Other sphingolipidoses (Gaucher disease): clinical guidelines

List of Abbreviations

ALT/AST — alanine/aspartate aminotransferases

aPTT — activated partial thromboplastin time

GD — Gaucher disease

GCB — glucosylceramidase, β-D-glucosidase

BBB — blood-brain barrier

CT — computed tomography

LSD — lysosomal storage diseases

MRI — magnetic resonance imaging

US — ultrasound

ERT — enzyme replacement therapy

HDL — high-density lipoproteins

BMD — bone mineral density

NSAIDs — drugs of the groups "Other analgesics and antipyretics" and "Non-steroidal anti-inflammatory and antirheumatic drugs"

TIBC — total iron-binding capacity

PT — prothrombin time

TMS — tandem mass spectrometry

RDS — respiratory distress syndrome

CT — chitotriosidase

CNS — central nervous system

ESR — erythrocyte sedimentation rate determination

ARFI (Acoustic Radiation Force Impulse) elastography

GBA — gene encoding glucocerebrosidase

Lyso-Gb1 — glucosylsphingosine

MCH (mean corpuscular hemoglobin) — determination of mean hemoglobin content and concentration in erythrocytes

MCV (mean corpuscular volume) — determination of erythrocyte size

OMA — oculomotor apraxia

Terms and Definitions

Enzyme replacement therapy — treatment consisting of the lifelong administration of a drug (recombinant enzyme) to patients with an inborn error of metabolism.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Gaucher disease — a rare inherited metabolic disorder classified as a lysosomal storage disease (LSD), in which a mutation in the GBA gene encoding the lysosomal enzyme glucocerebrosidase (GCB) results in decreased enzymatic activity, leading to the accumulation of glycosphingolipids in organs and tissues, predominantly in the bone marrow, spleen, and liver; this manifests as hepatosplenomegaly, anemia, thrombocytopenia, bone system involvement, and, in some cases, neurological disorders.

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

Gaucher disease is inherited in an autosomal recessive manner. The presence of two mutant GBA allele copies is associated with a significant reduction in GCB activity, the function of which is to break down glycosphingolipids (or glucocerebrosides, glucosylceramides) into glucose and ceramide. The accumulation of unutilized lipids in macrophage lysosomes leads to the formation of characteristic storage cells (Gaucher cells). The consequences of this metabolic defect include: chronic activation of the macrophage system, autocrine stimulation of monocytopoiesis and an increase in the absolute number of macrophages, and impaired macrophage regulatory functions [1]. The GBA gene encoding glucocerebrosidase is located in the chromosomal region 1q21. Approximately 600 different mutations have been described to date [2, 3, 4].

Isolated cases of Gaucher disease associated with mutations in the PSAP gene (10q22.1) are known. All of these cases were described in adult patients [4].

1.3 Epidemiology of the Disease or Condition

Gaucher disease is a panethnic disorder with an incidence ranging from 1:40,000 to 1:70,000 live births. It is inherited in an autosomal recessive manner [5, 7, 8].

Based on 49 epidemiological studies of Gaucher disease published between 1990 and 2015, the incidence of Gaucher disease ranges from 0.39 to 5.80 per 100,000 newborns, and the prevalence ranges from 0.70 to 1.75 per 100,000 population [9].

Among Ashkenazi Jews, the incidence of Gaucher disease is highest, reaching 1:450 to 1:2,500 newborns [5].

The carrier frequency of heterozygous mutations ranges from 1:640 to 1:3,969 in various ethnic groups, and is 1:10 to 1:18 among Ashkenazi Jews [10, 11, 12, 13]. In a number of countries, certain forms of the disease predominate: in Europe, Canada, the USA, and Australia, type 1 Gaucher disease is the most common, whereas in Egypt (Palestinian Arabs), Japan, Northern Sweden (Norrbotten region), and Poland, a high frequency of the chronic neuronopathic form is observed, with an average incidence of 1:50,000 [6, 8, 9, 14].

According to the pediatric registry of Gaucher disease in children in the Russian Federation, the prevalence of the disease is 0.32 per 100,000 child population [15].

1.4 Features of Coding the Disease or Condition

E75.2 — Other sphingolipidoses

1.5 Classification of the disease or condition

Gaucher disease is a chronic progressive disorder with variable age of onset and a heterogeneity of clinical manifestations ranging from asymptomatic to perinatally lethal forms [3, 18, 19].

Depending on the clinical course, 3 types of Gaucher disease are distinguished:

• Type 1 — non-neuronopathic (the most common);

• Type 2 — infantile or acute neuronopathic;

• Type 3 — subacute or chronic neuronopathic.

In types 2 and 3 Gaucher disease, the nervous system is involved in the pathological process, which is why they are termed neuronopathic [3, 16, 17, 18, 19].

1.6 Clinical presentation of the disease or condition

Clinical manifestations of type 1 Gaucher disease are diverse, and the age of onset varies.

Type 1 Gaucher disease (non-neuronopathic type) — the most common form of the disease, characterized by a highly variable age of onset at any time of life, varying rates of progression, a heterogeneous degree of organ involvement, and a severity of clinical manifestations ranging from practically asymptomatic forms to signs of severe visceral involvement (hepatosplenomegaly), hematopoietic system dysfunction (cytopenia), and musculoskeletal system pathology (chronic bone pain, bone crises, osteonecrosis, osteopenia, osteoporosis, pathological fractures) without specific neurological symptoms [16, 18, 19].

In the past, type 1 Gaucher disease was regarded exclusively as an adult clinical variant. However, the majority of patients manifest disease symptoms already in the first and second decades of life. Early onset correlates with a more severe course and a high risk of complications if specific treatment is not administered [8, 20].

Type 1 Gaucher disease differs from neuronopathic forms by the absence of early specific central nervous system involvement. Neurological manifestations such as peripheral neuropathy and parkinsonism are observed in older patients with type 1 Gaucher disease and significantly impair their quality of life [21, 22].

The prognosis of the disease is favorable in mild cases with timely initiation of pathogenetic therapy. For irreversible bone lesions, orthopedic surgical intervention is indicated, allowing for patient socialization.

Type 2 Gaucher disease (infantile/acute neuronopathic type) — the rarest form of the disease, debuting in the first six months of life with severe, rapidly progressive neurological symptoms and marked hepatosplenomegaly accompanied by secondary infectious complications.

A number of authors distinguish two clinical variants of type 2 Gaucher disease. In the perinatally lethal form of type 2 Gaucher disease, maternal pregnancy is usually complicated by fetal hydrops and antenatal death, or by premature birth and neonatal death within the first days of life. Ichthyosis is frequently detected in newborns. This phenotype is characterized by neurological, visceral, and facial dysmorphic features [3, 23, 24].

