebrovascular accident, cardiomyopathy, alopecia, liver dysfunction, and physical, motor, and psycholinguistic developmental delay [17, 27-29]. Cases of fatal outcome resulting from encephalopathy, cardiac arrest, apnea, and metabolic crisis are known [6, 30-32].

Brain computed tomography (CT) or magnetic resonance imaging (MRI) in patients with clinical symptoms of MCCD reveals grey and white matter atrophy [33], thinning of the corpus callosum, calcifications in the thalamic region [34], delayed myelination [35], as well as white matter lesions resembling leukodystrophy [36].

Biochemical changes characteristic of 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) are detected by quantitative and qualitative analysis of urinary organic acids using gas chromatography-mass spectrometry (GC-MS) and determination of the blood acylcarnitine profile using tandem mass spectrometry (MS/MS). Patients with 3-MCCD show elevated concentrations of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid [2], as well as a high blood concentration of 3-hydroxyisovalerylcarnitine (C5OH), an increased ratio of C5OH to propionylcarnitine (C3), and occasionally a high concentration of 3-methylcrotonylcarnitine (C5:1) [7]. Secondary free carnitine deficiency is frequently detected in 3-MCCD because free carnitine binds to the toxic metabolite 3-hydroxyisovaleric acid, and the conjugate is excreted in the urine.

Cases have been reported in the literature where elevated metabolite concentrations in newborns resulted from maternal 3-MCCD [38-40]. Almost all mothers were clinically asymptomatic, and only one case reported symptoms of muscle weakness in the mother during adulthood.

Furthermore, it has been reported that heterozygous carriers of variants in the MCCC1 or MCCC2 genes exhibited altered metabolite profiles characteristic of 3-MCCD [41, 38]. Therefore, 3-MCCD is not included in newborn screening programs [43-46].

Cases of intrafamilial phenotypic variability in 3-MCCD have been described in the literature [47-49].

2. Diagnostics, medical indications and contraindications for diagnostic methods

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.

Criteria for establishing the diagnosis and conditions

The diagnosis of 3-MCCD is established based on a combination of medical history, clinical findings, and laboratory test results (biochemical and molecular genetic analysis). The detection of elevated concentrations of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid upon quantitative and qualitative analysis of urinary organic acids, as well as elevated blood acylcarnitine concentrations (C5OH, C5:1, increased C5OH/C3 ratio), allows for a clinical diagnosis.

The identification of pathogenic and likely pathogenic variants in the MCCC1 (MCCA) or MCCC2 (MCCB) genes via DNA diagnostics confirms the diagnosis at the molecular genetic level.

2.1 Complaints and Anamnesis

When taking the medical history and collecting complaints, attention should be paid to the following complaints and anamnestical events:

• positive family history (similar symptoms in siblings of the proband, consanguineous marriage);

• manifestation of the disease before 3-5 years of age;

• arrest/ delay/ loss of previously acquired psychomotor skills;

• lethargy, weakness, fatigue;

• depressed level of consciousness ranging from drowsiness to coma;

• seizure episodes;

• feeding difficulties, refusal to eat;

• episodes of vomiting after high-protein meals;

• unexplained anxiety, crying, limb tremor, hyperexcitability;

• respiratory disorders, including episodes of apnea;

• fluctuating (crisis-like) disease course;

• attention deficit hyperactivity disorder;

• cardiomyopathy and cardiac arrhythmias;

• diffuse muscular hypotonia.

Complaints and anamnesis are also described in the "Clinical Presentation" section.

2.2 Physical Examination

During the examination, attention should be paid to the main clinical manifestations of 3-MCCD:

- diffuse muscular hypotonia ("floppy infant syndrome");

- psychomotor developmental delay;

- seizure episodes;

- hepatosplenomegaly (in 10% of cases).

2.3 Laboratory Diagnostics

The main laboratory methods to confirm the diagnosis of 3-MCCD include quantitative and qualitative analysis of urinary organic acids, blood acylcarnitine determination, and molecular genetic testing of the MCCC1 and MCCC2 genes. These tests are performed in specialized genetic laboratories.

Comments: the test is performed using gas chromatography-mass spectrometry (GC-MS). Urinary organic acid profiles in 3-MCCD are characterized by increased excretion of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid [6, 7].

Comments: characteristic findings in 3-MCCD include elevated blood levels of C5OH and an increased C5OH/C3 ratio. Patients sometimes show a high concentration of C5:1 and secondary free carnitine deficiency [7]. An algorithm for the differential diagnosis of 3-MCCD with other diseases associated with elevated C5OH levels is provided in Appendix B.

