Mitochondrial fatty acid β-oxidation disorders: clinical guidelines

List of Abbreviations

ALT – alanine aminotransferase;

AST – aspartate aminotransferase;

acyl-CoA – acyl group bound to coenzyme A;

dietary supplement – biologically active supplement;

GA2 – glutaric aciduria type 2;

LCFA – long-chain fatty acids (triglycerides);

FA – fatty acids;

CT – computed tomography;

CK – creatine kinase;

MRI – magnetic resonance imaging;

IEM – inherited errors of metabolism;

PUFA – polyunsaturated essential fatty acids;

CVS – cardiovascular system;

MCFA – medium-chain fatty acids (triglycerides);

MS/MS – tandem mass spectrometry;

ultrasound – ultrasound examination;

ECG – electrocardiogram;

ENMG – electroneuromyography;

CACT (Carnitine-acylcarnitine translocase) – carnitine acylcarnitine translocase;

CPT1 (Carnitine palmitoyltransferase I) – carnitine palmitoyltransferase 1;

CPT2 (Carnitine palmitoyltransferase II) – carnitine palmitoyltransferase 2;

DHA (Docosahexaenoic acid) – docosahexaenoic acid;

ETF (Electron transfer flavoprotein) – electron transfer flavoprotein;

ETF QO - ETF (Electron transfer flavoprotein ubiquinone oxidoreductase) - electron transfer flavoprotein ubiquinone oxidoreductase;

FAOD (Fatty acid oxidation disorders) – mitochondrial fatty acid β-oxidation disorders;

HELLP – syndrome acronym for its main components: hemolysis, elevated liver enzymes, and low platelet count;

LCHAD (Long-chain 3-hydroxyacyl-CoA dehydrogenase) – long-chain 3-hydroxyacyl-CoA dehydrogenase;

LCFA (Long chain fatty acids) – long-chain fatty acids;

LCT (Long-chain triglycerides) – long-chain triglycerides (long-chain fats);

MCFA (Medium-chain fatty acids) – medium-chain fatty acids;

MADD (Multiple acyl-CoA dehydrogenation deficiency) – multiple acyl-CoA dehydrogenase deficiency;

MCAD (Medium-chain acyl-CoA dehydrogenase deficiency) – medium-chain acyl-CoA dehydrogenase deficiency;

MCT (Medium chain triglycerides) – medium-chain triglycerides;

OCTN2 (Organic cation / carnitine transporter 2) – plasma membrane carnitine transporter;

SCAD (Short-chain acyl-CoA dehydrogenase) – short-chain acyl-CoA dehydrogenase;

TFP (Mitochondrial Trifunctional Protein) – mitochondrial trifunctional protein;

TFPD (Mitochondrial trifunctional protein deficiency) – mitochondrial trifunctional protein deficiency;

VLCAD (Very long-chain acyl-coenzyme A dehydrogenase) – very long-chain acyl-CoA dehydrogenase.

Terms and Definitions

Acylcarnitines – esters of fatty acid and carnitine;

Catabolism – the breakdown of complex substances;

Rhabdomyolysis – the destruction of muscle tissue cells;

Reye's syndrome – a disorder manifesting as acute non-inflammatory (toxic) encephalopathy combined with fatty degeneration of internal organs, predominantly the liver (acute microvesicular steatosis);

HELLP syndrome – a severe pregnancy complication characterized by a triad of features: hemolysis, hepatic parenchyma damage with elevated liver transaminases, and thrombocytopenia.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Mitochondrial fatty acid β-oxidation is one of the essential biochemical processes for energy production in mitochondria.

Inherited disorders of mitochondrial fatty acid β-oxidation (FAOD) are a group of monogenic diseases associated with impaired mitochondrial fatty acid β-oxidation and the transport of carnitine and fatty acids in mitochondria.

All FAODs are characterized by impaired energy production. Clinical symptoms therefore develop or worsen during catabolic states, such as intercurrent infections or fasting. Organs for which fatty acids serve as the primary energy source, such as the heart and skeletal muscles, are most frequently affected [1,2]. The patient's age at onset, spectrum of clinical symptoms, and disease severity may vary [1,3,4,5,6].

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

Fatty acids (FAs) are an essential source of energy, particularly in skeletal muscle, heart, and liver, and their energetic role increases during fasting. FAs are mobilized from adipose tissue and transported into the bloodstream, primarily bound to albumin. Most tissues are capable of breaking down FAs into carbon dioxide and water. In late stages of fasting, they become the predominant source of energy production via their oxidation in skeletal muscles and utilization for ketone body production in the liver. FAs are the main energy source for the heart: normally, 60–70% of the energy required by the myocardium is provided by FA oxidation, and these figures can be even higher in certain situations, such as fasting and diabetes.

Fatty acid oxidation requires a specific sequence of biochemical reactions: 1. Transport of fatty acids into the mitochondria (penetration of FAs through the outer and inner mitochondrial membranes); 2. Stepwise shortening of the carbon chain of fatty acids to yield the final product – acetyl-CoA (Fig. 1).

There are 11 known different forms of inherited FAOD. Data on the primary molecular-genetic defects in the most common diseases of this group are provided in Appendix A4. Relatively recently, new diseases from this group associated with mutations in the ACAD9 and ECHS1 genes have been identified [74].

Fig. 1 Transport and oxidation of fatty acids in mitochondria [105]

TFP – mitochondrial trifunctional protein; PM – plasma membrane; CI, CIII – mitochondrial respiratory chain complexes; MitoOM – outer mitochondrial membrane; MitoIM – inner mitochondrial membrane; ETF – electron-transferring flavoprotein; CPT1 – carnitine palmitoyltransferase 1; CACT – carnitine-acylcarnitine translocase; CPT2 – carnitine palmitoyltransferase 2; LCFA – long-chain fatty acids; MCFA – medium-chain fatty acids; OCTN2 – plasma membrane carnitine transporter; ETF QO – electron-transferring flavoprotein dehydrogenase.

The molecular mechanisms of FAOD pathogenesis and many clinical manifestations of these diseases are similar. Most FAODs are characterized by non-ketotic hypoglycemia following a period of fasting, which makes hypoglycemia particularly difficult for these patients to tolerate. The depletion of energy resources due to the inability to utilize FAs and the toxic effect of the latter lead to the development of a Reye-like syndrome. Many forms of FAOD are characterized by muscle tissue involvement with myopathy and/or cardiomyopathy, which is associated with both the depletion of energy resources and the toxic effect of blocked enzyme reaction substrates on muscle tissue.

1.3 Epidemiology of the Disease or Condition

Following the inclusion of FAODs in newborn screening programs, data on the prevalence of this group of inherited disorders have been refined. Their cumulative incidence is estimated to be 1:9,000, although there may be significant differences between populations [7]. One of the most common disorders in this group is medium-chain acyl-CoA dehydrogenase deficiency (MCAD) – 1:14,600–1:20,000. Data on the prevalence of disorders in this group are provided in Appendix A4.

1.4 Features of Coding the Disease or Condition

According to ICD-10, the disease belongs to Class IV (Endocrine, nutritional and metabolic diseases), E71.3 – Disorders of fatty acid metabolism.

1.5 Classification of the disease or condition

There are 11 main forms of FAOD. All of them are associated with dysfunction of proteins involved in fatty acid and carnitine metabolism (Appendix A4). A brief clinical description of individual forms is provided in Appendix A5. Depending on the metabolic block, a distinction is made between forms directly related to impairments in fatty acid oxidation enzymes and forms associated with defects in carnitine and fatty acid metabolism and transport.

Based on the leading symptom complex, the following forms of FAOD are distinguished:

- systemic with cardiac and hepatic involvement;

- hepatic;

- myopathic.

Based on the age of onset of initial signs, forms of FAOD are distinguished:

- neonatal;

- infantile, with manifestation in the first two years of life;

- late-onset.

1.6 Clinical presentation of the disease or condition

For all forms of FAOD, different disease manifestation variants are distinguished according to the timing.

General clinical manifestations of fatty acid oxidation disorders

FAODs share many common clinical manifestations. Typically, neonatal (early), infantile, and late (adult) forms of the disease are distinguished. The early form is particularly severe; metabolic disturbances often lead to altered consciousness, although comatose states can also occur in the infantile and late forms.

Main clinical manifestations: neurological disorders in the form of depressed consciousness ranging from somnolence to coma, general lethargy, recurrent vomiting, hepatomegaly, progressive cardiac involvement in the form of cardiomyopathy or cardiac arrhythmias. Children may experience psychomotor retardation. In older patients, myopathy and myocardial involvement predominate, characterized by episodes of muscle pain, rhabdomyolysis, and myoglobinuria, manifesting as brownish urine discoloration.

A characteristic feature of FAODs is that clinical symptoms develop or worsen during catabolic states, such as prolonged physical exertion, intercurrent infections, or fasting, when endogenous lipids are mobilized. Organs for which long-chain fatty acids serve as the primary energy source, such as the heart and skeletal muscles, are most frequently affected [3,8].

Frequent symptoms of FAOD include non-ketotic hypoglycemia, cardiomyopathy, and myopathy; these symptoms may manifest either in isolation or in combination.

Cardiac arrhythmias and cardiomyopathy most frequently manifest in the neonatal period and early childhood, but may also develop during a metabolic crisis at a later age.

In early childhood, cardiac involvement can be fatal. Left ventricular hypertrophy is quite common, and in severe cases, dilated cardiomyopathy with reduced ejection fraction occurs. Cardiomyopathy combined with pericardial effusion is sometimes observed [9,10].

Cardiac arrhythmias are described in virtually all FAODs and occur in combination with cardiomyopathy or in isolation [11].

Myopathy is a very frequent symptom in FAOD disorders. Patients may complain of myalgia, fatigue, and exercise intolerance. Most commonly, myopathy manifests in adolescence or the 2nd–3rd decade of life, but it can be a leading symptom earlier as well. Sometimes myopathy can be triggered by intensive physical exercise, but it may also be observed following anesthesia and viral infection [1-5].

Hepatomegaly occurs as a result of fatty acid accumulation in the liver, leading to fatty liver disease [25]. Patients with LCHAD and TFP deficiency may present with clinical signs of peripheral polyneuropathy, the exact etiology of which remains unclear [6, 113, 114].

Patients with LCHAD deficiency (and less frequently with TFP deficiency) develop pigmentary retinal degeneration [115-117].

The most common clinical symptoms for various forms of FAOD are summarized in Appendix A5a.

The specific clinical manifestations of individual FAOD forms are described below.

Disorders of Carnitine and Fatty Acid Transport and Metabolism

This group comprises several diseases that differ in age of onset, severity, and biochemical characteristics.

The transport of long-chain acyl-CoAs into mitochondria is mediated by the carnitine cycle, which includes 4 proteins: 1) the plasma membrane carnitine transporter (OCTN2), responsible for intracellular carnitine delivery; 2) carnitine palmitoyltransferase 1 (CPT 1) on the outer mitochondrial membrane, which transfers fatty acid acyl groups from CoA to carnitine; 3) carnitine/acylcarnitine translocase (CACT), which provides shuttle transport of acylcarnitines across the inner membrane in exchange for free carnitine; and 4) carnitine palmitoyltransferase 2 (CPT 2), which transfers fatty acid acyl groups from carnitine to CoA on the inner mitochondrial membrane. Mutations in the respective genes encoding these proteins lead to inherited disorders of carnitine and fatty acid transport.

Primary Carnitine Deficiency

An autosomal recessive disorder associated with mutations in the SLC22A5 gene, which encodes the carnitine transporter protein (OCTN2). The age of onset ranges from 1 month to 7 years (average 2 years).

In early childhood, the primary manifestation of primary carnitine deficiency is hypoketotic hypoglycemic encephalopathy (lethargy, drowsiness, recurrent vomiting) with an episodic course. Hepatomegaly is observed. Such patients frequently develop Reye syndrome with hyperammonemia and elevated transaminases. Increases in uric acid and CK levels are also noted. As a rule, children show mild psychomotor developmental delay. Later (typically at 2–3 years of age), progressive hypertrophic or dilated cardiomyopathy develops, combined with cardiac arrhythmias which, in the absence of treatment, inevitably lead to death from heart failure and sudden death syndrome. Children frequently suffer from intercurrent illnesses [12, 13, 14]. An unusual manifestation of the disease in infancy is the clinical presentation of peripheral polyneuropathy with absent tendon reflexes and profound psychomotor developmental delay [118].

In older patients, signs of skeletal myopathy and myocardial involvement predominate. Fat accumulation is detected in muscle biopsies of these patients. Gastrointestinal disturbances such as abdominal pain and diarrhea are frequently observed. Peripheral neuropathy of the upper and lower limbs has been reported in some cases [17, 18]. With timely diagnosis and initiation of therapy, complete resolution of clinical symptoms is observed.

Adults with this condition may remain asymptomatic or present with mild symptoms such as reduced endurance, mild fatigue, and poor tolerance to prolonged fasting periods [146, 147].

Carnitine-Acylcarnitine Translocase Deficiency

An autosomal recessive disorder associated with mutations in the SLC25A20 gene encoding carnitine-acylcarnitine translocase. This is a fairly rare condition, with no more than 60 cases described in the literature [95, 104]. The onset occurs in the neonatal period (first weeks of life) or in early childhood (first year of life). The disease manifests with acute cardiopulmonary failure (collapse) or ventricular arrhythmias, muscle weakness, and hypotonia. Hypoketotic hypoglycemia and hyperammonemia are observed. Sudden infant death syndrome occurs between 4 days and 24 months of age. The most frequent initial symptoms are hepatomegaly (34%), arrhythmia and/or bradycardia (32%), and respiratory failure (30%). Hypoketotic hypoglycemia (68%) and hyperammonemia (54%) are the most common laboratory abnormalities. Cardiac manifestations include hypertrophic or dilated cardiomyopathy combined with various cardiac arrhythmias. Liver failure or moderate hepatomegaly with metabolic acidosis and hypoketotic hypoglycemia are characteristic of this disorder. Acute neurological symptoms include altered consciousness (lethargy and coma) [23, 24, 102, 103]. The disease may present with muscle weakness and psychomotor developmental delay. An elevation in CK levels may also be observed. Late-onset cases exhibit less severe clinical manifestations [7, 27, 28].

