Fabry disease: clinical guidelines

List of Abbreviations

ALT — alanine aminotransferase

AST — aspartate aminotransferase

FD — Fabry disease

CT — computed tomography

LSD — lysosomal storage diseases

MRI — magnetic resonance imaging

NSAIDs — nonsteroidal anti-inflammatory and antirheumatic drugs

eGFR — estimated glomerular filtration rate

US — ultrasound

ERT — enzyme replacement therapy

CRF — chronic renal failure

ECG — electrocardiography

ENMG — electroneuromyography

EchoCG — echocardiography

EEG — electroencephalography

lyso-Gb3 — lysosomal globotriaosylsphingosine

Terms and Definitions

Enzyme replacement therapy is a treatment involving the administration of a drug (recombinant enzyme) to patients with an inherited metabolic disorder.

Lysosomal storage diseases are a group of inherited monogenic disorders associated with impaired lysosomal function.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Fabry disease (FD), or Anderson-Fabry disease is a hereditary disease belonging to the group of lysosomal storage diseases (LSDs), caused by a decrease or complete absence of the activity of the enzyme α-galactosidase. Enzyme deficiency leads to the accumulation of glycophospholipids in the lysosomes of cells in various organs, including the heart, kidneys, nervous system, and vascular endothelium. The disease is progressive and multisystemic in nature, characterized by a decrease in quality and life expectancy. Without appropriate treatment, a fatal outcome typically occurs in the 4th–5th decade of life due to cardiovascular, cerebrovascular complications, or renal failure [1, 4, 73].

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

The cause of FD is pathogenic variants in the GLA gene, which encodes the enzyme α-galactosidase (GLA; EC 3.2.1.22). The GLA gene is mapped to the long arm of chromosome Xq22.1, has a size of about 12 thousand base pairs, and consists of 7 exons.

To date, 1110 variants have been identified in the GLA gene, including over 1000 pathogenic variants that alter the properties and stability of α-galactosidase [1, 4]. Most mutations are unique to each family. FD is inherited in an X-linked manner.

The primary biochemical defect in FD is the deficiency of the enzyme α-galactosidase, which cleaves the terminal α-galactose residue of the oligosaccharide chain of neutral glycosphingolipids. Enzyme deficiency leads to the accumulation of glycosphingolipids in the lysosomes of various cells (vascular endothelial and smooth muscle cells, epithelial cells of most organs, the central nervous system, and the heart).

1.3 Epidemiology of the Disease or Condition

FD is a rare disease. The prevalence of the disease in various countries varies widely (from 1 in 117,000 to 1 in 476,000 live newborns) [1]. The incidence of new FD cases, estimated in newborn male samples, was 1:3100 in Italy [2] and 1:2400 in Taiwan [3]. Mild, atypical courses of FD with signs of single-organ involvement are likely more common.

When screening high-risk groups in men and women with early stroke, the proportion of FD was 4.2% and 2.15%, respectively; with left ventricular hypertrophy of unknown origin — 0.9–3.9% and 1.1–11.8%; and with end-stage renal disease — 0.33% and 0.10% [1, 18, 36, 72, 74, 75, 82].

1.4 Features of Coding the Disease or Condition

E75.2 – Other sphingolipidoses (Fabry disease)

1.5 Classification of the disease or condition

FD belongs to LSDs, a subgroup of sphingolipidoses. From a clinical perspective, two forms of FD are distinguished — classical (onset at any age, multisystem involvement) and non-classical (late onset, isolated involvement of a single organ system: brain, heart, or kidneys) [1, 4].

1.6 Clinical presentation of the disease or condition

Clinical manifestations in FD can be extremely diverse in both males and females, even among members of the same family. The severity of clinical manifestations of FD at different ages is given in Appendix A3.1 [1, 4].

External features. Men with hemizygous variants in the GLA gene often have a characteristic appearance resembling patients with acromegaly — prominent supraorbital ridges and frontal bones, a prominent lower jaw, enlarged lips, and a depressed nasal bridge.

Skin manifestations. Angiokeratomas are well-demarcated red, dark red, burgundy, purple, or blue-black papules measuring 0.2–1.0 cm, formed from clusters of individual blood vessels in the upper layers of the dermis and thickening of the epidermis in the form of superficial hyperkeratosis. Initial lesions are flat, lighter in color, and more easily compressible. Over time, they darken, become harder, and are slightly raised above the skin surface. They are usually located symmetrically in the inguinal region, on the buttocks, thighs, and in the umbilical region, as well as on the palms. Solitary angiokeratomas can outwardly resemble Kaposi sarcoma, pyogenic granuloma, pigmented basal cell and squamous cell carcinoma, and in some cases melanoma. Angiokeratomas appear in childhood and gradually increase in number and size over the years. Telangiectasias of the oral mucosa and conjunctiva may also occur. Cases of FD without angiokeratomas are known.

Peripheral nervous system. Involvement of the peripheral nervous system in FD is classified as small-fiber polyneuropathy. In 60–80% of cases, patients with FD experience chronic, severe, debilitating neuropathic pain presenting as three types of chronic pain syndromes: painful burning polyneuropathy, acroparesthesias, and Fabry pain crises.

Painful burning polyneuropathy is typically characterized by complaints such as prolonged burning symmetrical pain in the distal extremities (hands, feet) radiating proximally, shooting piercing pain, pain resembling an electric shock, as well as allodynia — pain in response to a non-painful stimulus, which can be tactile (pain from touch with a brush or cotton swab) or thermal (upon thermal exposure or increased ambient temperature), and hyperpathia — an excessive pain reaction to a painful stimulus.

Acroparesthesias are typically characterized by spontaneous unpleasant sensations such as needle-like pricking and crawling feelings in the hands and feet. Some patients also note freezing pain in the palms in cold weather.

Fabry pain crises often occur with weather changes, fever, physical exertion, stress, and after alcohol consumption. These episodes can occur in individuals of both sexes and begin as early as two years of age. During a Fabry crisis, the pain becomes more excruciating, can radiate from the distal extremities to the proximal ones, lasts from a few seconds to several weeks, and is not relieved by opioid analgesics. The pain is often accompanied by a rise in temperature to febrile levels [35].

The exact mechanism of neuropathic pain in FD remains not fully understood. It is hypothesized that pain results from structural damage to small nerve fibers due to the accumulation of globotriaosylceramide in nerve axons, dorsal root ganglia, and vasa nervorum (Latin for nerve blood vessels). This is the pain variant of small fiber polyneuropathy, i.e., peripheral neuropathic pain. Thalamic calcification in FD is also known (central neuropathic pain due to thalamic damage).

Impaired sweating. Patients with FD often experience hypohidrosis or anhidrosis. These changes are associated with the accumulation of globotriaosylceramide in sweat glands and the walls of their supplying blood vessels, as well as damage to autonomic nerve fibers (autonomic variant of small fiber polyneuropathy). Hyperhidrosis is observed in rare cases.

Central nervous system. FD can be classified as a small vessel disease (small arteries and arterioles). Patients with FD are at high risk of transient ischemic attacks and ischemic/hemorrhagic strokes at a young age. The stroke frequency is 6.9% in men and 4.3% in women. In the majority of patients, stroke develops between the ages of 20 and 50, including in every fifth of these patients under the age of 30. Hemorrhagic stroke is more common in men than in women. In 2/3 of patients, stroke is a consequence of an atypical course of the disease with isolated cerebrovascular involvement. In 50%, FD debuts with a cerebral stroke. Consequently, FD should be suspected in all patients with early-onset stroke, even in the absence of obvious causes and risk factors. In addition, chronic cerebral ischemia can lead to vascular dementia, which is characterized by memory impairment and behavioral disorders [1, 4, 7, 35].

Renal involvement. The first sign of nephropathy in FD is proteinuria, which is detected more often in adolescence and adulthood, and less commonly in the first decade of life. With age, proteinuria progressively increases and can reach nephrotic levels, although full-blown nephrotic syndrome usually does not develop. Tubular disorders are frequently noted. Proteinuria is not accompanied by changes in urinary sediment. Later, a gradual decline in renal function begins, leading to end-stage chronic kidney disease (CKD stage 5). The latter can be one of the causes of death in FD patients, although renal replacement therapy or kidney transplantation can prolong the lives of such patients. In patients with non-classical FD, renal involvement manifesting as parapelvic cysts is possible [1, 4].