Comments: the test is performed to search for biallelic pathogenic variants in the MCCC1 and MCCC2 genes.

Comments: performed during the initial examination and monitored at least once a year. If abnormalities are present, it is advisable to consider a referral for an initial consultation with a hematologist.

Comments: laboratory precursors of a metabolic crisis include a tendency toward metabolic acidosis with base deficit. It is advisable to perform these tests in adult patients when indicated.

Comments: patients with 3-MCCD may present with hypoglycemia, hyperammonemia, and elevated blood lactate levels.

2.4 Instrumental Diagnostics

Comments: brain CT/MRI in patients with 3-MCCD reveals cerebral gray and white matter atrophy [33], thinning of the corpus callosum, thalamic calcifications [34], delayed myelination [35], and white matter lesions resembling leukodystrophy [36]. It should be noted that these abnormalities are not highly specific and can be observed in other conditions. Anesthesia is performed as indicated; the technique is determined by the anesthesiologist-resuscitator and the attending physician based on the clinical status (combined endotracheal anesthesia, combined inhalation anesthesia (including the use of xenon), total intravenous anesthesia).

Comments: brain CT/MRI in patients with 3-MCCD reveals cerebral gray and white matter atrophy [33], thinning of the corpus callosum, thalamic calcifications [34], delayed myelination [35], and white matter lesions resembling leukodystrophy [36]. It should be noted that these abnormalities are not highly specific and can be observed in other conditions. Anesthesia is performed as indicated; the technique is determined by the anesthesiologist-resuscitator and the attending physician based on the clinical status (combined endotracheal anesthesia, combined inhalation anesthesia (including the use of xenon), total intravenous anesthesia).

Comments: cases of cardiomyopathy in patients with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency have been described in the literature [6, 48]. If necessary, Holter electrocardiographic monitoring and/or 24-hour ambulatory blood pressure monitoring may be performed (according to relevant clinical guidelines for cardiac arrhythmias and/or arterial hypertension). If abnormalities are detected, an initial consultation (examination) with a cardiologist is advisable.

Comments: cases of cardiomyopathy in patients with 3-MCC deficiency have been described in the literature [6, 48]. If necessary, Holter electrocardiographic monitoring and/or 24-hour ambulatory blood pressure monitoring may be performed (according to relevant clinical guidelines for cardiac arrhythmias and/or arterial hypertension). If abnormalities are detected, an initial consultation (examination) with a pediatric cardiologist is advisable.

Comments: 3-MCC deficiency is characterized by epileptic seizures of the infantile spasm type and the development of encephalopathy [6, 12, 32]. Video-electroencephalographic monitoring is performed when necessary. An initial consultation (examination) with a neurologist is required.

Comments: 3-MCC deficiency is characterized by epileptic seizures of the infantile spasm type and the development of encephalopathy [6, 12, 32]. Video-electroencephalographic monitoring is performed when necessary. An initial consultation (examination) with a neurologist is required.

2.5 Other Procedures

Specialist consultations and follow-up.

For the follow-up of patients with an established diagnosis of 3-MCC deficiency (presence of clinical symptoms, biochemical and molecular genetic data), a multidisciplinary approach is necessary because this disease is characterized by involvement of multiple organs and systems, which in turn dictates the need for joint management of the patient by specialists in various fields. Recommended are initial and follow-up consultations (examination) with a geneticist, neurologist, gastroenterologist, pediatrician / general practitioner (family physician), as well as initial and follow-up consultations with other specialists for patients with 3-MCC deficiency who have functional impairments of the respective organs and systems.

Comments: consultation with a medical geneticist at the diagnostic stage is necessary to determine DNA diagnostic tactics, correctly interpret the results of molecular genetic studies, and assess genetic risks within the family. Initial and follow-up consultations (examinations) by a pediatrician or nutritionist may also be scheduled for prescribing and adjusting therapy as needed. A high-carbohydrate, low-protein diet with leucine restriction is prescribed exclusively to patients with clinical symptoms of the disease; such therapy is not indicated for asymptomatic children identified through neonatal screening. Visit intervals should be determined individually, taking into account the patient's age, disease severity, metabolic stability, and dietary compliance.

Comments: patients with 3-MCC deficiency exhibit hyperexcitability, muscle hypotonia, depressed level of consciousness, lethargy, apnea, hypertonia, hyperkinetic disorders, encephalopathy, epileptic seizures of the infantile spasm type or convulsions against the background of metabolic ketoacidosis, hypoglycemia, sometimes combined with hyperammonemia [6, 16, 24-27]. Between metabolic crises, patients are often asymptomatic. In rare cases, patients with 3-MCC deficiency experience delayed physical, motor, and psycho-speech development [17, 27-29]. In some cases, an initial consultation (examination) with a psychiatrist may be required for children with suspected or confirmed mental disorders. The onset of mental disorders is associated with the accumulation of toxic metabolites. Adjustment of diet therapy helps resolve psychiatric symptoms. In adult patients, upon the appearance of corresponding complaints, an initial consultation (examination) with a neurologist is also required.

