Mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase deficiency, T2 deficiency): clinical guidelines

List of Abbreviations

2MAA-CoA — 2-methylacetoacetyl-CoA;

2M3HB-CoA — 2-methyl-3-hydroxybutyryl-CoA;

3HB — 3-hydroxybutyrate;

3HB dehydrogenase — 3-hydroxybutyrate dehydrogenase;

AcAc — acetoacetate;

C5:1 — 3-methylcrotonylcarnitine;

C5OH — 3-hydroxyisovalerylcarnitine;

HbA1c — glycated hemoglobin;

SCOT (succinyl-CoA:3-ketoacid CoA transferase) — succinyl-CoA:3-ketoacid CoA transferase;

AA-CoA — acetoacetyl-coenzyme A;

HMG-CoA — 3-hydroxy-3-methylglutaryl-CoA;

MAT — mitochondrial acetoacetyl-coenzyme A thiolase (T2);

mHMG-CoA synthase — mitochondrial HMG-CoA synthase;

MAT deficiency — mitochondrial acetoacetyl-coenzyme A thiolase (T2) deficiency;

T1 — mitochondrial 3-ketoacyl-CoA thiolase;

MS/MS — 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

Mitochondrial acetoacetyl-CoA thiolase deficiency (MAT deficiency, beta-ketothiolase deficiency, T2 deficiency, OMIM 203750) is a progressive inherited metabolic disorder caused by a defect in the ACAT1 gene, associated with impaired isoleucine and ketone body metabolism. The disease is characterized by episodes of ketoacidosis with accumulation of isoleucine metabolites detected by quantitative and qualitative analysis of urinary organic acids (2-methyl-3-hydroxybutyrate (2M3HB), 2-methylacetoacetate, tiglylglycine), as well as elevated blood concentrations of acylcarnitines (3-hydroxyisovaleroylcarnitine (C5OH) and 3-methylcrotonylcarnitine (C5:1)) with or without hypoglycemia [1].

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

MAT deficiency is a genetic disorder characterized by impaired isoleucine catabolism and ketone body utilization, which predisposes to episodes of ketoacidosis [2]. The disease was first described in 1971 in a 6-year-old boy with episodes of metabolic acidosis and elevated α-methylacetoacetate and α-methyl-β-hydroxybutyrate in urine [3]. Characteristic laboratory findings include marked ketonuria and increased urinary excretion of isoleucine catabolic intermediates such as 2-methyl-3-hydroxybutyrate (2M3HB), tiglylglycine, and 2-methylacetoacetate [2]. Cases of MAT deficiency presenting with acute ketoacidosis and "metabolic stroke" are known [1]. Identification of pathogenic variants in the ACAT1 gene by DNA diagnostics confirms the diagnosis of MAT deficiency at the molecular genetic level [4].

Ketone body metabolism begins in hepatocytes with fatty acid beta-oxidation, yielding acetyl-CoA and acetoacetyl-coenzyme A (AA-CoA). MAT, a mitochondrial matrix enzyme, converts acetyl-CoA into AA-CoA and vice versa. Mitochondrial HMG-CoA synthase (mHMG-CoA synthase) catalyzes the formation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) from acetyl-CoA and AA-CoA. HMG-CoA is converted by HMG-CoA lyase into acetoacetate (AcAc), which is partially reduced to 3-hydroxybutyrate (3HB) through the activity of 3-hydroxybutyrate dehydrogenase (3HB dehydrogenase) (Fig. 1). In the absence of glucose, the ketone bodies AcAc and 3HB serve as important energy sources for extrahepatic organs, particularly the brain, during periods of insufficient energy supply. Next, AcAc and 3HB are transported via the bloodstream to extrahepatic tissues, where 3HB is converted back into AcAc. Succinyl-CoA:3-ketoacid-CoA transferase (SCOT) converts AcAc into AcAc-CoA, which is then cleaved again by MAT to form acetyl-CoA (Fig. 1).