Carnitine Palmitoyltransferase 1 Deficiency

An autosomal recessive disorder associated with mutations in the CPT1A gene, which encodes liver-type carnitine palmitoyltransferase 1.

The onset of the disease typically occurs in the first year of life or in infancy. Patients usually exhibit mild hepatomegaly, and the disease presents as acute metabolic attacks resembling Reye syndrome, accompanied by tachypnea, vomiting, refusal to feed, seizures, lethargy, and coma. Laboratory findings include elevated transaminases and prolonged prothrombin and partial thromboplastin times. The disease frequently mimics sepsis.

Trigger factors may include fasting and intercurrent infections leading to hypoketotic/non-ketotic hypoglycemia. Metabolic acidosis is present at the peak of the attack. The attack can result in sudden death.

Psychomotor developmental delay may be observed. Isolated cases of skeletal myopathy and cardiomyopathy have been reported. Renal tubular acidosis occasionally develops, which is transient and frequently associated with myopathic syndrome and elevated CK levels [148]. Female patients may experience severe complications during pregnancy—HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count) [19].

Cognitive deficit in patients depends on the severity of hypoglycemic episodes experienced [119].

Carnitine Palmitoyltransferase 2 Deficiency

An autosomal recessive disorder associated with mutations in the CPT2 gene. Three clinical forms of the pathology are distinguished based on the age of onset: neonatal, infantile, and late (muscle) onset [13].

The course of the disease is acute or progressive. Disease onset occurs in the neonatal period. Patients with the neonatal form present with respiratory distress syndrome, cardiomyopathy, cardiac rhythm and conduction disorders [120, 121], hepatomegaly, liver failure, and encephalopathy. Without treatment, death from severe cardiac arrhythmia and multi-organ failure occurs in the first weeks of life. Dysmorphic features may be present: sloped forehead, microcephaly, high-arched palate, abnormal ears, long tapered fingers, contractures, and nail hypoplasia [31, 32]. Enlarged and polycystic kidneys are a frequent symptom of the disease [122].

Infantile-onset CPT2 deficiency is potentially fatal. This form most commonly manifests between 6 months and 2 years of age as non-ketotic hypoglycemia, hepatomegaly, and elevated blood creatine phosphokinase and ammonia, particularly following a prolonged fasting interval. These patients may also develop metabolic encephalopathy with seizures, respiratory distress syndrome, and metabolic acidosis. Cardiomyopathy and arrhythmias are occasionally observed.

The late-onset muscle form is more common, characterized by an intermittent course and onset in the 2nd to 3rd decade of life. The disease presents with episodes of muscle pain, muscle weakness, and paroxysmal myoglobinuria triggered by physical exertion (exercise intolerance). In rare cases, these attacks are triggered by fasting, intercurrent infections, emotional stress, or cold exposure. Episodes of acute decompensation or cardiac dysfunction are rare.

Renal failure secondary to myoglobinuria is identified in 25% of patients. This condition is the most frequent cause of inherited myoglobinuria. The disease course is relatively benign [23, 24, 106].

Disorders of Mitochondrial Fatty Acid β-Oxidation

In the mitochondrial matrix, fatty acid acyl-CoA esters enter β-oxidation, which transfers electrons for ATP synthesis (mitochondrial respiratory chain). As a result of β-oxidation, fatty acids are sequentially degraded to acetyl-CoA, which is then converted into ketone bodies in the liver. The first dehydrogenation reaction is carried out by acyl-CoA dehydrogenases. Short-chain, medium-chain, long-chain, and very long-chain acyl-CoA dehydrogenases (abbreviated as SCAD, MCAD, LCAD, and VLCAD, respectively) take part in fatty acid oxidation. The substrate specificity of all the listed enzymes differs and only partially overlaps.

Short-chain acyl-CoA dehydrogenase deficiency.

An autosomal recessive condition associated with mutations in the ACADS gene, which encodes short-chain acyl-CoA dehydrogenase (SCAD).

In many cases, the course is asymptomatic, which is why SCAD is now regarded as a biochemical phenotype rather than a disease. Most children with SCAD were identified through newborn screening, and the vast majority of them remain asymptomatic for several years.

Previously, severe and mild forms of the disease were distinguished [17, 53]. Subsequently, it was discovered that the homozygous or compound heterozygous presence of several common polymorphisms leads to reduced SCAD enzyme activity and the detection of biochemical changes in the acylcarnitine profile, but has no physiological consequences [75, 76].

Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (SCHAD)

An autosomal recessive disease associated with mutations in the HADH gene, which encodes short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD).

In most cases, the disease manifests in the first year of life, although a later onset of symptoms is also possible. About ten cases of SCHAD deficiency have been described in the literature. The main clinical manifestations of this metabolic disorder differ from other inherited defects of fatty acid β-oxidation because hypoglycemia is associated with hyperinsulinism. Patients also exhibit myoglobinuria (in adolescence), hypoketotic hypoglycemic encephalopathy, hypertrophic/dilated cardiomyopathy, muscle hypotonia, hepatic steatosis, and liver failure. Several cases of sudden death have been described. Stress and fasting can provoke symptoms.

Late diagnosis can lead to the development of epilepsy and intellectual disability due to recurrent hypoglycemia [77].

SCHAD should be classified as a congenital hyperinsulinism syndrome, since patients with proven HADH mutations may present with recurrent hypoglycemia accompanied by diazoxide-responsive hyperinsulinism [77-79].

Other frequent symptoms include delayed speech development and muscle hypotonia. Epileptic seizures, myopathy, physical growth retardation, and feeding difficulties are also frequently observed. Dysmorphic features and cardiomyopathy are less common [75].

Medium-chain acyl-CoA dehydrogenase deficiency

An autosomal recessive disease associated with mutations in the ACADM gene, which encodes medium-chain acyl-CoA dehydrogenase (MCAD).

In most cases, the disease manifests between 3 and 24 months of age. Frequently (in 10 to 40% of cases), the disease begins in the neonatal period. Attacks are severe and can be fatal. In 5% of cases, infant death occurs in the first days of life. About 20% of patients die before a diagnosis is established [11, 17]. In most cases, the main manifestations are hypoketotic hypoglycemia, which may be combined with lactic acidosis and hyperammonemia. Clinical manifestations include central nervous system depression syndrome, lethargy, and vomiting triggered by infectious diseases, fasting, or surgical interventions. Some patients experience a metabolic crisis despite an excessive accumulation of ketone bodies and normal blood glucose concentrations. Occasionally, patients exhibit a "paradoxically" pronounced ketosis during an attack. During a crisis, there is lethargy, vomiting, respiratory failure, seizures, hepatomegaly, and rapid development of heart failure. Brain damage that may occur during a metabolic crisis increases the risk of long-term neurological disorders. A specific polymorphic ventricular tachycardia may be observed, presenting as characteristic ECG changes known as torsades de pointes (French for "twisted ribbons"), or pirouette ventricular tachycardia. The direction of QRS complexes changes cyclically: several complexes point downward, and then in the same lead—upward. Physical examination reveals hepatomegaly and a cytolytic syndrome (Reye-like syndrome). The interictal period is favorable; 80% of patients show normal neuropsychological development with a complete absence of other pathological signs [15, 17, 48, 49].

Very long-chain acyl-CoA dehydrogenase deficiency

An autosomal recessive disease associated with mutations in the ACADVL gene, which encodes very long-chain acyl-CoA dehydrogenase (VLCAD).

Based on the timing of the onset of the first signs, three forms of the disease are distinguished: neonatal, childhood, and late-onset. For the neonatal and childhood forms, several clinical phenotypes are distinguished [8, 13, 36, 37].

The most common form of the disease is the severe infantile form (cardiac and multiorgan forms) with early onset and high mortality. These forms exhibit near-zero enzymatic activity, and the clinical picture is dominated by cardiac involvement in the form of hypertrophic or dilated cardiomyopathy, cardiac rhythm disturbances, and high mortality in the first year of life [123]; as well as muscle weakness and hypotonia against the background of hyperammonemia, non-ketotic/hypoketotic hypoglycemia, and lactic acidosis. Acute neurological symptoms include lethargy and coma. Sudden infant death syndrome in the neonatal period or during the first year of life is characteristic of this form [131].

A milder form of the disease with an equally early onset presents as Reye syndrome. The clinical picture—consisting of acute attacks accompanied by vomiting, poor suckling/refusal to feed, muscle hypotonia, hyporeflexia/areflexia, tachypnea, apnea, lethargy, and coma—develops as a reaction to fasting, viral infections, or gastrointestinal disorders leading to non-ketotic hypoglycemia. At the peak of the attack, metabolic lactic acidosis, hyperuricemia, hepatomegaly, and muscle weakness are observed. The attack can lead to sudden death. In some cases, hypoglycemic episodes are accompanied by seizures, diarrhea, myalgia, myoglobinuria, and proximal myopathy. Encephalopathy can be observed even in the absence of generalized metabolic disorders. Intellectual disability may develop after multiple attacks. Despite the relative ease of aborting attacks, the prognosis of the disease remains uncertain, whereas it is unfavorable in the neonatal cardiomyopathic form.

The late-onset form (about 15% of cases) usually manifests in the second to third decade of life with exercise intolerance, myalgia, myoglobinuria, and elevated creatine kinase (CK) levels in response to physical overexertion and fasting. Progressive proximal myopathy may develop [38].

Mitochondrial trifunctional protein (TFP) deficiency / long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency / long-chain 3-ketoacyl-CoA thiolase (LCKAT) deficiency.

Mitochondrial trifunctional protein (TFP) is a multienzyme complex consisting of 3 proteins. The most common is long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, while long-chain 3-ketoacyl-CoA thiolase (LCKAT) deficiency is extremely rare [125].

Mutations in 2 genes lead to this disease: HADHA and HADHB. These genes encode the α and β subunits of TFP. Mutations in these genes can lead to generalized TFP deficiency by causing its instability; furthermore, mutations in the HADHA gene are the cause of isolated LCHAD deficiency, and mutations in the HADHB gene cause isolated LCKAT deficiency.

The clinical phenotype of isolated LCHAD deficiency is exceptionally heterogeneous, resembling VLCAD deficiency in its manifestations. Furthermore, clinical phenotypes are conventionally subdivided into a severe neonatal cardiomyopathic form (1), a form predominantly presenting as Reye syndrome (2) combined with liver damage, and a mild form (3) with late onset and predominant skeletal muscle involvement. The course of the disease is acute (1) and intermittent or progressive (2 and 3).

Clinical manifestations of the disease in the neonatal period are most severe, typically leading to a fatal outcome: cardiomyopathy, hepatocyte steatosis, muscular hypotonia, neuropathy, and a sepsis-like condition.

In early childhood: characterized by an acute presentation (vomiting, generalized muscular hypotonia, tonic-clonic seizures, lethargy, somnolence, respiratory disorders, comatose states). Many children exhibit a combination of hypertrophic cardiomyopathy, hepatomegaly, muscular hypotonia, and weakness. Cardiac auscultation reveals muffled heart sounds and a gallop rhythm; physical examination highlights cardiomegaly, left ventricular hypertrophy, and impaired systolic function. Pericardial effusion has also been described. Non-ketotic/hypoketotic hypoglycemia as a response to fasting is characteristic.

The most common form of the disease has an age of onset within the first 2 years of life (2 days – 2 years). In the majority of patients, the disease manifests as Reye's syndrome. Clinical presentation in the form of acute and, as a rule, multiple attacks accompanied by vomiting, poor suckling/refusal to feed, muscular hypotonia, hepatomegaly, hyporeflexia/areflexia, tachypnea, lethargy, and coma develops as a response to fasting, viral infections, or gastrointestinal disorders leading to non-ketotic hypoglycemia. The attack can lead to sudden death. Some patients exhibit a progressive course of the disease in the form of progressive cardiomyopathy, muscular hypotonia, and hepatomegaly. Lactic acidosis and high CK activity are detected in all patients.

In older patients, attacks of muscle pain and myoglobinuria may appear. Some patients with late-onset disease develop a clinical form similar to the myopathic form of CPT II deficiency. This form typically manifests in the second to third decade of life (though earlier onset is possible) with exercise intolerance, myalgia, myoglobinuria, and elevated CK in response to physical overexertion and fasting. However, these patients are characterized by a combination of this clinical symptomatology with peripheral neuropathy and liver dysfunction.

Liver involvement is one of the most characteristic features of LCHAD deficiency and presents as hepatomegaly, cytolysis syndrome, and in rare cases, acute cholestatic jaundice and liver failure with massive total hepatic necrosis [13, 41]. In women, fatty liver of pregnancy or HELLP syndrome frequently occurs during gestation [16, 80].

The clinical picture of TFP defect is very similar to that of LCHAD deficiency, but is more severe and accompanied by early mortality. Onset of the disease is in the neonatal period: progressive muscular hypotonia, lethargy, feeding difficulties, progressive heart failure, sudden infant death syndrome (under 2 months of age). Very severe generalized neonatal hypotonia, clinically indistinguishable from congenital myopathy, was the presenting symptom in 5 patients. In one case, late onset of the disease (at 2.5 years) with a relatively mild intermittent course was noted. A unique clinical phenotype has been described in two patients presenting with progressive chronic polyneuropathy and myopathy in the absence of pathological changes in the liver and myocardium.

Glutaric aciduria type 2 (multiple acyl-CoA dehydrogenase deficiency)

An autosomal recessive, genetically heterogeneous disorder associated with mutations in the ETF-B, ETF-A, ETF-DH genes, which encode the alpha and beta subunits of the electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase. Impairment of the functions of either of these two flavoproteins leads to disrupted fatty acid oxidation.

Several clinical forms of GA2 are distinguished: 1) severe neonatal form with congenital anomalies; 2) severe neonatal form without congenital anomalies; 3) mild form or ethylmalonic/adipic aciduria. In addition, riboflavin-responsive and riboflavin-resistant forms are distinguished [13, 14].