Comments: patients need testing using approved methods to assess intellectual development. Psychological support for patients may require a course of sessions depending on the individual characteristics of the patient and their family.

Speech therapy services:

• Medical speech therapy assessment for dysphagia;

• Medical speech therapy assessment for aphasia;

• Medical speech therapy assessment for dysarthria;

• Medical speech therapy procedure for dysphagia;

• Medical speech therapy procedure for aphasia;

• Medical speech therapy procedure for dysarthria;

• Medical speech therapy tonal-rhythmic procedure;

• Medical speech therapy procedure using interactive information technologies.

2.5.2 Differential Diagnosis

Differential diagnosis is carried out with other organic acidurias, fatty acid oxidation disorders, and other conditions accompanied by Reye-like syndrome, as well as multiple carboxylase deficiency (biotinidase deficiency, holocarboxylase synthetase deficiency) [59].

The algorithm for the differential diagnosis of 3-MCC deficiency with other diseases associated with elevated C5OH levels is shown in Fig. 1B in Appendix B.

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

The main principles of therapy for 3-MCC deficiency are aimed at preventing metabolic decompensation (metabolic crisis), reducing the formation of toxic organic acids, preventing toxic damage to brain tissue and internal organs, while ensuring normal growth processes and nutritional status in children.

3.1 Pathogenetic treatment

Fasting and other provoking factors must be avoided, and regular monitoring of free carnitine concentration should be performed.

Comment: the main components of treatment for patients with 3-MCC deficiency are a high-carbohydrate, low-protein diet with leucine restriction to prevent hypoglycemia and metabolic crisis. Diet therapy is prescribed in the presence of clinical symptoms of the disease. In some cases, diet therapy is continued into adolescence and adulthood. Fasting and other provoking factors must be avoided.

Comment: further dose adjustment depends on the free carnitine level. Regular testing of free L-carnitine levels in the blood and comprehensive determination of amino acid and acylcarnitine concentrations in the blood by tandem mass spectrometry are required.

3.1.1 Management of patients during a metabolic crisis

In the event of a metabolic crisis, treatment must be initiated immediately. Therapeutic measures are aimed at stopping the production and accumulation of toxic organic compounds and eliminating them from the body. Treatment tactics for children during a crisis include the correction of metabolic acidosis and water-electrolyte disturbances, as well as energy support. In the event of a metabolic crisis, emergency hospitalization is necessary for immediate intensive care and the prevention of life-threatening complications.

Treatment of a metabolic crisis is carried out in the intensive care unit by an anesthesiologist-resuscitologist, as well as other specialist physicians (neurologist, nephrologist, gastroenterologist, etc.). During crises, intravenous administration of dextrose**(B05CX Other irrigating solutions)** is necessary even with normal glucose levels to maintain its concentration at the upper limit of normal, which suppresses ketogenesis. When the pH level drops (<7.1), sodium bicarbonate** (B05XA Electrolyte solutions) is administered as a bolus followed by continuous infusion. Acid-base status and electrolytes must be monitored to avoid hypernatremia and hypokalemia. In severe cases, peritoneal dialysis or mechanical ventilation may be required.

3.2 Symptomatic treatment

Depending on indications, antiepileptic drugs and other types of symptomatic therapy are prescribed.

Comments: the examination is performed at least once every 6 months. Patients with IMDNS exhibit increased excitability, muscle hypotonia, depressed level of consciousness, lethargy, apnea, increased muscle tone, hyperkinetic disorders, encephalopathy, epileptic seizures such as infantile spasms or convulsions against the background of metabolic ketoacidosis, hypoglycemia, sometimes combined with hyperammonemia [6, 16, 24-27]. Between metabolic crises, patients are often asymptomatic. In rare cases, patients with IMDNS experience physical, motor, and psychomotor developmental delay [17, 27-29]. In adult patients, upon the appearance of relevant complaints, an initial and follow-up clinical examination (inspection, consultation) by a neurologist is also required.

Comments: the examination is performed at least once every 6 months. Cases of cardiomyopathy development in patients with IMDNS have been described in the literature [6, 48].