In isoleucine catabolism, the MAT enzyme is responsible for converting 2-methylacetoacetyl-CoA (2MAA-CoA) into acetyl-CoA and propionyl-CoA. The conversion of tiglyl-CoA to 2-methyl-3-hydroxybutyryl-CoA (2M3HB-CoA) and the conversion of 2M3HB-CoA to 2MAA-CoA are reversible reactions. The latter reaction is catalyzed by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase. In T2D deficiency, there is an accumulation of 2MAA-CoA, 2M3HB-CoA, and tiglyl-CoA (Fig. 1).

Mitochondrial 3-ketoacyl-CoA thiolase (T1) compensates for T2 deficiency in ketogenesis; therefore, T2 deficiency primarily leads to ketosis.

The disease results from mutations in the ACAT1 gene, which encodes the MAT enzyme. The gene is mapped to the long arm of chromosome 11 (11q22.3-23.1) and consists of 12 exons spanning approximately 27 kb. To date, at least 105 mutations in the ACAT1 gene are known, the majority of which are missense mutations [5]. For example, pathogenic variants c.622C>T (p.R208*), c.1006–1G>C, and c.1124A>G (p.N375S) predominate in the Chinese population [6], whereas variant c.578T>G (p.Met193Arg) is predominant in the Indian population [7]. In Vietnam, the pathogenic variant c.622C>T (p.Arg208*) prevails [8, 9].

Currently, genotype-phenotype correlation in T2 deficiency has not been established [10].

1.3 Epidemiology of the Disease or Condition

The global prevalence of T2 deficiency is approximately 1 in 1 million newborns [11]. In Vietnam, the disease incidence between 2005 and 2016 was 1:190,000 newborns [8], while in China, based on newborn screening of 16 million neonates, the incidence of T2 deficiency was 1 in 1 million [6]. The prevalence of T2 deficiency in the Russian Federation has not been established.

Figure 1. Overview of ketone body metabolism and isoleucine catabolism.

T2 (MAT) is involved in isoleucine catabolism, hepatic ketogenesis, and extrahepatic ketolysis. CoA = coenzyme A, 2M3HB = 2-methyl-3-hydroxybutyrate, 2M3HB-CoA = 2-methyl-3-hydroxybutyryl-CoA, 2M3HB dehydrogenase = 2-methyl-3-hydroxybutyrate dehydrogenase, 2M-acetoacetate = 2-methylacetoacetate, 2M-acetoacetyl-CoA = 2-methylacetoacetyl-CoA, 3HB = 3-hydroxybutyrate, 3HB dehydrogenase = 3-hydroxybutyrate dehydrogenase, HMG-CoA = 3-hydroxy-3-methylglutaryl-CoA, HMG-CoA lyase = 3-hydroxy-3-methylglutaryl-CoA lyase, mHMG-CoA synthase = mitochondrial HMG-CoA synthase, SCOT = succinyl-CoA:3-ketoacid-CoA transferase, T1 = mitochondrial 3-ketoacyl-CoA thiolase, T2 = mitochondrial acetoacetyl-CoA thiolase (MAT).

1.4 Features of Coding the Disease or Condition

According to ICD-10, T2 deficiency belongs to Class IV — Endocrine, nutritional and metabolic diseases.

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

ICD-11: 5C50.DY — Other specified disorders of branched-chain amino acid metabolism.

OMIM: 203750

ORPHA code: 134

1.5 Classification of the disease or condition

Classification is absent.

1.6 Clinical presentation of the disease or condition

The age of onset for T2 deficiency ranges from 2 days to 8 years. In 80% of patients, the disease manifests in the first two years of life. The frequency of neonatal-period manifestation is low and does not exceed 3.5% [4].

T2 deficiency is characterized by alterations in the urinary organic acid profile, manifested by elevated concentrations of 2M3HB, 2-methylacetoacetate, and tiglylglycine, as well as elevated blood acylcarnitines (C5OH, C5:1). In the vast majority of patients, the disease debuts acutely with metabolic decompensation (crisis), severe ketoacidosis, vomiting, dehydration, hypotension, respiratory failure, seizures, and lethargy. In rare cases, the disease debuts with progressive neurological symptoms such as muscular hypotonia, seizures, delayed motor development, various movement disorders (chorea, myoclonus), ataxia, and paraplegia [5, 12, 13-16].

