Galactose metabolism disorders (Galactosemia): clinical guidelines

List of Abbreviations

D2/D2 – homozygous Duarte variant galactosemia

G/D2 – Duarte galactosemia

G/G – Type I galactosemia associated with mutations in the GALT gene

AMH – Anti-Müllerian hormone

aPTT – Activated partial thromboplastin time

GAL – Galactosemia

GALK – Galactokinase enzyme

GALT – Galactose-1-phosphate uridylyltransferase enzyme

GALE – UDP-galactose 4-epimerase enzyme

CT – computed tomography

LH – luteinizing hormone

INR – International normalized ratio

MRI – magnetic resonance imaging

NADPH – Nicotinamide adenine dinucleotide phosphate

NADH – Nicotinamide adenine dinucleotide

PT – Prothrombin time

UDP-galactose – Uridine diphosphate galactose

UDP-glucose – Uridine diphosphate glucose

US – ultrasound examination

EDTA – Ethylenediaminetetraacetic acid

ECG – electrocardiography

EchoCG – echocardiography

EEG – electroencephalography

LoR – level of conviction of recommendation

LCE – level of confidence of evidence

FSH – Follicle-stimulating hormone

OMIM (Online Mendelian Inheritance in Man) – Electronic database of human genes and genetic phenotypes

Terms and Definitions

Neonatal screening is a set of measures including universal screening of newborns for the purpose of early disease detection, timely treatment initiation, and prevention of severe clinical consequences.

Galactosemia – a group of inherited disorders of carbohydrate metabolism characterized by the accumulation of excess galactose and its metabolites in the body

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Galactosemia (GAL) – a group of inherited disorders of carbohydrate metabolism characterized by the accumulation of excess galactose and its metabolites in the body, which determines the clinical presentation and the development of delayed complications. The inheritance pattern of all forms of galactosemia is autosomal recessive.

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

Galactose (from the Greek word galaktos - milk) is a monosaccharide belonging to the hexose group, a glucose isomer. Despite the high similarity between glucose and galactose molecules, the conversion of the latter into glucose requires several enzymatic reactions that take place in the cell cytoplasm (Fig. 1). Galactose is essential for the growth and development of the organism and is a component of breast milk.

Galactose is not only a significant energy source for the cell, but it also plays an important prebiotic role and serves as an essential structural material for the synthesis of glycoproteins, glycolipids, and other complex compounds used by the body to form cell membranes, nervous tissue, neuronal myelination processes, etc. Impaired galactose metabolism, as observed in galactosemia, inevitably leads to dysfunction of many organs and body systems.

A large number of foods consumed daily (primarily dairy products) contain lactose, which undergoes intestinal hydrolysis to form galactose; some food products contain pure galactose. In humans, galactose can be produced endogenously; the vast majority of it is synthesized via enzymatic reactions between uridine diphosphate glucose (UDP-glucose) and UDP-galactose, as well as during glycoprotein and glycolipid metabolism.

Galactosemia belongs to inherited metabolic diseases of carbohydrates and encompasses several genetic forms of the disorder. Type I galactosemia (GAL I) is caused by mutations in the GALT gene mapped to 9p13.3, resulting in galactose-1-phosphate uridylyltransferase (GALT) deficiency. Type II galactosemia (GAL II) is caused by mutations in the GALK1 gene mapped to 17q25.1, resulting in galactokinase (GALK) deficiency. Type III galactosemia (GAL III) is caused by mutations in the GALE gene mapped to 1p36.11, resulting in uridine diphosphate (UDP)-galactose 4-epimerase (GALE) deficiency (Fig. 1).

As a result of the deficiency of any of the three enzymes – GALT, GALK, or GALE – the blood concentration of galactose increases. When the activity of GALT and GALE enzymes is reduced, in addition to excess galactose, excess galactose-1-phosphate also accumulates in the patient's body, which is currently considered the primary pathogenetic factor causing most clinical manifestations of GAL and the development of delayed complications. Excess galactose in the body can be metabolized via alternative biochemical pathways: it can be converted into galactitol. The accumulation of galactitol in blood and tissues and its increased urinary excretion are observed in all forms of GAL; in the lens of the eye, excess galactitol contributes to cataract formation. There is evidence that high galactitol content in brain tissues contributes to swelling of nerve cells and the development of pseudotumor cerebri in individual patients.

Pathological processes in GAL are caused not only by the toxic effects of these metabolites, but also by their inhibitory effect on the activity of other enzymes involved in carbohydrate metabolism (phosphoglucomutase, glucose-6-phosphate dehydrogenase), resulting in hypoglycemic syndrome. It is also hypothesized that the predisposition to sepsis in newborns with type I GAL is caused by the inhibition of leukocyte bactericidal activity.

The most common form of GAL is GAL I. The GALT gene consists of 11 exons spanning 4.3 kb on chromosome 9p13. The Human Gene Mutation Database (HGMD Professional, Version 2020.3) describes 346 pathogenic variants in the GALT gene [47]. The most common pathogenic variants include: c.563A>G (p.Q188R) and c.855G>T (p.K285N), which cause the development of GAL I. Among patients of European descent, the most frequent pathogenic variant is c.563A>G (p.Q188R), accounting for 64% of all observed pathogenic variants. The c.404C>T (p.S135L) variant is associated with a "mild" phenotype of GAL I and is found almost exclusively in patients of African descent. Other common pathogenic variants include: c.855G>T (p.K285N), c.626A>G (p.Y209C), c.413C>T (p.T138M), c.584T>C (p.L195P), and IVS2-2A>G. A deletion of approximately 5.5 kb is common among Ashkenazi Jews. All these variants are associated with near-total or complete loss of enzyme activity.

The Duarte galactosemia variant (GD2) results from compound heterozygosity for a pathogenic GALT variant (G) and a second allele known as p.N314D, Duarte 2 (D2). D2 is found in approximately 11% of the population in European-American populations. It is now known to comprise a haplotype of five variants: three intronic variants (- c.378-27G>C, c.508-24G>A, and c.507+62G>A), a 4 bp deletion in the gene promoter, and the c.940A>G (p.N314D) substitution. The D2 allele reduces GALT activity by approximately 50%, so when present in trans with a classical galactosemia allele, enzyme activity may be ~25% of normal. Current data support the hypothesis that the 4 bp deletion is responsible for the reduced enzyme activity. The second variant, Duarte 1 (D1, also known as the Los Angeles or LA variant), is not associated with reduced GALT activity. The D1 allele contains c.940A>G (p.N314D) as well as a synonymous nucleotide change in exon 7, c.652C>T (p.L218=), but lacks the 4 bp promoter deletion. The D1 variant allele is also considered benign and is associated with normal or slightly elevated erythrocyte GALT enzyme activity [16].