3.3 Surgical Treatment

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific rehabilitation is not required for patients with clinical symptoms of IMDNS. Rehabilitation measures for patients with IMDNS may include sessions with a psychologist, stays in specialized health resorts, as well as social adaptation with the participation of specialists and social workers, and courses of massage.

5. Prevention and Dispensary Observation

5.1 Prevention

Patients with IMDNS should receive prophylactic vaccination in accordance with the national immunization schedule, including vaccination against influenza and rotavirus infection (J07: Vaccines), observing age restrictions, against the background of strict adherence to medical prescriptions for the purpose of forming an effective immune response and preventing the development of metabolic crises. It is advisable to carry out 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. If fever >38.0°C is diagnosed, immediate prescription of antipyretic therapy (paracetamol^** or ibuprofen^**) is necessary.

Comments: Families with children diagnosed with IMDNS need to undergo medical genetic counseling to determine genetic risk. As with other autosomal recessive diseases, the risk of having an affected child for each pregnancy in IMDNS is 25%. Prenatal diagnosis of diseases that respond to effective therapy, as well as those with low penetrance, is possible, but ethically questionable; the decision to conduct it should be made after a detailed discussion of all risks and the specifics of the condition with the family.

5.2 Dispensary monitoring

Annually, patients with an established diagnosis of IMDNS must undergo an advanced medical check-up (dispensary evaluation). A multidisciplinary approach is required for the follow-up of patients with an established diagnosis of IMDNS. Initial and follow-up consultations by a geneticist, neurologist, gastroenterologist, pediatrician/general practitioner (family physician), as well as physicians of other specialties are indicated for patients with IMDNS who have dysfunctions of the respective organs and systems.

Patients with symptomatic epilepsy require monitoring by a neurologist with experience in working with epilepsy patients.

Necessary rehabilitation measures are also carried out. 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 procedures during the onset of a metabolic crisis.

Comments: monitored at least once a year. If abnormalities are present, it is advisable to consider a referral for an initial clinical examination (inspection, consultation) by a hematologist.

Comments: monitored at least once a year.

Comments: the levels of C5:1 and C5OH, as well as the C5OH/C3 ratio in the blood as a result of treatment, should be brought close to age-specific reference values.

Comments: the study is performed by gas chromatography-mass spectrometry (GC/MS). Organic acid profiles in urine in IMDNS are characterized by increased excretion of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid [7]. The frequency of tests depends on the patient's condition.

Comments: patients with IMDNS exhibit increased excitability, muscle hypotonia, depressed level of consciousness, lethargy, apnea, opisthotonos, hyperkinetic disorders, encephalopathy, epileptic seizures such as infantile spasms or convulsions against the background of metabolic ketoacidosis, hypoglycemia, sometimes combined with hyperammonemia [6, 16, 24-27]. Between metabolic crises, patients are often asymptomatic. In rare cases, patients with IMDNS experience physical, motor, and psychomotor developmental delay [17, 27-29]. In the presence of neurological disorders, adult patients also require a dispensary clinical examination (inspection, consultation) by a neurologist.

Comments: Patients with IMDNS require follow-up by a cardiologist (pediatric cardiologist) due to the risk of developing cardiomyopathy and cardiac arrhythmias [6, 48].

6. Organization of Medical Care

Indications for scheduled hospitalization in a medical organization:

1. Provision of diagnostics and treatment requiring prolonged (daytime or round-the-clock stay) medical observation and monitoring of clinical and laboratory parameters;

2. 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 threatening the development of complications that require urgent treatment, including intensive care, as well as round-the-clock medical observation and special types of examination and treatment.

Indications for discharging a patient from a medical organization:

1. Absence of threat to the patient's life and threat of complications requiring urgent treatment upon completion of diagnostic measures.

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.

7. Additional Information

Without pathogenetic treatment during a metabolic crisis, the overwhelming majority of children die. With timely correction and prevention of metabolic crises, adherence to and strict control of pathogenetic therapy and symptomatic treatment, the prognosis for life is favorable.

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

1. Inga V. Anisimova, Candidate of Medical Sciences, Head of the Department of Medical Care Organization, Academician N.P. Bochkov Research Centre for Medical Genetics, medical geneticist, member of the Association of Medical Geneticists.

2. Galina V. Baydakova, Candidate of Biological Sciences, Head of the Metabolom Shared Research Facility, Leading Research Fellow at the Laboratory of Hereditary Metabolic Diseases, Academician N.P. Bochkov Research Centre for Medical Genetics, member of the Russian Society of Medical Genetics

3. Alexander A. Baranov, Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pediatricians 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 of the Ministry of Health of Russia (Sechenov University), Chief Freelancer Pediatrician of the Ministry of Health of Russia

4. Polina V. Baranova, Researcher at the Metabolom Shared Research Facility, Academician N.P. Bochkov Research Centre for Medical Genetics.