The early infantile form debuts in the first 6 months of life as a clinical symptom complex comprising signs of central nervous system and visceral involvement: significant hepatosplenomegaly; bulbar syndrome (dysphonia, dysphagia, dysarthria); trismus; bilateral fixed strabismus; progressive pyramidal signs (tetraparesis, hyperreflexia, muscle spasticity with neck retraction, positive Babinski sign, and other pathological reflexes); progressive psychomotor developmental delay and regression of previously acquired skills; tonic-clonic and other types of seizure activity resistant to antiepileptic drugs [15, 23, 24].

The prognosis in type 2 Gaucher disease is extremely unfavorable; patient death occurs due to respiratory failure resulting from aspiration pneumonia or respiratory distress syndrome (RDS) against the background of bulbar neurological disorders (swallowing impairment, choking). The age of patient mortality ranges from the early neonatal period up to 4 years, averaging 9 months [25, 26].

Type 3 Gaucher disease (juvenile/chronic/subacute neuronopathic type) — an intermediate form between types 1 and 2 Gaucher disease, characterized by parenchymal organ involvement along with neurological manifestations similar to those in type 2 Gaucher disease, but less pronounced. In contrast to type 1 Gaucher disease, the degree of hepatosplenomegaly is more pronounced, and axial skeletal involvement is characterized by barrel-shaped chest deformity and spinal kyphoscoliosis [23, 24].

In most cases, type 3 Gaucher disease is characterized by a widely varying onset ranging from 1 month to 14 years, a slower rate of progression, and the appearance of neurological symptoms at an average age of 6–15 years [5, 8, 15].

The main and early neurological manifestations of type 3 Gaucher disease are: oculomotor disorders — oculomotor apraxia (OMA) and/or strabismus, which may remain the sole manifestation of the disease for a long time; myoclonus, gradually progressing and transforming into generalized tonic-clonic seizures. Over time, extrapyramidal rigidity, cognitive impairment (ranging from minor changes to severe dementia), speech and writing disorders progress, and diffuse muscular hypotonia is replaced by spasticity. Behavioral changes and episodes of psychosis are possible [5, 8, 23, 24, 27].

Several variants of type 3 Gaucher disease are distinguished:

Type 3A is characterized by a predominance of neurological manifestations (generalized myoclonic seizures, ataxia, OMA, cognitive impairment) and typically manifests in childhood or adolescence [23, 24].

In patients with type 3B GD, visceral and osteoarticular involvement predominates; CNS involvement may manifest solely as oculomotor disorders in the form of APOM and strabismus. Typically, type 3B GD manifests at an early age with hepatosplenomegaly, while bone pathology presents as chest deformities and marked kyphoscoliosis without bone pain or bone crises [23, 24].

Type 3C GD (cardiovascular form) is a rare variant of the chronic neuronopathic form, manifested by hepatosplenomegaly; non-atherosclerotic involvement of the heart and major vessels in the form of calcification of heart valves, aorta, and coronary arteries, leading to congestive heart failure; APOM; corneal opacity; mental retardation, hydrocephalus, and epilepsy refractory to standard antiepileptic drug therapy [23, 24, 27].

Life expectancy in type 3 GD varies from 4 to 60 years depending on clinical variants [25, 26].

Rare clinical manifestations of GD include pulmonary involvement, the development of gaucheromas (pseudotumors), and monoclonal gammopathy [1, 15, 28, 29].

Pulmonary involvement with the development of pulmonary hypertension is observed in 1% of cases and predominantly in patients after splenectomy. The genesis of respiratory system involvement is not entirely clear; presumably, the involvement is due to the infiltration of pulmonary vessels and alveoli by altered macrophages (Gaucher cells) [29].

Gaucheromas are tumor-like structures that are well visualized on ultrasound diagnostics and contrast-enhanced computed tomography (magnetic resonance imaging). These structures are predominantly detected in the spleen or liver and represent accumulations of Gaucher cells or replacing fibrosis, which require active surveillance [28].

According to statistics, the incidence of monoclonal gammopathy with the development of multiple myeloma is higher in patients with GD; however, this clinical manifestation is encountered exclusively in adult patients [1].

Certain genotype-phenotype correlations have been established for GD. It has been shown that the c.1226A>G, p.Asn409Ser mutation (p.Asn370Ser according to old nomenclature) in the homozygous state or in combination with any other allele leads to type 1 GD, whereas inactivating point mutations, recombinant alleles, and large deletions are associated with neuronopathic forms of the disease. The c.1448T>C, p.Leu483Pro mutation (p.Leu444Pro according to old nomenclature), one of the most frequent ones, has been described in type 2 GD [3].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis of Gaucher disease is based on a combination of clinical symptoms, history data, clinical and laboratory examination, confirmed by the results of enzyme diagnostics and molecular genetic analysis [6, 30].

Assessment of disease severity is usually performed using the Gaucher disease severity scoring system PGS3 (Appendix G1).

2.1 Complaints and Anamnesis

When taking the history and complaints, attention should be paid to the following signs:

• family history (presence of splenectomy or the above-mentioned symptoms in siblings, confirmed diagnosis in a relative) [2,3,16,17,18,19];

• growth and sexual development delay;

• weakness, increased fatigue, frequent respiratory infections;

• manifestations of spontaneous hemorrhagic syndrome (in the form of subcutaneous hematomas, mucosal bleeding) or prolonged bleeding during minor surgical interventions;

• enlargement of the abdomen;

• bone and joint pain; duration, nature, and localization of pain, history of bone fractures;

• previous splenectomy (total or partial);

• neurological symptoms (APOM or strabismus, ataxia, cognitive impairment, sensory disturbances, etc.);

• skeletal deformities (scoliosis, chest changes of the pigeon chest or barrel chest type) combined with neurological symptoms (APOM, strabismus)

2.2 Physical Examination

Clinical examination should include measurement of height and body weight, body temperature, assessment of the osteoarticular system, detection of signs of hemorrhagic syndrome, paying special attention to palpation and percussion examination of the liver and spleen, and a neurological examination [2,3,18,19].

Type 1 GD is characterized by the following features:

• growth retardation;

• spleno-/hepatosplenomegaly;

• hemorrhagic syndrome;

• bone pain (bone crises);

• joint mobility impairment;

• pathological fractures;

• delayed sexual development;

• asthenic syndrome.

Type 2 and 3 GD is characterized by the following features:

• growth retardation;

• delayed psychomotor development, speech and writing disorders;

• hemorrhagic syndrome;

• spleno-/hepatosplenomegaly;

• skeletal deformities (scoliosis, chest deformities);

• AMA;

• strabismus;

• seizures;

• asthenic syndrome;

• intellectual disability (from minor changes to severe dementia);

• extramyramidal rigidity;

• cerebellar disorders;

• behavioral changes, psychotic episodes;

• myoclonus, progressively increasing and progressing to generalized tonic-clonic seizures

2.3 Laboratory Diagnostics

Comments: The study should be performed at least once every 3-6 months or more frequently as clinically indicated (treatment ineffectiveness, changes in ERT dosing regimen, and/or drug substitution). In most patients with type 1 GD, anemia, thrombocytopenia, and less frequently leukopenia are detected as manifestations of hypersplenism and bone marrow infiltration by Gaucher cells. In type 2 and 3 Gaucher disease, hematological manifestations are less common.