Cardiac involvement. Cardiac involvement is a common and prognostically unfavorable manifestation of FD. Heart disease is the leading cause of death in patients with FD (34% among men and 57% among women). A characteristic sign of cardiac involvement in FD is left ventricular hypertrophy, which can be detected by ECG, echocardiography, and cardiac magnetic resonance imaging.

The thickening of the heart walls cannot be explained solely by the deposition of glycosphingolipids in myocytes and conduction tissue, as their share accounts for less than 3% of the total myocardial mass. Accordingly, myocyte hypertrophy and fibrosis are of greater importance. Myocardial hypertrophy and fibrosis are often accompanied by left ventricular diastolic dysfunction. Tissue Doppler echocardiography (Doppler echocardiography) is used to assess cardiac function. Diastolic dysfunction can lead to the development of heart failure. Signs of congestive heart failure are detected in 11% of men and 6% of women with FD. According to a Russian study of a cohort of 200 patients with Fabry disease, signs of congestive heart failure were observed in 1.5% in the setting of atrial fibrillation. Atrial and ventricular arrhythmias and conduction disorders frequently develop. Myocardial infarction has been diagnosed in only 2% of patients. Nevertheless, angina pectoris was observed in 13–20% of patients with FD and more frequently in the presence of left ventricular hypertrophy. Valvular heart disease in FD is common but usually clinically insignificant. There may be a monosymptomatic course of the disease with cardiac involvement only (non-classical FD) [1, 4, 13].

Lymphatic system involvement. The development of lymphedema is associated with the accumulation of glycolipids in the walls of lymphatic vessels. In patients with FD, lymphedema manifests in adolescence or adulthood and, in the absence of necessary treatment, can lead to severe trophic changes with skin ulceration of the lower extremities and be complicated by erysipelas and sepsis.

Ophthalmological disorders. A typical symptom of FD is vortex keratopathy (corneal opacity) (70–90% of patients) [1, 14, 15]. Posterior subcapsular cataract and retinal vessel involvement occur in approximately 5% of cases.

Hearing and vestibular disorders. Patients with FD may experience hearing loss, tinnitus, and dizziness.

Clinical features of FD in children. The initial clinical manifestations of FD most often occur in adolescence and youth, although sometimes signs of the disease can debut as early as 2–4 years of age [1, 4, 5, 83]. Initially, the symptoms of the disease are non-specific, which significantly complicates and delays diagnosis. These may include abdominal pain, abdominal discomfort, loose stools, dry skin, poor heat tolerance (sometimes leading to lipothymia and syncope), and episodic pain in the feet or hands. If pain in the upper extremities debuts at an age under 3 years, it is extremely difficult to verify, as outwardly the pain episode looks like a temper tantrum or psychomotor agitation. An indirect sign is that the child calms down in cool water (swimming pool) or experiences relief when lying on a cold surface (e.g., a tiled floor). Subsequently, complaints of pain in the extremities become more frequent and gradually acquire the manifestations typical of FD.

Gastrointestinal manifestations of the disease can be among the first symptoms in childhood and adolescence, occurring in the first decade of life; however, due to their low specificity, they serve as indirect markers of FD when combined with other more typical symptoms. The most frequently observed symptoms are cramping abdominal pain, abdominal distension, unstable stools, nausea, vomiting, decreased appetite, and weight deficiency.

Specific whorled corneal opacity (so-called vortex keratopathy or cornea verticillata) is a frequent symptom in the pediatric and adolescent patient population with FD. It can be detected at the age of 4–5 years. Such specificity makes it possible to suspect FD at an early stage. Changes such as lens opacities in the form of radial posterior subcapsular cataract (“Fabry cataract”) and bilateral anterior capsular and subcapsular cataract are more common in adult patients.

Typical skin manifestations of FD—angiokeratomas—can also be observed in patients already in childhood. The first elements often appear in adolescence, are usually solitary, and may have an atypical localization (ears, chest) or occur on the oral mucosa, so their detection requires a thorough examination.

Renal involvement also frequently debuts in childhood (at 3–5 years of age), yet it is clinically silent. It can only be detected by laboratory methods (24-hour urinary protein/albumin excretion). The first sign of renal involvement, frequently present in children and adolescents with FD, is episodic albuminuria (urinary albumin excretion ranging from 30 to 300 mg/24 h). Subsequently, albuminuria becomes persistent and its levels increase. As a rule, more severe renal impairment is not characteristic of children and adolescents, appearing more frequently in the third decade of life.

Symptoms of cardiovascular system involvement in FD during adolescence are very difficult to diagnose. In most cases, it is impossible to clearly differentiate early manifestations of FD from age-related autonomic disorders.

Other extremely rare neurological manifestations of FD in children are cerebrovascular disorders accompanied by an increased risk of stroke. There are literature data on patients with transient ischemic attacks starting from 12 years of age [5].

Hearing impairments belong to typical manifestations of FD. Earlier symptoms occurring in childhood and adolescence include tinnitus (ringing in the ears, unilateral or bilateral) and dizziness, which are joined by sensorineural hearing loss with age.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing a diagnosis of FD in males include a decrease in the activity of the lysosomal enzyme alpha-galactosidase in the blood, an increase in blood globotriaosylsphingosine (lyso-Gb3) levels, and the detection of pathogenic variants in the hemizygous state in the GLA gene. Criteria for establishing a diagnosis of FD in females include an elevated blood concentration of globotriaosylsphingosine (lyso-Gb3), a decrease in the activity of the lysosomal enzyme alpha-galactosidase in the blood (detected in a portion of female patients), and the detection of pathogenic variants in the heterozygous state in the GLA gene. It should be borne in mind that alpha-galactosidase activity in women often remains normal, and lyso-Gb3 levels increase to a much lesser extent than in men. When diagnosing FD in both men and women, characteristic “early” symptoms should be taken into account, including neuropathic pain, angiokeratomas, and/or vortex keratopathy, as well as the presence of relatives with a confirmed diagnosis of FD.

Suspecting FD is easier in the presence of the classical variant—a systemic disease with involvement of the kidneys, heart, skin, nervous system, gastrointestinal tract, and visual system [71]. However, cardiac or renal involvement may be the sole manifestation of FD. Such patients lack any symptoms of the disease in childhood. Atypical variants of FD can only be diagnosed through high-risk screening. FD should be suspected in all patients with left ventricular myocardial hypertrophy of unclear origin and stroke developed at a young age (under 40 years).

Differential diagnosis of angiokeratomas. The detection of angiokeratomas is an important diagnostic “clue” in FD. During crises accompanied by fever and pain, angiokeratomas can be mistaken for petechial rash, leading to a misdiagnosis of meningitis. Differential diagnosis should also be carried out with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease), Fordyce angiokeratoma, Mibelli angiokeratoma, and angiokeratoma corporis circumscriptum.

Angiokeratomas are also found in other lysosomal storage diseases: Schindler disease, fucosidosis, gangliosidosis, aspartylglucosaminuria, and sialidosis.

Pain syndrome. Pain syndrome in FD is often accompanied by low-grade fever and an elevated ESR, frequently leading to “false” diagnoses: rheumatoid arthritis, rheumatic fever, arthritis, erythromelalgia, and Raynaud's syndrome.

Renal pathology. In isolated renal involvement, urinary syndrome can be mistakenly interpreted as isolated proteinuria, low-symptom glomerulonephritis, or interstitial nephritis [76].

Cardiovascular system. Left ventricular hypertrophy and arrhythmias are observed.

Ophthalmologic abnormalities. Slit-lamp examination reveals vortex keratopathy (corneal verticillata).

Gastrointestinal tract. Gastrointestinal symptoms in Fabry disease resemble irritable bowel syndrome and Crohn's disease.

The differential diagnosis of FD is presented in Appendix A3.2.

2.1 Complaints and Anamnesis

The spectrum of potential complaints in patients with FD can be quite broad and depends on the disease form (classical or non-classical), the patient's sex (females usually present with a milder, more attenuated form), the age of disease manifestation, and individual features of the disease course.