Type II galactosemia (GAL II) is caused by variants in the GALK1 gene mapped to 17q25.1. Approximately 50 pathogenic variants have been described, with none being frequent. One variant, p.P28T, is more common among the Roma population [17].

Type III galactosemia (GAL III) is caused by pathogenic variants in the GALE gene mapped to 1p36.11. This is one of the rarest forms of GAL. About 30 causative variants are known, with none being frequent.

Figure 1. Galactose metabolism

GALT – Galactose-1-phosphate uridylyltransferase enzyme;

GALK – Galactokinase enzyme;

GALE – UDP-galactose 4-epimerase enzyme (Epimerase).

1.3 Epidemiology of the Disease or Condition

The incidence of galactosemia according to newborn mass screening data in Russia is 1:20,000. This value is not the true incidence of type I galactosemia in the Russian Federation, as it includes both clinical variants of type I galactosemia and Duarte galactosemia variants. There are no data on the incidence of type II and III galactosemia, since confirmatory diagnosis of galactosemia is not performed in the majority of cases in the Russian Federation.

Type I galactosemia occurs in 1:53,554 newborns in the United States [18]. The incidence of DG-galactosemia is approximately 10 times higher; the true incidence is unknown due to differences in screening.

The incidence of type II galactosemia ranges from 1:2,200,000 to 1:50,000 live births, with the highest incidence observed in the Roma population of Bulgaria and Bosnia [19].

The incidence of GALE deficiency detected by newborn screening—mostly asymptomatic (benign isolated or intermediate variant)—is 1:70,000 in infants of European descent and 1:6,700 in African Americans [20].

1.4 Features of Coding the Disease or Condition

E74.2 — Disorders of galactose metabolism (Galactokinase deficiency. Galactosemia)

1.5 Classification of the disease or condition

The modern classification of galactosemia is based on the etiological principle.

Depending on the defect in one of the three main enzymes involved in galactose metabolism, three types of galactosemia are distinguished:

I. Classical — type I galactosemia caused by a deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT) and the presence of homozygous or compound heterozygous mutations in the GALT gene (G/G). The Duarte variant (D/D) and Duarte galactosemia (G/D) are distinguished separately, in which the polymorphic variant is in a homozygous state or compound heterozygous state with a pathogenic mutation.

II. Galactokinase deficiency (GALK) (type II galactosemia).

III. Uridine diphosphate galactose 4-epimerase deficiency (GALE or epimerase deficiency) — type III galactosemia [25].

1.6 Clinical presentation of the disease or condition

Type I galactosemia (OMIM 230400) manifests in the neonatal period. Against the background of milk feeding or milk formula containing lactose and galactose, the newborn develops vomiting, diarrhea, muscle hypotonia, drowsiness, and lethargy. There is no weight gain, weak suckling and refusal of the mother's breast are observed, and signs of liver damage appear and progress, often accompanied by hepatomegaly/hepatosplenomegaly, jaundice, hypoglycemia, and frequent bleeding from injection sites.

The most severe manifestation of type I galactosemia in newborns is sepsis, which has a fatal course and is most often caused by Gram-negative microorganisms, in 90% of cases by Escherichia coli. As complications of sepsis, meningitis and osteomyelitis may develop. One patient developed gangrene of the toes and the posterior surface of one leg [21].

The disease usually manifests in the first days to weeks of life, progresses rapidly, and in the absence of treatment is life-threatening. From the first months of life, many children develop bilateral lenticular cataracts.

Some patients may experience intracranial hypertension syndrome, clinically manifested by bulging and tension of the anterior fontanelle. Brain CT/MRI reveals signs of intracranial hypertension [22].

Infants with G/D receiving breast milk or high-galactose formulas (infant milk formulas) usually have no clinical symptoms. Studies show no differences between groups of children with G/D galactosemia who received and did not receive therapeutic nutrition. Ovarian insufficiency, which is common in classical type I galactosemia, was not observed in girls or women with G/D [23].

Clinical symptoms in type II galactosemia (MIM 230200) in many patients may be limited solely to the formation of cataracts. Symptoms of the disease such as growth and weight retardation, dyspeptic disorders, etc., are mildly expressed, although they may be observed in infants. It is also suggested that, depending on milk consumption at an older age, there is a predisposition to presenile cataracts developing at 20–50 years of age [24, 25].

Type III galactosemia (MIM 230350) is extremely rare, and its exact incidence is unknown. There are 2 clinical forms of type III galactosemia associated with GALE deficiency: benign (isolated) and severe (generalized). Clinical manifestations in the benign form may be absent, and the disease is detected incidentally upon finding an elevated blood galactose level (during newborn screening, biochemical blood tests, etc.). However, follow-up observations show that some children subsequently experience motor and speech development disorders. In the severe form of the disease, initial symptoms resemble classical galactosemia, including jaundice, hepatomegaly, vomiting, muscle hypotonia, and psychomotor/physical developmental delay. Splenomegaly is subsequently observed. Despite early recognition of the disease and initiation of dietary treatment, clear psychomotor developmental delay and sensorineural hearing loss are often detected after 2–3 years. Some patients are at risk for developing cataracts. Children with the isolated form usually remain clinically healthy even on a normal milk diet and can be identified only through mass newborn screening [20].

A familial case of severe thrombocytopenia associated with pathogenic variants in the GALE gene has been described [26].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The criteria for diagnosing galactosemia are an elevated blood galactose level, decreased activity of the GALT enzyme (for type 1 galactosemia), and detection of pathogenic variants in a compound heterozygous/homozygous state in the GALT (type 1), GALK1 (type 2), or GALE (type 3) genes.

In the Russian Federation, neonatal screening for galactosemia is carried out, and many cases of the disease can be detected at the preclinical stage.

2.1 Complaints and Anamnesis

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

At any age

• family history of genetic disorders (similar cases of the disease in siblings);

• consanguineous marriage.

Infants in the first months of life:

• weak suckling, refusal to feed;

• poor weight gain;

• vomiting;

• diarrhea;

• jaundice;

• enlargement of the liver;

• hemorrhagic syndrome (bleeding from injection sites, gastrointestinal bleeding, etc.);

• drowsiness;

• lethargy;

• increased irritability;

• bulging anterior fontanelle.

Complaints and medical history are also described in section 1.6 "Clinical presentation".

2.2 Physical Examination

In the first 7 days of life, patients with type I galactosemia detected during mass screening may lack clinical symptoms. However, fulminant forms of the disease occur, and the first symptoms may appear on the 3rd–4th day of life, even before test results are received.