The metabolic crisis is typically characterized by severe metabolic acidosis (pH <7.0), ketosis, altered mental status, and coma. The frequency of episodes decreases with age, and between crises, the patient is usually asymptomatic. Ketoacidosis attacks are frequently triggered by stress: fasting, acute illnesses (e.g., gastroenteritis, respiratory infections), fever, infection, and vaccination [17]. During ketoacidotic crises in T2 deficiency, blood glucose levels vary from 0.6 to 23.3 mmol/L. As a rule, hypoglycemia during ketoacidotic attacks is rare [18]. A case of genetically confirmed T2 deficiency with multiple episodes of hypoketotic hypoglycemia in the neonatal and pediatric period has been documented [18]. A case of a ketoacidotic crisis in T2 deficiency without elevated C5OH and C5:1 levels was also reported in Japan [19].

Patients with T2 deficiency may also exhibit moderate hyperammonemia and elevated liver transaminases [4]. Some patients present with decreased plasma free carnitine [15, 20]. In a study of patients with T2 deficiency of various ethnicities [4], developmental delay was observed in 19.6% (40/204), frequently combined with neurological disorders. Movement disorders occurred in 6.3% of cases (13/204) and included muscle tone abnormalities, choreoathetosis, and myoclonic hyperkinesia. Epileptic seizures outside of crises are quite rare [4] and are associated with a prior metabolic crisis. Cardiomyopathy may develop in isolated patients [21].

Brain magnetic resonance imaging (MRI) reveals increased T2 signal in the basal ganglia, involving the globus pallidus, putamen, lentiform and caudate nuclei, and substantia nigra. Patients with T2 deficiency exhibit involvement of the internal and external capsules, cortical and subcortical cerebral atrophy, involvement of the midbrain, as well as scattered lesions in the periventricular and subcortical white matter of the brain [4].

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 diagnosis and conditions.

The diagnostic criterion for T2 deficiency is the detection of elevated urinary concentrations of 2M3HB, tiglylglycine, and 2-methylacetoacetate upon quantitative and qualitative organic acid analysis, alongside elevated blood acylcarnitines (C5OH, C5:1).

The diagnosis is established based on a combination of medical history, clinical data, and laboratory findings (biochemical and molecular genetic analysis). Identification of pathogenic and likely pathogenic variants in the ACAT1 gene 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);

− disease onset from 2 days to 8 years;

− stagnation, delay, or loss of previously acquired psychomotor skills;

− lethargy, weakness;

− depressed level of consciousness ranging from somnolence to coma;

− seizure episodes;

− feeding difficulties, vomiting;

− respiratory disorders.

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

2.2 Physical Examination

Physical examination should focus on the main clinical manifestations of T2 deficiency:

− muscular hypotonia ("floppy infant syndrome");

− delayed psychomotor development;

− hepatomegaly;

− seizure episodes.

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.

The main laboratory methods for confirming a diagnosis of T2 deficiency include quantitative and qualitative analysis of urinary organic acids, blood acylcarnitine testing, and molecular genetic testing of the ACAT1 gene. These tests are performed in specialized genetic laboratories.

Comments: Urinary organic acid profiles in T2 deficiency are characterized by increased excretion of tiglylglycine, 2M3HB, and 2-methylacetoacetate both during ketoacidotic crises and during the interictal period.

Comments: Characteristic markers of IEAD are high concentrations of C5:1 and C5OH. Some patients show decreased free carnitine [15, 20]. However, normal levels of these metabolites do not rule out IEAD: false-negative newborn screening results have been repeatedly documented in various laboratories using different cut-off points. Furthermore, a case of ketoacidotic crisis in IEAD with normal blood C5OH and C5:1 levels has been reported [19]. The screening algorithm for IEAD is provided in Appendix B.