Complaints and anamnestic data:

• positive family history (pain in the extremities, early strokes, myocardial infarctions, chronic kidney disease (CKD) in the family);

• fatigue;

• depression;

• angiokeratomas "below the belt": on the buttocks, lower back, genitalia, and lower extremities;

• hearing loss, tinnitus;

• dizziness;

• symmetric pain in the hands and feet (excruciating burning sensation or tingling/crawling sensations in the extremities, predominantly in the hands and feet [acroparathesias], which appear or worsen in hot weather, upon physical exertion, or with fever);

• increased sensitivity localized to the feet and hands;

• pain in the joints of the extremities, thighs, and lower legs;

• pain crises (a characteristic feature distinguishing FD from other small-fiber painful polyneuropathies);

• abdominal pain;

• fever/low-grade fever of unknown origin;

• poor tolerance to cold and heat;

• hypohidrosis or anhidrosis;

• chronic diarrhea;

• history of stroke(s);

• signs of renal involvement (proteinuria, elevated serum creatinine levels);

• signs of cardiovascular involvement (cardiac pain, palpitations, ECG abnormalities);

• cataract;

• corneal opacity.

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

2.2 Physical Examination

The severity of clinical manifestations of FD may vary at different ages; physical examination may reveal the following signs of FD:

• coarse facial features;

• angiokeratomas (inner thighs, hands, abdomen, oral mucosa);

• signs of cardiomegaly;

• signs of a prior stroke (paresis, speech disorders).

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

2.3 Laboratory Diagnostics

Diagnosis in males

Comments: in males, reduced α-galactosidase A activity is a fairly informative sign of FD [17]. Guidelines for collecting biological material for dried blood spot testing are provided in Appendix A3.6.

Comments: quantitative determination of lysoglobotriaosylsphingosine (lyso-Gb3) is a confirmatory test for the diagnosis of Fabry disease and is also used to resolve challenging diagnostic cases. The second important application of lyso-Gb3 — is monitoring the status and treatment efficacy of patients with Fabry disease. It has been shown that with adequate ERT, the amount of substrate in blood plasma decreases. Therefore, it is advisable to make the quantitative determination of lyso-Gb3 part of the monitoring protocol for Fabry disease patients, both those receiving disease-modifying therapy and those living without ERT. However, it should be noted that even in patients receiving ERT, the level of this metabolite almost never reaches normal values. Guidelines for collecting biological material for dried blood spot testing are provided in Appendix A3.6.

Comments: determination of GLA gene mutations by Sanger sequencing is indicated for all males with reduced α-galactosidase A enzyme activity and/or elevated lyso-Gb3 levels. The widespread prevalence of pseudodeficiency alleles leading to decreased α-galactosidase activity in dried blood spots and sometimes in leukocytes and blood plasma makes the inclusion of molecular genetic analysis mandatory in the laboratory diagnosis of FD. Determining the carrier status of a familial variant in the GLA gene via Sanger sequencing enables screening of the proband's relatives, as well as prenatal and preimplantation genetic diagnosis within the family. Most nucleotide substitutions in FD patients can be identified by Sanger sequencing of all exons and adjacent intron regions; however, in rare cases, the resolution of this method may be insufficient. In such cases, to search for other genetic variants in the GLA gene, it is advisable to use additional molecular genetic research methods, such as multiplex ligation-dependent probe amplification (MLPA) to screen for large deletions/duplications, or high-throughput sequencing (NGS) to search for pathogenic variants in untranslated regions of the GLA gene.

Diagnosis in females

Comments: quantitative determination of lysoglobotriaosylsphingosine allows the detection of FD in women, which is useful for clarifying their clinical status and resolving challenging diagnostic cases. The second important application of lyso-Gb3— is monitoring the status and treatment efficacy of patients with Fabry disease. It has been shown that with adequate ERT, the amount of substrate in blood plasma decreases. Therefore, it is advisable to make the quantitative determination of lyso-Gb3 part of the monitoring protocol for Fabry disease patients, both those receiving disease-modifying therapy and those living without ERT. However, it should be noted that even in patients receiving ERT, the level of this metabolite almost never reaches normal values. Guidelines for collecting biological material for dried blood spot testing are provided in Appendix A3.6.

Comments: in one-third of women with FD, the activity of alpha-galactosidase may be normal [17], which must be taken into account when evaluating enzyme activity in women. Guidelines for collecting biological material for dried blood spot testing are provided in Appendix A3.6.

Comments: detection of mutations in the GLA gene by Sanger sequencing is indicated for all females with clinical signs of Fabry disease who have normal enzyme activity and/or normal lyso-Gb3 levels. The high prevalence of pseudodeficiency alleles leading to decreased α-galactosidase activity in dried blood spots and sometimes decreased activity in leukocytes and blood plasma makes it mandatory to include molecular genetic analysis in the laboratory diagnosis of FD. Determining the carrier status of a familial variant in the GLA gene by Sanger sequencing makes it possible to screen the proband's relatives, as well as to perform prenatal and preimplantation genetic diagnosis. Most nucleotide substitutions in patients with FD can be detected by Sanger sequencing of all exons and adjacent intron regions; however, in rare cases, the resolution of this method may be insufficient. In such cases, to search for other genetic variants of the GLA gene, it is advisable to use additional molecular genetic research methods, such as multiplex ligation-dependent probe amplification (MLPA) to search for large deletions/duplications, or high-throughput sequencing (NGS) to search for pathogenic variants in the untranslated regions of the GLA gene.

Comments: quantitative determination of lysoglobotriaosylsphingosine makes it possible to identify not only males but also females with Fabry disease, which is useful for clarifying the clinical status of heterozygous females, as well as for resolving difficult diagnostic cases. The second important application of lyso-Gb3 — is monitoring the condition and treatment efficacy in patients with Fabry disease. It has been shown that with adequate ERT, the amount of substrate in blood plasma decreases. Therefore, it is advisable to make quantitative determination of lyso-Gb3 part of the monitoring of patients with Fabry disease, both those receiving pathogenetic therapy and those living without ERT. However, it should be borne in mind that even in patients receiving ERT, the level of this metabolite almost never reaches normal values, and in particular, women may not show a significant decrease in lyso-Gb3 during ERT. Rules for collecting biomaterial for studies in dried blood spots are given in Appendix A3.6.

Comments: a complete blood count includes determining total hemoglobin, red blood cells, white blood cells, platelets, assessing hematocrit, erythrocyte sedimentation rate, and differential leukocyte count (leukocyte formula).

Comments: a general biochemical blood test includes determining the activity of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase in the blood, assessing the levels of total bilirubin, conjugated (bound) bilirubin, cholesterol, albumin, glucose, creatinine, total protein, sodium, potassium, total calcium in the blood, as well as determining lactate dehydrogenase activity in the blood, and assessing blood urea, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides as clinically indicated.

Comments: patients with pronounced left ventricular hypertrophy show elevated troponin levels.

Comment: estimation of the glomerular filtration rate based on blood creatinine using a calculation method (eGFR) should be performed using the CKD-EPI formula based on blood creatinine levels and, in certain cases, based on cystatin C (blood cystatin C test) [91, 92, 93]. In children, the calculation can be performed using the Schwartz formula [63] and others (for details, see the Clinical Guidelines on "Chronic Kidney Disease" for the pediatric age group). If indicated, blood urea and blood uric acid tests may be performed [91].

2.4 Instrumental Diagnostics

Comments: according to the results of stimulative ENMG, children and adolescents generally show no abnormalities.

Comments: epilepsy in patients with FD most commonly occurs as a complication of stroke.

Comments: spirometry is most commonly performed; if necessary, a bronchodilator provocation test is performed to assess the reversibility of bronchial obstruction.

Glycosphingolipid accumulation has been described in pneumocytes, goblet cells, bronchial ciliated epithelium, bronchial smooth muscle cells, and pulmonary vessels on lung biopsy. It has also been noted that obstructive ventilation disorders are more common in patients with Fabry disease than in the general population [94]. Nevertheless, dyspnea, dry cough, and bronchospasm observed in patients with Fabry disease are often non-specific, as they can also be caused by cardiac involvement and require differential diagnosis [95].

The test may be performed during follow-up according to the clinical situation.

Comments: interstitial lung lesions in Fabry disease are rare and resolve with disease-modifying therapy.