5. Tatyana V. Bushuyeva, Doctor of Medical Sciences, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, member of the Union of Pediatricians of Russia.

6. 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 Ministry of Health of Russia

7. Anna V. Degtyareva, Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics, Institute of Neonatology and Pediatrics, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Professor at the Department of Neonatology, Institute of Child Health, Sechenov First Moscow State Medical University, member of the Council of the Russian Society of Neonatologists

8. Zakharova Ekaterina Yuryevna, Doctor of Medical Sciences, Head of the Laboratory of Inherited Metabolic Diseases, 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).

9. Viktoria S. Kakaulina, neurologist, epileptologist Morozov Children's City Clinical Hospital of the Moscow Healthcare Department, member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

10. Tatyana N. Kekeeva, Head of the Medical Genetics Department, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department, medical geneticist.

11. Krasnoshchekova Nina Alexandrovna, Pediatrician, medical geneticist, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department.

12. Lyudmila M. Kuzenkova, Doctor of Medical Sciences, Head of the Department of Psychoneurology and Psychosomatic Pathology, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, member of the Union of Pediatricians of Russia.

13. Sergey I. Kutsev, Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Director of the Academician N.P. Bochkov Research Centre for Medical Genetics, President of the Association of Medical Geneticists.

14. Anastasia Yu. Lobenskaya — Head of the Biochemical Laboratory, laboratory geneticist, Diagnostic Center (Medical Genetics), St. Petersburg.

15. Svetlana V. Mikhailova, Doctor of Medical Sciences, Head of Department, Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University.

16. 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 Russian Academy of Sciences, member of the Association of Medical Geneticists.

17. Leyla S. Namazova-Baranova, Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Union of Pediatricians 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 Ministry of Health of Russia, Chief Freelancer Pediatric Specialist in Preventive Medicine of the Ministry of Health of Russia

18. 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 Genetics, member of the Association of Medical Geneticists

19. Natalia L. Pechatnikova, Head of the City Center for Orphan and Other Rare Diseases in Children and Adolescents, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department.

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

21. Liliya R. Selimzyanova, Candidate of Medical Sciences, Head of Department, 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 of the Ministry of Health of Russia (Sechenov University), Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, member of the Union of Pediatricians of Russia

22. Olga Ya. Smirnova, medical geneticist, Senior Research Fellow at the Department of Standardization and Study of Evidence-Based Medicine Foundations, Research Institute of Pediatrics and Child Health, Central Clinical Hospital of the Russian Academy of Sciences.

23. Strokova Tatyana Viktorovna, D.Sc. (Med.), Professor of the RAS, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Clinic of the Federal Research Centre of Nutrition and Biotechnology.

24. Dmitry M. Subbotin, medical geneticist, Academician N.P. Bochkov Research Centre for Medical Genetics, member of the Association of Medical Geneticists.

25. Sumina Maria Gennadyevna, Head of the Department of Medical Genetic Counseling, Medical Geneticist, Clinical and Diagnostic Center "Maternal and Child Health Protection" of the Sverdlovsk Region.

26. Natalia N. Taran, Candidate of Medical Sciences, Senior Research Fellow at the Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Federal Research Center of Nutrition and Biotechnology, Assistant at the Department, Pirogov Russian National Research Medical University of the Ministry of Health of Russia.

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.

Clinical guidelines are based on a systematic literature review for 1970–2022 of Medline (Pubmed version), Embase (Dialog version), and Cochrane Library databases, using established protocols of current international clinical guidelines for the diagnosis, treatment, and management of patients with metabolic diseases.

3-methylcrotonyl-CoA carboxylase deficiency is a rare hereditary disease, which precludes conducting large cohort and randomized controlled trials; therefore, only expert case studies published over the past two decades are used to create diagnostic and treatment protocols.

The evaluation of the quality of evidence and the strength of recommendations for the application of medical technologies was performed in accordance with the standardized scale presented in Tables 1–3.

Target audience for these clinical guidelines:

1. General practitioners (family physicians);

2. Pediatricians;

3. General practitioners;

4. Medical geneticists;

5. Laboratory geneticists;

6. Cardiologists;

7. Pediatric cardiologists;

8. Neurologists;

9. Radiologists;

10. Functional diagnostics physicians;

11. Gastroenterologists;

12. Medical psychologists;

13. Medical students;

14. Residents and postgraduate students.

Table 1. Levels of Evidence (LoE) rating scale for diagnostic methods (diagnostic interventions).

