Pompe disease: clinical guidelines

List of Abbreviations

ALT — alanine aminotransferase

AST — aspartate aminotransferase

LOPD — late-onset Pompe disease

PD — Pompe disease

LSD — lysosomal storage diseases

GAA — acid alpha-glucosidase

CT — computed tomography

CK — creatine kinase

IOPD — infantile-onset Pompe disease

MRI — magnetic resonance imaging

US — ultrasound

ERT — enzyme replacement therapy

ECG — electrocardiography

ENMG — electroneuromyography

EchoCG — echocardiography

AMD (acid maltase deficiency) — acid maltase deficiency

GSD-II (glycogen storage disease type II) — glycogen storage disease type II

Terms and Definitions

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

Lysosomal storage diseases — a group of hereditary monogenic disorders associated with impaired lysosomal function.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Glycogen storage disease type II, or Pompe disease (PD), is an autosomal recessive disorder belonging to rare inherited storage diseases (OMIM #232300) associated with a deficiency of the enzyme acid maltase (acid alpha-glucosidase, GAA) in lysosomes. Predominant glycogen accumulation is observed in skeletal muscles, but to varying degrees it can also be detected in other organs and tissues, including the heart, liver, nervous system, smooth muscle, etc. The following generally accepted synonyms for PD are used in literature: glycogen storage disease type II (GSD-II); acid maltase deficiency (AMD); glycogenosis type II [1].

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

PD is caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), which belongs to the group of lysosomal hydrolases. The GAA gene encoding GAA is localized on the long arm of chromosome 17 (17q25.2-q25.3), consists of 20 exons, and is approximately 20,000 base pairs in size. More than 700 pathogenic variants of the gene have been identified, and their number is constantly growing [2]. Although certain nucleotide variants of the GAA gene occur predominantly in a specific ethnic group, for most populations there are no so-called "major" variants that make up any significant proportion of all pathogenic variants in the population and are therefore suitable for targeted detection.

Pathogenic variants of the GAA gene lead to varying degrees of enzyme deficiency. Infantile-onset Pompe disease (IOPD) develops with a significant decrease or complete absence of GAA activity, while late-onset Pompe disease (LOPD) develops with a less pronounced deficiency of GAA activity due to "mild" variants of the GAA gene [1, 3, 4].

Glycogen deposition or utilization depends on the body's demand for glucose. Biochemical transformations of glycogen in the liver help maintain normal blood glucose levels. In skeletal muscles, glycogen metabolism produces glucose-6-phosphate, which is involved in oxidation and the production of energy necessary for normal muscle function (contraction and relaxation). The absence or significant deficiency of GAA leads to massive glycogen accumulation in the lysosome and impaired cell function. In PD, regardless of the form, glycogen can accumulate in almost any tissue, but there is a predominant accumulation in various organs and tissues that depends on the form of the disease. Thus, in IOPD, glycogen accumulates in skeletal muscle, heart muscle, liver, and tongue muscles. Less commonly, abnormal glycogen deposits may occur in the muscular layer of the vascular wall, determining the development of aneurysms and malformations, as well as in cells of the central and peripheral nervous system [1, 3, 12]. In LOPD, unlike IOPD, skeletal muscle is affected the most, while damage to other organs and tissues is much less common and incomparable in severity to IOPD [5, 6]. PD is characterized by a steadily progressive course with various progression variants. Diagnosis of PD, regardless of the form, is based on the evaluation of clinical symptoms, instrumental and laboratory examination data.

1.3 Epidemiology of the Disease or Condition

The exact prevalence of PD is unknown. According to various authors, the frequency of the disease, depending on the country and ethnicity, ranges from 1:40,000 to 1:300,000 [7–11]. For example, in southern China and Taiwan, the frequency of the classical infantile form of PD is 1:40,000–50,000, making it the most frequent glycogenosis. When considering data for Taiwan separately, the incidence was 1:33,134 [10, 11]. Based on newborn screening using dried blood spots in Austria, the frequency of PD was 1:8,684 [9]. In the Netherlands, the frequency of glycogen storage disease type II in infants is 1:138,000, and of the late-onset form of PD is 1:57,000 [8].