Comments: A general clinical biochemical blood test reveals: decreased concentrations of lipoproteins, iron, vitamin B12, folic acid, ionized calcium; increased immunoglobulin levels [15, 34, 35].

The activity of "liver" enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) may be slightly or moderately elevated, with aspartate aminotransferase (AST) predominating over alanine aminotransferase (ALT) in GD patients. The presence of cytolysis syndrome does not correlate with the degree of hepatomegaly or the severity of liver damage [15, 31].

Comments: Hyperferritinemia against the background of a normal total iron-binding capacity (TIBC) of serum is very common in patients with GD (up to 87% of untreated subjects). Serum ferritin levels correlate with GD severity and the presence of splenectomy, and decrease significantly during therapy [31, 36]. At the same time, ferritin may also be elevated in the presence of acute/chronic inflammation due to comorbid pathology.

For a correct assessment of iron metabolism, it is necessary to examine not only ferritin, but also transferrin, iron-binding capacity of serum (total or unsaturated iron-binding capacity), transferrin saturation, and serum iron. When determining an incomplete panel of parameters, especially in the case of inflammatory hyperferritinemia characteristic of Gaucher disease, it is easy to miss concomitant iron deficiency or iron overload.

Comments: The coagulogram shows prolongation of APTT and PT [15, 41].

Comments: Bone marrow morphological examination helps to identify characteristic diagnostic elements—Gaucher cells—while ruling out hemoblastosis or lymphoproliferative disease as the cause of cytopenia and hepatosplenomegaly. However, the bone marrow aspiration procedure is painful for the patient, and the cytology result may not always be unambiguous: there is a fairly high risk of false-negative results due to the inexperience of the pathologist describing the specimen and the sparse distribution of Gaucher cells in the myelogram. False-positive results are associated with the detection of pseudo-Gaucher cells (alternatively activated macrophages) found in a number of other conditions: myelodysplastic syndrome, chronic myeloid leukemia, pulmonary tuberculosis, mycobacterioses, congenital dyserythropoietic anemia. At the same time, false-negative results do not allow for the complete exclusion of GD, since Gaucher cells are mechanically fragile and easily destroyed during the preparation and staining of smears. In addition, marker cells may be located at the periphery of the bone marrow smear and not always fall into the field of view of the morphologist [1, 3, 15].

May be performed to rule out lymphoproliferative disorders and other hematologic diseases presenting with cytopenia and splenomegaly.

Comments: The biochemical criterion for a definitive diagnosis is a decrease in $\beta$-D-glucosidase enzyme activity in blood cells [8, 11, 16]. Currently, enzyme activity is most often determined in dried blood spots using tandem mass spectrometry (MS/MS). The advantages of this method are minimal requirements for blood collection, shipping, and storage of biological samples [42].

Comments: molecular genetic diagnosis of GD makes it possible to detect pathogenic variants of the GBA gene in the vast majority of cases. At the first stage, a search for the most common mutations is performed, which allows the detection of up to 80% of significant gene variants (especially in populations with a predominance of certain mutations). At the second stage, rare and novel mutations are searched for. In some cases, it is possible to predict the severity of GD based on the genotype [11, 12].

Comments: The biomarker (Lyso-Gb1) is a derivative of glucocerebroside and has high specificity and sensitivity; its determination is important both for the diagnosis and for monitoring the treatment of GD [43, 44, 45]. It is advisable to determine the concentration of this biomarker simultaneously with measuring enzyme activity in order not to miss extremely rare forms of GD with saposin deficiency, as well as cases of GD with high residual enzyme activity.

2.4 Instrumental Diagnostics

Comments: Ultrasound and MRI of the liver and spleen (abdominal ultrasound (comprehensive) and abdominal MRI) are necessary to assess the course of the disease and subsequent monitoring of enzyme replacement therapy efficacy. According to literature data, 20% of patients have large hypoechoic areas of irregular shape, homogeneous structure, with fuzzy blurred borders and without clear localization within the organ structure — the so-called "Gaucher nodes" or gaucheromas, which represent foci of excessive accumulation of Gaucher cells [15, 28].

Anesthesia — as indicated.

Comments: used to detect skeletal deformities, fractures, and determine the thickness of the cortical layer of bones [19, 30]. Bone tissue changes on tubular bone radiography may present as periosteal thinning, endosteal scalloping and reduced trabeculation; diffuse osteoporosis, characteristic Erlenmeyer flask deformity of the distal femurs and proximal tibias, increased radiolucency of bone tissue; presence of cystic radiolucencies, foci of osteolysis, osteosclerosis and osteonecrosis, pathological fractures [46, 47, 48].

Comments: general anesthesia as clinically indicated.

Comments: X-ray densitometry of the lumbar spine is the quantitative diagnostic imaging method for children with GD, representing the "gold standard" for detecting reduced bone mineral density (BMD). The method is based on determining areal BMD, detects changes in the early stages of GD, and allows for monitoring treatment efficacy. The degree of BMD reduction in children is determined using the Z-score, which is the number of standard deviations (SD) by which the measured result differs from the mean value for a given age and sex. Non-invasiveness, wide availability, low radiation dose, rapid results, and high accuracy of quantitative analysis make X-ray densitometry suitable for use in children. The analysis of results is performed taking into account the child's bone age, which is determined preliminarily from radiographs of the hand bones [15, 51, 52].

Comments: in the presence of lung involvement, follow-up examinations are performed, with the frequency determined individually.

Pulmonary function testing (spirometry assessing unforced respiratory volumes and flows) is performed in children starting from 5 years of age.

Comments: ocular symptoms can occur in various types of GD: oculomotor apraxia (OMA) and/or strabismus are observed in types 2 and 3 GD, and special attention should be paid to patients with suspected or confirmed type 3c GD due to the likelihood of corneal opacity development.

Comments: cases of cortico-subcortical brain atrophy have been described in patients with neuronopathic types of GD. These methods also allow for differential diagnosis among diseases with similar clinical manifestations. Anesthesia as clinically indicated.

Comments: ultrasound of the coronary arteries and aorta (duplex scanning of the aorta, duplex scanning of the coronary vessels) may also be performed to diagnose and monitor cardiac and vascular calcification [61].