Comment: brain magnetic resonance imaging with contrast enhancement may be performed. Brain MRI can be performed using combined endotracheal anesthesia, total intravenous anesthesia, or regional anesthesia. Brain MRI in patients may reveal ischemic stroke, microhemorrhages and intracerebral hematomas, white matter changes (leukoaraiosis) and gray matter changes (calcification of the posterior thalamus), as well as vascular malformations predominantly represented by vertebrobasilar artery dolichoectasia. These changes are not highly specific for Fabry disease and can occur in patients with other pathologies. In some cases, brain computed tomography may be performed.

Comments: a characteristic sign of cardiac involvement in Fabry disease is left ventricular hypertrophy, which can be detected using ECG, echocardiography, and MRI. Tissue Doppler echocardiography (Doppler echocardiography) is used to assess cardiac function.

Comments: if necessary, cardiac magnetic resonance imaging with contrast enhancement is performed. Total intravenous anesthesia or combined inhalation anesthesia may be used. A characteristic sign of cardiac involvement in Fabry disease is left ventricular hypertrophy, which can be detected using ECG, echocardiography, and MRI. Tissue Doppler echocardiography (Doppler echocardiography) is used to assess cardiac function.

Comments: a consultation with an otorhinolaryngologist-surdologist is performed. Hearing loss of varying severity is characteristic of this condition. It can be conductive, sensorineural, or mixed. Early detection of hearing loss helps improve patients' quality of life, enabling communication and learning through treatment of the conductive component of hearing loss or hearing aid fitting for sensorineural hearing loss [96].

Comments: currently, there are no clear guidelines regarding gastrointestinal tract studies in Fabry disease. The choice of study and their number are determined by the clinical situation; other studies may be performed. Differential diagnosis is carried out with irritable bowel syndrome, diverticular disease, colon cancer, appendicitis, celiac disease, gastritis, gastroesophageal reflux, Whipple's disease, mitochondrial pathology, and transthyretin familial amyloid polyneuropathy.

Most gastrointestinal manifestations resolve with disease-modifying therapy.

2.5 Other Procedures

Comment: a consultation (examination) with a general practitioner (family physician) is also possible.

Comments: biomicroscopy of the anterior segment of the eye and fundus is performed, as well as assessment of corneal surface defects (dye test). Slit-lamp examination reveals vortex keratopathy (corneal opacities in the form of whorls). Similar corneal changes are observed with the use of aminoquinoline drugs or class III antiarrhythmic drugs (amiodarone**). Fundus examination frequently reveals posterior subcapsular cataract and retinal vascular involvement, which can lead to severe vision loss.

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

For pathogenetic treatment of Fabry disease, enzyme replacement therapy has been developed, but all patients simultaneously receive symptomatic treatment for the main complications of the disease. The decision to prescribe enzyme replacement therapy must be made at a federal medical center with experience in the evaluation and management of patients with Fabry disease. The management of patients with Fabry disease implies a multidisciplinary approach involving a neurologist, geneticist, cardiologist/pediatric cardiologist, anesthesiologist-intensivist, general practitioner/pediatrician/family physician, nephrologist, pulmonologist, gastroenterologist, physical therapist, and specialists in other fields experienced in treating this rare disease.

3.1 Pathogenetic treatment

For Agalsidase alfa** and Agalsidase beta** — Strength of recommendation – A (level of evidence 1)

For Pegunigalsidase alfa — Strength of recommendation – A (level of evidence 2)

Comments: during the first infusion of enzyme replacement therapy, an initial consultation (examination) by an anesthesiologist-intensivist is advisable.

Criteria for prescribing ERT are given in Appendix A3.3. In the Russian Federation, 3 drugs are registered for ERT of Fabry disease: agalsidase alfa**, agalsidase beta**, and pegunigalsidase alfa. These medicinal products were approved globally based on the results of randomized, placebo-controlled trials in which enzyme replacement therapy reduced the severity of neuropathic pain, caused regression of left ventricular hypertrophy, and stabilized renal function compared with placebo. According to a systematic literature review, the efficacy of enzyme replacement therapy has been studied in at least 52 prospective studies (controlled or observational). Of these, 22 used agalsidase alfa**, 22 — agalsidase beta**, 4 studies summarized the results of using both drugs [19-22], and 4 studies used pegunigalsidase alfa [116-119].

Overall, the results of these studies confirmed the beneficial effect of ERT on cardiac and renal function, neuropathic pain, and patients' quality of life. After 12 months, plasma lyso-Gb3 levels improved in male patients and improved or remained stable in female patients.

Agalsidase alfa** (approved per the Instructions from 7 years of age) is administered intravenously at a dose of 0.2 mg/kg once every two weeks, and Agalsidase beta** (approved per the Instructions from 8 years of age) — is administered intravenously at a dose of 1.0 mg/kg once every two weeks. Pegunigalsidase alfa (approved per the Instructions from 18 years of age) is administered intravenously at a dose of 1 mg/kg of body weight once every two weeks. The first administrations of the drugs must be carried out in a hospital setting. The drugs must be administered immediately after preparing the infusion solution.

More detailed information on these medicinal products is presented in Appendix A3.7.

ERT must not be used concomitantly with hydroxychloroquine**, amiodarone**, or gentamicin**, as these substances potentially inhibit intracellular α-GAL A activity. Patients who experience severe hypersensitivity reactions during infusion should be re-administered the drug with extreme caution, and appropriate medical support measures must always be available in such cases.

Comments: criteria for ERT discontinuation are given in Appendix A3.4. Experts believe that treatment should not be discontinued in patients with severe renal failure (GFR < 45 ml/min/1.73 m² adjusted for age (> 40 years: – 1 ml/min/1.73 m²/year)). Similarly, treatment should not be discontinued in patients on dialysis, even if they are not eligible for kidney transplantation, and in patients with cognitive decline of any etiology. Initiation and continuation of ERT in such patients should be considered on an individual basis.

During pregnancy — there are reports of no adverse events regarding the woman and the fetus, but extensive experience has not yet been accumulated [109, 110].

3.2 Symptomatic therapy

There are no randomized controlled trials on the symptomatic treatment of Fabry disease. Publications provide recommendations that reflect the expert opinion of specialists from various countries and the experience of treating different patient cohorts in various clinics.

Comments: in patients with chronic neuropathic pain and acroparesthesias, factors provoking the onset of pain, such as heavy physical exertion, emotional stress, and temperature changes, should be eliminated whenever possible.

Approximate starting doses, titration, and maintenance doses of drugs that may be prescribed to patients with neuropathic pain in Fabry disease [107].

Comment: a consultation (examination) with a general practitioner (family physician) is also possible.

Comment: chronic neuropathic pain characteristic of Fabry disease can lead to prolonged depressed mood, depression, lack of motivation for treatment, and sleep disturbances.

If necessary, consultations with other specialists are carried out as indicated to prescribe symptomatic treatment.

3.3 Surgical Treatment

Comments: kidney transplantation in patients with Fabry disease upon the development of end-stage renal disease is performed in accordance with the clinical guidelines "Kidney Transplantation, Presence of a Transplanted Kidney, Kidney Transplant Failure and Rejection" ID: 934_1 (http://cr.rosminzdrav.ru/).

Comments: this treatment is administered to patients with Fabry disease in accordance with the clinical guidelines "Bradyarrhythmias and Conduction Disorders", "Ventricular Rhythm Disorders. Ventricular Tachycardias and Sudden Cardiac Death".

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

5.1 Vaccination

Comments: Fabry disease is not a contraindication to vaccination using vaccines of any type [86, 87], nor to vaccination against the novel coronavirus infection (COVID-19), in accordance with the product instructions [88, 89]. Routine immunization for a patient with Fabry disease is carried out in accordance with the national immunization schedule during a period of stable status of the underlying disease against the background of maintenance therapy [90].

Immunization of patients before and after kidney transplantation is carried out according to generally accepted principles.

5.2 Follow-up observation

Dynamic follow-up examinations are performed in a round-the-clock or day hospital setting of a multidisciplinary clinic.

Comments: Hemizygous males have a single affected X chromosome, which determines the classic phenotype of the disease. They transmit this chromosome only to their daughters, but not to sons. Thus, daughters of affected fathers have one normal and one defective chromosome, i.e., they are heterozygotes. Unlike other X-linked disorders, it has been shown that some heterozygous females with a GLA gene mutation develop severe manifestations of Fabry disease requiring medical care and intervention. The mechanism by which heterozygous females develop life-threatening symptoms is not fully understood. Most of them have nearly normal circulating enzyme levels because random X-chromosome inactivation (lyonization) results in a mosaic of enzyme-deficient and normal cells.