In the severe neonatal form with congenital anomalies, the child is typically born premature. From the first days of life, children develop respiratory disorders (tachypnea, apnea), muscular hypotonia, lethargy, somnolence progressing to lethargy, vomiting, hepatosplenomegaly, an unusual urine odor ("sweaty feet"), and severe anemia. Facial features are dysmorphic, resembling those of Zellweger syndrome: high forehead, hypertelorism, midface hypoplasia, dysplastic low-set ears. Congenital malformations are characteristic: anterior abdominal wall muscle defects, hypospadias, penile curvature, "rocker-bottom foot". Death occurs in the neonatal period (in the first week of life) against the background of lethargy and coma.

The neonatal form without congenital anomalies, similar to the previous one, is distinguished by early onset, a severe course, and frequently leads to death. Children exhibit psychomotor and physical developmental delays. The development of a Reye-like syndrome and cardiomyopathy is characteristic. The disease course is paroxysmal. In some cases, the disease in the absence of overt clinical manifestations may be the cause of sudden infant death in early life [6].

The late-onset form is characterized by a milder course. The main clinical signs are: nausea, vomiting, hepatomegaly, jaundice, muscle weakness, and hypotonia. Mental development is not impaired. In the late-onset form of the disease, attacks of hypoketotic hypoglycemia are mild and typically not accompanied by metabolic acidosis and hyperammonemia.

In some patients, clinical improvement is observed upon administration of riboflavin (dietary supplement) [143]. Biochemical markers of GA2 may overlap with changes detected in riboflavin transporter defects, which are characterized by significant clinical improvements upon administration of therapeutic doses of riboflavin (dietary supplement). Brief clinical descriptions of these disorders are provided below.

Secondary defects of mitochondrial fatty acid β-oxidation / other inherited disorders resembling GA2

A number of inherited disorders are known in which alterations in acylcarnitines occur, resembling fatty acid β-oxidation defects.

Riboflavin transporter deficiency

Brown-Vialetto-Van Laere syndrome (BVVL) (MIM211530) is a rare neurological disorder manifested by sensorineural hearing loss, bulbar palsy, and respiratory disorders. Age of onset varies from infancy to adulthood [124]. Clinical signs and symptoms of BVVL are similar to Fazio-Londe disease (MIM211500), which was initially considered a separate form but is now known to be an allelic variant of BVVL [124]. These disorders are caused by mutations in the SLC52A3 gene, which encodes the riboflavin transporter (RFVT3), or in the SLC52A2 gene, which encodes another plasma membrane riboflavin transporter (RFVT2). Clinical manifestations in patients with RFVT2 and RFVT3 deficiencies are virtually indistinguishable. Many patients with this pathology reveal an altered blood acylcarnitine profile resembling GA2 [125].

High-dose riboflavin (dietary supplement) is highly effective for the treatment of Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease, which necessitates studies for the differential diagnosis of these disorders from GA2 [125].

FAD synthase deficiency (FADS)

FAD synthase deficiency (FADS) was first described in 2016 in 7 unrelated families, with neurological manifestations and a biochemical profile pointing to GA2 [126]. Riboflavin (dietary supplement) is also used in the treatment of this pathology.

Mitochondrial FAD transporter deficiency

Mitochondrial FAD transporter deficiency was described in 2016 in a 14-year-old girl with exercise intolerance [127]. Laboratory tests revealed a profile similar to GA2. Mutations were identified in the SLC25A32 gene, which encodes a protein from the transporter family (mitochondrial FAD transporter). A second patient with this disorder, but with a more severe clinical picture (ataxia, dysarthria, myoclonus, muscle weakness, and exercise intolerance), was described in 2017. The patient's condition improved after riboflavin (dietary supplement) administration [128].

Differential diagnosis of FAODs is carried out with a wide range of inherited and exogenous disorders: mitochondrial diseases associated with defects of the mitochondrial respiratory chain, inherited forms of hypertrophic cardiomyopathies, carbohydrate metabolism disorders, myopathies, organic acidurias, and urea cycle disorders.

Differential diagnosis should also be made with hypoxic injuries of the nervous system, intrauterine infections, as well as cardiomyopathies and hepatitis of various origins [4, 9, 10, 11].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The criteria for establishing disorders of mitochondrial fatty acid β-oxidation are the changes in blood carnitine levels characteristic of each form and the identification of pathogenic variants in the corresponding genes in a homozygous/compound heterozygous state [5, 7, 159].

2.1 Complaints and Anamnesis

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

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

• Cases of sudden infant death;

• HELLP syndrome or fatty liver of pregnancy in a woman;

• Vomiting (at any age);

• Seizures (at any age);

• Changes in urine color (reddish-brown urine) (at any age);

• Episodes of altered consciousness (at any age);

• Episodes of cardiac arrhythmias (at any age);

• Intolerance to prolonged fasting intervals;

• Exercise intolerance (adults and older children);

• Muscle pain (adults and older children);

• Rapid fatigue (adults and older children);

• History of hypoketotic hypoglycemia episodes.

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

2.2 Physical Examination

Upon examination, attention should be paid to the main clinical manifestations of FAOD:

• Drowsiness, lethargy;

• Episodes of altered consciousness;

• Seizures;

• Muscle hypotonia;

• Muscle weakness;

• Muscle pain upon palpation;

• Hepatomegaly;

• Cardiac arrhythmia;

• Signs of heart failure.

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

2.3 Laboratory Diagnostics

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

Comments: Each form of FAOD is characterized by its own acylcarnitine profile, Appendix A6. Low levels of free carnitine can also be observed in a number of disorders from the FAOD group. It should be noted that if the free carnitine level is low, the elevation of specific acylcarnitines will be less pronounced, which may lead to false-negative analysis results. When identifying an acylcarnitine profile characteristic of GA2, it is necessary to perform differential diagnosis with riboflavin metabolism defects (see the Clinical presentation of the disease or condition section).

The rules for blood collection onto filter paper are given in Appendix A7.

Comments: in the urine of patients with FAOD, concentrations of dicarboxylic acids, lactate, and glutaric acid may be elevated compared to reference values. In most cases, these changes are nonspecific, except for GA2 (Appendix A7).

Comment: Novel variants of unknown significance require functional studies, for example, in skin fibroblast culture, to establish whether they are the cause of the disease.

Comments: in patients with FAOD, and most significantly during a period of metabolic decompensation, levels of transaminases and creatine phosphokinase increase, and hypoglycemia and metabolic acidosis are observed. A list of essential laboratory tests that can assist in providing medical care during acute metabolic decompensation is given in Appendix G 18.

Comments: due to the high risk of intercurrent infections in patients with FAOD, it is recommended to perform this test at least 5 times a year

2.4 Instrumental Diagnostics

Comments: regular ECG and EchoCG are necessary for patients with this pathology, as cardiovascular disorders are noted from an early age.

In accordance with Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services": electrocardiographic monitoring, Holter heart rhythm monitoring, decoding, description, and interpretation of electrocardiographic data,

Electrocardiogram recording.

2.5 Other Procedures

Specialist consultations may be provided to patients at various stages of medical care, including during the disease diagnosis period.

Comments: showing initial and follow-up consultations by a geneticist, ophthalmologist, neurologist, nutritionist, gastroenterologist, endocrinologist, cardiologist, pediatric cardiologist, nephrologist, pediatrician/general practitioner (family physician), as well as physicians of other specialties for patients with FAOD who have functional disorders of the respective organs and systems

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

3.1 General recommendations for diet therapy in patients with FAOD

The treatment strategy for patients with FAOD is comprehensive in nature, based on the correction of metabolic disorders through diet, which consists of reducing dietary fat intake as a backup component of tissue bioenergetics, minimizing fatty acid catabolism, and decreasing their role in meeting cellular energy demands while ensuring normal processes of anabolism, growth, and nutritional status. The main goal of dietary therapy is the prevention of starvation, prevention of hypoglycemia, and the minimally permissible reduction in the intake of pathogenetically significant fatty acids and their sources.

Adequate energy intake via carbohydrates is a key aspect of FAOD dietary therapy. The anabolic process suppresses fatty acid oxidation and lowers circulating acylcarnitine levels. Caloric calculations should ensure adequate energy intake to prevent catabolism while avoiding overfeeding and pathological weight gain. Based on studies in patients with FAOD, the following metabolic features have been noted [81]:

- lower energy expenditure;

- preferential carbohydrate oxidation for energy production;

- low muscle mass and high fat mass.

Comment: Appendix A8 summarizes recommendations on the duration of fasting periods according to age. However, these values apply to healthy children and stable states, when glycogen stores are utilized during prolonged overnight fasting for glucose production under normocaloric nutrition. The individual characteristics of the child must be taken into account; some patients require shorter intervals between meals to maintain a stable condition.

Starting at 8–12 months, to prevent nocturnal catabolism, raw cornstarch can be given before bedtime (1 g/kg/day, diluted in infant formula or water 1:2; if nocturnal hypoglycemia is documented, additional cornstarch may be administered at the same dose) to ensure adequate energy supply throughout the night; this tactic is usually used only in severely affected patients prone to hypoglycemia. Appendix A9 provides the average daily physiological energy requirements for children.

Comments: depending on the form of the disease, different treatment regimens are recommended. Appendix A10 provides basic recommendations on the fat-to-carbohydrate ratio in the diet.

3.1.1 Management of patients with FAOD during intercurrent infections

In patients with FAOD, episodes of metabolic decompensation can be triggered by intercurrent illnesses or gastroenteritis.

Comments: drinks containing a 20–25% dextrose solution or cornstarch (cornstarch for patients older than 8 months at a single dose of 1 g/kg) should be initiated at the first signs of illness and then evenly distributed throughout the day. For patients with a feeding tube, continuous enteral nutrition or repeated boluses of the nutrient solution already used at night can be administered throughout the day. In cases of clinical deterioration with food refusal and vomiting, hospitalization is necessary to provide infusion therapy (Appendix G 9).

3.1.2 Recommendations for the management of patients with FAOD during metabolic decompensation

In all patients with FAOD, regardless of the presence or absence of clinical symptoms, catabolic states require an emergency protocol.

A metabolic crisis is an indication for hospitalization and intensive care, including infusion therapy, which must be initiated immediately. Treatment tactics for children during a crisis include the administration of additional dextrose** for energy support and reduction of catabolic processes, correction of metabolic acidosis, hyperammonemia, and water-electrolyte disturbances, as well as adjustment of dietary therapy.

Eliminating hypoglycemia and energy deficiency is of paramount importance for preserving the life and health of patients with FAOD.

Comments: Intravenous administration of dextrose** solution calculated as follows: newborns and children under 3 years old 10-12 mg/kg/min, 3 to 10 years old 8-10 mg/kg/min, older than 10 years 5-8 mg/kg/min. If blood glucose drops below 2.5 mmol/L, an intravenous bolus of at least 10% dextrose** at 2-3 ml/kg is required, followed by continuous intravenous infusion of 10% dextrose** at a rate of 7 - 9 mg/kg/min until blood glucose normalizes.) The administration of dextrose** not only replenishes tissue energy deficits, but also suppresses lipolysis and reduces the production of toxic fatty acid derivatives.

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

Intravenous infusion solutions containing dextrose** should be used even when blood glucose levels are normal. Patients with FAOD depend entirely on glucose for their energy requirements, and their reserves can quickly become depleted. If a patient develops significant hyperglycemia (e.g., blood glucose greater than 13.8 mmol/L) with glucosuria and signs of metabolic decompensation, the initiation of #soluble insulin (human genetically engineered)** infusion should be considered instead of reducing the dextrose** infusion rate, to promote an anabolic state. The initial dose for #soluble insulin (human genetically engineered)** infusion is 0.01 IU/kg/min. Insulin levels should be titrated to maintain blood glucose between 5.5 and 8.3 mmol/L [153, 160].

It should be noted that infusion of a more concentrated dextrose** solution at a lower infusion rate via a central catheter may be required if cardiac function is impaired. In addition, caution should be exercised when discontinuing intravenous infusion—the rate must be reduced slowly to avoid reactive hypoglycemia.

Comments: according to intensive care guidelines, bicarbonate deficit is corrected by intravenous administration of alkaline solutions: sodium bicarbonate**. Sodium bicarbonate** is used as an 8.4% and 4.2% solution for convenience in recalculating to mmol NaHCO3. Its dosage (mmol) is determined by the formula: (-BE) × body weight (kg) × 0.3. Patients may also be prescribed alkaline drinks—a soda solution at a rate of 1⁄2–1 teaspoon per 200 ml of water, or alkaline mineral waters.

Depending on the severity of the condition, monitor blood acid-base balance, sodium, and potassium levels every 6–12 hours in patients with FAOD who develop a metabolic crisis [5,12,13,14].

Comments: in case of persistent dehydration, this is performed by intravenous administration of sodium chloride** 0.9%). However, it should be kept in mind that the primary measure in intensive care is the administration of dextrose** and alkaline solutions.

Comments: Sodium benzoate (dietary supplement) is prescribed at a dosage of 250 mg/kg/day (maximum up to 500 mg/kg/day; if body weight exceeds 20 kg, up to 5.5 g/m²/day).

Blood ammonia levels must be monitored every 6–12 hours. Blood sodium and potassium levels should be measured at least once every 2 hours.

According to international clinical guidelines for the management of hyperammonemia, intravenous administration of ammonia-lowering agents is indicated; however, these drugs are currently not registered in the Russian Federation. Therefore, all ammonia-lowering agents are used off-label or are unregistered, requiring approval by a medical committee and informed consent from the parents/legal representatives and the patient aged 15 years or older. Administration of these drugs is essential for life-saving indications in hyperammonemia.

Comments: for VLCAD and LCHAD, dietary restrictions during a crisis: completely eliminate the intake of natural (LCT) fats during the acute crisis period (for 24–48 hours). The daily fat requirement is met exclusively through MCTs. After 24–48 hours, gradually reintroduce natural fats until the recommended age-appropriate requirement is reached, under the monitoring of laboratory parameters and the patient's condition. The caloric value of the diet during a metabolic crisis should be increased by at least 10% above the daily age-specific norm, primarily through carbohydrates; avoid fasting when infusions are discontinued.

Comments: independently by mouth, via a feeding tube, or through a gastrostomy.

Nasogastric tube feeding as part of long-term therapy is generally discouraged, but is recommended in the event of illness during the initial stage of metabolic derangement. In routine practice, oral administration of dextrose** or corn starch is not required and is used only when a metabolic crisis is imminent or ongoing.