1.4 Features of Coding the Disease or Condition

According to ICD-10, the disease belongs to class IV, endocrine, nutritional and metabolic diseases, E74.0 — glycogen storage disease (Pompe disease).

1.5 Classification of the disease or condition

PD belongs to glycogenoses — a group of rare inherited diseases of glycogen metabolism impairment associated with alterations in several enzymes involved in glycogen synthesis and breakdown. Clinical manifestations of the disease are associated with the pathological accumulation of glycogen and its metabolic products in cells. Today, eight main types of glycogenoses are distinguished. PD belongs to glycogen storage disease type II — a glycogenosis associated with lysosomal α-1,4-glucosidase deficiency, leading to the excessive accumulation of glycogen of normal chemical structure in the heart, skeletal muscles, liver, and brain.

All patients with PD, regardless of the time of onset, are characterized by a steadily progressive course of the disease. Ongoing glycogen deposition in target organs impairs their function and ultimately leads to irreversible structural tissue changes and death of the PD patient. PD is characterized by multiorgan pathology, but depending on the age at manifestation, the frequency of involvement of certain organs and systems will also vary. Attempts to classify PD according to literature data based on the age of onset, distinguishing infantile form with debut in the first year of life (subdivided into early, late infantile form, form with/without cardiomyopathy, etc.), childhood, juvenile, and adult forms of the disease, have not found unanimous support among specialists.

Taking into account the unified pathogenesis of PD, two forms are distinguished depending on the time of symptom manifestation [1, 3, 12]:

— Infantile Pompe disease (IOPD) — manifests in the neonatal period or infancy;

— Late-onset Pompe disease (LOPD).

1.6 Clinical presentation of the disease or condition

Each of the distinguished forms has its own clinical features, diagnostic algorithms, and patient management tactics.

IOPD is characterized by a severe progressive course and rapid development of multiorgan pathology — muscle hypotonia and weakness, heart failure resulting from hypertrophic cardiomyopathy, respiratory failure due to weakness of the diaphragm and intercostal muscles, feeding difficulties due to facial muscle weakness and macroglossia, and hepatomegaly. Death in IOPD most often occurs in the first year of life from cardiorespiratory failure.

Main symptoms of IOPD

LOPD differs from IOPD by milder clinical manifestations and course, absence of multiorgan pathology (heart involvement is extremely rare), and later respiratory complications resulting from weakness of the diaphragm and intercostal muscles. Patients usually die from respiratory failure and infectious pulmonary complications. The time of death in LOPD depends on the time of onset and subsequent course of the disease and may occur in childhood, adolescence, adulthood, or old age. The clinical picture of the distinguished forms is discussed in more detail below.

Main clinical symptoms of LOPD

Clinical manifestations of infantile-onset Pompe disease

In all cases of suspected inherited metabolic disorders, taking a family history is mandatory (identifying early deaths in the family, death of children in early childhood, unusual muscular manifestations, myopathy); given the development of multiorgan pathology, extended laboratory and instrumental evaluation is indicated.

The first signs and symptoms of infantile Pompe disease appear as early as 2–3 months of life. Physical examination reveals muscle hypotonia and progressive muscle weakness. The child's face acquires a characteristic appearance: the mouth is slightly open, the oral cavity is filled with an enlarged tongue (in 1/3 of infants), and facial expression is weakened. The mother often complains that the child has difficulty latching on and is falling behind in weight, tires quickly during feeding, and swallows poorly. Further examination reveals increased muscle firmness, signs of respiratory and cardiac failure: skin pallor, central and acrocyanosis, hyperhidrosis, grunting respiration, participation of accessory muscles in breathing, "cardiac hump" chest deformity, enlargement of relative cardiac dullness boundaries, weakening of peripheral pulsation, hepatomegaly, peripheral edema. Auscultation of the lungs reveals harsh breath sounds, frequently accompanied by transmitted wheezes, diminished breath sounds on the left, tachypnea; muffled heart sounds, a systolic murmur over the entire precordium, and cardiac arrhythmias (tachycardia, bradycardia, ventricular arrhythmia). Classic infantile Pompe disease is characterized by the development of pulmonary atelectasis in infants, predominantly in the lower lobe of the left lung. The liver is enlarged. Chest X-ray reveals cardiomegaly. With a later onset of Pompe disease, frequent respiratory infections are noted.