2.5 Other Procedures

Comments: initial and follow-up consultations are indicated with a pediatrician / general practitioner (family physician), hematologist / pediatric hematologist-oncologist, gastroenterologist, geneticist, neurologist, ophthalmologist, trauma surgeon / orthopedist, pediatric cardiologist, pulmonologist, otolaryngologist-audiologist, psychiatrist, medical psychologist, as well as specialists in other fields depending on the clinical situation [58, 62, 63, 64].

Comments: with the current level of laboratory diagnostics, there is no need to search for Gaucher cells. Tests may only be performed in the case of differential diagnosis or searching for another pathology

2.5.1 Differential Diagnosis

The diagnosis of Gaucher disease is established based on a combination of clinical data and laboratory research results, including biochemical and molecular genetic analysis.

Considering the pronounced phenotypic heterogeneity, wide variability in the age of GD onset, and non-specificity of early clinical manifestations, differential diagnosis must be performed with a large number of hematological, hepatic, bone, and neurological disorders, as well as other inherited metabolic diseases [3, 15, 19].

GD should be suspected in a patient with unexplained spleno- and hepatomegaly, cytopenia, and symptoms of bone involvement.

For type 1 GD, depending on the type of manifestation, differential diagnosis includes various exogenous and hereditary diseases accompanied by visceromegaly, acute bone pain, and bleeding in the absence of neurological symptoms.

Cytopenic and hemorrhagic syndromes most often need to be differentiated from lymphoproliferative and myeloproliferative disorders, myelodysplastic syndrome, anemias of other etiologies, immune thrombocytopenia, thrombocytopathies, and coagulopathies (hemophilia) [1, 66].

Differential diagnosis of hepatosplenomegaly is performed with other diseases characterized by enlargement of the liver and spleen, primarily sphingolipidoses (Niemann-Pick disease type A/B), liver diseases with the development of cirrhosis and portal hypertension (congenital infections, viral hepatitis, autoimmune hepatitis, Wilson's disease, glycogen storage disease, alpha-1 antitrypsin deficiency, tyrosinemia, lysosomal acid lipase deficiency, hemochromatosis, histiocytosis) [5, 13, 15, 67].

Differential diagnosis of avascular necrosis of the femoral head is performed with Perthes disease; bone crises with osteomyelitis; chronic ossalgia and arthralgia with growing pains, rheumatological pathology (arthritis), hemoblastoses, Banti's syndrome, and bone tuberculosis [15, 16, 68].

When diagnosing hepatosplenomegaly with neurological symptoms (types 2 and 3 GD), all infantile forms of sphingolipidoses (Niemann-Pick disease type C), GM1 gangliosidosis, galactosialidosis, Wolman disease, Farber disease (atypical forms), as well as congenital oculomotor apraxia must be excluded [5, 13, 15].

It is also recommended to differentiate it from GM2 gangliosidosis. The main clinical manifestations of the disease include the regression of motor and psycholinguistic skills, deterioration of cognitive processes, progressive macrocephaly, diffuse muscular hypotonia (paralysis is possible), and seizure syndrome. Almost all patients with this condition exhibit a "cherry-red spot" in the macula upon ophthalmoscopy [69].

2.5.2. Medical genetic counseling and comprehensive examination for prenatal diagnosis of child developmental disorders (prenatal diagnosis)

Comments: as with other autosomal recessive disorders, the risk of having a child with Gaucher disease in each pregnancy is 25%. In families with a child affected by Gaucher disease, it is possible to perform comprehensive examinations for the prenatal diagnosis of child developmental disorders (prenatal diagnosis) and preimplantation genetic testing (PGT).

A comprehensive examination for the prenatal diagnosis of child developmental disorders (intrauterine) is carried out using molecular genetic methods by analyzing DNA extracted from a chorionic villus biopsy at 9–11 weeks.

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

3.1 Conservative Treatment

Comments: ERT provides sustained clinical improvement in patients: it normalizes hemoglobin concentration, platelet count, and the size of the liver and spleen (in non-splenectomized patients); relieves bone pain; prevents the development of osteonecrosis and bone crises; normalizes growth; and significantly improves the quality of life of children with Gaucher disease.

Due to the heterogeneity of the disease, the drug dose must be selected individually, depending on the severity of manifestations, and may be increased or decreased based on the success of achieving therapeutic goals evaluated through clinical, laboratory, and instrumental assessments [2, 3, 16, 17, 71]. The advantages of ERT include a high safety and efficacy profile for managing the main manifestations of Gaucher disease, while its disadvantages are related to frequent infusions that reduce patients' quality of life and the lack of impact on neurological symptoms (even at high doses) due to the inability of the enzyme to cross the blood-brain barrier (BBB) and the absence of mannose receptors on neuronal membranes [15, 71, 72].

The following 3 medicinal products for ERT are registered in the Russian Federation:

o #imiglucerase^**;

o velaglucerase alfa^**;

o taliglucerase alfa^**.

#Imiglucerase^** is a modified form of human acid β-glucosidase, indicated for the treatment of children and adults with a confirmed diagnosis of Gaucher disease. Approved from birth. In children with Gaucher disease, the starting dose of #imiglucerase is:

o for type 1 Gaucher disease without tubular bone involvement — 15–30 U/kg per single dose once every 2 weeks [3, 73, 74]

o for type 1 Gaucher disease with tubular bone involvement (bone crises, pathological fractures, foci of lytic destruction, avascular necrosis of the femoral heads) — 60 U/kg per single dose once every 2 weeks [6, 56, 57, 58, 59, 60];

o for type 3 Gaucher disease — 60 U/kg per single dose once every 2 weeks.

Velaglucerase alfa^** is indicated for the long-term treatment of children with type 1 Gaucher disease, from birth. The recommended dose is 30–60 U/kg once every 2 weeks.

The dose can be adjusted individually based on achieving and maintaining the expected clinical response, although the use of doses higher than 60 U/kg has not been studied [3, 75, 76, 77, 78].

It may have an effect on visceral manifestations in patients with type 3 disease, but does not affect the neurological outcome [32]. Doses of #velaglucerase alfa** in type 3 Gaucher disease: 60 U/kg per single infusion [79, 80].

#Taliglucerase alfa^** is indicated for the treatment of children and adults with a confirmed diagnosis of type 1 Gaucher disease. For the treatment of children aged 2 to 18 years with visceral or hematological manifestations of Gaucher disease. The recommended dose is 30–60 U/kg once every 2 weeks, depending on the clinical evaluation performed by the attending physician [81, 82, 83].

Comments: In addition to ERT, which has been shown to improve bone tissue status in patients with Gaucher disease, children with this condition receive symptomatic therapy that includes a calcium-enriched diet and calcium supplements combined with vitamin D and its analogues. Medications are prescribed in accordance with guidelines for osteoporosis/osteopenia.