Physical examination may reveal:

• weight loss;

• jaundice (less commonly, pallor) of the skin;

• abdominal distension;

• hepatomegaly or hepatosplenomegaly;

• hemorrhagic syndrome;

• neurological symptoms — depression syndrome, less commonly excitation, signs of intracranial hypertension.

In cases where screening was impossible for any reason or results were not obtained, galactosemia must be ruled out if the patient has the following clinical manifestations:

• combination of jaundice and hemorrhagic syndrome in the first 2 weeks of life;

• signs of hepatocellular insufficiency;

• onset of cataracts at an early age, especially in the first year of life;

• sepsis in a full-term newborn caused by E. coli;

• combination of weight gain retardation, liver enlargement, muscle hypotonia, motor development delay, and cataracts in infants.

2.3 Laboratory Diagnostics

Laboratory diagnostics in neonatal screening include determining the total galactose concentration in a dried blood spot; if positive, determining GALT enzyme activity and mutations in the GALT gene ("blood galactose level test", "complex of tests for diagnosing galactosemia"). If diagnostics are performed in a patient with already identified clinical symptoms, against the background of diet therapy or infusion therapy, laboratory tactics may include determining GALT enzyme activity or performing DNA diagnostics alone. After ruling out type I galactosemia in patients with high galactose levels, studies should be performed to rule out other forms of galactosemia.

GALT enzyme activity testing should not be performed within 1 month after packed red blood cell transfusion, as the enzyme assay is performed in erythrocytes.

Comments: in accordance with Order No. 274n of the Russian Ministry of Health dated April 21, 2022, "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases," mass neonatal screening for galactosemia is performed in the Russian Federation 3 hours after feeding at the age of 24–48 hours of life for full-term infants and on the 7th day (144–168 hours) of life for premature infants. A blood sample (a few drops) is taken from the newborn's heel onto a special filter paper test card. Total galactose levels are determined in dried blood spots using a fluorescent assay (03.E04.01.005.000 Determination of galactose in dried blood spot), which represents the sum of galactose and galactose-1-phosphate concentrations. Evaluation of neonatal screening results for GAL is presented in Appendix G1.

Comment: confirmatory diagnosis at the first stage includes determination of GALT enzyme activity [8, 9, 10, 11, 27, 28]. Cut-off values for total galactose levels vary from 7 to 20 mg/dL across different countries. There is no document in the Russian Federation regulating the critical values of this indicator. Each laboratory must establish its own operating range and threshold level for this parameter. GALT enzyme activity is determined in erythrocytes obtained from heparinized whole blood or in dried blood spots. In patients with type I GAL who have undergone packed red blood cell transfusion, GALT activity persists for 4 months post-transfusion, which causes false-negative results. Reference values are determined by the manufacturer's kit [27].

The GALT enzyme is stable in whole blood stored in a refrigerator (+4 °C) or at room temperature for 2 weeks; however, certain nucleotide variants exist, including the Duarte variant (p.N314D), the presence of which produces a more thermolabile protein compared to normal, potentially leading to false-positive test results [28].

A reduction in GALT activity to ≤10% of normal is typically diagnostic of classical galactosemia (Appendix G1). GALT activity in patients with Duarte galactosemia (G/D) is approximately 25% of control, whereas activity in heterozygotes for classical GAL (G/N), homozygotes for the Duarte variant (D2/D2), or GAL with the LA variant (D1/G) is approximately 50% of normal activity. Heterozygotes for the Duarte allele (D2) typically have 75% of normal enzymatic activity and may not always be distinguished from normal controls or carriers solely based on enzyme activity. Carriers of the Los Angeles variant, LA (D1), have enzymatic activity ranging from normal to supernormal.

Diagnostic test systems are not registered for determining GALK and GALE enzyme activity; their measurement is possible in research and diagnostic laboratory settings.

In cases of extremely high galactose levels, one should not wait for a retest or confirmatory diagnostics, and dairy products should be discontinued immediately (see the "Treatment" section)

Comment: confirmatory DNA diagnostics for classical GAL include two stages: 1) screening for the most frequent mutations in the GALT gene and the Duarte variant; 2) complete gene analysis using direct automated sequencing to identify rarer mutations. At the first stage, it is most appropriate to screen for the following mutations in the GALT gene: p.Gln188Arg, p.Lys285Asn, IVS3-2a->c, p.Met142Lys, p.Leu358Pro, which together account for 82.1% of mutant alleles in the Russian population, and p.Asn314Asp (N314D, Duarte variant). The diagnostic algorithm for type I GAL is presented in Appendix G1.

If a child has clinical manifestations of type I GAL with high blood galactose levels and normal GALT enzyme activity, mutation screening is performed in the GALE gene, which encodes the uridine diphosphate galactose 4-epimerase (GALE) enzyme, to rule out type III galactosemia, and in the GALK gene to rule out type II GAL.

Comments: despite the absence of specific changes, a complete blood count (CBC) with differential is performed in patients with galactosemia during diagnosis and dynamic monitoring due to the increased frequency of infectious complications. The frequency of dynamic monitoring is determined individually, at least once a year.

Comments: a number of patients receiving diet therapy with soy-based formulas exhibit renal dysfunction and elevated urinary oxalate salt content.

Comments: required blood chemistry parameters: glucose level testing, total protein, protein fractions (blood albumin testing, albumin/globulin ratio determination), total, free, and conjugated bilirubin, creatinine, urea, total and ionized calcium, sodium, potassium, inorganic phosphorus, blood ferritin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase activity determination in blood.

Due to the fact that lipid metabolism is impaired in liver damage, tests are also performed for cholesterol, triglycerides, low-density and high-density lipoprotein cholesterol (blood lipoprotein testing) [50].

Comments: required coagulogram parameters: APTT, INR, prothrombin time, fibrinogen.

Comments: E. coli sepsis is one of the frequent and severe complications of galactosemia.

Comments: Conditions that require differential diagnosis include:

- Alpha-1 antitrypsin deficiency (alpha-1 antitrypsin is measured in the blood to rule it out)

- Urea cycle disorders, type II citrullinemia, fatty acid beta-oxidation defects, etc. (amino acid and acylcarnitine profiles as well as blood ammonia levels are determined to rule them out). Caution should be exercised when interpreting amino acid analysis results, as elevated levels of phenylalanine, tyrosine, and methionine are frequently observed in conditions associated with severe liver damage.