Neurological examination reveals marked developmental delay manifested by impaired motor skill development: spontaneous and voluntary motor activity is reduced, the child does not hold up their head, does not roll over independently, and does not sit. Proximal muscle weakness in the supine position gives the child a characteristic "frog-leg posture," and when lifted by the arms, the head falls backward. When held in arms, the child presents with the typical "floppy infant" appearance. Selective hypertrophy and palpable firmness of the lower extremity muscles may be present. Deep tendon reflexes may be preserved at onset but fade as the disease progresses. Appendix G1 presents the main symptoms of infantile Pompe disease [1,3,12,14]. Quite frequently, the aforementioned changes are accompanied by nonspecific manifestations such as general malaise, child irritability, excessive sweating, vomiting, and constipation. A rare but alarming sign of multiorgan pathology is hearing loss. Hydrocephalus develops as a result of impaired cerebrospinal fluid resorption.

Clinical manifestations of late-onset Pompe disease (LOPD)

The infantile form of Pompe disease features relative homogeneity of clinical manifestations, which cannot be said of LOPD, significantly complicating the diagnosis of this type II glycogen storage disease. Despite the identical pathogenesis of the infantile and late-onset forms of Pompe disease, the clinical spectrum and severity of organ and system involvement depend on the patient's age. Following relatively normal development in infancy, LOPD can manifest at any age. Regardless of the age of onset in children or adults, the disease follows a steadily progressive course, and the severity of muscular and other manifestations may not correlate with the rate of disease progression.

When LOPD manifests in childhood but after the first year of life (sometimes referred to in literature as the juvenile form to emphasize onset in childhood after the first year of life), a myopathic syndrome and moderate organomegaly are detected. Delayed acquisition of motor skills is observed. Cardiac muscle involvement is variable, and respiratory failure due to diaphragmatic and intercostal muscle weakness develops most frequently.

Examination of a patient with childhood-onset LOPD reveals clinical symptoms whose frequency may decrease as the child ages, with the exception of skeletal and respiratory muscle involvement [1,15,16].

It should be noted that in childhood-onset Pompe disease, a moderate elevation of serum creatine kinase (CK) levels (2-10 fold) is observed in 95% of cases, whereas a significant elevation (2000 IU/L and higher) is characteristic of the infantile form of Pompe disease. According to literature data, serum CK activity is inversely proportional to age (ρ = -0.71, p < 0.001), disease duration (ρ = -0.45, p < 0.001), and the presence of muscle atrophy (ρ = -0.53, p < 0.001) [15].

Parents often misinterpret the child's condition, considering them "lazy," and fail to consult a specialist. Subsequently, the child develops postural abnormalities, hyperlordosis, scoliosis, and a waddling (antalgic or myopathic) gait. The muscles of the legs and pelvic girdle are more affected than those of the shoulder girdle. Children frequently develop regional pseudohypertrophy of the back muscles, as well as rigid spine syndrome. Disease progression leads to respiratory disorders, most commonly in the form of nocturnal hypoventilation, frequent colds, and aspiration pneumonia. The child may complain of headaches; behavioral traits include rapid fatigue and reduced endurance during routine activities, primarily running and other active games. Facial muscle weakness, moderate ptosis (often asymmetric), macroglossia, decreased deep tendon reflexes, and osteopenia should also raise suspicion of LOPD in a child. In contrast to infants, cardiomyopathy is significantly less common in children with LOPD, and cardiac pathology practically never manifests as a primary symptom.

LOPD is characterized by clinical heterogeneity, variable age at the appearance of initial obvious signs and symptoms, varying rates of disease progression, and severity of muscle weakness. Even with an identical genotype, the age of onset can differ by decades and vary across all the aforementioned manifestations.

A retrospective analysis of complaints from patients with LOPD showed that the initial manifestations or signs of the disease, which were not subjectively viewed by the patient as deviations from the norm, involved difficulties with sports in 77% of cases (patients ran poorly, could not do pull-ups), 28% tired quickly when climbing stairs, 20% experienced difficulty rising from a low chair, 17% tired during routine walking, and 11% could not rise from a supine position without using their arms [6,17–23].