Comments: Most mutations in patients with IEAD can be detected by Sanger sequencing of all exons and adjacent intron regions of the ACAT1 gene, but in a small percentage of cases, mutations cannot be detected using standard methods. To date, at least 105 mutations in the ACAT1 gene are known, the majority of which are missense mutations [5]. For example, in the Chinese population, prevalent pathogenic variants include c.622C>T (p.Arg208Ter), c.1006–1G>C, and c.1124A>G (p.Asn375Ser) [6]; in the Indian population, the c.578T>G (p.Met193Arg) variant [7]; and in Vietnam, the c.622C>T (p.Arg208Ter) pathogenic variant prevails [8, 9].

Comments: Laboratory precursors of a metabolic crisis include a tendency toward metabolic acidosis with base deficit. The main biochemical marker in IEAD is a high concentration of ketone bodies. During ketoacidotic crises, blood ketone body concentrations in patients with IEAD exceed 7 mmol/L [11].

Comments: patients with IEAD may exhibit moderate hyperammonemia [4]. Lactic acid (lactate) concentrations should be measured during the first metabolic crises in undiagnosed patients to rule out congenital lactic acidosis [11]. Blood glucose levels are usually within the normal range, but in isolated cases, hypoglycemia (<2.5 mmol/L) or hyperglycemia (>7.8 mmol/L) may be observed. Thus, blood glucose levels during ketoacidotic crises in patients with IEAD range from 0.6 to 23.3 mmol/L [18].

Comments: testing is performed for blood levels of albumin, total protein, total bilirubin, free and conjugated bilirubin, urea, creatinine, potassium, sodium, and serum iron; and determining the activity of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase in the blood. Patients with IEAD show elevated transaminase activity [4].

2.4 Instrumental Diagnostics

Comments: computed tomography/magnetic resonance imaging of the brain reveals an increase in T2 signal in the basal ganglia with involvement of the globus pallidus, putamen, lentiform and caudate nuclei, and substantia nigra. Involvement of the internal and external capsule, cortical and subcortical atrophy of the cerebral hemispheres, involvement of the midbrain, and scattered lesions in the periventricular and subcortical white matter of the brain are also observed [4]. It should be noted that these abnormalities are not highly specific and may be observed in other diseases. Anesthesia is performed according to indications.

Comments: Epileptic seizures outside of crises are quite rare [4] and are associated with a prior metabolic crisis. Studies are performed during diagnostics and follow-up observations, as needed.

Comments: Rare cases of cardiomyopathy development in patients with IEAD have been reported in the literature [21].

2.5 Other Procedures

Monitoring patients with an established diagnosis of IEAD requires a multidisciplinary approach because the disease is characterized by damage to many organs and systems, which in turn necessitates joint management of the patient by specialists in various fields. Indicated are initial and follow-up consultations by a geneticist, ophthalmologist, neurologist, gastroenterologist, cardiologist, pediatrician/general practitioner/family physician, as well as other specialists for IEAD patients with impaired functions of the respective organs and systems.

Comments: consultation with a geneticist at the diagnostic stage is necessary to determine DNA diagnostic tactics, correctly interpret the results of molecular genetic studies, and assess genetic risks in the family. Intervals between visits in the event of prescribing/adjusting diet therapy should be determined individually, taking into account age, disease severity, metabolic stability, and adherence to the diet.

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

Comments: In rare cases, IEAD presents with progressive neurological symptoms such as muscle hypotonia, seizures, motor development delay, various hyperkinesias (chorea, myoclonus), ataxia, and paraplegia [5, 12, 13-16]. The Alberta Infant Motor Scale is provided in Appendix G1.

Comments: 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 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.

Differential diagnosis.

In ketosis combined with hypoglycemia, differential diagnosis should be performed with conditions accompanied by ketotic hypoglycemia, such as endocrine disorders (e.g., glucocorticoid deficiency, growth hormone deficiency) and inherited disorders of carbohydrate metabolism (e.g., glycogen synthase deficiency, glycogen storage diseases) [15]. The severity of ketoacidosis in ISAD is quite pronounced, which helps distinguish this disorder from other causes of ketotic hypoglycemia. When ketoacidosis is combined with hyperglycemia, diabetes mellitus and organic acidemias should be included in the differential diagnosis. SCOT deficiency (OMIM: 245050) can present with ketoacidotic attacks mimicking ISAD. Unlike ISAD, SCOT is characterized by neonatal manifestation (50% of cases), persistent ketosis (even postprandially), and the absence of the organic acid profile characteristic of ISAD. When ketoacidosis is combined with hyperammonemia, differential diagnosis with organic acidemias is performed [11].