- Type 1 tyrosinemia (to rule this out, 03.E04.01.003.032 blood amino acid and acylcarnitine testing by tandem mass spectrometry and/or 03.E04.01.006.032 succinylacetone testing in dried blood spots by tandem mass spectrometry is performed);

- Congenital bile acid synthesis defects;

- Mitochondrial hepatopathies (to rule these out, acid-base balance, blood gases, and blood lactate levels are assessed);

- Peroxisomal disorders (very long-chain fatty acids are measured in the blood to rule them out);

- TORCH infections and viral hepatitis (screening for TORCH infections and viral hepatitis markers is performed to rule them out);

- Malformations and/or anomalies of the biliary system (fasting gallbladder ultrasound and imaging of other abdominal organs are performed to rule these out);

- Congenital portal system anomalies (portal system duplex sonography is performed to rule these out);

- Hereditary disorders presenting with cholestasis (molecular genetic testing using gene panels is performed to rule them out).

The choice and scope of diagnostic tests are determined individually based on the clinical situation.

2.4 Instrumental Diagnostics

Comments: To assess blood flow as part of the ultrasound examination, Doppler sonography of the vessels of the liver, spleen, and kidneys is also performed (duplex scanning of liver vessels, duplex scanning of splenic vessels, duplex scanning of the inferior vena cava and renal veins, duplex scanning of renal arteries).

Comments: Cataracts develop in patients who do not receive dietary therapy in the first weeks of life and typically can only be detected upon examination with a slit lamp.

2.5 Other Procedures

Comments: Nutritional counseling is provided by a clinical nutritionist if available. Additionally, in cases where clinical and laboratory findings indicate the disease and/or following newborn screening results suggestive of galactosemia, dietary therapy must be prescribed by a neonatologist, pediatrician, or general practitioner (family physician).

Comments: In the absence of a clinical nutritionist, initial and follow-up geneticist consultations (examinations) may be performed. Additionally, in cases where clinical and laboratory findings indicate the disease and/or following newborn screening results suggestive of galactosemia, dietary therapy must be prescribed by a neonatologist or pediatrician.

Comments: In cases where clinical and laboratory findings indicate the disease and/or following newborn screening results suggestive of galactosemia, dietary therapy must be prescribed by a neonatologist or pediatrician. In some cases, daily examinations by a neonatologist with monitoring and nursing care by intermediate and junior medical staff in an inpatient unit may be required.

Comments: Depending on the clinical situation, initial and follow-up consultations (examinations) may be required with a nephrologist / urologist / pediatric urologist-androtherapist for oxalate urolithiasis management; an infectious disease specialist, anesthesiologist-resuscitologist, or clinical pharmacologist in the presence of infectious, including septic, complications; an endocrinologist / pediatric endocrinologist / obstetrician-gynecologist in case of female reproductive system dysfunction; as well as a medical psychologist, speech-language pathologist, etc.

2.6 Differential Diagnosis

Comments: Differential diagnosis is carried out with:

- diseases accompanied by cholestasis and/or hepatomegaly (hepatitis, Alagille syndrome, progressive familial intrahepatic cholestasis of 4 types, neonatal hemochromatosis, urea cycle disorders, mitochondrial hepatopathies, neonatal lupus, congenital disorders of glycosylation, alpha-1 antitrypsin deficiency, type I tyrosinemia, Niemann-Pick disease type C, Wolman disease, citrin deficiency, hepatic hemangioendothelioma, etc.);

- congenital malformations and anomalies of the biliary system (biliary atresia, choledochal cyst, etc.)

- congenital anomalies of the portal system (patent ductus venosus, portosystemic shunt between the portal vein and the inferior vena cava, intrahepatic portal vein hypoplasia)

- transient hypergalactosemia, which is observed with late closure of the venous duct (Ductus venosus) and disappears within 2-3-5 months after its closure, as well as in heterozygous carriers of major mutations in the GALT and GALE genes.

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

3.1 Conservative Treatment

Comments: the diet may be based on, for example, soy, casein hydrolysate, or an amino acid-based elemental formula; Appendix A3.1 contains a list of specialized dietary therapeutic nutrition products for infants with galactosemia included in Russian Government Decree No. 3551-r dated December 11, 2023, "On Approval of the List of Specialized Therapeutic Nutrition Products for Disabled Children."

Comments: it is necessary to completely exclude from the patient's diet any type of milk (including breast milk, cow's milk, goat's milk, infant formulas, etc.) and all dairy and fermented milk products, as well as non-dairy products containing milk (bread, sausages, cured meats, caramel, sweets, margarines, etc.). The use of low-lactose and lactose-free whey-predominant formulas, as well as low-lactose and lactose-free unadapted dairy products (which may retain galactose), is also prohibited. A number of plant-based products (legumes, soy [but not soy protein isolate], cocoa, chocolate, nuts, spinach) contain oligosaccharides—galactosides (raffinose, stachyose)—and animal-based products (offal) contain glycoproteins, which are potential sources of galactose (see Appendix G5); therefore, they are excluded from the diet of pediatric patients and restricted in the diet of adult patients.

Currently, a diet with the strictest possible exclusion of galactose/lactose is the only way to reduce the accumulation of the toxic component, galactose-1-phosphate, in the tissues of a patient with classic galactosemia, and galactitol in patients with galactokinase deficiency. In mild galactosemia caused by UDP-galactose 4'-epimerase deficiency, a low-galactose diet may be used in accordance with the permissible amounts of galactose in the diet under the control of its serum level.

When formulating therapeutic diets for patients with galactosemia, the amounts of basic nutrients and energy must comply with the recommended physiological consumption norms. In the nutrition of infants in the first year of life, breast milk and/or infant formulas must be replaced with nutritionally adapted formulas. Specialized formulas based on soy protein isolate or highly hydrolyzed milk formulas are used for the treatment of patients with galactosemia. Formulas based on synthetic amino acids and lactose-free casein-predominant milk formulas are also used.

It is necessary to treat patients with type I and II galactosemia using a lifelong diet with restricted galactose content, which excludes only sources of lactose and galactose from dairy products, but allows obtaining galactose from non-dairy sources that contain minimal amounts of galactose in the diet. Within this definition, we accept that small amounts of galactose are present in certain aged cheeses and caseinates. Currently, there is insufficient evidence to support a specific age-related recommendation regarding the amount of galactose permitted in the diet.

The list of products containing galactosides and rich in glycoproteins is given in Appendix A3.2

Comments: when using soy formulas in infant nutrition, allergic reactions to soy protein may occur.