As symptomatic therapy for skeletal complications of type 1 Gaucher disease, topical and oral NSAIDs are used for pain management, and systemic antimicrobial drugs are used in some cases for secondary infection [85]. When the platelet count is below 50 × 10⁹/L, NSAIDs should not be prescribed due to the risk of hemorrhagic complications.

3.2 Surgical Treatment

Comments: Impairment of the structure and function of these organs due to "misdirection" leads to irreversible consequences: development of liver cirrhosis, bone and joint deformity, pulmonary fibrosis, and severe cor pulmonale. Among patients who have undergone splenectomy, an association has also been noted between elevated blood platelet counts and osteonecrosis, which may be associated with the development of intraosseous thrombosis [2, 17, 19, 68]

Comments Surgical interventions carry an increased risk of bleeding and infection

GGR CLeE 5Grade of Recommendation C (Level of Evidence – 5)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: the presence of pain, visceral features, delayed growth and puberty, and feelings of weakness can negatively affect the patient's self-esteem, which may require psychological support.

Comments:

o Moderate-intensity physical exercise >3 times per week, healthy diet [96];

o Before deciding to practice sports, a consultation with the attending physician is required to assess the patient's capabilities based on their condition;

o Patients with splenomegaly should avoid contact sports due to the risk of bleeding, and all patients should avoid them due to the potential risk of fractures;

o Swimming is one of the most preferred types of physical activity for most patients with GD due to the reduction of gravity. Swimming strengthens muscles and minimizes joint stress;

o Patients after joint arthroplasty should not engage in jumping, downhill skiing, and other traumatic activities [89].

5. Prevention and Dispensary Observation

5.1 Prevention

Level of Evidence 5 (Grade of Recommendation — C)

Comments: as with other autosomal recessive disorders, in GD the risk of having a child with GD in each pregnancy is 25%. In families with a child with GD, comprehensive testing is available for prenatal diagnosis of developmental disorders (prenatal diagnosis) and preimplantation genetic testing (preimplantation diagnosis). Comprehensive testing for the prenatal diagnosis of developmental disorders (prenatal diagnosis) of GD is possible using DNA diagnostic methods. However, given the treatability of this condition, all risks and prognoses associated with early initiation of therapy must be discussed with the family.

5.1.1 Vaccination

Patients with GD are at risk for infectious diseases [90].

There is no data on contraindications for routine vaccination according to the national immunization schedule in patients with GD without splenectomy [91].

Comments: Vaccination against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis is also performed.

Children should be vaccinated against the background of a stable somatic condition and ongoing therapy.

Also, since influenza is associated with an increased risk of pneumococcal pneumonia, all patients with splenic dysfunction should be vaccinated annually against the seasonal influenza virus.

For patients prior to splenectomy, vaccination (including against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis) should be completed ≥14 days prior to the procedure, if possible, ideally 10–12 weeks prior. If vaccines cannot be administered during this period, they should be given 14 days after splenectomy.

In addition to vaccination, prophylactic use of systemic antimicrobial agents further reduces the risk of severe infections in patients with splenic dysfunction [93, 94]. Table 1 provides information on vaccination in children with splenic dysfunction and splenectomized children.

5.2 Monitoring the condition of patients with Gaucher disease

Patient management should be carried out in accordance with the recommendations for the minimum necessary monitoring of patients with type 1 GD developed by the International Collaborative Gaucher Group.

Patients with GD under the age of 18 are followed up by: a pediatrician, pediatric hematologist-oncologist, gastroenterologist, and if necessary, an orthopedic traumatologist, neurologist, ophthalmologist, medical psychologist, otorhinolaryngologist-audiologist, physical and rehabilitation medicine physician, physical therapist, exercise therapy physician, general practitioner (family physician), and others as clinically indicated, on average annually and when a change in the ERT dosage regimen or drug switch is necessary — referral to a clinic specializing in the treatment of GD.

Comments: The frequency of testing is at least once every 3–6 months or more often as indicated (treatment failure, change in ERT dosage regimen and/or drug switch).

Comments: The frequency of testing is determined individually.

Comments: The frequency of testing is determined individually.

Comments: The frequency of testing is determined individually.

Comments: The frequency of testing is determined individually.

Comments: The choice of method is individual. Frequency of examination on average once every 6–12 months, as well as when changing the drug dosage or in case of significant clinical complications (Appendix A3.1) [2, 3, 16, 18, 19]. Anesthesia as indicated.

Comments: frequency is determined individually.

Comments: frequency is determined individually.

Comments: The frequency is determined individually. General anesthesia is performed as indicated.

Comments: The frequency is on average once a year until the condition stabilizes, then as indicated, usually when changing the drug dose or when switching to another ERT drug.

Comments: The test is performed before initiating treatment, to monitor therapy and disease progression once a year, as well as when changing the dosage regimen or switching the ERT drug.

Comments: the frequency is determined individually.

Comments: The frequency is determined individually.

Comments: The frequency of the study is determined individually. General anesthesia is performed as indicated.

Comments: ultrasound of the coronary arteries and aorta (duplex scanning of the aorta, duplex scanning of the coronary vessels) may also be performed to diagnose and monitor cardiac and vascular calcification [61]. The frequency of the study is determined individually

Comments: The frequency is determined individually.

Comments: The frequency of the study is determined individually.

Comments: The frequency is determined individually.

ERT in children with GD is administered regularly as indicated in complicated cases in an inpatient setting, and in a stable condition in a day hospital, inpatient setting, or outpatient setting once every 2 weeks. Until the goals of ERT are achieved, all GD patients must undergo follow-up examinations to adjust the ERT dose in an inpatient or day hospital setting, on average twice a year; thereafter, examinations are performed once a year.

Table 1 outlines the principles of patient monitoring in Gaucher disease.

Table 1. Principles of monitoring in Gaucher disease

Note: US — ultrasound, MRI — magnetic resonance imaging.

6. Organization of Medical Care

GD patients may receive medical care of any type, under any conditions, and in any form provided for by the legislation of the Russian Federation, as clinically necessary.

The management of children with GD is typically performed by a pediatrician, pediatric hematologist-oncologist, gastroenterologist, pediatric orthopedist-traumatologist, neurologist, and other specialists as clinically indicated.

Hospitalization is most frequently carried out in a hematology/pediatric/gastroenterology department or a surgical/orthopedic-trauma department; treatment may also be provided in a neurology, pulmonology, or other departments depending on the dominant symptoms of the disease.

Routine vaccination in GD patients is carried out in accordance with the National Immunization Schedule. For vaccination details, see section 5.1.1

The required specialist consultations, laboratory and instrumental examinations, and their recommended frequency are presented in section 5.2

6.1 Indications for planned hospitalization

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 medical examinations in a medical institution when they cannot be performed in an outpatient setting (including issuing a federal consilium or medical commission conclusion);

3. a condition requiring active treatment and round-the-clock medical observation (surgical correction of skeletal deformities, selection of anticonvulsant therapy, etc.);

4. a condition requiring high-tech medical treatment methods (including monitoring the effectiveness of ERT)

5. the inability to provide ERT in outpatient and day-care settings;

6. the need for various expert evaluations or examinations in a medical institution when outpatient performance is not feasible and dynamic observation is required.