Male patients also undergo differential diagnosis with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (2M3HB-CoA dehydrogenase deficiency, OMIM 300438), a rare X-linked neurodegenerative disease caused by pathogenic variants in the HSD17B10 gene. The classical infantile form of this disease is characterized by progressive nervous system involvement with retinopathy and cardiomyopathy. Since 2M3HB-CoA dehydrogenase deficiency involves the same isoleucine catabolic pathway as ISAD, acylcarnitine analysis in patients with this disease also shows elevated blood concentrations of C5:1 and C5-OH, as well as increased urinary concentrations of 2M3HB and tiglylglycine. The only difference is the absence of 2MAcAc in urine, though sometimes due to its instability it is not detected even in ISAD [11].

The algorithm for the differential diagnosis of ISAD with other diseases characterized by a ketoacidotic crisis is presented in Fig. 2B in Appendix B.

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

The main principles of therapy in ISAD are aimed at preventing metabolic decompensation (metabolic crisis), reducing the production of toxic organic acids, preventing the development of toxic damage to the brain tissue and internal organs, while ensuring normal growth and development processes in children.

The main components of treatment for patients with ISAD are dietary therapy. Antiepileptic drugs and other types of symptomatic therapy are prescribed according to indications.

3.1 Pathogenetic treatment

Comments: a ketogenic diet is contraindicated.

Comment: initial dose of A16AA01 Levocarnitine at 50–200 mg/kg/day, subsequent dose adjustment depending on free carnitine levels. Regular testing of blood free carnitine levels is necessary (comprehensive determination of amino acid and acylcarnitine concentrations in the blood by tandem mass spectrometry).

3.1.1 Management of patients during a metabolic crisis

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

Treatment of a metabolic crisis is carried out in the intensive care unit by an anesthesiologist-intensivist, as well as other medical specialists (neurologist, nephrologist, gastroenterologist, etc.). During crises, intravenous administration of dextrose** (B05CX other irrigational solutions) is necessary even with normal glucose levels to maintain its concentration at the upper limit of norm, which suppresses ketogenesis. When the pH drops (<7.1), a bolus injection of sodium bicarbonate** (B05XA electrolyte solutions) (1 mmol/kg over 10 minutes) is administered, followed by continuous infusion. Acid-base balance and electrolytes should be monitored to avoid hypernatremia and hypokalemia. In severe cases, peritoneal dialysis or mechanical ventilation may be required.

3.2 Symptomatic treatment

Comments: at least once every 6 months. In rare cases, ISAD debuts with progressive neurological symptoms such as muscle hypotonia, seizures, motor delay, various movement disorders (chorea, myoclonus), ataxia, and paraplegia [5, 12, 13-16].

3.3 Surgical Treatment

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific rehabilitation is not required for patients with ISAD. The range of rehabilitation measures for patients with ISAD may include sessions with a psychologist/neuropsychologist, speech therapist-defectologist, stays in specialized sanatoriums, as well as social adaptation with the participation of specialists and social workers, and massage courses.

5. Prevention and Dispensary Observation

5.1 Prevention

Patients with ISAD should undergo routine vaccinations in accordance with the national immunization schedule, including vaccination against influenza and rotavirus infection, observing the age restrictions of J07 vaccine group drugs while strictly following medical prescriptions to build an effective immune response and prevent the development of metabolic crises. Vaccination should preferably be carried out under the supervision of specialists with experience in working with patients with metabolic diseases. In the post-vaccination period, vaccinated individuals should be closely monitored with repeated body temperature measurements. If a fever of >38.0°C is diagnosed, antipyretic therapy (paracetamol^** or ibuprofen^**) must be prescribed immediately.

A case of ketoacidotic crisis after vaccination in a child with ISAD has been described in the literature [17].