In such cases, it is advisable to prescribe formulas based on extensively hydrolyzed milk proteins. Depending on the child's condition, a combined use of a soy formula and a casein hydrolysate-based formula in a 1:1 ratio is possible. In case of combined allergy to soy and cow's milk protein, the use of amino acid-based formulas is recommended. The use of casein-predominant lactose-free milk formulas is possible.

Comments: these formulas may contain trace amounts of galactose.

Comments: the first complementary foods are introduced during the period from 4 to 6 months of life. Only dairy-free products and complementary dishes are used in nutrition: dairy-free porridges, egg yolk, as well as vegetable, meat, and fruit purees. All dairy products, including whole cow's milk, fermented milk products, and cottage cheese, are prohibited for patients with galactosemia.

The type of first complementary food is determined by the state of the gastrointestinal tract and the nutritional status of the child. This can be a vegetable puree for baby food without added milk (and without legumes in the composition) or dairy-free porridges based on corn, rice, or buckwheat flour, which must be diluted with the specialized formula that the child is receiving. Meat complementary foods are introduced into the diet from 6 months of age. Preference is given to specialized commercially produced baby meat canned foods containing no milk or its derivatives, and no offal (based on rabbit, chicken, turkey meat, etc.). Approximate timelines for introducing complementary foods to infants in the first year of life with galactosemia are given in Appendix G4.

In patients with Duarte galactosemia (GD), GALT activity is 15-25% of normal and the condition is usually asymptomatic. Infants with GD consuming a galactose-containing diet (e.g., breast milk or regular formula) have elevated erythrocyte Gal-1-P levels. These biochemical abnormalities normalize on a lactose-restricted diet; however, even with an unrestricted diet, levels usually normalize within the first year of life. Despite biochemical abnormalities, patients with GD who did not receive elimination diet therapy showed no adverse clinical outcomes in all studies conducted to date. The latest clinical guidelines for the management of patients with galactosemia do not recommend treatment for patients with the GD variant; however, if clinical symptoms indicating liver damage appear or if total galactose levels exceed 20 mg/%, dietary lactose restriction may be considered.

Approximate introduction timelines and complementary food products for patients with galactosemia are presented in Appendix A3.3

Comments: lactose is frequently used as an excipient in homeopathic medicinal products. Ethanol** inhibits the elimination of galactose from the liver.

Comments: although all fermented soy-based products contain more galactose, they may be permitted in small quantities in the diet of children over 1 year of age.

Comments: patients with this form of GAL require trace amounts of galactose in their diet: infants should be fed a formula (e.g., soy formula) that contains small amounts of galactose or lactose. While dietary restriction of high-galactose dairy products is necessary, non-dairy sources of galactose (legumes, certain fruits and vegetables, organ meats) should not be restricted. Permanent dietary restriction of dairy products is recommended in older children.

Comments: indications for infusion therapy include hypoglycemia, hypovolemia, hypocoagulation, laboratory signs of hepatic and renal impairment, and malnutrition.

Comments: according to the guidelines for sepsis

Comments: patients with GAL show a decrease in bone mineral density if calcium and cholecalciferol** preparations are not administered (ATC code A11CC), which often leads to early osteoporosis and an increased risk of bone fractures. Calcium preparations (calcium glycerophosphate, calcium gluconate** (ATC code A12AA)), and cholecalciferol** (combination preparations containing Calcium carbonate + Cholecalciferol may also be prescribed) are indicated for patients with hypocalcemia after 1 year of age (or children older than 2 years according to the instructions), against the background of eliminating formulas that serve as the main sources of calcium and vitamin D.

Comments: the principles of puberty induction and hormone replacement therapy in girls with GAL do not differ from the general principles of replacement therapy for primary hypergonadotropic hypogonadism. There is evidence of the feasibility of cryopreservation of ovarian tissue at a prepubertal age, therefore girls are indicated for an appointment (examination, consultation) with an obstetrician-gynecologist (reproduction specialist) [38]. All tablet preparations contain a small amount of lactose, but the total dose is very small compared to endogenous production.

3.2 Surgical Treatment

Comments: cataracts in patients with galactosemia are characterized as small, transient, or neonatal and resolve on a lactose-free/galactose-free diet; however, in certain late-diagnosed cases, surgical treatment is required (in accordance with clinical guidelines for cataracts).

3.3 Other Treatment

Comments: in cases of diagnosed hypergonadotropic hypogonadism in girls with absent secondary sexual characteristics, puberty induction is necessary. The age of puberty induction depends on many factors. First, it is necessary to diagnose hypergonadotropic hypogonadism based on the absence of secondary sexual characteristics combined with elevated blood levels of follicle-stimulating hormone. Second, the timing of estrogen therapy initiation depends on the ratio of height, body proportions, and bone age. The average age for initiating therapy is 11–13 years. Puberty induction is performed by endocrinologists and/or obstetrician-gynecologists according to the protocol outlined in the clinical guidelines for delayed puberty and hypogonadism.

Comments: an individualized speech therapy rehabilitation program is developed. Some patients with GAL remain at risk for delayed complications: developmental delay (height-for-age Z-score <-2), speech development disorders ("verbal dyspraxia"), motor functions (ataxia), and osteoporosis (in the absence of supplemental calcium therapy).

Psychological developmental delay observed in some patients with GAL receiving dietary treatment is generally mild; it may be detected at an early age, but usually becomes apparent during school years when the child experiences difficulties with reading or mastering mathematics. Some patients may exhibit a moderate decline in intellectual development or mild intellectual disability. Motor disturbances in the form of ataxia, fine motor clumsiness, balance and coordination disorders, muscle dystonia, and tremor during goal-directed movements may be noted in some individuals. Speech development delay in young children with GAL may manifest as articulation difficulties and a limited vocabulary.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

5.1 Prevention

Comments: In a family with a child with GAL, there is a 25% recurrence risk of having another child with GAL in each subsequent pregnancy. At-risk relatives may also be mutation carriers if mutations have been identified in the family. Prenatal diagnosis of GAL is possible using DNA analysis on chorionic villus sampling. The issue of prenatal diagnosis of GAL should be discussed with the parents before making a final decision, as the disease is treatable.

Comments: vaccination should preferably be carried out under the supervision of specialists experienced in working with patients with metabolic disorders.

5.2 Dispensary monitoring

To prevent intellectual, cognitive, speech, and learning impairments, as well as to ensure harmonious physical development, dispensary monitoring includes tracking laboratory, clinical, and instrumental parameters that reflect treatment efficacy

Monitoring treatment adequacy

Comments: the frequency of blood galactose monitoring should be at least once every 3 months during the first year of life, and at least once a year thereafter for life; additional testing may also be performed in cases of increased galactose intake and/or suspected intoxication.