• In case of the need for epinephrine** administration in all patients with FAOD, it is recommended to administer it together with a 10% dextrose** solution [97, 151].

Level of evidence C (confidence level of recommendation – 5).

Comments: Epinephrine** can stimulate lipolysis, therefore dextrose** should be added when prescribing it to these children.

International clinical treatment guidelines have been developed only for specific forms of FAOD—medium-chain acyl-CoA dehydrogenase deficiency, very long-chain acyl-CoA dehydrogenase deficiency, and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. For other forms of FAOD, dietary therapy recommendations may vary across countries. Below are the core recommendations that, in the opinion of the working group, are the most comprehensive.

3.2 Recommendations for the treatment of specific forms of FAOD

Depending on the primary metabolic defect, therapeutic approaches may differ significantly or have minor variations.

3.2.1 Recommendations for the treatment of systemic carnitine deficiency

Comments: carnitine replacement is the mainstay of treatment for this pathology. Patients should also avoid fasting (see general recommendations for FAOD and Appendix A7).

Comments: #Levocarnitine is prescribed at a dose of 50–400 mg/kg/day divided into three doses. The exact dose of #levocarnitine should be adjusted based on plasma carnitine levels. Carnitine concentration should be measured at least 4 hours after the last dose. Free carnitine concentration in patients with primary carnitine deficiency remains below normal even during therapy [14]. There is no established "therapeutic" level to be achieved, and a free carnitine concentration > 20 µM is considered adequate. Plasma carnitine levels drop rapidly after discontinuation of #levocarnitine therapy, followed by depletion of tissue stores. This explains why patients with primary carnitine deficiency who miss doses remain asymptomatic for several months, which may lead them to stop taking #levocarnitine. These patients are at risk of sudden death due to cardiac arrest. It is crucial to continue therapy daily to avoid severe cardiac complications. Long-term #levocarnitine therapy completely resolves the clinical manifestations of the disease, with normalization of heart size and ECG within a month and recovery of muscle tone, although tissue (muscle) carnitine concentrations remain very low (< 10% of normal) for a prolonged period.

High-dose #levocarnitine intake may cause increased gastrointestinal motility, diarrhea, and trimethylamine production, which causes a "fishy odor" of urine and body odor. Reducing the carnitine dose can mitigate these side effects. If the unpleasant odor persists, a course of oral #metronidazole** at a dose of 10 mg/kg/day for 7–10 days may be prescribed [82, 83, 155, 156].

3.2.2 Recommendations for the treatment of carnitine-acylcarnitine translocase deficiency

Clinical guidelines based on sufficient evidence and certainty levels for the treatment and monitoring of this specific disease have not been developed globally. Only expert-opinion-based recommendations regarding clinical and biochemical monitoring of patients with FAOD have been published. There is no consensus on the use of levocarnitine in this form of the disease. Some authors do not recommend it, as the accumulation of long-chain acylcarnitines can be toxic to cardiac rhythm [84]. Nevertheless, other authors consider it appropriate to use it during episodes of metabolic decompensation to restore the mitochondrial coenzyme A pool [66, 85–89].

Comments: MCTs low in C10 are recommended because C10 fats require active CACT function for oxidation [90].

Comments: there is no consensus on safe feeding intervals; in these clinical guidelines, we have selected those published by a working group of European experts. The maximum permissible safe interval for various age groups is given in Appendix A9 [66].

Comments: The fatty acid content of various oils is given in Appendix A16 [66].

Comments: for detailed recommendations, see section 3.1.2 Treatment recommendations for patients with FAOD. During metabolic decompensation, reduction in long-chain acylcarnitine levels is considered an important marker of treatment efficacy.

3.2.3 Dietary recommendations for carnitine palmitoyltransferase I and II deficiency

Clinical guidelines based on sufficient evidence and certainty levels for the treatment and monitoring of CPT2 and CPT1 deficiency have not been developed globally. Only recommendations based on expert experience regarding the clinical and biochemical monitoring of patients with FAOD have been published.

Comments: Frequent feedings every 3–4 hours are recommended, especially for children, given their limited glycogen stores. Adding cornstarch at night and for night feeds is determined by glycemic levels and provides a continuous source of slow-release carbohydrates to prevent hypoglycemia during sleep. Older children should not have overnight fasting intervals exceeding 12 hours, and during an infectious illness, fasting intervals must be even shorter. Adult patients should be informed about the risks associated with fasting, and both they and their attending physician must be aware of the risks during surgical procedures and anesthesia. Intravenous administration of dextrose** should be recommended if fasting is necessary for more than 12 hours due to illness or medical procedures. The maximum permissible safe interval for different age groups is given in Appendix A8

Comments: C6–C10 fatty acids do not require the carnitine shuttle to enter the mitochondrion, therefore MCTs can be used as a primary energy source.

• To prevent episodes of myoglobinuria, it is recommended that patients diagnosed with CPT 1 and CPT 2 deficiency avoid physical exertion during intercurrent infections and during prolonged fasting intervals [91, 92].

Level of evidence C (confidence level of recommendation – 5).

• For adult patients diagnosed with CPT 1 and CPT 2 deficiency during a metabolic crisis accompanied by rhabdomyolysis and myoglobinuria, it is recommended to apply the standard treatment protocol for this complication to prevent acute renal failure [13, 92, 93].

Level of evidence C (confidence level of recommendation – 5).

Comments: During an episode of myoglobinuria, intravenous administration of 0.9% sodium chloride** and sodium bicarbonate** (sodium chloride** 110 mmol/L, sodium bicarbonate** 40 mmol/L) in a 5% dextrose** solution is performed, with the addition of 10 g of #mannitol** per liter (from a 10% or 15% solution). The solution should be administered to a young adult weighing 75 kg at a rate of 12 L/day to achieve a diuresis of 8 L/day and maintain a pH above 6.5. This therapeutic regimen allows for the control of hyperkalemia and acidosis and, consequently, can prevent acute renal failure. If patients do not respond to rehydration, hemodialysis may be required. Hemodialysis corrects metabolic acidosis and electrolyte disturbances and promotes the removal of myonecrotic toxins from the plasma. Dialysis is indicated for renal failure if the patient has anuria and diuresis is not restored after rehydration. There is reason to believe that early initiation of hemodialysis may improve outcomes by removing nephrotoxins and preventing life-threatening complications such as hyperkalemia and profound metabolic acidosis. Treatment of acute renal failure should be carried out in accordance with clinical guidelines developed by professional nephrology associations.

3.2.4 Dietary recommendations for SCAD deficiency

Since the majority of patients with SCADD are asymptomatic, treatment is not required; there are no generally accepted guidelines for dietary therapy or the use of levocarnitine and riboflavin (dietary supplement).

3.2.5 Dietary recommendations for MCAD deficiency

Neonatal screening for MCAD deficiency is carried out in many countries, so patients are identified before the onset of clinical symptoms. Dietary recommendations vary depending on age and confirmation status of the diagnosis.

Comments: The professional community has not developed unified guidelines on the use of Levocarnitine in MCAD. Some authors recommend 100 mg/kg/day of levocarnitine to compensate for secondary carnitine deficiency and improve the excretion of toxic metabolites, while others believe this is unnecessary [94]. Exercise tolerance studies in patients with MCAD deficiency have shown that exercise tolerance increases after taking Levocarnitine at 100 mg/kg/day [95]. Although patients with MCAD deficiency experienced no severe side effects from Levocarnitine intake, some patients complained of nausea, diarrhea, abdominal pain, and a fishy body odor at a dose of 100 mg/kg/day [96]. Given this information, some physicians recommend using low doses of Levocarnitine if blood free carnitine levels are below normal.

3.2.5.1 Recommendations for dietary therapy in newborns with MCAD identified through neonatal screening

Comments: It is believed that newborns with MCAD deficiency are at the highest risk of developing hypoglycemia during the first 72 hours of life, especially when breastfed. Regular feedings must be maintained; skipping night feedings is not permitted!

Comments: Safe feeding intervals were determined based on the experience of countries screening for MCAD deficiency.

Comments: Breastfed infants with MCAD are at particular risk because the energy content of breast milk is low during the first few days and volumes are small. Therefore, it is recommended to supplement feeding with adapted infant formulas at 60 ml/kg/day. It is advisable to evenly divide the formula volume between 6 and 8 feedings and administer it after breastfeeding. If the child does not tolerate a sufficient volume of formula and breast milk, nasogastric tube feeding or an intravenous infusion of 10% dextrose** should be prescribed to meet the required caloric needs.

3.2.5.2 Dietary recommendations for patients with MCAD

Comments: The diet for older children and adult patients should be regular and include three main meals (breakfast, lunch, dinner) as well as 2–3 snacks (second breakfast, afternoon snack, and a high-carbohydrate product before bedtime [bakery items, crackers, grain dish] with a beverage [kissel, compote, tea]). The fasting interval at night should not exceed 12 hours.

Comments: Small amounts of MCTs are present in regular infant formulas, but their quantity is minimal and cannot be harmful. MCTs are added in high concentrations to certain specialized formulas, which are not recommended for children with this form of the disease. Special dietary products containing large amounts of MCTs should be avoided.

Dietary fats are not restricted in patients with MCAD deficiency [98].

Medium-chain triglycerides are found in certain foods, such as butter and cow's milk, in small quantities, and they can be included in the diet without major restrictions. Coconut is the sole exception, where 5% of fatty acids have a chain length of C8 or C10. It is recommended to avoid consuming pure coconut and coconut oil, as the effect of large quantities on the health of patients with MCAD deficiency is unknown. MCTs are added to certain specialized infant formulas and energy supplements, and they should not be included in patients' diets. It is important to check the current ingredients of all products for the presence of MCTs.

Comments: It is also recommended to exclude fats during illness, although compelling evidence of the necessity of this for MCAD deficiency has not been obtained. As the child's condition improves, a normal diet may be resumed, but additional "energy" drinks should be given, especially at night, until the child has fully recovered and transitioned to a normal diet.

Comments: Infusion therapy with dextrose** solutions should be initiated when one of the following indications is present: repeated vomiting, hypoglycemia, low PO₂, dehydration, altered consciousness, metabolic acidosis. This is described in detail in Section 3.1.2 Guidelines for the management of patients with FAOD during metabolic decompensation

Comments: Acetylsalicylic acid** increases mitochondrial fatty acid oxidation, which contributes to their accumulation, and also inhibits peroxisomal oxidation. This leads to clinical deterioration, since peroxisomal fat oxidation serves as an alternative metabolic pathway that partially compensates for the biochemical defect in FAOD.

3.2.6 Dietary recommendations for LCHAD and TFP deficiency

LCHAD deficiency is one of the most severe forms of FAOD, most frequently presenting with metabolic crises. Dietary compliance is recommended for all patients in early childhood regardless of the presence or absence of clinical symptoms [101].

Comments: Neonates are indicated to receive a specialized formula low in LCT and high in MCT (MCT-containing formula). The specialized MCT-containing formula meets all nutritional requirements. However, this necessitates additional supplementation with essential long-chain fatty acids.

Comments: Since infants may exhibit active lipolysis, the concentration of certain acylcarnitines may exceed normal values, causing false-positive assay results. If the diagnosis is not confirmed, diet therapy may be discontinued.

Comments: A beneficial effect of increased protein intake on energy balance and metabolic control has been described in children with LCHAD or TFP deficiency [134].

In long-chain fatty acid oxidation defects, long-chain fat intake should be restricted (calculated as a percentage of total energy derived from fats). When restricting long-chain fatty acids in the diet, essential fatty acid supplements are necessary to meet daily fat requirements (Appendix A 8). To maintain an optimal omega-3 to omega-6 fatty acid ratio, walnut oil, soybean oil, or wheat germ oil is preferred [102].

3.2.7 Dietary recommendations for VLCAD deficiency

Currently, there are no evidence-based guidelines for the management of patients with long-chain fatty acid oxidation disorders [62]. Clinical phenotype heterogeneity is a well-established fact [5], which, with the introduction of newborn screening into practice, also implies cases of asymptomatic disease [6]. In addition, molecular heterogeneity makes it difficult to predict disease severity or outcome at the time of newborn screening. Determining whether patients with a mild phenotype require a reduction in the proportion of long-chain fats in their diet, or if regular feeding and MCT supplements alone are sufficient—especially given increased caloric needs—requires longer follow-up [66].

Depending on the child's condition, enteral nutrition is delivered orally, as well as via a nasogastric tube or gastrostomy; calculations are made strictly on an individual basis.

Comments: some newborns with asymptomatic VLCAD deficiency, whose acylcarnitine profiles completely normalized after the first week of life, did not receive a low-fat, modified-fat diet in the first months of life and have not yet developed VLCAD-associated clinical symptoms. Given the molecular heterogeneity in VLCADD, it is very difficult to establish a clear genotype-phenotype correlation and predict the clinical course of the disease. However, the p.V243A mutation, at least one copy of which is found in many asymptomatic patients detected by newborn screening, is generally associated with a mild phenotype. Patients with this mutation may develop hypoglycemia during severe illnesses or myopathy during heavy physical exertion, but an asymptomatic course is also possible.

For patients who develop only exercise-related myopathic symptoms at an older age, enrichment of the diet with MCTs (especially before physical exertion) may play an important role, and the need for LCT restriction may be absent.

Comments: in symptomatic cases, total fat content should be 25–30% of total caloric intake, with 20–25% derived from MCTs and 5–10% from LCTs (Appendix A15) [61].

Since clinical symptoms during long-term follow-up in patients with VLCAD deficiency are predominantly characterized by episodic muscle pain and rhabdomyolysis, indicating a lack of muscle energy, the diet must be enriched with MCTs, which should account for 20% of total caloric intake (Table 3). In patients with muscle weakness and exercise-induced pain, increasing the intake of MCTs (or carbohydrates) immediately before more intense physical exertion (e.g., at a dosage of 0.25–0.5 g MCT/kg) is helpful.