Thus, when Pompe disease is suspected in an adult patient, it is necessary to thoroughly investigate the details of motor development during childhood and adolescence.

Muscle weakness is the primary complaint in adult patients with late-onset Pompe disease (LOPD). Limb muscle weakness is the main complaint in patients with LOPD, observed in 93% of cases [22,23]. Regarding the distribution pattern of muscle weakness, there is somewhat less variability among patients. In most cases, maximal weakness affects the paraspinal muscles and anterior abdominal wall muscles, proximal leg muscles, and shoulder girdle muscles. Proximal weakness predominates over decreased strength in the distal muscles (if present). Furthermore, when limb muscle weakness is detected and evaluated one year after the initial patient examination, a progressive decrease in muscle strength is noted more for the legs than the arms. On average, leg muscle strength drops by 7.1%, and arm muscle strength by 4% [22,23]. Regarding the pattern of muscle weakness distribution, different authors note the following regularities. A greater symmetric involvement of the hip abductors and gluteal muscles with relative sparing of the hip flexors, relative sparing of the thigh muscles compared to the pelvic girdle muscles, and weakness of the hip extensors have been described. In the early stages of the disease, muscle changes may manifest solely as a waddling "ducks-like" gait with lumbar hyperlordosis. Shoulder girdle muscle weakness is most commonly detected upon examination and is diffuse in nature. Patients may not complain of changes in forearm and hand muscle strength even in advanced stages of the disease, when signs of primary muscular involvement resembling "limb-girdle myopathy" become obvious. Quite often, weakness and changes in muscle volume (atrophy) of the shoulder girdle can be asymmetric, which may manifest as scapular winging (scapula alata) on only one side or significant asymmetry of this symptom.

As mentioned above, the paraspinal and anterior abdominal wall muscles can be affected in the earliest stages of LOPD, leading to rapid fatigue and reduced tolerance to standard physical loads in both early and advanced stages of the disease. It is important to detect respiratory dysfunction resulting from weakness of the diaphragm and intercostal muscles. Up to 1/3 of adult patients with LOPD have respiratory system disorders.

During the examination, it is necessary to test various muscle groups by performing simple tasks (see the table below), the results of which can substantiate with high probability the need to screen the patient for LOPD.

Performance of motor tests in LOPD

1.7 Differential Diagnosis

The diagnostic complexity of LOPD is determined by the absence of specific clinical symptoms characteristic of most neuromuscular disorders, as well as the diversity of their combinations, time of onset, and severity during disease progression. The list of main diseases included in the differential diagnosis of LOPD is presented in Appendix A3.2.

Differential diagnosis of infantile-onset Pompe disease is performed with all disorders whose main clinical manifestation is the "floppy infant" syndrome.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of Pompe disease is established based on a combination of medical history, clinical findings, and laboratory test results (biochemical and molecular genetic analysis).

Criteria for establishing the diagnosis/condition: reduced enzyme activity in a blood sample, reconfirmed in another biomaterial sample (preferably muscle tissue, skin fibroblast culture) or confirmation of the biochemical diagnosis by DNA diagnostic methods (detection of two pathogenic/likely pathogenic variants in the GAA gene in confirmed trans-position; the presence of variants identified by massively parallel sequencing confirmed by Sanger direct automated sequencing).

2.1 Complaints and Anamnesis

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

At any age

- history of familial disease (similar cases in siblings);

- consanguineous marriage.

Infants of the first months of life

- psychomotor developmental delay;

- weak suck, poor weight gain;

- abdominal breathing;

- dyspnea;

- enlargement of the tongue (macroglossia);

- progressive course.

For older children

- tachycardia;

- daytime sleepiness;

- fatigue;

- frequent colds;

- muscle weakness;

- difficulty climbing stairs;

- exercise intolerance;

- gait abnormality;

- limb muscle atrophy.

For adolescents and adults

- morning headache;

- tachycardia;

- fatigue;

- muscle weakness;

- progressive course;

- muscle atrophy;

- difficulty climbing stairs;

- exercise intolerance;

- gait abnormality.

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

2.2 Physical Examination

During the examination, attention should be paid to the main physical manifestations of Pompe disease:

Infants of the first months of life

- "floppy infant" symptom complex;

- psychomotor developmental delay;

- hypomimia;

- macroglossia;

- respiratory rhythm disorder.