6.2 Indications for emergency/urgent hospitalization

1. acute life-threatening conditions and conditions that may develop severe complications requiring emergency treatment, including intensive care, as well as 24-hour medical supervision and special diagnostic and therapeutic procedures.

6.3 Indications for hospital discharge

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. completion of the patient's diagnostic and treatment plan, with recommendations provided for further follow-up and management.

4. need to transfer the patient to another medical facility or social care institution.

7. Additional Information

7.1 Outcomes and prognosis

The prognosis of type 1 GD depends on the severity of clinical manifestations. The administration of disease-modifying therapy in the early stages of the disease ensures a favorable prognosis and improves the quality of life of children with type 1 GD (when ERT is indicated), preventing disability.

In type 2 GD, the prognosis is extremely unfavorable (fatal outcome in the 1st–2nd year of life).

In type 3 GD, the prognosis is unfavorable (progressive cognitive impairment, fatal outcome on average by 30 years of age due to progressive lung and CNS involvement).

Criteria for Evaluating the Quality of Medical Care

Table 3 Organizational and technical conditions for the provision of medical care

Table 4 Quality criteria for the provision of medical care

References

Appendix A1. Working Group Composition

1. Inga V. Anisimova — Cand. Sci. (Med.), geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, member of the Association of Medical Geneticists

2. Galina V. Baydakova — Cand. Sci. (Biol.), Leading Researcher 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

3. Aleksandr A. Baranov — Academician of the RAS, Professor, D. Sci. (Med.), Honorary President of the Union of Pediatricists 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 Pediatrician of the Russian Ministry of Health

4. Nato D. Vashakmadze — D. Sci. (Med.), Head of the Department of Rare Diseases, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, member of the Union of Pediatricists of Russia, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health

5. Elena A. Vishnyova — D. Sci. (Med.), Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, member of the Union of Pediatricists of Russia

6. Olga S. Gundobina — Cand. Sci. (Med.), Leading Researcher, Gastroenterologist at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, member of the Union of Pediatricists of Russia

7. Elena A. Dobrynina — Cand. Sci. (Med.), Senior Researcher at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, member of the Union of Pediatricists of Russia

8. Ekaterina Y. Zakharova — D. Sci. (Med.), 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)

9. Elena V. Kaitukova — Cand. Sci. (Med.), Chief Physician of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, 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 Pediatricists of Russia

10. Elena V. Komarova — D. Sci. (Med.), Deputy Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Gastroenterologist, member of the Union of Pediatricists of Russia

11. Sergey I. Kutsev — Corresponding Member of the RAS, D. Sci. (Med.), Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Chief Freelance Specialist in Medical Genetics of the Russian Ministry of Health, President of the Association of Medical Geneticists of Russia (AMG)

12. Alla E. Lavrova — D. Sci. (Med.), Highest Qualification Category Physician in Pediatrics, Acting Head of the Institute of Pediatrics, University Clinic of Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation, Head of the 2nd Pediatric Department with Medical Rehabilitation, Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation

13. Svetlana V. Mikhailova — D. Sci. (Med.), Head of Department, Pirogov Russian National Research Medical University, Russian Children's Clinical Hospital of the Russian Ministry of Health

14. Goar B. Movsisyan — Cand. Sci. (Med.), Physician at the Gastroenterology Department, National Medical Research Center for Children's Health of the Russian Ministry of Health

15. Lyudmila P. Nazarenko — Professor, D. Sci. (Med.), Deputy Director for Research and Clinical Work, Head of the Laboratory of Hereditary Pathology, Research Institute of Medical Genetics, Tomsk National Research Medical Centre of the RAS, member of the Association of Medical Geneticists (AMG)

16. Leyla S. Namazova-Baranova — Academician of the RAS, Professor, D. Sci. (Med.), President of the Union of Pediatricists 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 Specialist in Preventive Pediatrics of the Russian Ministry of Health

17. Ekaterina A. Nikolaeva — D. Sci. (Med.), Professor, Head of the Department of Clinical Genetics, Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University, member of the Russian Society of Medical Geneticists

18. Tatyana M. Pervunina — Cand. Sci. (Med.), Director of the Institute of Perinatology and Pediatrics, Almazov National Medical Research Centre of the Russian Ministry of Health

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

20. Nelly S. Pogosyan — Representative of the All-Russian Society of Orphan Diseases

21. Aleksandr S. Potapov — D. Sci. (Med.), Professor, Gastroenterology Department, National Medical Research Center for Children's Health of the Russian Ministry of Health, Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University)

22. Aleksandr A. Pushkov — Cand. Sci. (Med.), Leading Researcher at the Laboratory of Molecular Genetics and Medical Genomics, National Medical Research Center for Children's Health of the Russian Ministry of Health, member of the Association of Medical Geneticists (participation in the original version of the document)

23. Svetlana A. Repina — Cand. Sci. (Med.), Geneticist at the 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

24. Kirill V. Savostyanov — D. Sci. (Biol.), Head of the Center for Fundamental Research in Pediatrics, National Medical Research Center for Children's Health of the Russian Ministry of Health, member of the Association of Medical Geneticists (participation in the original version of the document)

25. Liliya R. Selimzyanova — Cand. of Sci. (Med.), Leading Research Scientist, Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery; Associate Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Associate Professor, Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Member of the Union of Pediatrists of Russia

26. Olga Ya. Smirnova — Medical Geneticist, Senior Research Scientist, Department of Standardization and Study of Evidence-Based Medicine Fundamentals, Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery; Member of the Union of Pediatrists of Russia

27. Nataliya S. Smetanina — Dr. of Sci. (Med.), Professor, Deputy Director of the Institute of Hematology, Immunology and Cell Technologies, Director of the Department of Scientific and Organizational Work with Regions, Deputy General Director, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health; Member of the National Hematological Society, Member of the National Society of Pediatric Hematologists/Oncologists

28. Tatyana V. Strokova — Dr. of Sci. (Med.), Professor of the RAS, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Clinic of the Federal Research Centre of Nutrition and Biotechnology

29. Andrey N. Surkov — Dr. of Sci. (Med.), Head of the Pediatric Gastroenterology Department, Children's Inpatient Hospital; Head of the Department of Scientific Foundations of Pediatric Gastroenterology, Hepatology and Metabolic Disorders, Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery; Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health

30. Marina V. Fedoseenko — Cand. of Sci. (Med.), Head of the Department for the Development of Scientific Approaches to the Immunization of Patients with Health Status Deviations and Chronic Diseases, Leading Research Scientist, Pediatrician, Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery; Associate Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Member of the Union of Pediatrists of Russia

31. Tatyana T. Batysheva - Chief freelance pediatric specialist in medical rehabilitation at the Russian Ministry of Health, Chief freelance pediatric specialist in neurology at the Moscow Healthcare Department, Director of the Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Healthcare Department, Honored Doctor of the RF, Head of the Department of Neurology, Physical and Rehabilitation Medicine and Pediatric Psychology, Faculty of Continuing Medical Education, RUDN University, Professor, Dr. of Sci. (Med.)