3.2.8 Recommendations for the management of patients with GA2

Comments: a detailed description is given in 3.1.2 Guidelines for the treatment of patients with FAOD during the period of metabolic decompensation

3.3 Recommendations for the use of specific medicinal products

In addition to dietary therapy for fatty acid oxidation disorders, a number of medicinal products and vitamins are also necessary to compensate for the deficiency of essential fatty acids, carnitine, and fat-soluble vitamins in the body.

3.3.1 Guidelines for the use of individual medicinal products containing levocarnitine

Comments: Levocarnitine is the mainstay of therapy for patients with primary carnitine deficiency. It can also be used in other forms of FAOD when blood carnitine levels are low, in order to enhance the binding of fatty acid metabolites and their excretion in the urine. However, the use of levocarnitine in FAOD is controversial, as evidence of its efficacy in secondary carnitine deficiency is lacking. In TFP and LCHAD deficiencies, Levocarnitine supplements may induce further production of 3-hydroxyacylcarnitines, which can cause irreversible neuropathic symptoms and arrhythmia. Studies in a VLCAD-deficient mouse model have also shown that carnitine deficiency induces its endogenous biosynthesis, which, however, is suppressed by the exogenous administration of Levocarnitine. In many patients with fatty acid oxidation defects not receiving Levocarnitine supplements, plasma free carnitine concentrations also vary from low to normal, which also suggests endogenous carnitine biosynthesis in humans. Thus, supplements containing Levocarnitine should be prescribed with caution, especially when dealing with TFP and LCHAD deficiencies. There is a consensus that, in particular, intravenous administration of Levocarnitine should be avoided during acute metabolic disorders, as such situations increase the production of potentially toxic acylcarnitines, which has led to sudden death in patients.

3.3.2 Recommendations for the use of essential fatty acids

FAOD patients on a low-fat diet are at high risk of fat-soluble vitamin deficiency. It is important to avoid essential fatty acid deficiency, and the majority of long-chain fat intake should come from oils rich in essential fatty acids. To meet essential fatty acid requirements, the addition of special oils, such as walnut or flaxseed oil (Appendix G 13), may be required [105].

Comments: Linoleic acid and α-linolenic acid are precursors for the endogenous synthesis of longer fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are crucial for the development of nervous and immune system functions and the visual analyzer [105]. Ensuring optimal concentrations of these fatty acids in plasma solely through dietary oils is difficult, so patients require pure supplements to achieve normal levels. It is believed that DHA supplements can stabilize and slow down the progression of retinitis pigmentosa in FAOD. According to a study [157], optimal dietary therapy administered based on low 3-hydroxyacylcarnitine and high plasma DHA concentrations preserved retinal function and visual acuity in children with LCHAD or MTP deficiency.

• During the interictal period for FAOD patients on a long-chain fat-restricted diet, it is recommended to add natural vegetable oils (coconut oil, walnut oil) to compensate for fatty acid deficiency [105].

Level of evidence C (confidence level of recommendation – 5).

Comments: The ratio of essential fatty acids in various oils is given in Appendix A16.

Comments: Appendix G 8 provides the main recommendations on prescribing essential fatty acids in a low-fat diet.

3.3.3 Recommendations for the use of medium-chain triglycerides

Comments: The MCT content in various medical nutrition products is given in Appendix A17. Episodic muscle symptoms, such as rhabdomyolysis, are pathogenetically linked to energy deficiency and can be overcome with carbohydrates or MCTs. In particular, data indicate that exercise-related rhabdomyolysis can be prevented by taking a sufficient amount of MCTs immediately before exercise

Comments: Medium-chain fatty acids can enter mitochondria without being bound to carnitine, bypassing the step where fatty acid oxidation is normally regulated. Therefore, MCT intake can lead to more severe metabolic disorders than the use of long-chain fats.

3.3.4 Recommendations for the use of vitamins

Comments: Vitamins are prescribed in age-appropriate prophylactic doses in courses of 2-3 months.

Comments: A similar metabolic profile can be observed in riboflavin transporter defect, therefore oral administration of riboflavin (dietary supplement) at a dose of 100-200 mg/day completely relieves the clinical and biochemical symptoms of the disease.

3.4 Symptomatic treatment

Comments: In patients with mitochondrial fatty acid β-oxidation defects, the use of valproic acid** can lead to severe liver failure.

3.5 Surgical treatment

If indications for surgical interventions arise, a collegial decision on the tactics of their performance is recommended [5, 12].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

A personalized rehabilitation course, including massage, exercise therapy, physiotherapeutic procedures (general magnetotherapy, thermotherapy, shock wave therapy, biofeedback therapy, and other procedures), is developed for patients by a physical therapist and an exercise therapy doctor.

Rehabilitation courses (massage, exercise therapy, physiotherapy, psychological and pedagogical support) are recommended in a day hospital setting 3–4 times a year [1, 2, 14].

Comments: The primary goal of palliative care services is to create all necessary conditions for patients to remain at home rather than within a medical facility. This not only improves the quality of life for patients and their families but also significantly reduces public expenditures on permanent inpatient treatment for such patients [1, 2, 14].

5. Prevention and Dispensary Observation

5.1 Prevention

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

Genetic counseling

Comment: Genetic counseling is recommended for families with affected children to determine genetic risk. As with other autosomal recessive disorders, the risk of having an affected child is 25% for each pregnancy. Prenatal and preimplantation genetic diagnosis are available for families with an affected child.

Prenatal diagnosis is performed using molecular genetic methods by analyzing DNA extracted from chorionic villus biopsy samples at 9–11 weeks of pregnancy and/or amniotic fluid cells or fetal blood at 20–22 weeks of pregnancy. In mild forms of FAOD that respond well to therapy, the decision to perform prenatal diagnosis should be made only after a detailed discussion with the family regarding all risks, the prognosis of the disease in offspring, and treatment options available upon early diagnosis.

Healthy lifestyle

Adolescents and adults with FAOD should be aware of the risks associated with excessive alcohol consumption. Alcohol inhibits gluconeogenesis; therefore, both fatty acid oxidation and gluconeogenesis—which supply the body with metabolic energy during fasting—are impaired. Alcohol consumption should be limited and always combined with food.

Children diagnosed with FAOD should be taught a "healthy lifestyle" through diet and exercise. Some parents are concerned that their child is not eating enough. If the child does not consume the recommended volume or portion, they can be given supplemental feeding or a snack later, if necessary, to meet their physiological energy needs.

Individuals with MCAD deficiency do not require extra calories; overeating should be avoided due to the risk of obesity.

Comments: Long-term study results have shown that individuals treated for MCAD deficiency are prone to excessive weight gain [108]. Prepubertal children may be overweight due to frequent feedings as part of their treatment. Height and weight parameters should be closely monitored at every clinic visit. Follow-up monitoring should include weight control recommendations, healthy lifestyle education—including frequent regular meals adhering to physiological caloric norms—and physical activity recommendations.

Monitoring during pregnancy

Comment: Women who have had a child with FAOD are at risk for HELLP syndrome during subsequent pregnancies. This is especially true for the following disorders: LCHAD, VLCAD, CPT1, CPT2, and CACT deficiencies.

5.2 Dispensary monitoring

Comments: Acylcarnitines are measured at the following frequency: every 1–2 months for patients under 1 year of age, every 3–6 months for children under 6 years of age, every 6–12 months for patients over 6 years of age, and as clinically indicated during or when suspecting a metabolic crisis. It should be noted that acylcarnitine levels may increase with Levocarnitine administration (Appendix A19).

Comments: due to the high risk of intercurrent infections, a complete blood count is performed in patients with FAOD every 6 months for patients under 6 years of age, and every 6–12 months for patients over 6 years of age.

Comment: the test is performed at least once every 6 months and as clinically indicated in case of deterioration and during a metabolic crisis.

Comments: due to the high risk of intercurrent infections in patients with FAOD, it is recommended to perform this test at least 5 times a year

General urinalysis in patients with FAOD is typically performed every 6 months for patients under 6 years of age, every 6–12 months for patients over 6 years of age, and more frequently as clinically indicated in case of deterioration and during a metabolic crisis.

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

Comments: Frequency in the absence of abnormalities is at least once a year; in the presence of liver pathology, as clinically indicated.

Comments: Frequency in the absence of abnormalities is at least once a year; in the presence of pathology, as clinically indicated.

Comments: Dietary therapy is adjusted by geneticists or nutritionists with a frequency of once a month during the 1st year of life, then once every 3 months and as clinically indicated up to 3 years of age; once every 6 months after 3 years of age.

Comments: initial and follow-up consultations are indicated with a geneticist, ophthalmologist, neurologist, gastroenterologist, endocrinologist, cardiologist, pediatric cardiologist, nephrologist, pediatrician / general practitioner / family physician, as well as other specialists for patients with FAOD who have functional impairments of the respective organs and systems

Comments: Parents of the child should always carry an emergency information card outlining urgent measures during the onset of a metabolic crisis (Appendix A20).

6. Organization of Medical Care

Indications for elective hospitalization:

- the need for various types of expert evaluations or examinations in a medical organization when they cannot be performed on an outpatient basis and require dynamic observation (including issuing a federal medical board conclusion).

Indications for emergency hospitalization:

- acute diseases;

- exacerbations of chronic diseases;

- poisoning and trauma, conditions requiring intensive care and transfer to intensive care units or critical care units, as well as round-the-clock medical monitoring and specialized diagnostic and therapeutic procedures.

Indications for discharging a patient from a medical organization:

- no threat to the patient's life;

- absence of a threat of complications requiring urgent treatment;

- stabilization of the patient's condition and main clinical and laboratory parameters of the pathological process regarding the underlying disease;

- no need for continuous medical supervision and round-the-clock monitoring regarding the underlying disease;

- need to transfer the patient to another hospital or social care institution.

Patients with FAOD are indicated for a comprehensive evaluation in multidisciplinary inpatient facilities every 6–12 months (depending on the severity of the condition).

The duration of hospitalization depends on the rate of correction of metabolic disorders, the timing of positive central nervous system and other organs' response, the rate of restoration of blood glucose and acid-base balance levels; treatment response is observed within 5–7 days. The average hospital stay is 21 days.

After discharge from the hospital, children require follow-up by a pediatrician, neurologist, cardiologist, gastroenterologist, ophthalmologist, nutritionist, geneticist, and an ECG (as clinically indicated).

Outpatient monitoring of patients in primary care settings must be carried out on a continuous basis.

7. Additional Information

Life expectancy largely depends on the severity of the disease and the implementation of pathogenetic and symptomatic therapy. Cardiopulmonary failure is most frequently the cause of death.

If dietary therapy is indicated, treatment should be initiated as early as possible to prevent the progression of complications [1–4, 11–14].

The prognosis for the patient's condition and mental development depends on the severity of the disease, the degree of internal organ (heart, liver) and central nervous system involvement, the timing of treatment initiation, and the efficacy of intensive care during metabolic decompensation. Early-onset systemic forms of the disease typically have a more severe course and a less favorable prognosis.

Unfavorable laboratory signs indicating unbalanced therapy and the risk of a metabolic crisis include a decrease in free carnitine and glucose levels, a tendency toward a lower blood glucose/pH and base deficit, an increase in very long-chain acylcarnitines (with a decrease in free carnitine) in the blood, and increased excretion of organic acids.

Nutritional support inadequacy is indicated by decreased levels of hemoglobin, iron, total protein, and albumin. Low blood levels of essential fatty acids (linoleic, linolenic, arachidonic, docosahexaenoic, etc.) and an altered linoleic/linolenic acid ratio (normal is 5:1 to 10:1) can cause delayed psychomotor and speech development, impaired immune system maturation, and decreased visual acuity.

Mass newborn screening is one of the effective approaches for the early diagnosis of FAOD. Neonatal screening for FAOD is performed in selected regions of the Russian Federation [1–3].

All individuals should have a frequently updated emergency letter that can be provided, if necessary, to medical personnel who may not be familiar with FAOD. An example of such a card is given in Appendix A20.

Criteria for Evaluating the Quality of Medical Care

Criteria for evaluating the quality of primary health care

Criteria for evaluating the quality of specialized medical care

References

Appendix A1. Working Group Composition

1. Anisimova Inga Vadimovna — Candidate of Medical Sciences, Head of the Medical Care Organization Department, Medical Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

2. Bagaeva Madlena Enverovna — Candidate of Medical Sciences, Senior Research Fellow at the Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Federal Research Centre of Nutrition and Biotechnology, Assistant at the Department, Pirogov Russian National Research Medical University of the Ministry of Health of Russia.

3. Baydakova Galina Viktorovna — Candidate of Biological Sciences, Head of the "Metabolom" Shared Research Facility, Leading Research Fellow at the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Russian Society of Medical Geneticists.

4. Baranov Aleksandr Aleksandrovich — 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 of the Central Clinical Hospital of the Russian Academy of Sciences, Professor at the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chief freelance pediatric specialist of the Ministry of Health of Russia.

5. Bushueva Tatyana Vladimirovna — Doctor of Medical Sciences, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Member of the Association of Medical Geneticists, Member of the Scientific and Practical Society "Children's Health Association".

6. Vashakmadze Nato Dzhumberovna — Doctor of Medical Sciences, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, National Medical Research Center No. 2, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia

7. Vishnyova Elena Aleksandrovna — Doctor of Medical Sciences, Deputy Head for Research at the Research Institute of Pediatrics and Child Health of the Central Clinical Hospital of the Russian Academy of Sciences (Ministry of Science and Higher Education), 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.

8. Degtyareva Anna Vladimirovna — Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Member of the Russian Society of Neonatologists

9. Dokshukina Alina Alekseevna — Neonatologist, Junior Research Fellow at the Department of Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Member of the Russian Society of Neonatologists

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

11. Zhurova Nataliya Vyacheslavovna — PhD in Medical Sciences, Leading Researcher, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Centre of Surgery, Member of the Union of Pediatricians of Russia, Member of the Association of Medical Geneticists

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

13. Kuzenkova Lyudmila Mikhailovna — 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

14. Kutsev Sergey Ivanovich — Academician of the RAS, Doctor of Medical Sciences, Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, President of the Association of Medical Geneticists

15. Lavrova Alla Evgenyevna — Doctor of Medical Sciences, Director of the Institute of Pediatrics, Head of Pediatric Department No. 2, University Clinic of the Privolzhsky Research Medical University of the Russian Ministry of Health, Excellence in Public Health Awardee.