Comments: families with children diagnosed with ISAD need to undergo medical genetic counseling to determine genetic risk. As with other autosomal recessive diseases, the risk of having a child with ISAD for each pregnancy is 25%. Prenatal diagnosis of treatable conditions is possible, but ethically questionable. The decision to perform it should be made after a detailed discussion of all risks with the family.

5.2 Dispensary monitoring

Annually, patients with a confirmed diagnosis of ISAD must undergo a comprehensive health check-up. A multidisciplinary approach is necessary for monitoring patients because these diseases are characterized by damage to multiple organs and systems, which in turn dictates the need for co-management of the patient by specialists in various fields. To ensure comprehensive therapy and its timely correction when necessary, initial and follow-up consultations by a geneticist, ophthalmologist, neurologist, gastroenterologist, cardiologist, pediatrician/general practitioner/family physician, as well as other specialists are indicated for ISAD patients 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: Blood biochemistry is monitored at least once a year. Testing is performed for blood levels of albumin, total protein, total bilirubin, free and conjugated bilirubin, urea, creatinine, potassium, sodium; serum iron; and the activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase in the blood.

Comments: Blood levels of C5OH and C5:1 as a result of treatment should be brought close to age-specific reference values.

Comments: The frequency of analyses depends on the patient's condition, at least once a year.

Comments: Laboratory precursors of a metabolic crisis include a tendency toward metabolic acidosis with base deficit. The main biochemical marker in BKTD is a high concentration of ketone bodies. During ketoacidotic crises, the blood concentration of ketone bodies in patients with BKTD exceeds 7 mmol/L [11].

Comments: The Alberta Infant Motor Scale is provided in Appendix G1. Assessment is performed once every 6 months.

Comments: Visits at least 4 times a year during the adjustment of diet therapy. The frequency of specialist examinations is individual after diet therapy has been established. As a rule, after 8 years of age, specialist visits occur less frequently due to metabolic compensation.

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

The prognosis of the patient's condition and mental development level depends on the severity of the disease, as well as the timing of initiation of specialized therapy.

With timely correction and prevention of metabolic crises, adherence to and strict control of pathogenetic and symptomatic treatment, the prognosis for life is favorable. In a large number of patients, neurological manifestations do not develop even after a metabolic crisis.

One of the most important approaches to the early diagnosis of BKTD is newborn screening.

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 Core Facility "Metabolom", Research Centre for Medical Genetics.

5. Bushuyeva Tatyana Vladimirovna, MD, PhD, Leading Research Scientist, 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 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)

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 Yurievna, MD, PhD, Head of the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics (Bochkov Research Centre), Member of the Russian Society of Medical Geneticists, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

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. Kutsev Sergey Ivanovich, Academician of the RAS, MD, PhD, Director of the Research Centre for Medical Genetics (Bochkov Research Centre), President of the Association of Medical Geneticists of Russia

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

15. Mikhailova Svetlana Vitalievna, Doctor of Medical Sciences, Head of Department, FSAI "Russian Children's Clinical Hospital" of the 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. Smirnova Olga Yakovlevna, Medical Geneticist, Senior Researcher, Department of Standardization and Study of Evidence-Based Medicine Fundamentals, National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery.

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. Taran Natalia Nikolaevna, Candidate of Medical Sciences, Senior Researcher, Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Federal Research Center of Nutrition and Biotechnology, Assistant at the Department, FSAI HE Pirogov Russian National Research Medical University of the Russian Ministry of Health.

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

Appendix A2. Methodology for Developing Clinical Guidelines

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.

The clinical guidelines were developed based on a systematic review of the literature from 1971–2022 in the Medline (PubMed version), Embase (Dialog version), and Cochrane Library databases, utilizing established protocols from current international clinical guidelines for the diagnosis, treatment, and management of patients with inherited metabolic disorders.

Mitochondrial acetoacetyl-CoA thiolase deficiency (MATD) is a rare inherited disorder, which precludes large-scale cohort and randomized controlled trials; therefore, protocols for diagnosis and therapy are based solely on expert case studies published over the past two decades.