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

Table 3. Scale for grading levels of recommendation evidence (LRE) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions).

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

1. Federal Law No. 323-FZ dated November 21, 2011 (as amended on December 28, 2022) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" (with rev. and add., effective January 11, 2023).

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

3. Order of the Ministry of Health of Russia No. 804n dated October 13, 2017 (as amended on September 24, 2020, with rev. dated October 26, 2022) "On Approval of the Nomenclature of Medical Services".

4. Order of the Ministry of Health of Russia No. 203n dated May 10, 2017 "On Approval of Criteria for Assessing the Quality of Medical Care".

5. Order of the Ministry of Health of Russia No. 205n dated May 2, 2023 (as amended on December 4, 2023) "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers".

6. Order of the Ministry of Health of Russia No. 700n dated October 7, 2015 (as amended on December 9, 2019) "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education".

7. Order of the Ministry of Health of Russia No. 103n dated February 28, 2019 (as amended on June 23, 2020) "On Approval of the Procedure and Deadlines for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

8. Information on medicinal products: https://grls.rosminzdrav.ru/

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

Collection of biomaterial for diagnosis using dried blood spots.

Preparation for blood collection

Preparation for blood collection is standard: medical personnel must observe sterility rules, wiping the puncture site with an antiseptic solution (D08: Antiseptics and disinfectants), using disposable lancet needles and gloves.

Obtaining a dried blood spot

As a rule, to obtain dry spots [61], blood is collected from a finger; venous blood collected from a tube containing EDTA can also be used (depending on the test kits used).

In newborns, blood for neonatal screening and retesting is collected exclusively from the heel, and in exceptional cases from a finger (if heel blood collection is impossible).

The puncture site (heel, finger) should be cleaned with a sterile wipe moistened with 70% ethanol**, and then blotted with a dry sterile wipe. The first drop formed at the puncture site is discarded — it is wiped away with a dry cotton swab. Subsequent drops are applied one by one into the circles on the absorbent membrane of the test card. The circles on the card must be saturated evenly and completely, without white spots on the reverse side of the card (Fig. 1D). Obtaining a single spot requires 80–100 µl of blood. After applying the blood to the test card, the sample is allowed to dry completely for at least 2 hours at room temperature, without contacting other test cards. After drying, the test cards are placed into individual packaging, ensuring the blood spots do not touch or overlap with each other.

Figure 1D. Dry blood spots on the test card.

For molecular genetic and biochemical studies outside of neonatal screening, in addition to droplet application, the required volume of whole blood may be applied to the test form using a semi-automatic dispenser, for example, from a tube containing the analyzed biological material.

Transportation of test forms is carried out at a temperature not exceeding 25°C [MR SPK].

Algorithm of actions for medical personnel during blood sample collection:

• wash hands (hygienic level), put on gloves;

• wash the patient's hands (the child's heel if blood is collected from the heel);

• wipe the puncture area with a sterile wipe moistened with 70% ethanol**, and blot with a dry sterile wipe; — puncture with a sterile disposable lancet;

• remove the first drop of blood with a sterile dry swab;

• gently press to obtain a second drop of blood;

• apply the test card perpendicularly to the drop of blood and saturate it completely through with blood;

• apply 6–8 drops to the test form in a similar manner; the appearance of the blood spots should be identical on both sides.

• dry the test card in a horizontal position on a clean, grease-free surface for at least 4 hours without heat treatment and direct sunlight;

• package the test cards in a clean envelope so that the blood spots do not touch.

Specifics during infusion therapy

Certain patients may receive infusion therapy or blood component transfusions, which can affect test results. For example, plasma transfusions may yield false-negative results because the enzymes being determined are present in both plasma and blood cells. It is recommended to perform blood collection for enzyme and DNA diagnostics no earlier than 6–7 days after plasma transfusion and 7–10 days after blood component transfusion.

Blood collection is not permitted:

• immediately after the patient undergoes infusion therapy;

• immediately after an exchange blood transfusion.

Storage and transportation of biological material

Dried blood spot samples can be stored in a standard refrigerator compartment at +4°C until shipment. The storage period prior to shipment must not exceed 7 days. The temperature during transportation of the biological material must be between 0°C and +10°C. If stored longer and at a higher temperature, enzyme activity may decrease even in normal ranges, leading to false-positive results.

Percentile values

Appendix B. Physician Action Algorithms

If 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is detected, it is necessary to call the family in for a consultation and examine the child to address the issue of hospitalization. Since an elevated C5OH concentration is not specific to this disease, additional tests and confirmatory diagnostics are required (Fig. 1B). The prognosis is favorable and largely depends on the timing of diagnosis and initiation of treatment.