16. Svetlana V. Mikhailova — Dr. of Sci. (Med.), Head of Department, Russian Children's Clinical Hospital of the Ministry of Health of Russia

17. Namazova-Baranova Leyla Seymurovna — Academician of the RAS, 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 of the Central Clinical Hospital of the RAS, Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief freelance pediatric specialist in preventive medicine of the Russian Ministry of Health

18. Nazarenko Lyudmila Pavlovna — Professor, Doctor of Medical Sciences, Deputy Director for Research and Clinical Work, Head of the Laboratory of Hereditary Pathology, Research Institute of Medical Genetics, Tomsk National Research Medical Center of the RAS, Member of the Association of Medical Geneticists

19. Nikolaeva Ekaterina Aleksandrovna — Doctor of Medical Sciences, Chief Researcher of the Department of Clinical Genetics, Veltischev Research and Clinical Institute of Pediatrics, Professor of the Department of Innovative Pediatrics and Pediatric Surgery, Institute of Continuing Education and Professional Development, Pirogov Russian National Research Medical University of the Russian Ministry of Health

20. Pervunina Tatyana Mikhailovna — Doctor of Medical Sciences, Pediatrician, Pediatric Cardiologist, Associate Professor at the Department of Pediatrics, Faculty of Medicine, Saint Petersburg State University, Director of the Institute of Pediatrics and Perinatology, Almazov National Medical Research Centre.

21. Pechatnikova Natalya Leonidovna — 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.

22. Repina Svetlana Afanasyevna — PhD in Medical Sciences, Medical Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Russian Society of Medical Geneticists, Member of the Association of Medical Geneticists

23. Sviridova Valeriya Valeryevna — Medical Geneticist, Department of Medical Care Organization, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Junior Researcher, Laboratory of Mutagenesis, Research Centre for Medical Genetics named after Academician N.P. Bochkov

24. Seitova Gulnara Narimanovna — PhD in Medical Sciences, Chief Physician of the Medical Genetics Center (Genetics Clinic), Research Institute of Medical Genetics, Tomsk National Research Medical Center of the RAS

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

26. Smirnova Olga Yakovlevna – Medical Geneticist, Senior Researcher, Department of Standardization and Study of Evidence-Based Medicine Fundamentals, Research Institute of Pediatrics and Child Health, Central Clinical Hospital of the RAS

27. Strokova Tatyana Viktorovna — Doctor of Medical Sciences, Professor of the RAS, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Federal Research Centre of Nutrition and Biotechnology, Head of the Department of Gastroenterology and Dietology, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

28. Subbotin Dmitry Mikhailovich — Medical Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

29. Taran Nataliya Nikolaevna — PhD in Medical Sciences, Senior Researcher, Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Federal Research Centre of Nutrition and Biotechnology, Assistant Professor, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

30. Fisenko Andrey Petrovich – Doctor of Medical Sciences, Professor, Honored Doctor of the Russian Federation, Director of the National Medical Research Center for Children's Health of the Russian Ministry of Health.

Representatives of patient advocacy organizations:

Pogosyan Nelly Sergeevna – Representative of the All-Russian Association of Orphan Diseases

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

Appendix A2. Methodology for Developing Clinical Guidelines

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

These guidelines establish the types, scope, and quality indicators of medical care for patients with fatty acid oxidation disorders and were reviewed on June 1–2, 2018, at the Scientific and Practical Congress "Orphan Diseases" in Moscow.

The clinical guidelines are based on a systematic review of the 1992–2013 literature from 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.

Fatty acid oxidation disorders are rare hereditary diseases, which precludes conducting large cohort and randomized controlled studies; therefore, only expert case studies published over the past two decades are used to create diagnostic and therapeutic 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. Functional diagnostics physicians;

10. Medical psychologists;

11. Medical students;

12. Residents and interns.

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

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative 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 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. Order of the Ministry of Health of the Russian Federation No. 274n dated April 21, 2022, "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases"

2. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Healthcare Protection in the Russian Federation".

3. Decree of the Government of the Russian Federation No. 890 of July 30, 1994, "On State Support for the Development of the Medical Industry and Improvement of the Provision of Medications and Medical Devices to the Population and Healthcare Institutions" (with amendments and addenda)

4. Order of the Ministry of Health of the Russian Federation No. 834n of December 15, 2014, "On Approval of Unified Forms of Medical Documentation Used by Medical Organizations Providing Outpatient Medical Care and Procedures for Their Completion".

5. Order of the Russian Ministry of Health No. 1051n dated November 12, 2021, "On Approval of the Procedure for Giving Informed Voluntary Consent to Medical Intervention and Refusal of Medical Intervention, the Form of Informed Voluntary Consent to Medical Intervention, and the Form of Refusal of Medical Intervention"

6. Order of the Russian Ministry of Health No. 1094n dated November 24, 2021, "On Approval of the Procedure for Prescribing Medicinal Products, Prescription Forms for Medicinal Products, the Procedure for Issuing Said Forms, Their Accounting and Storage, Prescription Form Forms Containing Prescriptions for Narcotic Drugs or Psychotropic Substances, the Procedure for Their Manufacture, Distribution, Registration, Accounting and Storage, as Well as the Rules for Issuing Prescription Forms, Including in the Form of Electronic Documents"

7. Order of the Ministry of Health of the Russian Federation No. 302n dated May 16, 2019, "On Approval of the Procedure for Minors Undergoing Dispensary Observation, Including During the Period of Education and Upbringing in Educational Organizations"

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

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

Main regulatory legal acts governing the provision of palliative medical care

1. Federal Law No. 18-FZ dated March 6, 2019, "On Amendments to the Federal Law 'On the Basics of Protecting the Health of Citizens in the Russian Federation' Regarding the Provision of Palliative Medical Care."

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

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

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

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

   Other information resources and regulatory documents used in the development of the clinical guidelines:

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

7. Order of the Ministry of Health of the Russian Federation No. 205n dated May 2, 2023, "On Approval of the Nomenclature of Positions for Medical and Pharmaceutical Workers"

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

9. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Fundamentals of Public Health Protection in the Russian Federation' regarding Clinical Guidelines".

10. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for the Development and Revision of Clinical Guidelines, Their Template Form, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

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

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

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

14. Information Letter of the Russian Ministry of Health on the possibility of procuring a medicinal product by trade name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu);

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

Appendix A4. Classification of inherited fatty acid oxidation disorders

Appendix A5. Clinical manifestations of fatty acid oxidation disorders

Appendix A5a. General clinical manifestations of FAOD

Appendix A6. Laboratory abnormalities in fatty acid oxidation disorders

Appendix A7. Collection of biological material for dried blood spot testing

Algorithm of actions for medical personnel during blood sample collection

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

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

• wipe the puncture site with a sterile wipe moistened with 70% alcohol, blot with a dry sterile wipe; - puncture with a sterile single-use lancet;

• wipe away the first drop of blood with a sterile dry non-woven or gauze swab, or a sterile medical gauze napkin;

• 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

Some patients may receive infusion therapy or blood component transfusions, which can affect test results. For example, blood plasma transfusions can yield false-negative results. It is recommended to collect blood for diagnostics no earlier than 6-7 days after a blood plasma transfusion and 7-10 days after blood component transfusions

Blood sampling 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 +4⁰C until shipping. Storage time prior to shipping should not exceed 7 days. Storage for a longer period at a higher temperature will lead to false-positive results.

Appendix A8. Maximum fasting duration (in stable metabolic states)

Maximum fasting intervals for patients with long-chain fatty acid oxidation disorders [66].

Caution! If children have no feeding difficulties, nighttime fasting may be extended up to 6 hours starting from 3 months of age, and up to 8 hours starting from 6 months of age. Authorize fasting exceeding 10 hours with caution, even after the first year of treatment. The risk of nocturnal hypoglycemia decreases as the child grows older, and most children after 4 years of age can tolerate periods without food for 10–12 hours if they feel well.

These recommendations apply only if the children's condition is stable. During periods of metabolic decompensation, infectious diseases, and stressful situations, fasting periods should be shorter.

Children with severe forms of diseases and recurrent metabolic crises require stricter recommendations.

Maximum feeding intervals for patients with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (https://www.ncbi.nlm.nih.gov/books/NBK583531/)

Maximum feeding intervals for patients with medium-chain acyl-CoA dehydrogenase deficiency (https://www.ncbi.nlm.nih.gov/books/NBK560837/)

Caution! It is recommended to check blood glucose levels before morning feeding to determine tolerance to nighttime fasting and, if necessary, develop individualized recommendations.

During childhood, an age-appropriate schedule of meals and snacks should be followed.

In MCADD, skipped meals and weight-loss diets that recommend fasting should be avoided. Prolonged and/or intense exercise must be "covered" by sufficient carbohydrate intake and hydration.

Appendix A9. Average daily physiological energy requirements

Appendix A10. Fat-to-carbohydrate ratio in the diet for various forms of FAOD

Appendix A11. Essential fatty acid supplements in low-fat diets (D-A-CH)

Appendix A12. Use of carbohydrates in suspected metabolic crisis and intercurrent illnesses

[81]

Correlation between child age and dextrose** dose for enteral administration in suspected metabolic crisis.

[130] 

Appendix A13. MCT content in specialized nutritional supplements used in patients with LCHAD

[105]

Chemical composition of specialized fat products (modules) (g / 100 ml)¹

¹ – MCTs are also found in a number of formulas for preterm infants, semi-elemental formulas based on extensively hydrolyzed cow's milk protein, and amino acid-based elemental formulas

² - Specialized product based on medium-chain triglyceride oil

Appendix A14. Diet in TFP/LCHAD deficiency (expert consensus)

a The recommended LCT proportion in the diet of healthy infants is 40–45% of total caloric intake, and in school-age children, 30–35% (D-A-CH recommendations)

b In practice, LCT intake exceeds the recommended values due to a limited choice of food products; as a rule, only 15% of total calories are provided by MCTs, and another 15% by LCTs (including 3–4% essential fatty acids).

Appendix A15. Diet in VLCAD deficiency (expert consensus)

MCT – medium-chain triglycerides; LCT – long-chain triglycerides; D-A-CH – recommendations of the German, Austrian, and Swiss Nutrition Societies.

a recommended LCT intake for healthy infants is 40–45% of total caloric intake, and for school-age children, 30–35%, according to D-A-CH recommendations,

b in practice, LCT intake exceeds the recommended values due to a limited choice of food products; as a rule, only 15% of total calories are provided by MCTs, and another 15% from LCTs (including 3–4% essential fatty acids).

Appendix A16. Natural sources of essential fatty acids

[105] 

Appendix A17. Composition of formulas for dietary nutrition with reduced fat and long-chain fatty acid content

The following table is proposed:

Appendix A18. Example of diet calculation in patients with fatty acid oxidation disorders

Example No. 1 Diagnosis: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

Age 12 days (diagnosis period)

Weight – 3.2 kg.

Prescription of a specialized product «Nutrigen Low Fat»/ «Monogen»

1. Discontinuation of breastfeeding

2. Complete transition to a specialized low-fat formula, taking into account that this formula initially has the correct fat ratio; the amount of formula is calculated based solely on energy requirements.

Diet calculation:

A) The child's energy requirement at 12 days of age averages 113 kcal/kg/day.

Recommended daily caloric intake – 3.2 × 113 = 361.6 kcal

100 ml of the specialized product «Nutrigen Low Fat»/ «Monogen» contains 74.5 kcal,

74.5 kcal – 100 ml

361 kcal – x

X = 361 × 100/74.5 = 484.6 (495) ml of the specialized product «Nutrigen Low Fat»/ «Monogen» per day

B) Frequency of feeding: 8 times a day (3-hour interval), calculate the volume of a single portion:

485 ml / 8 = 61 ml

Example No. 2 Diagnosis: Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) with early onset

Age 12 months.

Weight – 12 kg.

Diet calculation based on energy requirements and fat ratios:

A) Calculate energy requirements:

At 12 months of age, the energy requirement is 80 kcal/kg/day

Recommended daily caloric intake – 12 × 80 = 960 kcal

B) Calculate fats:

25%–30% of energy should be provided by fats, of which 20%–25% should be MCTs; calculate the required amount in grams.

Total fat amount:

25% of 960 kcal – 240 kcal/day

9 kcal – 1 g of fat

240 – x

X = 240/9 = 27 g of total fat

MCT amount:

20% of 960 kcal – 192 kcal

8.3 kcal – 1 g of MCT

192 – x

X = 192/8.3 = 23 g of MCT

C) Maximum intervals between feedings: 4 hours during the day, 6 hours at night (under glycemic control), corresponding to 6 meals.

Caloric content of a single feeding is approximately 960 kcal / 6 = 160 kcal

Total fat content in a single feeding is approximately 27 g / 6 = 4.5 g

MCT content in a single feeding is approximately 23 g / 6 = 3.8 g

Sample menu for a 12-month-old child

Example 3 Diagnosis: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

Age 4 years

Weight – 16 kg

Diet calculation based on energy requirements and fat ratios:

A) Calculate energy requirements:

At 4 years of age, energy requirement is 79.7 kcal/kg/day

Recommended daily caloric intake – 16 x 79.7 = 1275 kcal

B) Calculate fats:

25%-30% of energy should be provided by fats, of which 20%-25% as MCT; we calculate the required amount in grams.

Total fat amount:

30% of 1275 kcal – 382.5 kcal/day

9 kcal – 1 g of fat

382.5 – x

X = 382.5/9 = 42.5g total fat

MCT amount:

25% of 1275 kcal – 318.7 kcal

8.3 kcal – 1 g of MCT

318.7 – x

X = 318.7/8.3 = 38g MCT

C) Maximum intervals between feedings: 4 hours during the day, up to 8 hours at night, which corresponds to 5 meals.

Caloric content of a single feeding is approximately 1275 kcal / 5 = 255 kcal

Total fat content in a single feeding is approximately 35g / 5 = 7g

MCT content in a single feeding is approximately 30g / 5 = 6g

Appendix A19. Frequency of examinations in patients with fatty acid oxidation disorders

Appendix A20. Example of an "emergency card"

Emergency Card

Caution! The patient is at risk of developing an acute metabolic crisis associated with an inherited disorder.