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. Gastroenterologists;

10. Radiologists;

11. Ophthalmologists;

12. Functional diagnostics physicians;

13. Medical psychologists;

14. Medical students;

15. Residents and postgraduate students.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

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

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The update mechanism for 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 well-founded 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 the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services"

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).

Sampling of biological material for dried blood spot testing

Preparation for blood collection

Preparation for blood collection is standard: medical personnel must observe sterility rules, wiping the puncture site with an antiseptic solution (D08A: Antiseptics and disinfectants), using single-use lancets 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 treated with a sterile wipe soaked in 70% ethanol**, 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 consecutively into the circles on the absorbent test card. The circles on the card must be saturated evenly and completely through, with no 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 left to dry completely for at least 2 hours at room temperature, without touching other test cards. After drying, the test cards are placed in individual packaging without touching or overlapping blood spots.

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 soaked in 70% ethanol**, blot with a dry sterile wipe; - puncture with a sterile single-use 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.

Appendix B. Physician Action Algorithms

If the C5:1 concentration is elevated during neonatal screening, blood must be collected for a repeat acylcarnitine assay (retest). If the C5:1 level remains elevated after the retest, the samples are sent to a reference center for confirmatory diagnosis. Parents are informed about the clinical manifestations of the disease and the testing schedule. The reference center performs molecular genetic testing and determines urine organic acids by gas chromatography-mass spectrometry.

In the absence of mutations in the ACAT1 gene and a characteristic urine organic acid profile, differential diagnosis with other diseases sharing similar biochemical changes is necessary (Fig. 1B and Fig. 2B in Appendix B).

In the presence of clinical symptoms, which is extremely rare for MATD during the neonatal period, the child must be transferred to a multidisciplinary hospital with an intensive care unit and therapy initiated in accordance with clinical guidelines. Following confirmation of the diagnosis, medical genetic counseling for the family is required. Further management of the patient is carried out in accordance with clinical guidelines.

Figure 1B. Screening algorithm for the detection of mitochondrial acetoacetyl-CoA thiolase deficiency (MATD) by measuring blood 3-methylcrotonylcarnitine (C5:1) and urine ketone bodies, along with molecular genetic testing of the ACAT1 gene.

Figure 2B. Screening algorithm for the detection of mitochondrial acetoacetyl-CoA thiolase deficiency (MATD).

2M3GHB-CoA dehydrogenase = 2-methyl-3-hydroxybutyryl-CoA dehydrogenase; MAT = mitochondrial acetoacetyl-CoA thiolase; OA = organic acidurias/acidemias; FFA/TKB = free fatty acids / total ketone bodies; HbA1c = glycated hemoglobin; MCT1 = monocarboxylate transporter 1; SCOT (succinyl-CoA:3-ketoacid CoA transferase) = succinyl-CoA:3-ketoacid CoA transferase.

The cut-off point (= 0.3) for FFA/TKB is not an absolute value. Prolonged fasting can lead to a decrease in the FFA/TKB ratio. Dextrose infusion** decreases FFA levels faster than TKB, which also lowers this ratio. Severe hyperglycemia with elevated HbA1c is typically diagnosed as diabetic ketoacidosis, although cases of ketoacidosis resembling diabetic ketoacidosis are known in certain OAs. Thus, a normal HbA1c level does not rule out diabetic ketoacidosis (indicated by the dashed line). A non-specific urine organic acid profile in ketoacidosis also does not rule out MATD (indicated by the dashed line). In such cases, molecular genetic testing or MAT and SCOT enzymatic activity analysis is recommended.

Appendix C. Patient Information

Why does the disease occur?

Mitochondrial acetoacetyl-CoA thiolase deficiency (MATD) is a rare inherited disorder associated with defects (mutations) in the ACAT1 gene. The gene is located on chromosome 11. When a mutation occurs in the ACAT1 gene, it can no longer serve as the «instruction» for producing the MAT enzyme. Consequently, the resulting enzyme functions improperly or is not produced in the body at all. MATD is inherited in an autosomal recessive manner. This means that a child develops the disease only if both parents are carriers and, while they are healthy themselves, transmit two copies of the «damaged» gene (the mutated gene) to the child. A carrier inherits only one «damaged» copy: either from the father or the mother. Carriers are healthy and show no signs of the disease. The risk of having a child with MATD in a family where both parents are carriers of the «broken» gene is 25% for each pregnancy (Fig. 1B). Boys and girls are affected with equal frequency.