32. Olga V. Bykova Head of the Research Department, Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Healthcare Department; Professor, Department of Neurology, Physical and Rehabilitation Medicine and Pediatric Psychology, Faculty of Continuing Medical Education, Medical Institute, RUDN University, Dr. of Sci. (Med.)

33. Yuri A. Klimov - Lead Lecturer, Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Healthcare Department; Associate Professor, Department of Physical and Rehabilitation Medicine, Psychology and Pediatric Neurology, RUDN University, Cand. of Sci. (Med.)

34. Sergey V. Tikhonov - Scientific Secretary, Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Healthcare Department; Associate Professor, Department of Neurology, Physical and Rehabilitation Medicine and Pediatric Psychology, Faculty of Continuing Medical Education, Medical Institute, Peoples' Friendship University of Russia (RUDN University), Cand. of Biol. Sci.

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;

• general practitioners (family physicians);

• gastroenterologists;

• medical geneticists;

• pediatric hematologists-oncologists;

• pediatric surgeons;

• neurologists;

• medical psychologists;

• medical university students, interns, residents.

Table 1 Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

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

Table 3 Scale for assessing grades of recommendation (GR) 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 when justified additions/comments to previously approved clinical guidelines are available, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012 "On approval of the Procedure for providing pediatric care"

2. 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"

3. State Register of Medicines: 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."

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

1. Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724);

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

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

4. 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."

5. 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".

6. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines."

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

8. 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 Assessment of Citizens by Federal State Medical and Social Assessment Institutions";

9. Order of the Ministry of Health of the Russian Federation 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, forms of prescriptions containing appointments of 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"

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

Appendix A3.1 Clinical manifestations in different types of Gaucher disease [32]

Classification and clinical manifestations of GD by type (adapted from Hughes D. et al. [31])

Appendix A3.2 Minimal clinical protocol for the initial assessment of primary neurological involvement in Gaucher disease [32]

Note: GD — Gaucher disease, MRI — magnetic resonance imaging, CT — computed tomography, EEG — electroencephalography

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What is Gaucher disease?

Gaucher disease (GD) is an inherited disorder belonging to the group of lysosomal storage diseases. The cause of Gaucher disease is a decrease in the activity of the lysosomal enzyme β-D-glucosidase (glucocerebrosidase), which is responsible for the breakdown of complex fat-like molecules. Impaired enzyme activity leads to the accumulation of uncleaved lipids in specific cells — macrophages, and the formation of characteristic storage cells — “Gaucher” cells.

Gaucher disease is a very rare disorder with an incidence of 1:40,000 to 1:70,000 newborns, but among Ashkenazi Jews (of Eastern European descent), the incidence of GD reaches 1:450 to 1:1,000 newborns.

How does Gaucher disease manifest?

Gaucher disease can manifest in various ways: symptoms may appear at different ages and vary in severity. The age of onset ranges from 0 to 60 years. There are forms of Gaucher disease with nervous system involvement (types 2 and 3) and without nervous system involvement (type 1).

Gaucher disease type 1 is the most common form, occurring without nervous system involvement, with the main signs being enlargement of the liver and spleen (hepatosplenomegaly), reduced platelet count (thrombocytopenia), and decreased red blood cells and hemoglobin (anemia). A constant and earliest sign of the disease is enlargement of the spleen (splenomegaly). Upon palpation, the spleen is enlarged, and sometimes its size can exceed normal by 5–80 times. As splenomegaly progresses, infarctions (hemorrhages) and fibrous changes (replacement of splenic tissue with connective tissue) can develop in the spleen, which do not always have clinical manifestations but are dangerous complications of the disease. Hepatomegaly (enlargement of the liver) in Gaucher disease is less pronounced than splenomegaly and typically develops at later stages. The exception is patients after splenectomy (removal of the spleen), who, in the absence of treatment, may exhibit a significant increase in liver size. Liver function is generally not impaired. As Gaucher disease progresses, portal hypertension (blood stagnation in the liver veins) may develop. Increased bleeding tendencies (hemorrhagic syndrome) develop due to decreased platelet count (thrombocytopenia) and impaired platelet function. It manifests as subcutaneous bruises (hematomas), bleeding of mucous membranes, and prolonged bleeding after minor surgical procedures. Lung involvement is rare (1–2% of patients), predominantly in splenectomized patients, and presents as interstitial lung disease or pulmonary vascular involvement with the development of pulmonary hypertension symptoms. A typical manifestation of type 1 Gaucher disease is skeletal system involvement, which ranges from asymptomatic decreased bone density and deformity of the distal femurs (Erlenmeyer flask deformity) to severe osteoporosis with multiple pathological fractures and ischemic necrosis, leading to secondary osteoarthritis and, consequently, irreversible orthopedic defects. Most patients with Gaucher disease experience chronic bone pain. Bone crises are characteristic, accompanied by excruciating pain, hyperemia and tenderness in the joint areas, decreased motor activity, fever, and chills. It is the skeletal system involvement that determines the severity of GD and the quality of life of patients.

In Gaucher disease types 2 and 3, the nervous system is involved in the pathological process, which is why they are called neuronopathic. The clinical picture is characterized by internal organ involvement (liver and spleen) similar to type 1, blood clotting disorders due to thrombocytopenia, and bone pathology, along with various neurological disorders. The main symptoms of GD type 2 occur in the first 6 months of life, marked by progressive psychomotor retardation and loss of previously acquired skills, increased muscle tone, swallowing disorders, and seizures.

The main feature of the clinical manifestations of GD type 3 is that along with parenchymal organ involvement (hepatosplenomegaly), there are neurological manifestations similar to those in GD type 2, but less pronounced and usually appearing between the ages of 6 and 15 years or later. Patients may exhibit decreased intelligence, behavioral disturbances, gait abnormalities, speech and writing difficulties, and seizures may develop.

How is Gaucher disease diagnosed?

The “gold standard” of modern Gaucher disease diagnosis is the determination of β-D-glucosidase enzyme activity. Enzyme activity can be determined in peripheral blood leukocytes as well as on dried blood spots. However, the degree of decreased enzyme activity does not correlate with the severity of clinical manifestations and the course of the disease. A decrease in β-D-glucosidase enzyme activity is the basis for establishing a diagnosis.