Considering the inheritance pattern of this disease (X-linked), for each subsequent pregnancy:

— for a female carrier, the risk of bearing an affected male is 50%, and the risk of bearing a female carrier is 50%;

— for a male mutation carrier, the risk of bearing a daughter who is a mutation carrier is 100%.

In families with patients carrying an identified mutation, preimplantation and prenatal diagnostics are available. Prenatal diagnosis is possible by measuring α-galactosidase activity in chorionic villus cells, as well as by direct or indirect DNA diagnostics for families with a known genotype.

Comment: frequency — as indicated. A complete blood count includes measuring total hemoglobin, red blood cells, white blood cells, and platelets, assessing hematocrit, measuring the erythrocyte sedimentation rate (ESR), and performing a differential leukocyte count (leukogram).

Comment: frequency — as clinically indicated.

Comment: the glomerular filtration rate based on blood creatinine levels using a calculation formula (eGFR) should be calculated using the CKD-EPI formula based on blood creatinine levels, and, in certain cases, based on cystatin C (blood cystatin C test) [91, 92, 93]. If indicated, the following tests may be performed: blood urea test and blood uric acid test [91]. These tests must be performed in patients with a diagnosis of Fabry disease confirmed by molecular genetic methods, including asymptomatic carriers identified during family screening.

Comment: frequency — as clinically indicated.

Comments: patients with marked left ventricular hypertrophy show elevated troponin levels. Frequency: at least once a year.

Comments: frequency at least once a year.

Comments: a characteristic sign of cardiac involvement in Fabry disease is left ventricular hypertrophy, which can be detected using ECG, echocardiography, and magnetic resonance imaging.

Comments: if necessary, cardiac magnetic resonance imaging with contrast enhancement is performed. Total intravenous anesthesia or combined inhalation anesthesia may be used. A characteristic sign of cardiac involvement in Fabry disease is left ventricular hypertrophy, which can be detected using ECG, echocardiography, and MRI. Tissue Doppler echocardiography (Doppler echocardiography) is used to assess cardiac function.

Comment: brain magnetic resonance imaging with contrast enhancement may be performed, as well as combined endotracheal anesthesia, total intravenous anesthesia, and regional anesthesia. Brain MRI in patients may reveal ischemic stroke, microbleeds and intracerebral hematomas, white matter changes (leukoaraiosis), gray matter changes (posterior thalamus calcification), as well as vascular malformations, predominantly vertebrobasilar artery dolichoectasia. These changes are not highly specific for Fabry disease and may occur in patients with other pathologies. In some cases, computed tomography of the brain may be performed.

Comment: frequency — as clinically indicated.

Comment: frequency — as clinically indicated.

Comment: frequency — as clinically indicated.

Comment: an initial and follow-up appointment (examination, consultation) with a general practitioner (family physician) and/or a dispensary appointment (examination, consultation) with a general practitioner (family physician) may also be conducted.

5.3 Dispensary follow-up

Dispanserizatsiya (regular clinical follow-up) of patients with Fabry disease requires a multidisciplinary approach involving a neurologist, cardiologist/pediatric cardiologist, general practitioner/family physician/pediatrician, nephrologist, gastroenterologist, and other specialists experienced in treating this rare disease. Follow-up care is indicated for patients with Fabry disease both receiving disease-modifying enzyme replacement therapy (ERT) and those who are not receiving ERT for various reasons (e.g., have not reached the criteria for starting ERT, or have not given consent for treatment) in order to promptly monitor health status and adjust therapeutic management [99]. A tentative examination plan for patients with Fabry disease is provided in Appendix A3.5; however, the timeline and scope of investigations may be adjusted by the attending physician based on the specific clinical course of the disease in a particular patient.

Comments: quantitative determination of lysoglobotriaosylsphingosine (lyso-Gb3) is a confirmatory test for the diagnosis of Fabry disease and is also used to resolve challenging diagnostic cases. The second important application of lyso-Gb3 — is monitoring the status and treatment efficacy of patients with Fabry disease. It has been shown that with adequate ERT, the amount of substrate in blood plasma decreases. Therefore, it is advisable to make the quantitative determination of lyso-Gb3 part of the monitoring protocol for Fabry disease patients, both those receiving disease-modifying therapy and those living without ERT. However, it should be noted that even in patients receiving ERT, the level of this metabolite almost never reaches normal values. Guidelines for collecting biological material for dried blood spot testing are provided in Appendix A3.6.

Comment: estimation of the glomerular filtration rate based on blood creatinine levels using a calculation method (e.g., eGFR) should be performed using the CKD-EPI formula based on blood creatinine levels and, in certain cases, based on cystatin C (blood cystatin C assay) [91, 92, 93]. If indicated, blood urea and blood uric acid assays may be performed [91]. These tests must be performed in patients with a genetically confirmed diagnosis of Fabry disease, including asymptomatic carriers identified through family screening.

Comments: a characteristic sign of cardiac involvement in Fabry disease is left ventricular hypertrophy, which can be detected using ECG, echocardiography, and magnetic resonance imaging.

Comment: frequency — as clinically indicated.

Comment: an initial and follow-up appointment (examination, consultation) with a general practitioner (family physician) and/or a dispensary appointment (examination, consultation) with a general practitioner (family physician) may also be conducted.

6. Organization of Medical Care

Patients with Fabry disease may be provided with any type, condition, and form of medical care stipulated by the legislation of the Russian Federation, as clinically indicated.

Indications for planned hospitalization in a medical organization:

• Provision of diagnosis and treatment requiring round-the-clock medical supervision;

• A condition requiring active treatment and round-the-clock medical supervision;

• A condition requiring high-tech treatment methods (including organ transplantation, pacemaker implantation, cardioverter-defibrillator implantation);

• Inability to provide ERT in outpatient and day-care settings;

• The need for various types of expert evaluations or examinations in a medical organization when outpatient evaluation is not feasible, requiring dynamic monitoring (including issuing a federal medical board conclusion).

Indications for emergency hospitalization in a medical organization:

• Acute diseases, exacerbations of chronic conditions, poisonings and injuries, conditions requiring intensive care and transfer to intensive care units or critical care units (including adverse reactions occurring during or on the day of ERT infusion and other life-threatening acute conditions), as well as round-the-clock medical supervision and special diagnostic and therapeutic procedures.

Indications for patient discharge from a medical organization:

• Absence of a threat to the patient's life;

• No threat of complications requiring emergency treatment;

• Stabilization of the condition and key clinical and laboratory parameters of the pathological process regarding the underlying disease;

• No need for continuous physician supervision and round-the-clock medical monitoring regarding the underlying disease;

• No need to transfer the patient to another hospital or social welfare institution.

7. Additional Information

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for primary health care

Quality assessment criteria for specialized medical care

References

Appendix A1. Working Group Composition

1. Anisimova Inga Vadimovna — PhD in Medical Sciences, Head of the Medical Care Organization Department, Research Centre for Medical Genetics named after Academician N.P. Bochkov, member of the Association of Medical Geneticists.

2. Baranov Aleksandr Aleksandrovich — Academician of the RAS, Professor, MD, Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health, National Medical Research Center No. 2 (Central Clinical Hospital of the RAS) of the Petrovsky National Research Centre of Surgery, Professor at the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chief freelance pediatric specialist of the Russian Ministry of Health.

3. Vashakmadze Nato Dzhumberovna — MD, Head of the Department of Rare Diseases, Research Institute of Pediatrics and Child Health, National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, member of the Union of Pediatrists of Russia, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia.

4. Volgina Svetlana Yakovlevna — MD, Professor at the Department, Kazan State Medical University of the Ministry of Health of Russia.

5. Voronin Sergey Vladimirovich — PhD in Medical Sciences, Chief Physician, Research Centre for Medical Genetics, Chief freelance specialist in medical genetics of the Russian Ministry of Health in the Far Eastern Federal District.

6. Zhirov Igor Vitalievich — MD, Leading Researcher at the Department of Myocardial Diseases and Heart Failure, National Medical Research Center for Cardiology named after Academician E.I. Chazov of the Ministry of Health of Russia, Professor at the Department of Cardiology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia.