Figure 1B. Inheritance pattern of mitochondrial acetoacetyl-CoA thiolase deficiency (MATD). With two copies of the «affected» gene («r») inherited from both carrier parents, the risk of having a child with MATD is 25% («rr»).

What metabolic processes are disrupted in MATD?

The MAT enzyme plays an essential role in breaking down dietary proteins and fats. Specifically, MAT is responsible for metabolizing isoleucine, an amino acid found in many proteins. MAT also processes ketones, which are produced during fat breakdown. If a mutation in the ACAT1 gene reduces or eliminates the activity of this enzyme, the body cannot properly metabolize isoleucine and ketones. As a result, harmful compounds can accumulate, causing the blood to become overly acidic (ketoacidosis), which impairs tissue function, particularly in the central nervous system. Ketoacidosis is a life-threatening pathological condition that requires immediate medical intervention.

How does MATD manifest?

The age of onset for MATD ranges from two days to eight years. In the majority of cases (80%), the disease manifests before the age of two.

The disease is characterized by episodes of ketoacidosis (alteration of the acid-base balance in the body due to intense synthesis (production) of ketone bodies), manifesting as vomiting, respiratory disorders, weakness, and lethargy, which occur in infancy and typically cease by adolescence. Ketoacidosis can lead to coma and death if left untreated. However, with timely diagnosis and appropriate treatment, the prognosis for patients with MATD is favorable. The disease typically debuts as an episode of ketoacidosis (ketoacidotic crisis), most commonly triggered by stress, fasting, acute illnesses, and/or infections (e.g., gastroenteritis) and, rarely, by high dietary protein intake. Ketoacidosis is usually signaled by a fruity odor of the breath. In some patients, severe episodes lead to neurological sequelae (e.g., developmental delay). Rarely, patients exhibit signs of metabolic encephalopathy (speech disorders, rapid, jerky movements (chorea)). Between episodes, patients are usually asymptomatic.

How is the diagnosis established?

Initial diagnostics are performed by a pediatrician. The diagnosis is established based on the clinical presentation, urinalysis (showing elevated levels of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and 2-butanone), and brain CT. Screening for MATD is performed as part of several newborn screening programs using tandem mass spectrometry (TMS), a standard newborn screening methodology. Newborn screening programs are available in certain countries, including the Russian Federation. To confirm the diagnosis, molecular genetic testing of the ACAT1 gene is required.

How are patients with MATD treated?

The main therapeutic principles in MATD aim to prevent ketoacidosis. During a ketoacidotic crisis, the physician administers intravenous electrolyte solutions and a dextrose solution**. Levocarnitine-containing preparations are sometimes prescribed if patients exhibit low free carnitine levels. Patients are advised to avoid prolonged fasting and a high-fat (ketogenic) diet, as well as to restrict protein intake (1.5–2 g/kg/day).

How are patients treated during a metabolic crisis?

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

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 is required for patients with MATD?

A multidisciplinary approach involving specialists from various fields is necessary for the follow-up and management of patients with MATD to ensure comprehensive therapy and timely adjustment when necessary. Regular examinations are required for patients with MATD. Table 2B provides an exemplary list and schedule of examinations, though the exact monitoring plan is coordinated individually with the attending physician.

Table 2B. Examination schedule for patients with MATD.

How do patients receive treatment in the Russian Federation?

MATD is classified among rare inherited metabolic disorders and is included in the list of rare (orphan) diseases funded through regional budgets. Following diagnosis, the patient must be enrolled in the regional segment of the registry for life-threatening rare (orphan) diseases to ensure ongoing provision of necessary medical nutrition and pharmaceuticals. Different specialists are responsible for maintaining the registry across various regions, but most commonly they are clinical geneticists; therefore, consulting a regional clinical geneticist after diagnosis is mandatory.

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

Percentile values