Newborns with suspected 3-MCCD are subject to hospitalization in a neonatal pathology or pediatric intensive care unit (depending on their condition), where blood is collected for a retest, as well as urine samples for organic acid analysis (samples are sent to a reference center). Depending on the urine organic acid results, the diagnosis of 3-MCCD can be biochemically confirmed or another diagnosis established. Upon receiving positive results, the newborn should be immediately referred to a specialist (medical geneticist, pediatrician) to prescribe pathogenetic therapy, perform confirmatory diagnostics, provide family training and counseling, and organize follow-up care. Confirmatory diagnostics include molecular genetic testing of the MCCC1 and MCCC2 genes and is performed at a reference center.

Figure 1B. Algorithm for the differential diagnosis of 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) with other diseases associated with elevated levels of 3-hydroxyisovalerylcarnitine (C5OH): holocarboxylase synthetase deficiency and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

Appendix C. Patient Information

What is 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD)?

3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is a rare inherited amino acid metabolism disorder associated with defects (mutations) in the MCCC1 or MCCC2 genes.

Genes represent a DNA sequence that encodes instructions for making proteins or RNA (ribonucleic acid). Genes are located on chromosomes. Humans have 23 pairs of chromosomes. One chromosome with its corresponding set of genes is inherited from the mother, and the second from the father.

When a mutation occurs in the MCCC1 or MCCC2 genes, they can no longer serve as "instructions" to produce the MCC enzyme. Normally, the MCC enzyme plays an important role in processing leucine, an amino acid found in many proteins. Thus, in patients with 3-MCCD, the resulting enzyme functions improperly or is not produced in the body at all. When patients with 3-MCCD eat protein-rich foods, a large amount of leucine accumulates in the blood and turns into dangerous toxic substances that harm the body.

How does 3-MCCD manifest?

The severity of the disease varies greatly from an asymptomatic form to a life-threatening condition. Most children who have been found to have biochemical and molecular genetic alterations remain asymptomatic and do not require treatment. However, a small number of children may experience symptoms resembling poisoning (intoxication): frequent regurgitation, vomiting, refusal to eat, muscle weakness, lethargy, seizures, and increased drowsiness. They may experience "metabolic crises," which typically develop between the ages of 2 months and 3–5 years. Crises are usually triggered by adverse factors such as viral and bacterial infections, stressful situations, trauma, surgical interventions, and emotional and physical exertion. Prodromal signs of a crisis include decreased emotional tone, lethargy, and drowsiness. Subsequently, the child refuses to eat, may vomit, and may develop a fever, especially at the onset of an infectious disease, along with seizures.

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

How is 3-MCCD inherited?

3-MCCD is inherited in an autosomal recessive manner. This means that both parents are carriers and transmit two copies of the altered gene to the child. A carrier inherits only one "damaged" copy: either from the father or the mother. Carriers do not have the disease and show no signs of illness. The risk of having a child with 3-MCCD in a family where both parents are carriers of the "mutated" gene is 25% for each pregnancy (Fig. 1C). The disease manifests only when two copies of the damaged gene (the gene with the mutation) are present. Boys and girls are affected with equal frequency.

Siblings of a child with 3-MCCD may also have the disease, even if they had 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 can also be carriers, just like their parents. Regarding other family members, it is important to inform them that they may be carriers. This means they are also at risk of having a child with this condition.

All families with 3-MCCD must undergo genetic counseling and receive complete information from a medical geneticist regarding the risk of recurrence of this disease in the family, and discuss all questions related to disease inheritance with a specialist. In Russia, medical genetic clinics operate in every region.

Figure 1C. Inheritance pattern of 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD). When two copies of the "affected" gene ("r") are inherited from both carrier parents, the risk of having a child with 3-MCCD is 25% ("rr").

How is 3-MCCD diagnosed?

Initial diagnosis of the disease is performed by a pediatrician. Based on clinical symptoms, the physician may suspect the diagnosis and refer the patient for laboratory testing. Tandem mass spectrometry (TMS) is used to determine the levels of compounds such as carnitine, acylcarnitines, and amino acids in the blood, while gas chromatography-mass spectrometry (GC/MS) is used to determine urine organic acid levels. In 3-MCCD, there is an elevation in blood concentration of 3-hydroxyisovalerylcarnitine (C5OH), often an elevated C5OH/C3 ratio, and sometimes an elevated level of 3-methylcrotonylcarnitine (C5:1). Urine analysis reveals increased concentrations of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid. Patients with biochemical changes characteristic of 3-MCCD undergo molecular genetic testing to identify mutations in the MCCC1 or MCCC2 genes to confirm the diagnosis.