1. Indications for hospitalization:

- recurrent vomiting, diarrhea;

- hypoglycemia;

- intercurrent infections with high fever;

- dehydration;

- severe fatigue or excessive somnolence;

- muscle pain, weakness, or reddish-brown urine

2. Action plan:

2.1. Daily caloric intake 110–120% of the usual diet.

2.2. When the child is at home, increase carbohydrate intake to meet caloric needs using a dextrose or maltodextrin solution (if unavailable – sweet tea, juice, compote)

Correlation between the child's age and the enteral dose of dextrose upon suspicion of a metabolic crisis.

2.3 Upon admission to the inpatient facility, initiate continuous infusion with a 10% dextrose solution** at the following rate: newborns and children under 3 years old 10–12 mg/kg/min, children aged 3 to 10 years 8–10 mg/kg/min, over 10 years old 5–8 mg/kg/min

2.4 Laboratory monitoring:

- Acid-base balance, electrolytes, ammonia

- General clinical blood chemistry panel (CK, ALT, AST, glucose, total and direct bilirubin, urea, creatinine, GGT, ALP, total protein, albumin)

acylcarnitine profile – amino acid and acylcarnitine profile by tandem mass spectrometry

3. Management of the patient after an emergency situation:

- If oral feeding is impossible or cannot be maintained, insert a nasogastric tube.

- Continue infusion with dextrose solutions until condition stabilizes, under the control of blood glucose and acid-base balance (ABB)

4. Contraindications:

- Intravenous administration of lipid emulsions

- Intravenous administration of carnitine, except for OCTN2-related carnitine deficiency

- Fasting when discontinuing IV infusions

Appendix A21. List of core laboratory tests that can assist in providing medical care during acute metabolic decompensation

* Laboratory tests should be ordered based on the patient's clinical presentation. This is not an exhaustive list, and some of the tests listed here may not be indicated.

Appendix A22. Legend for abbreviations and notes

…^** – the drug is included in the list of vital and essential drugs (Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 "On Approval of the List of Vital and Essential Drugs for 2020, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for Medical Care", Decree of the Government of the Russian Federation No. 3073-r dated November 23, 2020)

# - off-label use – outside the indications registered in the drug instructions, carried out by decision of the medical commission, with the permission of the Local Ethics Committee of the medical organization (if any), subject to the signed informed consent of the parents (legal representative) and the patient over 15 years of age;

…**** - specialized clinical nutrition product included in the list of specialized clinical nutrition products for disabled children (Decree of the Government of the Russian Federation No. 3242-r dated December 7, 2020 "On Approval of the List of Specialized Clinical Nutrition Products for Disabled Children for 2021")

Appendix B. Physician Action Algorithms

Neonatal screening algorithm for systemic carnitine deficiency

Neonatal screening algorithm for carnitine palmitoyltransferase IA deficiency

Neonatal screening algorithm for carnitine palmitoyltransferase II deficiency

Algorithm of actions for suspected long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency / mitochondrial trifunctional protein deficiency

Algorithm of actions for suspected long-chain acyl-CoA dehydrogenase deficiency

Algorithm of actions for suspected medium-chain acyl-CoA dehydrogenase deficiency

Appendix C. Patient Information

METABOLISM AND METABOLIC DISORDERS

The term “metabolism” refers to all processes necessary for the functioning and development of the organism, during which energy is produced and expended. Proteins, fats, and carbohydrates are the main dietary nutrients used as raw materials for the synthesis of new cells or oxidized to supply the body with energy.

Metabolic processes occur in the human body every second. Even under complete rest, a person uses a certain amount of energy. It is continuously spent on physiological processes that never stop for a minute.

Part of the energy is required to build new tissue components, while another part is expended during cell functioning: muscle contraction, nerve impulse transmission. The remaining energy is released as heat. To produce energy, we use food, and in its absence, reserve stores of nutrients present in our body. Each stage (biochemical reaction) in energy production is managed by a specific protein, an enzyme. Each of them has its own function. It is an entire assembly line of chemical reactions. If one enzyme fails to work, the entire chain stops, and the body does not receive the end product, which leads to metabolic disorders and the development of inherited metabolic disorders (IMD).

FAT METABOLISM

Fats (triglycerides) are compounds of carboxylic acids and the trihydric alcohol glycerol. There are various types of fats. Depending on the type of fatty acids that predominantly form the fats, and on the degree of unsaturation (number of double or triple bonds) of the fatty acids, a distinction is made between: saturated fats (solid) - fats of animals and poultry, and unsaturated fats (liquid) - found in abundance in vegetable oils, nuts, or marine fish.

Saturated fats become a key source of energy for the body in situations of heavy physical exertion. Unsaturated fatty acids are involved in cell regeneration and immune defense. One of the most important functions of fat is energy provision. Fat provides twice as many calories (energy) as carbohydrates.

Fig. 1. Classification of fatty acids

β-FATTY ACID OXIDATION

Mitochondrial fatty acid oxidation is one of the main sources of energy, providing up to 80% of total demand during fasting. When glucose levels drop and glycogen stores become insufficient to cover all energy needs (during fasting and prolonged physical exertion), lipolysis is activated. Long-chain fatty acids (C16-C20) and glycerol are formed from triacylglycerols stored in adipose tissue. Lipolysis is regulated by hormone-sensitive lipase, which is activated by hormones secreted during fasting and stress: glucagon and cortisol.

In the liver, within the mitochondria, the process of ketone body formation takes place – mitochondrial fatty-acid oxidation. Ketone bodies are a vital energy source for the brain.

For β-oxidation, fatty acids must be delivered into the mitochondria. The inner mitochondrial membrane is impermeable to long-chain fatty acids, and they penetrate inside with the help of the carnitine shuttle system. Carnitine-dependent enzymes – carnitine acylcarnitine translocase, carnitine palmitoyltransferases I and II – ensure the transport of long-chain fatty acids in the form of esters (acylcarnitines) from the cytoplasm across the outer and inner mitochondrial membranes into the mitochondrial matrix. In the process of fatty acid oxidation, their chains are shortened at each step, with a specific enzyme responsible for each stage along this path.

Fig. 2. Scheme of fatty acid β-oxidation.

In the cytoplasm, long-chain fatty acids bind to carnitine via the enzyme carnitine palmitoyltransferase I (CPTI), forming acylcarnitines.

Acylcarnitine is transported into the mitochondria by the transporter enzyme carnitine-acylcarnitine translocase (CACT).

Acylcarnitine is cleaved again by the enzyme carnitine palmitoyltransferase II (CPTII), releasing carnitine, which can return to the cell and be reused. Long-chain fatty acids are shortened to medium-chain fatty acids by the enzymes VLCAD, LCHAD, and TFTPFP. The shortening of fatty acids is called β-oxidation

DISORDERS OF β-FATTY ACID OXIDATION

In case of a deficiency of enzymes that help fatty acids penetrate the mitochondria (the site where the ketone bodies needed by our body are synthesized), and a deficiency of enzymes that break down fatty acids, mitochondrial β-oxidation is blocked (or sharply reduced), which forces our body to look for alternative pathways for fatty acid utilization, leading to the accumulation of toxic substances that have a detrimental effect on the tissues of the brain, heart, liver, etc.

Normally, the activation of mitochondrial fatty acid oxidation is a physiological response of the body to fasting or excessive intake of fatty foods, an infectious process, and increased physical (with high muscle activity) or emotional stress. However, in pathology (disrupted fatty acid oxidation process), this leads to metabolic acidosis, hyperammonemia, worsening of hypoglycemia, and damage to internal organs.

Fig. 3. Scheme of fatty acid β-oxidation in normal and pathological states

CLASSIFICATION OF β-FATTY ACID OXIDATION AND CARNITINE TRANSPORT DISORDERS

More than 15 different forms of mitochondrial fatty acid oxidation disorders are known. All of them are associated with defects in proteins or enzymes involved in fatty acid metabolism. Since the names of the enzymes are very long and complex, it is customary to use a shortened abbreviation, either English or Russian (in Russian articles and books).

1. Fatty acid transport disorders

• Primary carnitine deficiency (SLC22A5 gene)

• Clinical manifestations: cardiomyopathy, arrhythmia, heart failure, muscle weakness, liver damage.

• Carnitine palmitoyltransferase I deficiency (CPTI gene)

• Clinical manifestations: severe liver damage, impaired liver function, cholestasis.

• Carnitine translocase deficiency (SLC25A20 gene)

• Clinical manifestations: severe cardiomyopathy, arrhythmias, liver damage.

• Carnitine palmitoyltransferase II deficiency (CPTII gene)

Clinical manifestations: in early onset (neonatal form), cardiomyopathy, liver damage.

Late onset, in adults, a milder form, presenting with episodes of muscle weakness, difficulties with physical exertion.

2. Disorders of fatty acid oxidation

• Short-chain acyl-CoA dehydrogenase deficiency (SCAD) (gene ACADS): usually asymptomatic.

• Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) (gene ACADM)

• Clinical manifestations: can present at any age, manifesting as a rapidly progressive metabolic crisis after prolonged fasting or physical exertion. Nausea, vomiting, often with normal blood glucose levels. If left untreated, can lead to seizures, coma, and cardiac arrest.

• Multiple acyl-CoA dehydrogenase deficiency – glutaric aciduria type II (gene ETFA)

• Clinical manifestations are highly variable: brain malformations, cystic kidney disease, hypoglycemia, acidosis, epilepsy, cardiomyopathy.

• Mitochondrial trifunctional protein (MTP) deficiency / long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (gene HADHA)

• Clinical manifestations: early onset, may include cardiomyopathy, liver dysfunction, muscle weakness, neuropathy, retinopathy.

• Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) (gene ACADVL)

• Clinical manifestations: this disorder ranges from mild, subtle symptoms in some individuals to more severe problems in others. Initial symptoms can appear either from birth or later in adulthood.

Infantile form - more severe, resembles LCHAD, presents between birth and 4 months of age, may include cardiomyopathy, liver dysfunction, muscle weakness, neuropathy, retinopathy

Childhood form - symptoms usually appear in early childhood and are typically triggered by illness or a prolonged period of fasting. They manifest as symptoms of hypoglycemia and a metabolic crisis. It may also include the following signs: hepatomegaly, muscle weakness, especially after intense physical exertion. Cardiac abnormalities are usually absent in this type. In some children, the symptoms of this disease are so mild that they are recognized only after diagnosis in a sibling.

Late (adult) form - clinical manifestations: rhabdomyolysis. Initial symptoms begin to appear in adolescence or adulthood. Generalized muscle weakness develops, which becomes persistent and more pronounced after physical exertion. Muscle weakness is accompanied by pain and cramps. A reddish-brown urine color may appear.

In this type, renal failure may develop without treatment. However, heart problems and metabolic crises are not typical for this form, and blood glucose levels remain relatively stable.

• HMG-CoA synthase deficiency (gene HMGCS2)

Clinical manifestations: acute hypoketotic hypoglycemia, relatively low tolerance to fasting.

• HMG-CoA lyase deficiency (gene HMGCL)

Clinical manifestations: acute hypoketotic hypoglycemia, metabolic acidosis, liver damage.

GENETIC CAUSES OF FATTY ACID OXIDATION DISORDERS

Genes represent DNA sequences that contain instructions for "making" proteins and RNA. 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. There are also two sex chromosomes that determine the child's sex – girls have two X chromosomes, and boys have one X and one Y chromosome.

All disorders in this group are inherited in an autosomal recessive manner. This means that both parents are carriers of the mutation but are healthy because they have a second copy of the normal gene. The risk of having an affected child in this case is 25%. An affected child inherits one copy of the "mutated" gene from the father and one from the mother. The disease manifests only when two copies of the damaged gene are present. Boys and girls are affected with equal frequency.

Fig. 4. Inheritance pattern of autosomal recessive disorders

DIAGNOSIS OF FATTY ACID OXIDATION DISORDERS

The main diagnostic methods for this group of diseases are biochemical tests. Acylcarnitines in the blood are determined using tandem mass spectrometry.

Elevated levels of specific acylcarnitines are observed in various forms of these disorders.

Acylcarnitines are designated by letters followed by a number indicating the number of carbon atoms in the compound; other designations refer to the presence of double bonds, a hydroxyl group, etc. Methods for determining enzyme activity have also been developed, but they are performed by only a very small number of laboratories worldwide and should be recommended if DNA diagnostics fail to detect mutations in the gene.

Table 1. Correlation between certain FAODs and changes in acylcarnitine levels

DNA DIAGNOSTICS

A mutation (defect) in a gene can be identified using molecular genetic methods via DNA diagnostics. However, there are cases where a mutation cannot be found using standard methods. In such instances, physicians rely on clinical symptoms and biochemical changes to make a diagnosis.

If mutations are identified, this makes it possible to detect carriers within the family and perform prenatal and/or preimplantation genetic diagnosis.

CAN OTHER FAMILY MEMBERS BE AFFECTED OR BE CARRIERS?

Siblings of an affected child may also be affected, even if they had no symptoms at the time of family screening. In this case, diagnostics must be performed as early as possible to initiate treatment and prevent 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 also have a risk of having a child with this condition.

If a family already has one child with a fatty acid oxidation disorder, any subsequent newborn sibling must be immediately tested for the presence of this condition in order to initiate timely treatment.

CLINICAL FEATURES OF THE DISORDERS

Disorders from this group can begin at any age—from the first days or even hours of life, in the first months, or manifest only in childhood or adolescence. Everything depends on the form of the disease, the severity of the mutation, and external factors (how often the child is fed, how frequently they fall ill, etc.).

Some forms are more commonly characterized by skeletal muscle involvement, while others affect the heart muscle. Certain disorders present predominantly with liver involvement and the development of metabolic crises with hypoglycemia.

Metabolic crises are very dangerous. It is during this period that irreversible damage can occur to the brain, which has an extreme requirement for a supply of metabolic energy in the form of glucose or ketone bodies. While many other inherited metabolic disorders accompanied by hypoglycemia (e.g., glycogen storage diseases) exhibit high levels of ketone bodies allowing the brain to derive energy through their metabolism, fatty acid oxidation disorders feature low levels of ketone bodies, causing brain damage to develop very rapidly.