7. Zhurkova Nataliya Vyacheslavovna — PhD in Medical Sciences, Leading Researcher, Research Institute of Pediatrics and Child Health, National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, member of the Union of Pediatrists of Russia, member of the Association of Medical Geneticists.

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

9. Zakharova Elena Viktorovna — PhD in Medical Sciences, Head of Nephrology Department No. 24, Nephrologist, City Clinical Hospital named after S.P. Botkin of the Moscow Healthcare Department.

10. Kopishinskaya Svetlana Vasilyevna — PhD in Medical Sciences, Associate Professor at the Laval University Research Center (Quebec, Canada), member of the European Academy of Neurology, member of the EAN Pain Panel, member of the European Huntington's Disease Network, member of the Presidium of the National Council of Experts on Orphan Diseases, member of the Russian Society of Neuromuscular Diseases.

11. Kostik Mikhail Mikhailovich — MD, PhD, Professor, Department of Hospital Pediatrics, St. Petersburg State Pediatric Medical University, Russian Ministry of Health, St. Petersburg.

12. Kuzenkova Lyudmila Mikhailovna — MD, PhD, Professor, Head of the Center for Pediatric Psychoneurology, Head of the Department of Psychoneurology and Psychosomatic Pathology, National Medical Research Center for Children's Health, Russian Ministry of Health.

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

14. Larionova Valentina Ilyinichna — MD, PhD, Institute of Experimental Medicine, Member of the Russian Society of Medical Geniticists.

15. Maksimova Yulia Vladimirovna — MD, PhD, Professor, Head of the Department of Medical Genetics and Biology, Novosibirsk State Medical University, Russian Ministry of Health, Head of the Medical Genetics Department, City Clinical Hospital No. 1, Novosibirsk Region, Member of the Association of Medical Geneticists.

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

17. Moiseev Sergey Valentinovich — MD, PhD, Head of the Department of Internal, Occupational Diseases and Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Russian Ministry of Health.

18. Myasnikov Roman Petrovich — PhD, Leading Research Scientist, Department of Clinical Cardiology, Head of the Heart Failure Clinic, National Medical Research Center for Therapy and Preventive Medicine, Russian Ministry of Health.

19. Namazova-Baranova Leila Seymurovna — Academician of the RAS, Professor, MD, PhD, President of the Union of Pediatrists of Russia; Past-President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery, Head of the Department of Faculty Pediatrics, Pirogov Russian National Research Medical University, Russian Ministry of Health, Chief freelance pediatric specialist in preventive medicine of the Russian Ministry of Health.

20. Pashkov Alexander Vladimirovich — PhD, Head of the Department of Otorhinolaryngology and Audiology, Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery.

21. Podkletnova Tatyana Vladimirovna — PhD, Senior Research Scientist, Laboratory of Nervous Diseases in Children, National Medical Research Center for Children's Health, Russian Ministry of Health.

22. Popova Veronika Mikhailovna — Medical Geneticist, Research Scientist, Scientific and Consultative Department No. 2, Research Institute of Pediatrics, Petrovsky National Research Centre of Surgery.

23. Pushkov Alexander Alekseevich — PhD in Biology, Leading Research Scientist, Laboratory of Medical Genomics, National Medical Research Center for Children's Health, Russian Ministry of Health, Member of the Association of Medical Geneticists.

24. Repina Svetlana Afanasyevna — PhD, Medical Geneticist, Department of Medical Care Organization, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists.

25. Savostyanov Kirill Viktorovich — DSc in Biology, Head of the Medical Genetics Center, Head of the Laboratory of Medical Genomics, National Medical Research Center for Children's Health, Russian Ministry of Health, Professor, Department of Pediatrics and Public Health, National Medical Research Center for Children's Health, Russian Ministry of Health, Member of the Association of Medical Geneticists.

26. Salogub Galina Nikolaevna — PhD, Associate Professor, Head of the Department of Internal Diseases, Almazov National Medical Research Centre, Russian Ministry of Health.

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

28. Selimzyanova Liliya Robertovna — PhD, Head of the Department of Standardization and Study of Evidence-Based Medicine, Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery, Associate Professor, Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Russian Ministry of Health, Associate Professor, Department of Faculty Pediatrics, Pirogov Russian National Research Medical University, Russian Ministry of Health, Member of the Union of Pediatrists of Russia.

29. Semyachkina Alla Nikolaevna — MD, PhD, Chief Research Scientist, Department of Clinical Genetics, Moscow Research Institute of Pediatrics and Pediatric Surgery, Russian Ministry of Health, Member of the Association of Medical Geneticists.

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

31. Sokolov Alexey Albertovich — MD, PhD, Professor, Department of Internal Diseases and Nephrology, Mechnikov North-Western State Medical University, Senior Research Scientist, Head of the Clinical Center for Extracorporeal Detoxification, Military Medical Academy, Leading Research Scientist, Head of the Rare Disease Study Group, Research Institute of Experimental Medicine, North-Western Branch of the Russian Academy of Medical Sciences, Member of the St. Petersburg Society of Medical Genetics, Chairman of the Expert Council of the National Association of Organizations for Patients with Rare Diseases "Genetica", Member of the CEE GN (Central and Eastern European Genetic Network) Medical Expert Council.

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

33. Surkov Andrey Nikolaevich — MD, PhD, Head of the Pediatric Gastroenterology Department (Inpatient Unit for Children), 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, Pirogov Russian National Research Medical University, Russian Ministry of Health.

34. Tomilina Natalia Arkadievna — MD, PhD, Professor, Head of the Department of Nephrology, A.I. Evdokimov Moscow State University of Medicine and Dentistry.

35. Udalova Olga Vasilievna — PhD, Medical Genetics Center "Genom" LLC, Chair of the Nizhny Novgorod Branch of the Russian Society of Medical Geneticists, Head of the Center for Medical Genetics, Privolzhsky Research Medical University, Russian Ministry of Health, Nizhny Novgorod.

36. Fedoseenko Marina Vladislavovna — PhD, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health 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, Pirogov Russian National Research Medical University, Russian Ministry of Health, Member of the Union of Pediatrists of Russia.

37. Fomin Viktor Viktorovich — Corresponding Member of the RAS, MD, PhD, Vice-Rector for Clinical Work and Additional Professional Education, Head of the Department of Faculty Therapy No. 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), Russian Ministry of Health.

38. Kharlap Maria Sergeevna — PhD, Leading Research Scientist, Department of Cardiac Arrhythmias and Conduction Disorders, National Medical Research Center for Therapy and Preventive Medicine, Russian Ministry of Health.

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

Appendix A2. Methodology for Developing Clinical Guidelines

These guidelines are intended for use by medical organizations and institutions of federal, territorial, and municipal healthcare management bodies, systems of compulsory and voluntary health insurance, and other medical organizations of various legal forms whose activities are aimed at providing medical care. The clinical guidelines are based on a systematic literature review (1992–2022) of the Medline (PubMed version), Embase (Dialog version), and Cochrane Library databases, using established protocols for the treatment of Fabry disease:

Biegstraaten M. et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document// Orphanet J Rare Dis. 2015. №10. P.36;

Ramaswami U., Whybra C., Parini R. et al. FOS European Investigators. Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey// Acta Paediatr. 2006.V. 95. №1. P. 86–92;

El Dib R., Gomaa H., Ortiz A., Politei J., Kapoor A., Barreto F. Enzyme replacement therapy for Anderson-Fabry disease: A complementary overview of a Cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies// PLoS ONE. 2017. V.12. №3. P. e0173358;

Alegra T., Vairo F., de Souza M.V., Krug B.C., Schwartz I.V. Enzyme replacement therapy for Fabry disease: A systematic review and meta-analysis// Genet Mol Biol. 2012. V. 35. P. 947-54;

Spada M., Baron R., Elliott P.M. et al. The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease - A systematic literature review by a European panel of experts. Mol Genet Metab. 2019. V.126. №3. P.212-23;

Germain D.P., Elliott P.M., Falissard B. et al. The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts// Mol Genet Metab Rep. 2019.V.19. P.100454;

Germain D.P., Arad M., Burlina A. et al. The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease - A systematic literature review by a European panel of experts// Mol Genet Metab. 2018. V.126. №3. P.224-35 .

Grades of Recommendation (GR) and Levels of Evidence (LE) are given in Tables 1–3.