How are patients with 3-MCCD treated?

The main therapeutic principle in cases where clear clinical symptoms indicate 3-MCCD is the prescription of medications containing levocarnitine if patients exhibit low levels of free carnitine. Levocarnitine is a safe and natural substance that helps cells produce energy. Antiepileptic drugs are also prescribed according to indications.

In the presence of clinical symptoms and metabolic crises, patients with 3-MCCD must adhere to a diet consisting of foods low in leucine. The physician will create a meal plan containing the required amount of protein, nutrients, and energy. This meal plan must be followed throughout life. A medical geneticist and nutritionist will help calculate the diet, introduce complementary foods correctly, and teach the basic rules of medical nutrition therapy. It is extremely crucial to follow all medical recommendations to prevent the development of metabolic crises.

How are patients treated during a metabolic crisis?

At home, at the very first signs of illness, especially when the child has a decreased appetite (e.g., during a cold, flu-like symptoms, viral infections, any illnesses accompanied by a temperature >37°C, tonsillitis, gastroenteritis), therapy to prevent a crisis should be initiated. If parents are unsure whether the child is showing the early signs of an impending illness (pallor, lethargy, irritability, loss of appetite, fever, headache, body aches and generalized pain, cough, sore throat, or earache), as a precautionary measure, the child should be given a glucose polymer solution—maltodextrin—to drink once.

The earliest signs are usually minor behavioral changes that are easily noticed by parents. If the child is relatively healthy and has no vomiting, presenting only with weakness and mild drowsiness, oral rehydration with a glucose polymer solution should be given in frequent, small fractions (Table 1B). 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 suitable for your child. Some children dislike the taste of the glucose polymer and prefer store-bought beverages, but the carbohydrate concentrations in such drinks are lower. Store-bought beverages should be used with caution. Low-calorie and sugar-free drinks contain very little or no carbohydrates and therefore should not be used.

Upon the first signs of a metabolic crisis, without waiting for a doctor, protein intake should be discontinued (for 24, maximum 48 hours), the dose of oral levocarnitine increased to 50–100 mg/kg/day, and the dose of glycine** doubled. 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 seek medical evaluation at a hospital. Emergency medical personnel must be provided with the medical summary containing the doctor's conclusion and therapy recommendations for the metabolic crisis period. Parents should bring all information about the used solutions to the hospital, and ideally the solutions themselves.

Table 1B. Maltodextrin volume during a metabolic crisis (European registry and network for intoxication type metabolic diseases (E-IMD) 2014).

What monitoring should be performed for patients with 3-MCC deficiency?

A multidisciplinary approach to the follow-up and treatment of patients with 3-MCC deficiency by specialists of various profiles is necessary to ensure comprehensive therapy and its timely correction if needed. Regular examinations are required for patients with 3-MCC deficiency. Table 2B provides an exemplary list and frequency of examinations, however, the exact examination plan is agreed upon individually with the attending physician.

Table 2B. Frequency of examinations in 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency.

How do patients receive treatment in the Russian Federation?

Since 3-MCC deficiency is generally asymptomatic, it is not included in the list of rare (orphan) diseases and is not part of the expanded neonatal screening program. For children with clinical manifestations of the disease, therapy is prescribed in accordance with clinical guidelines after the diagnosis is established.

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 requires a special diet, and close relatives must master the skills of diet calculation. Parents of a patient with 3-MCC deficiency, and subsequently the patient themselves, must be trained in the rules of managing therapy during the intercritical period and during the threat of a metabolic crisis.

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

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

Appendix G1. Alberta Infant Motor Scale

Russian title: Alberta Infant Motor Scale.

Original title: Alberta Infant Motor Scale (AIMS).

Source (official developer website, validation publication): Piper MC, Pinnell LE, Darrah J, Maguire T, Byrne PJ. Construction and validation of the Alberta Infant Motor Scale (AIMS). Can J Public Health. 1992;83: S46-50.

Type (underline):

- assessment scale

Purpose: The Alberta Infant Motor Scale (AIMS), an observational rating scale, was designed to measure gross motor maturation in infants from birth through independent walking.

Content (template): Based on literature, 58 skills were generated and categorized into four positions: prone, supine, sitting, and standing. Each skill is assigned a specific score.

Key (interpretation): scores are summed, an overall assessment of motor development and deviation/conformity to normal development in percentiles is performed

Alberta Infant Motor Scale

Total score: ______ percentile: ______

Notes/Recommendations:

INFANT MOTOR DEVELOPMENT RATING SCALE