Children, adolescents, adults

- progressive muscle weakness with predominant involvement of proximal muscles;

- decreased motor activity;

- decreased tendon reflexes;

- positive Gowers' maneuvers;

- myopathic gait;

- anterior abdominal wall muscle weakness;

- paraspinal muscle weakness (lordosis, kyphosis, scoliosis);

- gluteal muscle weakness and difficulty maintaining balance when standing up

- preserved strength of the quadriceps muscles amidst weakness in other muscle groups

- neck flexor weakness;

- diaphragmatic weakness, dyspnea;

- lingual muscle weakness;

- facial muscle weakness, particularly asymmetrical;

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

2.3 Laboratory Diagnostics

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

Comments: GAA activity can be determined in various biological materials (cultured fibroblasts, muscle biopsy specimens, peripheral lymphocytes, etc.), but currently, measuring GAA activity in dried blood spots by tandem mass spectrometry is the optimal approach. This test combines high sensitivity with ease of performance and applicability for screening a large number of patients. Measuring GAA activity in dried blood spots is the optimal screening test and the "gold standard," allowing for a minimally invasive, rapid, and accurate assessment of enzyme activity deficiency. Patients with Pompe disease show a significant decrease in enzyme activity (less than 10% of normal). However, biochemical test results must be interpreted with caution, as pseudodeficiency alleles have been described that can affect enzyme activity in vitro. According to international expert guidelines, to confirm a diagnosis of Pompe disease after detecting reduced enzyme activity in a blood sample, it is necessary to re-evaluate enzyme activity in another biological sample (preferably muscle tissue, skin fibroblast culture) or confirm the biochemical diagnosis using DNA diagnostic methods.

Comments: The GAA gene can be analyzed by direct automated Sanger sequencing, high-throughput sequencing methods (determination of structural gene variants in a biological sample using another or unspecified method not classified elsewhere via high-throughput sequencing), Sanger sequencing; determination of gene variants in a biological sample using another or unspecified method not classified elsewhere via high-throughput/targeted high-throughput sequencing; determination of structural gene variants in a biological sample using another or unspecified method not classified elsewhere via multiplex ligation-dependent probe amplification, DNA microarray molecular karyotyping). Most patients are compound heterozygotes, meaning they carry two different pathogenic variants of the GAA gene on both homologous chromosomes. Due to the large number of unique variants, polymorphisms, and variants of uncertain significance described in the GAA gene, difficulties may arise in identifying previously undescribed nucleotide sequence alterations [2]. Pathogenic variants of the GAA gene leading to Pompe disease can be detected using next-generation sequencing methods (whole exome/genome sequencing, targeted sequencing), Sanger sequencing, detection of exon or whole-gene deletions using MLPA, and chromosomal microarray analysis. Molecular genetic analysis methods are necessary to confirm Pompe disease if the proband's biological material is unavailable, as well as for prenatal and preimplantation diagnostics.

Comments: These tests are performed as part of a general therapeutic blood biochemistry panel at the time of diagnosis and subsequently at least once every 6 months. The detected changes may indicate muscle tissue involvement. In childhood-onset Pompe disease, a moderate increase in serum CK levels (2- to 10-fold) is observed in 95% of cases, while a significant increase up to 2000 U/L and higher is characteristic of the infantile form of Pompe disease. According to the literature, serum CK activity is inversely proportional to age (ρ = -0.71, p < 0.001), disease duration (ρ = -0.45, p < 0.001), and the presence of muscle atrophy (ρ = -0.53, p < 0.001). ALT and AST are enzymes active in all cells of the body, but are most abundant in the heart, liver, kidneys, and muscles. The impairment of liver and muscle tissue function characteristic of Pompe disease leads to elevated "liver enzyme" activity in blood serum. AST is a more informative marker than ALT. In patients with the infantile form, AST activity is 3 to 10 times the upper limit of normal, while ALT varies from normal to 2- to 7-fold elevation. In late-onset Pompe disease, ALT activity is elevated in 94% and AST in 95% of cases.

Comments: Due to the high risk of intercurrent infections and aspiration pneumonia in patients with Pompe disease, this test must be performed at least 6 times a year.