Comments: an examination (consultation) by a pediatric endocrinologist is required. Assessment of sexual development and bone age is important. Girls with organic acidemias develop primary ovarian insufficiency, which can manifest either in the prepubertal period, requiring estrogen therapy to initiate puberty, or after the onset of puberty, requiring hormone replacement therapy [36, 37]. A decline in the follicular pool may occur at an early age; therefore, an early consultation with an obstetrician-gynecologist (reproductive specialist) is indicated, although spontaneous pregnancies have been described in patients with organic acidemias.

Comments: frequency of examinations: as clinically indicated, no more than once a year and no less than once every 5 years.

Comments: following a restrictive diet may lead to dysproteinemia, impaired mineral metabolism, and deficiencies in essential micronutrients. It is advisable to determine the levels of glucose, total protein, protein fractions, total bilirubin, cholesterol, triglycerides, low- and high-density lipoproteins, alkaline phosphatase, creatinine, urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and ionized calcium, sodium, potassium, inorganic phosphorus, iron, ferritin, and the main vitamin D metabolite in the blood (testing 25-OH vitamin D levels in the blood to evaluate the balance of essential nutrients during diet therapy, assess calcium-phosphorus metabolism, and evaluate renal and hepatic function) with a frequency of once a year.

Comments: the frequency of tests is determined individually.

Comments: Ultrasound of the abdominal organs and kidneys is performed at least once a year. In infants under one year of age, more frequent examinations are recommended to monitor their condition, especially during decompensation.

Comments: according to the opinion of the Russian expert working group, it is advisable to conduct consultations:

- under the age of 6 months – at least once every 2 months; from 6 months to 1 year – at least once every 3 months;

- from 1 year to 12 years – at least once every 6 months;

- over 12 years – at least once a year.

Comments: diet therapy is the pathogenetic method of treatment for organic acidemias. The frequency of visits to the nutritionist is based on clinical indications. According to the opinion of the Russian expert working group, it is advisable to conduct consultations:

- under the age of 6 months – at least once every 2 months; from 6 months to 1 year – at least once every 3 months;

- from 1 year to 12 years – at least once every 6 months;

- over 12 years – at least once a year.

The WHO classification of nutritional status disorders is presented in Appendix A3.4.

Comments: at least once every 6 months. Usually every 3 months during the first year of life, every 4 months during the second year of life, every 6 months up to 14 years of age, and annually thereafter. During adolescence, more frequent examinations may be required due to the need to monitor sexual development [29].

Comments: at least once a year.

Comment: on average, starting from the age of 2–3 years, at least once every 6 months, and at least once a year for adult patients. If neurological disorders are identified, ongoing monitoring of these manifestations is required [7].

Comments: appropriate programs and tests are used to assess intelligence and other types of mental activity in patients with galactosemia. During the transitional period, adolescents particularly need psychological support regarding communication within the family and society, as well as career guidance; for women with galactosemia, the emphasis should be placed on issues related to pregnancy.

Comment: a physical and rehabilitation medicine physician, as well as other medical rehabilitation specialists with relevant experience, may also participate in providing medical rehabilitation services to patients with nutritional and metabolic disorders.

Comments: initial and follow-up consultations with a pediatric nephrologist/urologist/andrological urologist, infectious disease physician, anesthesiologist-intensivist, clinical pharmacologist, endocrinologist/pediatric endocrinologist, obstetrician-gynecologist, medical psychologist, speech therapist, etc., may be required depending on the clinical situation.

Comments: in the presence of comorbidities, clearance for vaccination is given by the relevant specialist. These recommendations are based on many years of experience of physicians specializing in the treatment of patients in the Russian Federation.

6. Organization of Medical Care

Indications for scheduled hospitalization in a medical organization:

1. provision of diagnosis and treatment requiring prolonged (day or round-the-clock) medical observation and monitoring of clinical and laboratory parameters;

2. the need for various types of expert evaluations or examinations in a medical organization when they cannot be performed on an outpatient basis (including issuing a conclusion of a federal concilium / medical commission).

Indications for emergency hospitalization in a medical organization:

1. acute, life- and development-threatening conditions requiring emergency treatment, including intensive care, as well as round-the-clock medical monitoring and specialized examinations and treatments.

Indications for discharging a patient from a medical organization:

1. absence of a threat to the patient's life and risk of complications requiring emergency treatment upon completion of diagnostic procedures.

2. stabilization of the patient's condition and main clinical and laboratory parameters of the pathological process, no need for prolonged medical supervision (day or inpatient care);

3. the need to transfer the patient to another medical organization or social security institution.

7. Additional Information

The outcome and course of the disease are influenced by the timing of diagnosis, timely and adequate diet therapy, and emergency care measures (blood transfusion, blood components, infusion therapy).

The prognosis of the disease is unfavorable in late-diagnosed severe forms of galactosemia (due to the lack of screening). With early initiation of dietary treatment, children can develop normally.

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 I.V. — PhD in Medicine, Head of the Department of Medical Care Organization, Medical Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

2. Baidakova G.V. — Candidate of Biological Sciences, Head of the Shared Research Facility "Metabolom", Leading Research Fellow at the Laboratory of Hereditary Metabolic Diseases, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists

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

4. Borovik T.E. — Doctor of Medical Sciences, Professor, Head of the Laboratory of Nutrition for Healthy and Sick Children, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

5. Bushueva T.V. — Doctor of Medical Sciences, Leading Research Fellow at the Laboratory of Nutrition for Healthy and Sick Children, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

6. Vashakmadze N.D. — Doctor of Medical Sciences, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health

7. Vishnyova E.A. — Doctor of Medical Sciences, Professor of the Russian Academy of Sciences, Deputy Head for Scientific Work at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

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

9. Degtyarev D.N. — Doctor of Medical Sciences, Professor, Deputy Director for Scientific Work, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Head of the Department of Neonatology, Institute of Child Health, Sechenov First Moscow State Medical University, Council Member of the Russian Society of Neonatologists

10. Zhurkova N.V. — Candidate of Medical Sciences, Leading Research Fellow, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Member of the Union of Pediatricians of Russia, Member of the Association of Medical Geneticists

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

12. Zvonkova N.G. — Candidate of Medical Sciences, Senior Research Fellow, Laboratory of Nutrition for Healthy and Sick Children, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Member of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)

13. Kareva M.A. — Doctor of Medical Sciences, National Medical Research Center for Endocrinology of the Russian Ministry of Health

14. Kuzenkova L.M. — Doctor of Medical Sciences, Professor, 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

15. Kutsev S.I. – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Director of the Academician N.P. Bochkov Research Centre for Medical Genetics, President of the Association of Medical Geneticists of Russia

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

17. Nazarenko L.P. — Professor, Doctor of Medical Sciences, Deputy Director for Scientific and Clinical Work, Head of the Laboratory of Hereditary Pathology, Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Member of the Association of Medical Geneticists (AMG).