LIFESTYLE, DAILY THERAPY, AND DIET

Long-term management for this group of disorders is dietary therapy.

Goals:

• Normal physical and intellectual development.

• Weight and height gain appropriate for age.

• Prevention of characteristic symptoms, such as muscle pain and muscle weakness.

• Prevention of dangerous manifestations, such as heart muscle damage.

• Prevention of catabolic states that can lead to metabolic crises with hypoglycemia and muscle cell breakdown.

To achieve these goals, dietary therapy must meet the following requirements:

• Ensure adequate protein intake appropriate for age and physiological needs.

• Provide essential fatty acids, vitamins, and minerals.

• Cover energy expenditure.

• Avoid prolonged periods of fasting.

• Limit the intake of long-chain fatty acids.

• Suit the child's taste preferences, age, and needs.

• Be compatible with daily life.

Disorders for which diet is not used:

• Primary carnitine deficiency

• Short-chain acyl-CoA dehydrogenase deficiency (SCAD)

• Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)

Disorders managed with dietary therapy:

• Carnitine palmitoyltransferase I (CPT I) deficiency

• Carnitine palmitoyltransferase II (CPT II) deficiency

• Mitochondrial trifunctional protein (MTP) deficiency / long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

• Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD)

• Multiple acyl-CoA dehydrogenase deficiency

• HMG-CoA synthase deficiency

• HMG-CoA lyase deficiency

1. Moderate dietary fat restriction:

• Carnitine palmitoyltransferase I deficiency

2. Moderate or significant dietary fat reduction:

• Carnitine palmitoyltransferase II deficiency

• Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (asymptomatic form)

• Multiple acyl-CoA dehydrogenase deficiency

3. Significant fat reduction using MCT (medium-chain triglycerides) + nighttime feedings:

• Mitochondrial trifunctional protein (MTP) deficiency / long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

• Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency

Table 2. Maximum fasting period by age:

Caution! If children have no feeding difficulties, nighttime fasting can be extended up to 6 hours starting from 3 months of age, and up to 8 hours starting from 6 months of age. Allow fasting for more than 10 hours with caution, even after the first year of treatment. The risk of nocturnal hypoglycemia decreases as the child grows older, and most children after 4 years of age can tolerate periods without food for 10–12 hours if they are feeling well.

These recommendations apply only if the children's condition is stable. During periods of metabolic decompensation, infectious illnesses, and stressful situations, fasting periods must be shorter.

Children with severe forms of diseases and recurrent metabolic crises require stricter guidelines.

Table 3. Average daily physiological energy requirements

Dietary therapy for asymptomatic very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency:

• 0–4 months: 50% breast milk + 50% specialized MCT formula

• >4 months: moderate fat reduction to 30% of total caloric intake, of which 10–15% from MCTs and 3–4% from essential fatty acids.

Dietary therapy for early-onset very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, mitochondrial trifunctional protein (MTP) deficiency, and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency:

• 0–4 months: 100% specialized MCT formula

• >4 months: fat reduction to 25–30% of total caloric intake, 20–25% of which from MCTs and 3–4% from essential fatty acids. Reduce long-chain fatty acid intake as much as possible.

For all types: avoid catabolic situations!

DIET CALCULATION EXAMPLE

Diet calculation for a child diagnosed with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency:

Age 1.5 years, weight 10 kg.

Energy:

At 1.5 years, the daily caloric intake of the diet is 90 kcal/kg/day, therefore, your child should receive 10 × 90 = 900 kcal per day.

Fats:

25% of energy should be provided by fats.

1 g of fat equals 9 calories (kcal).

Based on this, the child should receive:

Fats (g/day) = 25% × 900 / 9 / 100% = 25 g of fat per day.

20% of energy should be provided by medium-chain fatty acids, therefore:

MCT (g/day) = 20% × 900 / 9 / 100% = 20 g of MCT per day.

Consequently, long-chain fats account for only: 25 g – 20 g = 5 g per day.

3–4% of energy must be provided by essential fatty acids (polyunsaturated fatty acids, PUFAs).

Let's calculate:

PUFAs (g/day) = 3% × 900 / 9 / 100% = 3 g per day.

Proteins:

1 g of protein equals 4 calories (kcal).

In early-onset very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, a high-protein diet of 1.5–2.5 g/kg/day is more appropriate.

In the example above, for a child weighing 10 kg, the daily protein requirement is 15–25 g.

Protein at 2 g/kg/day is 20 g, which as a percentage of total caloric intake is:

Proteins (%) = 4 × 20 / 900 × 100% = 9%

Carbohydrates:

1 g of carbohydrates equals 4 calories (kcal).

Thus, we calculated that our child's daily caloric intake is 900 kcal, of which 25% of energy is provided by fats and 9% by proteins; the remaining energy must be covered by carbohydrates:

100% -25% -8%= 66% 

Convert to grams:

Carbohydrates (g/day) = 66% × 900 / 4 / 100% = 148 g.

POLYUNSATURATED ESSENTIAL FATTY ACIDS (PUFAs)

There are 2 types of PUFAs: omega-3 and omega-6.

PUFAs make up the majority of the protective membrane (shell) of any cell. The body is able to convert fatty acids of one class into another, but cannot synthesize both classes from simpler substances, so they must be present in the diet, much like trace elements.

In our body, PUFAs have the property of being renewed within these same membranes as the cell goes through its natural life cycle.

The body always uses the fatty acids that are available. That is why it is advisable to include omega-3 and omega-6 PUFAs in the diet in the correct ratio.

Omega-3: ALA (alpha-linolenic acid), DHA (docosahexaenoic acid), and EPA (eicosapentaenoic acid).

Omega-6: linoleic acid, arachidonic acid.

Table 4. PUFAs in a low-fat diet, optimal ratio:

Table 5. PUFA content in vegetable oils:

Docosahexaenoic acid

Given that only a small fraction of DHA is synthesized from alpha-linolenic acid, plant sources alone are insufficient to maintain required Omega-3 levels. Therefore, it is recommended to include supplements containing adequate amounts of docosahexaenoic acid (DHA) in the diet. The PUFA dosage is determined by a physician.

CARNITINE

In primary carnitine deficiency, levocarnitine preparations are prescribed in high doses of 50-400 mg/kg/day.

In other cases, carnitine is prescribed in small doses with caution per os (the dose is determined by a physician)

CONTRAINDICATED intravenous administration of carnitine solution in case of impaired fatty acid beta-oxidation!!!

HOW THE CHILD'S DIET CAN BE ADAPTED TO FAMILY MEALS

By the end of the first year of life, the child begins to transition to family foods, and their diet increasingly resembles adult nutrition. Food has a firmer consistency, and the range of individual products and dishes expands.

Fig. 1. Food pyramid illustrating the composition of the daily diet of a child with a long-chain fatty acid oxidation disorder.

Most foods comply with the recommendations for a healthy, diverse diet for children with healthy metabolism. Sugar-free drinks such as mineral water, herbal tea, and a small amount of fruit juice mixed with sparkling water are very important. Fruits and vegetables are a priority. They contain virtually no fat, so they can be consumed in large quantities. As with everyone, it is recommended to eat 5 portions of fruits and vegetables a day.

The next level of the food pyramid contains grain products, cereals, and potatoes. A minimal amount of fat should be used when preparing them.

Skimmed milk and dairy products enrich the daily diet and are complemented by smaller amounts of lean meats and fish.

Oils and solid fats should be replaced with MCTs and essential fatty acids in the correct ratio.

At the top of the pyramid are low-fat sweets.

METABOLIC CRISIS

Metabolic crisis is a critical, life-threatening condition triggered by adverse factors causing enhanced fat breakdown with the formation of fatty acids, impairment of their oxidation, and leading to the formation of toxic metabolites.

What can trigger a metabolic crisis:

• prolonged fasting

• infection

• heavy physical and emotional exertion

Signs of hypoglycemia (low blood sugar):

• Fatigue

• Shivering

• Dizziness

• Sticky cold sweat.

First symptoms of a metabolic crisis:

Extreme drowsiness, behavioral changes, irritability, decreased appetite. The crisis is often triggered by an infection, so initial manifestations may begin with fever, nausea, diarrhea, and vomiting. This is followed by a drop in blood sugar. If treatment is not started in a timely manner, the child may develop shortness of breath, seizures, and coma.

WHEN TO SEEK IMMEDIATE MEDICAL ATTENTION

If you notice any of these symptoms in your child:

• Poor appetite

• Severe weakness or excessive drowsiness

• Vomiting

• Diarrhea

• Fever

• Persistent muscle pain, weakness, or reddish-brown urine.

WHAT TO DO IF YOU NOTICE THESE SYMPTOMS IN YOUR CHILD?

Deterioration of the condition usually occurs at a time when the body lacks energy and begins to search for it by all possible means, one of which is the breakdown of its own tissues (catabolism). This must be avoided at all costs. The first thing we must do is try to replenish energy through glucose. Give the child carbohydrates; this can be fruit juice, sweet tea, or a glucose solution.

Given the high risk of developing a metabolic crisis when the above symptoms appear, you must immediately seek medical attention. It is necessary to take blood tests for electrolytes (K+, Na+, Ca+), glucose, acid-base balance (ABG), ALT, AST, CK, LDH, cholesterol, HDL, LDL, triglycerides, NH3, and initiate intravenous glucose administration according to the protocol:

If enteral feeding is impossible, a nasogastric tube must be inserted

THERAPY

Principles of therapy:

• Avoid fasting

• Reduction of long-chain fatty acids in the diet

• Enrichment of the diet with medium-chain fatty acids

• Prevent hypoglycemia

• Additional metabolic support during the development of infectious diseases

• Carnitine supplements (see section Carnitine)

PHYSICAL ACTIVITY

Physical activity always requires additional energy—those calories that we must pay to our body for increased work.

Therefore, if you know that you are going to expend more energy than usual, you must be prepared for it.

30 minutes before physical activity, it is recommended to take 0.2–0.5 g of MCT per kg of body weight. For greater effectiveness, it can be mixed with carbohydrates, for example, apple juice.

After physical activity, it is necessary to replenish the expended energy with a protein-carbohydrate snack, with a carbohydrate-to-protein ratio of 3:1

Specialized Nutrition

For patients with fatty acid oxidation disorders, several options for specialized nutrition and separate medical products have been developed. They differ from one another. This must be taken into account when switching from one formula to another and from one product to another!

Table 7. Composition of specialized low-fat formulas for feeding patients with FAOD, starting from birth (ingredient content per 100 g of dry product) *

*Used as the main source of nutrition

Table 8. Composition of specialized fat formulas for feeding patients with FAOD, starting from birth (ingredient content per 100 g of dry product) **

** Used only as a supplement to the main food product

DISPENSARY FOLLOW-UP

Patients with fatty acid oxidation disorders require regular examinations. The table shows an example list and frequency of examinations, but in each case, you must coordinate the examination plan with your attending physician.

Table 8. Frequency of various examinations in FAOD

PREGNANCY IN FETAL FATTY ACID OXIDATION DISORDERS

During pregnancy, certain forms of the disease carry a high risk of complications. The most common among them include: severe toxicosis, frequent vomiting, jaundice, abdominal pain, hypertension, and hemorrhage.

PROGNOSIS WITH TIMELY DIAGNOSIS

The prognosis depends on the form of the disease and its clinical manifestation. In most cases, with timely diagnosis and therapy, children with the condition can look forward to a full life that, at first glance, is no different from that of others. However, therapy is lifelong, and the outcome depends on strict adherence to medical recommendations.

ADDITIONAL INFORMATION

When searching for "fatty acids oxidation defects" online, you will find thousands of English-language links. There are currently very few useful websites on this topic in the Russian-language internet. These sites are created by parents themselves, with the support of doctors and specialists. Therefore, if you have the energy and desire, create such a site for other families and for yourself.

The Internet is of great benefit, but sometimes the information found online may not align with the recommendations you follow. Do not rush to follow instructions from social media pages and websites, even if the information seems trustworthy! Discuss it with your attending physician; you must be certain that you are doing everything correctly.

In compiling this material, we used the following recommendations and sources:

Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop - Spiekerkoetter U, Lindner M, Santer R, Grotzke M, Baumgartner MR, Boehles H, Das A, Haase C, Hennermann JB, Karall D, de Klerk H, Knerr I, Koch HG, Plecko B, Röschinger W, Schwab KO, Scheible D, Wijburg FA, Zschocke J, Mayatepek E, Wendel U. (Department of General Pediatrics, University Children"s Hospital, Düsseldorf, Germany)

2009, Apr 28.

Vademecum Metabolicum - Johannes Zschoke (Innsbruck, Austria), Georg F. Hoffmann, Heidelberg, Germany)

http://www.fodsupport.org 

ABBREVIATIONS AND CONCEPTS

• CPT1 - Carnitine palmitoyltransferase 1 deficiency

• CPT2 - Carnitine palmitoyltransferase 2 deficiency

• SCAD - Short-chain acyl-CoA dehydrogenase deficiency

• MCAD - Medium-chain acyl-CoA dehydrogenase deficiency

• MTP - Mitochondrial trifunctional protein deficiency

• LCHAD - Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

• VLCAD - Very long-chain acyl-CoA dehydrogenase deficiency

• MCFA (MCT) - Medium-chain fatty acids (triglycerides)

• LCFA - Long-chain fatty acids (triglycerides)

• PUFA - Polyunsaturated essential fatty acids

• ACYLCARNITINES - Fatty acids bound to carnitine

• CARDIOMYOPATHY - A heart condition in which the heart muscle is structurally and functionally altered

• HYPOTONIA - Muscle weakness

• HYPOGLYCEMIA - Decreased blood sugar levels

• RHABDOMYOLYSIS - Breakdown of muscle tissue cells

• METABOLIC ACIDOSIS - An acid-base balance disorder manifested by low blood pH values and low blood bicarbonate concentration

• HYPOGLYCEMIA - Decreased blood sugar levels

• HYPERAMMONEMIA - Elevated blood ammonium levels

• NEUROPATHY - Damage to a nerve involving the disruption of its integrity or the integrity of its myelin sheath

• RETINOPATHY - Damage to the retina

• CATABOLISM - The breakdown of complex substances

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

Not applicable.