Target audience for these clinical guidelines:

1. General practitioners (family physicians);

2. Pediatricians;

3. General practitioners;

4. Medical geneticists;

5. Laboratory geneticists;

6. Nephrologists;

7. Cardiologists;

8. Pediatric cardiologists;

9. Neurologists;

10. Gastroenterologists;

11. Endoscopists;

12. Radiologists;

13. Dermatovenereologists;

14. Ophthalmologists;

15. Functional diagnostics physicians;

16. Psychiatrists;

17. Medical psychologists;

18. Medical students;

19. Residents and interns.

Appendix 1. Levels of Evidence (LE) scale for diagnostic methods (diagnostic interventions)

Appendix 2. Levels of Evidence (LE) scale for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Appendix 3. Grades of Recommendation (GR) scale for methods of prevention, diagnostics, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

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

2. Clinical guidelines "Hypertrophic Cardiomyopathy" ID: KR283 (http://cr.rosminzdrav.ru/).

3. Clinical guidelines "Kidney Transplantation, Presence of a Transplanted Kidney, Failure and Rejection of Kidney Transplant" ID: 934_1 (http://cr.rosminzdrav.ru/).

4. Order of the Russian Ministry of Health dated November 24, 2021, No. 1094n "On approval of the Procedure for prescribing medicinal products, prescription form templates for medicinal products, the Procedure for issuing these forms, their accounting and storage, prescription form templates containing prescriptions for narcotic drugs or psychotropic substances, the Procedure for their manufacture, distribution, registration, accounting and storage, as well as the Rules for issuing prescription forms, including in the form of electronic documents."

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

6. Order of the Ministry of Health of the Russian Federation dated May 2, 2023, No. 205n "On approval of the nomenclature of positions of medical workers and pharmaceutical workers."

7. Order of the Ministry of Health of the Russian Federation dated July 23, 2010, No. 541н "On approval of the Unified Qualification Directory of Positions of Managers, Specialists, and Employees, section 'Qualification characteristics of positions of workers in the healthcare sector'."

8. 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 Healthcare Legislation in the Russian Federation' Regarding Clinical Practice Guidelines."

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

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

Appendix A3.1 Severity of clinical manifestations of FD at different ages

Note: in female patients with FD, symptoms manifest later and their severity varies.

Appendix A3.2 Differential diagnosis of Fabry disease

Appendix A3.3 Criteria for prescribing ERT

Appendix A3.4 Criteria for discontinuing ERT

Appendix A3.5 Monitoring of patients with Fabry disease

Note:

^1-initiation 6 months after starting ERT and then every 12 months.

² - every visit

³ - more frequently as indicated

Appendix A3.6 Collection of biological material for diagnostics in dried blood spots

Algorithm of actions for medical personnel during blood sample collection

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

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

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

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

• gently press to obtain a second drop of blood;

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

• similarly apply 6–8 drops onto the test card; the appearance of the blood spots must be identical on both sides;

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

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

Specifics during infusion therapy

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

Blood sampling is not permitted

• immediately after the patient undergoes infusion therapy;

• immediately after an exchange blood transfusion.

Storage and transportation of biological material

Dried blood spot samples can be stored in a regular refrigerator compartment at +4 °C until shipment. The storage period prior to shipment must not exceed 7 days. Storing them longer or at a higher temperature may cause enzyme activity to drop below normal levels, leading to false-positive results.

Appendix A3.7 Enzyme replacement therapy drugs used for Fabry disease

In the Russian Federation, 3 drugs are registered for FD ERT: agalsidase alfa**, agalsidase beta**, and pegunigalsidase alfa. These medicinal products were approved globally based on the results of randomized, placebo-controlled trials in which replacement therapy reduced the severity of neuropathic pain, induced regression of left ventricular hypertrophy, and stabilized renal function compared to placebo. According to a systematic literature review, the efficacy of replacement therapy has been studied in at least 52 prospective studies (controlled or observational). Of these, 22 used agalsidase alfa**, 22 used agalsidase beta**, 4 studies summarized the results of using both drugs [19–22], and 4 studies used pegunigalsidase alfa [116–119].

Overall, the results of these studies confirmed the beneficial effect of ERT on cardiac and renal function, neuropathic pain, and patients' quality of life. After 12 months, plasma lyso-Gb3 levels improved in male patients and improved or remained stable in female patients.

Pegunigalsidase alfa has a longer half-life, which may provide more stable drug levels in the blood throughout the dosing interval. However, the administration frequency of pegunigalsidase alfa (every 2 weeks) matches that of agalsidase alfa** and agalsidase beta**. In addition, pegylation masks immunogenic protein epitopes, resulting in reduced immunogenicity to the protein drug and potentially improving the medicinal product's ability to reach its target by increasing its solubility and stability in the body. In a head-to-head comparative study, pegunigalsidase alfa was non-inferior to agalsidase beta** in preventing the decline of renal function and showed advantages in tolerability. Furthermore, in this study, the group receiving pegunigalsidase alfa showed a decrease in the proportion of patients with antibodies to the medicinal product (recombinant alpha-galactosidase A) compared to the group that continued treatment with agalsidase beta** [115, 124]. Head-to-head comparative studies of pegunigalsidase alfa and agalsidase alfa** have not been conducted. In a prospective clinical study switching patients from agalsidase alfa** to pegunigalsidase alfa, the majority of patients with deteriorating renal function showed a positive change in the annual eGFR slope.

The number of patients with moderately or rapidly progressive kidney disease decreased, and the majority of patients achieved a stable condition after switching treatment drugs [114].

In patients with intolerance to agalsidase alfa** or agalsidase beta**, as well as in cases of disease progression during their use, the administration of pegunigalsidase alfa is advisable.

Agalsidase alfa** (approved per the Instructions from 7 years of age) is administered intravenously at a dose of 0.2 mg/kg once every two weeks; agalsidase beta** (approved per the Instructions from 8 years of age) is administered intravenously at a dose of 1.0 mg/kg once every two weeks. Pegunigalsidase alfa (approved per the Instructions from 18 years of age) is administered intravenously at a dose of 1 mg/kg of body weight once every two weeks. Initial drug administrations must be performed in a hospital setting. The drugs must be administered immediately after preparing the infusion solution.

There is no reason to change therapy if the patient has been stable on the drug for a long time, shows a positive response to the ongoing therapy, and the safety profile remains comfortable. Switching therapy in a stabilized patient with a chronic progressive disease may pose health risks.

Switching from one drug to another is only possible in the event of uncontrollable serious adverse events (AEs) that recur despite adequate pre-infusion premedication. The decision to switch must be made solely by a medical council (consilium) of a Federal Center. The patient or their legal representatives must be informed of the reason for the drug substitution and the further management strategy. Patient monitoring is necessary when switching therapy to evaluate treatment efficacy and safety.

During the first three months (6 infusions) of treatment with pegunigalsidase alfa, the previous premedication regimen should be continued with gradual tapering based on individual tolerability.

ERT administration can be performed in an inpatient setting (in case of infusion reactions or a complicated disease course), in a day care unit, or on an outpatient basis once every 2 weeks. Attention should be paid to maintaining the intervals between infusions and avoiding treatment interruptions, as failure to comply with the treatment regimen carries a potential risk of patient deterioration and progression of FD symptoms.

In the event of severe hypersensitivity or anaphylactic reactions, the infusion must be stopped immediately and emergency medical therapy initiated in accordance with current standards.

The most common adverse effects associated with ERT are post-infusion reactions, hypersensitivity reactions, and asthenia. Most of them are mild to moderate, do not lead to treatment discontinuation, and resolve with subsequent infusions. To minimize their severity, the infusion rate can be reduced, and premedication with systemic antihistamines, nonsteroidal anti-inflammatory and antirheumatic drugs, and/or systemic corticosteroids can be administered. ERT must not be used concomitantly with chloroquine, amiodarone**, benzoquinone, or gentamicin**, as these substances potentially inhibit intracellular α-GAL A activity. Patients who have experienced severe hypersensitivity reactions during the infusion should be retreated with extreme caution, and appropriate medical support measures must always be available.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Fabry disease (FD), or Anderson-Fabry disease, is a rare hereditary disorder classified among lysosomal storage diseases.

Clinical manifestations.