18. Namazova-Baranova L.S. — Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Union of Pediatricians of Russia; Past-President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief freelance pediatric specialist in preventive medicine of the Russian Ministry of Health

19. Nikolaeva E.A. — D.Sc. in Medicine, Head of the Department of Clinical Genetics, Research and Clinical Institute of Pediatrics named after Academician Yu.E. Veltischev of the Pirogov Russian National Research Medical University, Member of the Russian Society of Medical Geneticists, Member of the Association of Medical Geneticists

20. Lavrova A.E. — D.Sc. in Medicine, Director of the Institute of Pediatrics, Head of Pediatric Department No. 2, University Clinic of the Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation, Excellence in Public Health

21. Larshina E.A. — Laboratory Physician, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists

22. Pyryeva E.A. — Ph.D. in Medicine, Head of the Laboratory of Age-Related Nutrition, Federal Research Center of Nutrition, Biotechnology and Food Safety

23. Repina S.A. — Ph.D. in Medicine, Medical Geneticist, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Association of Medical Geneticists of Russia

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

25. Selimzyanova L.R. — Ph.D. in Medicine, Head of Department at the Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery, Associate 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), 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

26. Smirnova O.Ya. — Medical Geneticist, Senior Researcher at the Department of Standardization and Study of Evidence-Based Medicine Foundations, Petrovsky National Research Centre of Surgery

27. Strokova T.V. — Professor, RAS, D.Sc. in Medicine, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Federal Research Center of Nutrition, Biotechnology and Food Safety; Head of the Department of Gastroenterology and Dietology, Pirogov Russian National Research Medical University of the Ministry of Health of Russia

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

29. Taran N.N. — Ph.D. in Medicine, Senior Researcher at the Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Federal Research Center of Nutrition, Biotechnology and Food Safety; Assistant Professor at the Department of Gastroenterology and Dietology, Pirogov Russian National Research Medical University of the Ministry of Health of Russia

30. Fedoseenko M.V. — Ph.D. in Medicine, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Status Deviations and Chronic Diseases, Leading Researcher, Pediatrician at the Research Institute of Pediatrics and Children's Health of the Central Clinical Hospital of the Russian Academy of Sciences of the Ministry of Science and Higher Education of the Russian Federation, 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

31. Fisenko A.P. — Professor, D.Sc. in Medicine, Director of the National Medical Research Center for Children's Health of the Ministry of Health of Russia

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

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• Pediatricians

• Geneticists

• Dietitians

• Gastroenterologists

• Endocrinologists

• Internists

• General practitioners (family physicians)

• Neonatologists

• Neurologists

• Medical psychologists

• Medical students, residents.

Methods used for evidence collection/selection:

electronic database searching.

Description of methods used for evidence collection/selection:

The evidence base for the recommendations includes publications from the Cochrane Library, EMBASE, and MEDLINE databases. The search depth was 25 years.

Methods used to assess the quality and strength of evidence:

• Expert consensus;

• Assessment of significance in accordance with the rating scale.

Methods used for evidence analysis:

• Reviews of published meta-analyses;

• Systematic reviews with evidence tables.

Description of methods used for evidence analysis:

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

The evaluation process is undoubtedly subject to potential subjectivity. To minimize potential errors, each study was assessed independently, i.e., by at least two independent members of the working group. Any discrepancies in evaluations were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Evidence tables:

Evidence tables were completed by the members of the working group.

Methods used to formulate the recommendations:

Expert consensus.

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

Table 2.Levels of Evidence (LoE) grading scale for prevention, treatment and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading levels of recommendation certainty (LRC) 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 regarding 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. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012 "On approval of the Procedure for providing pediatric care"

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

4. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Protecting Citizens' Health in the Russian Federation' Regarding Clinical Guidelines"

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

6. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services"

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

Appendix A3.1 Chemical composition of lactose-free infant formula mixtures that can be used in the dietary management of infants with galactosemia (g / 100 ml)

(included in the Decree 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 A3.2 Foods containing galactosides and rich in glycoproteins

Appendix A3.3 Approximate schedule for introducing complementary foods to infants in their first year of life with galactosemia

Approximate schedule for introducing foods to infants in the first year of life with galactosemia

Note. * ― from 6 months, ** ― no earlier than 10 months.

Appendix A3.4 WHO: Diagnostic criteria for malnutrition

Appendix A3.5 Legend to notes

** a medicinal product for medical use included in the list of vital and essential drugs for medical use

# a medicinal product for medical use used not in accordance with the indications for use, contraindications, methods of administration, and doses contained in the instructions for medical use (off-label), 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

**** a specialized medical nutrition product included in the list of specialized medical nutrition products for disabled children.

Appendix B. Physician Action Algorithms

Appendix B1 Screening algorithm for galactosemia

Appendix C. Patient Information

WHAT IS GALACTOSEMIA?

Galactosemia is one of the inherited metabolic disorders. The disease occurs when a child lacks the ability to break down the sugar found in milk. This is due to a mutation in the structure of the gene responsible for synthesizing the enzyme involved in the metabolism of galactose, one of the simple sugars. Galactose and its derivatives accumulate in the blood and tissues, exerting a toxic effect on the central nervous system, liver, and the lens of the eye, which determines the clinical manifestations of the disease.

HOW COMMON IS GALACTOSEMIA?

Galactosemia is a rare disease. The average global prevalence of galactosemia is 1:60,000 to 1:70,000. There are several forms of galactosemia, depending on which gene has mutated, with the vast majority of cases being caused by mutations in the GALT gene (encoding the enzyme galactose-1-phosphate uridylyltransferase), leading to type 1 galactosemia. There is also a distinct variant of type 1 galactosemia—Duarte galactosemia—in which the activity of the GALT enzyme is somewhat reduced, galactose levels are elevated, but severe clinical manifestations of the disease do not develop, and most individuals with this variant do not require dietary therapy.

The other two types of galactosemia—type 2 and type 3—are extremely rare.

HOW DOES GALACTOSEMIA MANIFEST?

The initial signs of type 1 galactosemia can appear as early as the first week of a newborn's life and are associated with impaired liver function. The newborn exhibits jaundice, decreased blood glucose levels, and abdominal distension. Subsequently, symptoms of nervous system damage may occur, along with vomiting, regurgitation, and other gastrointestinal disturbances. Untreated patients with type 1 galactosemia develop liver cirrhosis and cataracts. These severe clinical manifestations of galactosemia can be avoided if treatment is started in a timely manner. Without treatment, children with type 1 galactosemia die within the first year of life.