An additional biochemical marker characteristic of Gaucher disease is a significant increase in the activity of chitotriosidase — a hydrolytic enzyme synthesized by activated macrophages (Gaucher cells) — in blood plasma. In patients with Gaucher disease, enzyme activity increases hundreds of times. During therapy, a decrease in chitotriosidase activity is observed, which is one of the indicators of treatment efficacy. However, 6% of the general population are carriers of a homozygous chitotriosidase gene mutation, which is expressed as an absence of enzyme activity in blood plasma. Therefore, in rare cases, determining chitotriosidase activity cannot be used for the diagnosis and monitoring of GD.

Recently, a compound that can also be determined on dried blood spots — glucosylsphingosine (Lyso-Gb1) — has been used as a more specific biomarker.

Carrying out molecular genetic analysis to search for mutations in the GBA gene is important for conducting comprehensive testing for prenatal diagnosis of developmental disorders in the child (prenatal diagnosis) within the family. Also, in some cases, identifying a specific mutation allows for clarification of the Gaucher disease type, its severity, and the rate of progression.

Comprehensive testing for prenatal diagnosis of child developmental disorders (prenatal diagnosis) is performed at 9–11 weeks of pregnancy. In the material called chorionic villi (from which the placenta subsequently forms), enzyme activity is determined and testing is performed to identify mutations in the gene. Based on the analysis performed, a conclusion is made whether the unborn child is sick or healthy. Modern technologies also allow for preimplantation genetic testing (preimplantation diagnosis). Fertilization is performed in vitro, then only those fertilized embryos at the stage of several blastomeres that do not carry the familial mutation are selected and implanted into the mother's body. This procedure carries certain risks, which can be explained by a geneticist.

How is Gaucher disease inherited?

The glucocerebrosidase enzyme gene (GBA) is located on chromosome 1q21. Patients with Gaucher disease have alterations in this gene — “mutations”.

GD is inherited in an autosomal recessive manner. This means the disease manifests only if both parents are carriers of the disease ("mutations") and, while not sick themselves, each transmits the altered gene to the child. Most families with a child affected by this disorder have not previously encountered such a problem. The risk of having another child with Gaucher disease in a family that already has children with this condition is 25% for each pregnancy.

The disease does not always manifest identically within the same family, and initial symptoms can appear at different ages. A patient's siblings may have Gaucher disease even if they were asymptomatic at the time of diagnosis. In this case, diagnostics must be performed as early as possible to initiate therapy and avoid complications. They may also be carriers, just like their parents. As for other family members, it is important to inform them that they could be carriers. This means they also carry a risk of having a child with this condition.

All families affected by this disease must undergo medical genetic counseling and receive comprehensive information from a geneticist regarding the risk of recurrence in the family, and discuss all questions related to inheritance with a specialist. Treating physicians do not always have the opportunity to speak with the family and explain the risks and possibilities that modern genetics can offer. A geneticist can determine the risk of having an affected child in the family, examine relatives if necessary, and discuss comprehensive testing for prenatal diagnosis of fetal developmental disorders (prenatal diagnostics) and preimplantation genetic testing (preimplantation diagnostics). In Russia, medical genetic clinics operate in every region.

To perform comprehensive testing for prenatal diagnosis of fetal developmental disorders (prenatal diagnostics) and preimplantation genetic testing (preimplantation diagnostics), the couple must first undergo screening for carrier status of mutations in the GBA gene causing this disease by contacting specialized diagnostic laboratories and medical centers.

How is Gaucher disease treated?

Treatment of Gaucher disease consists of lifelong enzyme replacement therapy (ERT). Administration of the missing enzyme improves the patient's condition and, in some cases, achieves practically complete resolution of the main clinical manifestations of the disease. ERT is indicated for patients with a confirmed diagnosis of type 1 GD without nervous system involvement or with chronic nervous system involvement (type 3 GD) who have clinically significant non-neurological manifestations of the disease.

Several ERT medications with proven efficacy are registered in the Russian Federation.

The main goals of treatment are:

• reduction of splenomegaly and increase in platelet count;

• cessation of bone crises;

• regression of pathological changes in affected organs and restoration of their functions;

• improvement of physical development indicators;

• prevention of irreversible osteoarticular damage;

• improvement of patients' quality of life

ERT is initiated in an inpatient setting. The medication is administered intravenously as an infusion over 1.5–2 hours, with a frequency of once every 14 days. Due to the heterogeneity of GD, the dose of the medication must be selected individually for each patient. It is crucial to start ERT as early as possible to avoid severe complications of the disease.

Additionally, supportive symptomatic therapy is administered depending on the patient's condition.

What monitoring is required for patients with Gaucher disease?

A multidisciplinary approach involving specialists from various fields is necessary for the monitoring and treatment of patients with Gaucher disease to ensure comprehensive care and timely adjustment of therapy when needed. Patients with Gaucher disease require regular examinations, including abdominal ultrasound (ultrasound diagnostics), general clinical blood tests, and blood chemistry panels. Patients should ask their doctor for recommendations on the frequency of these tests.

How do patients receive treatment in the Russian Federation?

Gaucher disease is classified as a rare inherited metabolic disorder and is included in the high-cost nosologies (HCN) programs, which are funded by the federal budget. Since 2023, drug provision for children with GD has been financed by the "Circle of Good" foundation.

How can family and loved ones help?

Remember—treatment success also depends on the family. It is necessary to follow recommendations, avoid long interruptions in therapy, and pay attention to rehabilitation and scheduled check-ups. All family members must know that the patient requires enzyme replacement therapy. It is extremely important to strictly follow all prescriptions for medications prescribed by the doctor.

The prognosis depends on the form of the disease and therapy. When treatment is initiated in a timely manner for type 1 Gaucher disease, the prognosis is generally favorable, and patients can lead a normal lifestyle.

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

Appendix G1. Patient severity assessment in GD using the PGS3 scale

Original title (if applicable): A disease severity scoring system for children with type 1 Gaucher disease (Pediatric Gaucher Severity Scoring System) - PGS3

Russian title: PGS3 Severity Scoring Scale for Patients with Type 1 GD

Source (official developer website, validation publication):[27]

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: assessment of type 1 GD severity

Content (template), Key (interpretation):

GD Patient Severity Assessment using the PGS3 Scale (Kallish S. and Kaplan P.) [27]

Explanations

Note: SD (standard deviation) is the standard deviation

The mean score is calculated for each group of disorders. For example, when evaluating skeletal disorders, if the first group of signs scores 0 points, the second 1, the third 3, and the fourth 2, the mean score is calculated as follows: (0+1+3+2)/4 = 1.5. Next, the mean scores for other groups of disorders are evaluated. Finally, all mean scores are summed up.

Based on the total score, the severity of Gaucher disease is assessed:

0–6 — mild

6–9 — moderate

> 9 — severe.