Fabry disease affects almost all organ systems. Many patients experience neuropathic pain (burning pain in the hands and feet, worsening in hot weather or during physical exertion), skin manifestations (angiokeratomas), sweating abnormalities (hypohidrosis, anhidrosis), involvement of the peripheral and central nervous systems (stroke), kidneys, heart, eyes (cornea verticillata), and the gastrointestinal tract.

In the classical form, the disease manifests at 4–12 years of age and is characterized by periodic pain primarily in the hands and feet; sometimes the pain is localized in the abdomen, mimicking appendicitis. Pain worsens with fever, physical exertion, and in hot or cold weather. Pain may occur in the form of crises. With age, pain crises generally become less frequent.

One of the striking symptoms is angiokeratomas, which are present in almost all patients. In size, these are small, pinhead-sized lesions—red or purplish, flat or raised above the skin surface. Angiokeratomas most commonly appear in the lower abdomen and spread to other parts of the body. They cause little discomfort unless they cover the entire body surface.

Renal involvement in FD is observed in almost all men and many women after 40 years of age, leading to renal failure and requiring hemodialysis.

With age, many patients develop myocardial hypertrophy, cataracts, and hearing impairment.

Causes of Fabry disease.

The disease is caused by mutations in the GLA gene, which encodes the enzyme α-galactosidase A (α-GAL A). This enzyme is involved in the breakdown of specific lipids known as glycosphingolipids. Enzyme deficiency leads to the accumulation of glycosphingolipids in various organs and tissues.

The GLA gene is located on the X chromosome, and the disease has an X-linked inheritance pattern. However, unlike many other X-linked recessive disorders, 60–70% of heterozygous female carriers exhibit clinical manifestations, sometimes as severe as those in affected males.

For a long time, FD was considered an extremely rare disease, but a screening study in Italy revealed a surprisingly high prevalence: 1 in 3,100 newborn males had low α-GAL A activity and GLA gene mutations. Therefore, many cases may remain undiagnosed.

To detect FD, many countries, including Russia, screen patients in hemodialysis, neurology, and cardiology departments.

How the diagnosis is established.

Physicians may suspect the disease based on clinical symptoms. Subsequently, laboratory tests and instrumental examinations are performed.

A definitive diagnosis can be established by measuring enzyme activity or determining the blood concentration of the lysosphingolipid lyso-Gb3. For this purpose, it is sufficient to collect capillary blood on a filter paper card from a finger or venous blood. Such cards are available in any medical genetic counseling clinic and outpatient polyclinic.

An accurate diagnosis is essential for genetic counseling, prenatal diagnosis, and carrier detection.

Treatment.

An effective treatment has been developed for FD—enzyme replacement therapy (ERT); therefore, early diagnosis is of great practical importance. Unfortunately, a proportion of cases are diagnosed at late stages of the disease, which prevents achieving the full therapeutic benefit of ERT. Nevertheless, initiating ERT at any stage of the disease helps slow progression and mitigate clinical symptoms.

Role of the family and the patient.

Fabry disease illustrates the importance of taking a family pedigree and screening relatives. It is estimated that once a diagnosis is made in a index patient, screening relatives can identify 5 more affected individuals at various stages of the disease, ranging from nearly asymptomatic to severe.

FD patients can help their relatives simply by informing them of the need for screening. If the diagnosis is established early—before irreversible internal organ damage occurs—treatment is much more effective. The attending physician or geneticist is bound by medical confidentiality, so the fate of relatives rests entirely in the hands of the patients themselves.

Siblings and all maternal relatives—uncles, aunts, and maternal cousins—should be informed of the need for testing. The disease can manifest differently within families. In men, a frequent complication after the age of 40 is renal failure. At a young age, however, the main complaint is acro-paresthesias and angiokeratomas. Women may experience pain, whereas renal failure is less common and may develop at an older age. Molecular genetic testing aimed at identifying the familial GLA gene mutation is indicated for the following relatives of the patient:

For a male proband:

1. mother,

2. daughters,

3. siblings,

4. maternal half-siblings,

5. maternal grandfather,

6. maternal grandmother,

7. daughters of daughters,

8. maternal aunts and uncles,

9. daughters of brothers,

10. children of sisters,

11. daughters of nephews,

12. children of nieces,

13. maternal first cousins,

14. daughters of granddaughters (great-granddaughters) through the maternal line,

15. children of granddaughters (great-grandsons and great-granddaughters) through the maternal line.

For a female proband:

1. mother,

2. father,

3. children,

4. maternal grandmother,

5. maternal grandfather,

6. paternal grandmother,

7. paternal grandfather,

8. siblings,

9. maternal half-siblings,

10. paternal half-sisters,

11. grandsons and granddaughters,

12. maternal aunts and uncles,

13. paternal aunts and uncles,

14. daughters of brothers,

15. children of sisters,

16. daughters of grandchildren (great-granddaughters),

17. children of granddaughters (great-grandsons and great-granddaughters),

18. maternal first cousins,

19. paternal first cousins,

20. daughters of nephews,

21. children of nieces.

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

Appendix G1. BRIEF PAIN INVENTORY Short Form

Source: [Poquet N, Lin C. The Brief Pain Inventory (BPI). J Physiother. 2016 Jan;62(1):52. doi: 10.1016/j.jphys.2015.07.001. Epub 2015 Aug 21. PMID: 26303366].

Type: rating scale.

Purpose: subjective assessment of pain tolerance.

Assessment tool: scale.

Content and scoring:

The patient is instructed to rate shortness of breath during physical exertion: from 0 points—calm breathing, no sensation of shortness of breath—up to 10 points, when shortness of breath is maximal. Rate your current sensations.

1. Everyone experiences pain throughout their life—headaches, toothaches, joint or muscle pain. Have you experienced any pain today

other than those listed?

1 — yes, 2 — no.

2. Shade the area where you feel pain. Mark the site of greatest pain with an X.

3. Please circle the number that best describes the worst pain you have experienced in the past 24 hours.

None 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 As bad as you can imagine

4. Please circle the number that best describes the least pain you have experienced in the past 24 hours

None 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 As bad as you can imagine

5. Please circle the number that best describes the average pain you have experienced in the past 24 hours

None 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 As bad as you can imagine

6. Please circle the number that best describes the pain you are feeling right now

None 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 As bad as you can imagine

7. What medications do you take to relieve pain?

8. How much has pain been relieved by medications in the past 24 hours

0 % 10 % 20 % 30 % 40 % 50 % 60 % 70 % 80 % 90 % 100 %

Not changed Completely relieved

9. How much during the past 24 hours has pain interfered with your

A. General activity

Does not interfere 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 Completely interferes

B. Mood

Does not interfere 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 Completely interferes

C. Walking ability

Does not interfere 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 Completely interferes

D. Normal work (includes both work outside the home and housework)

Does not interfere 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 Completely interferes

E. Relations with other people

Does not interfere 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 Completely interferes

F. Sleep

Does not interfere 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 Completely interferes

G. Enjoyment of life

Does not interfere 0 — 1— 2 — 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 Completely interferes

Notes:

Two main scores: pain severity score and pain interference score. The pain severity score is calculated based on four pain intensity items. Each item is rated from 0 (no pain) to 10 points (pain as bad as you can imagine) and contributes equally to the total score ranging from 0 to 40. Interference score: seven sub-items are rated from 0 (does not interfere) to 10 (completely interferes) and contribute equally to the total score ranging from 0 to 70. Items 1, 2, and 24 are not included in the calculation.

Appendix G2. Rating of Perceived Exertion Scale (Borg scale) (Borg scale)

Source: [Borg GAV. Psycho-physical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377–381, Borg, G. Borg's Perceived Exertion and pain Scales. USA: Human Kinetics, 1998, p. 2, Grant S, Aitchison T, Henderson E, Christie J, Zare S, McMurray J, Dargie H. A comparison of the reproducibility and the sensitivity to change of visual analogue scales, Borg scales, and Likert scales in normal subjects during submaximal exercise. Chest. 1999 Nov;116(5):1208-17].

Type: rating scale.

Purpose: subjective assessment of exercise tolerance.

Assessment tool: scale.

Content and scoring:

The patient is instructed to rate shortness of breath during physical exertion: from 0 points—calm breathing, no sensation of shortness of breath—up to 10 points, when shortness of breath is maximal. Rate your current sensations.