HOW IS GALACTOSEMIA INHERITED?

Galactosemia is an inherited disorder transmitted in an autosomal recessive manner. This means the disease only manifests if both parents are carriers and, while unaffected themselves, pass on two mutated genes to the child. Most families with a child affected by this disorder have no prior history of the problem. The risk of recurrence in a family that already has children with galactosemia is 25% for each pregnancy.

All families affected by galactosemia must undergo medical genetic counseling and receive complete information from a geneticist regarding the risk of having another child with this condition, and discuss all aspects of monitoring and treatment with a specialist. In Russia, medical genetic counseling services operate in almost every region.

WHAT IS NEWBORN SCREENING FOR GALACTOSEMIA?

To prevent the development of severe clinical manifestations of galactosemia, newborns must be screened for the condition, i.e., undergo neonatal screening. Screening begins by collecting a few drops of blood from the heel of a full-term newborn at 24–48 hours of life (or on the 7th day, i.e., 144–168 hours of life, for a premature infant), which is applied to a special filter paper test card. The blood is dried, and the card—containing the newborn's name and other identification details—is sent to the laboratory of the regional medical genetic counseling center. The laboratory performs a specialized assay to detect newborns with elevated blood galactose levels, which raises a suspicion of galactosemia. The laboratory, with the help of the pediatrician, recalls such infants for re-testing. Re-testing the infant's blood sample is decisive.

WHAT TO DO IF THE GALACTOSEMIA DIAGNOSIS IS CONFIRMED ON SCREENING?

If the blood galactose level remains high upon re-testing, or if the measured enzyme level is low, it means the child has galactosemia, and the family is immediately invited to the medical genetic counseling center. Here, the family is educated about galactosemia and treatment is prescribed. If treatment is initiated early, the child will not develop clinical symptoms of galactosemia and can grow up healthy, indistinguishable from peers. The success of treatment largely depends on how well the parents understand the importance of dietary therapy and how strictly they adhere to it. All of this and much more will be explained to the family by a geneticist or nutritionist during their first visit to the medical genetic counseling center. Subsequently, such visits will become regular. The child's blood galactose levels will be constantly monitored and, depending on laboratory values, the composition of foods will be adjusted to ensure they do not raise galactose levels while providing for normal growth and development. Ongoing contact between the family and the doctor is the key to successful treatment of galactosemia.

Duarte galactosemia is a variant of classical galactosemia in which dietary treatment is not indicated. However, if clinical symptoms indicating liver damage appear, or if total galactose levels are high (greater than 20 mg/dL), dietary lactose restriction may be considered [53].

HOW IS GALACTOSEMIA TREATED?

The core of treatment is the elimination of foods containing galactose, primarily breast milk and other infant formulas. They can be replaced with special soy-based formulas that are free of galactose and lactose. When formulating therapeutic diets for galactosemia patients, the amounts of macronutrients and energy must comply with recommended intake norms. For infants in their first year of life, breast milk and/or infant milk formulas must be replaced with nutritionally adapted lactose-free formulas. Specialized formulas based on soy protein isolate or extensively hydrolyzed milk formulas are used to treat galactosemia patients. Formulas based on synthetic amino acids and lactose-free casein-predominant milk formulas are also used.

It is necessary to completely eliminate any type of milk (including human, cow, goat, infant milk formulas, etc.) and all dairy products from the patient's diet, and strictly avoid consuming foods to which they might be added (bread, pastries, sausages, cold cuts, caramel, sweets, margarines, etc.). The use of low-lactose formulas and milk is also prohibited.

A number of plant-based foods contain oligosaccharides—galactosides (raffinose, stachyose)—and animal-based foods contain glycoproteins, which can be potential sources of galactose (galactosides: peas, common beans, broad beans, lentils, chickpeas, spinach, cocoa, chocolate; glycoproteins: liver, kidneys, liver sausage); therefore, they are excluded from the diet of pediatric patients and restricted in the diet of adult patients.

Complementary foods are introduced starting at 4 months of age. Only dairy-free foods and dishes are used in the diet: dairy-free porridges mixed with lactose-free/galactose-free formulas, as well as vegetable, meat, and fruit purees. All dairy products, including whole cow's milk, fermented milk products, and cottage cheese, are prohibited for patients with galactosemia.

The choice of the first complementary food is determined by the condition of the gastrointestinal tract and the child's nutritional status. It can be vegetable puree made from natural vegetables or canned fruit and vegetable baby foods without added milk (and without legumes) or milk-free porridges based on corn, rice, or buckwheat flour, which must be diluted using the specialized formula that the child is receiving. Meat complementary foods are introduced into the diet from 6 months of age. Preference is given to specialized commercially produced baby meat purees that do not contain milk or its derivatives (rabbit, chicken, turkey, etc.).

WHAT IS THE PROGNOSIS FOR GALACTOSEMIA?

The prognosis of the disease is unfavorable in severe forms and late-diagnosed galactosemia. With early initiation of dietary treatment, children can develop normally. However, despite adequate treatment from the first days of life, patients with galactosemia remain at risk for delayed complications—physical growth retardation, speech and motor development disorders, and osteoporosis. Girls have an increased risk of premature ovarian failure. Many experience growth retardation during adolescence. However, after puberty, height usually reaches normal limits.

Intellectual disability detected in some children with galactosemia receiving dietary treatment is not severe; it may be identified at an early age, but more often becomes apparent during school years when the child experiences difficulties with reading or mastering mathematics. Approximately 18% of children older than 5 years exhibit motor disorders in the form of ataxia, fine motor clumsiness, balance and coordination disorders; tremor during targeted actions and muscle dystonia may be present. About one-third of treated patients with classic galactosemia have speech disorders of the "verbal dyspraxia" type. Such children have delayed speech development at an early age, articulation difficulties, and a poor vocabulary. Cataracts are observed in approximately 30% of patients. Patients with galactosemia exhibit a decrease in bone mineral density, which often leads to the development of early osteoporosis and an increased risk of bone fractures.

PREVENTION OF GALACTOSEMIA

In a family with an affected child, there is a 25% risk of having another affected child with each subsequent pregnancy. Relatives in risk groups may also be identified as carriers of mutations if they were identified in the affected child in that family.

The issue of prenatal diagnostics for galactosemia should be thoroughly discussed with interested couples before making a final decision, as the disease is treatable.

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

Not applicable.