Comments: Natriuretic peptide levels are usually significantly elevated in patients with infantile-onset Pompe disease. This parameter is a crucial biomarker of cardiac involvement and an indicator of heart failure and right ventricular dysfunction.

2.4 Instrumental Diagnostics

The listed clinical and instrumental research methods are necessary for the diagnosis and differential diagnosis of myopathic syndromes, including in infants under one year of age.

Comments: These methods make it possible to differentiate Pompe disease from disorders associated with impaired peripheral motor fiber function and neuromuscular transmission.

Comments: The tests are performed at the time of diagnosis, subsequently at least once every 6 months, and upon initiation of enzyme replacement therapy — every 7-14 days during the first 12-24 weeks of therapy. ECG allows for the detection of cardiac rhythm disturbances, while echocardiography detects cardiomegaly, myocardial hypertrophy, and other cardiac abnormalities. ECG markers of progressive cardiomegaly include giant QRS complexes (due to left or biventricular hypertrophy), a very short PR interval, T-wave inversion, and ST-segment depression [36].

Comments: assessment of pulmonary function is mandatory in both standing and supine positions, with determination of the difference in parameters. According to indications, diffusing capacity of the lungs, chest computed tomography / spiral computed tomography of the lungs, and tracheobronchoscopy / videotracheobronchoscopy for differential diagnosis may be performed [54].

Comments: upon diagnosis establishment, if not performed within the last 6 months. Unlike other glycogen storage diseases, Pompe disease is characterized by a moderate hepatomegaly.

Comments: Patients and family members should be informed about all the consequences of an inadequate attitude towards the issue of osteoporosis.

Comments: upon diagnosis establishment and subsequently at least once every 3 years.

2.5 Other Procedures

2.5.1 Specialist Consultations and Monitoring

Comments: infantile-onset Pompe disease is characterized by muscular hypotonia and feeding difficulties due to facial muscle weakness. Motor development delay is observed. Late-onset Pompe disease is characterized by progressive muscle weakness, gait disturbance, exercise intolerance, and chronic muscle pain.

Comments: infantile-onset Pompe disease is characterized by splenomegaly and hepatomegaly.

Comments: patients with Pompe disease require both initial and follow-up appointments (examinations, consultations) with a geneticist: upon suspicion of the disease, for prescribing biochemical and molecular genetic tests, for interpreting the results obtained, and during family pregnancy planning when there is an affected individual with Pompe disease.

Comments: the management of patients with Pompe disease involves a multidisciplinary approach with the mandatory participation of neurologists, geneticists, cardiologists / pediatric cardiologists, pulmonologists, gastroenterologists, physical therapy doctors, and specialists in other fields with experience in treating this rare disease — in the presence of target organ damage symptoms, a consultation with the relevant specialist is required at a minimum.

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

Treatment of Pompe disease includes both pathogenetic treatment — the administration of enzyme replacement therapy (ERT), and symptomatic therapy.

3.1 Pathogenetic treatment

Comments: in the Russian Federation, EU countries, and the USA, 2 drugs are registered for ERT in Pompe disease: alglucosidase alfa and avalglucosidase alfa.

Comments: the choice of pathogenetic therapy drug is made by the attending physician. Avalglucosidase alfa is a human acid alpha-glucosidase produced in Chinese hamster ovary (CHO) cells using recombinant DNA technology. The drug is registered in the Russian Federation. It is used in children from 6 months of age, adolescents, and adult patients with a confirmed diagnosis of Pompe disease. Treatment should be carried out under the supervision of a physician experienced in managing patients with Pompe disease or other inherited metabolic or neuromuscular disorders. Patients with late-onset Pompe disease are prescribed the following dosage regimen of avalglucosidase alfa: 20 mg/kg of body weight once every 2 weeks. Patients with infantile-onset Pompe disease are prescribed the following dosage regimen of avalglucosidase alfa: 40 mg/kg of body weight once every 2 weeks. The safety and efficacy of avalglucosidase alfa in children aged 6 months and younger have not yet been established. No data are available for patients aged 6 months and younger.

Comments: one of the drugs for pathogenetic ERT of Pompe disease is alglucosidase alfa, which is registered in the Russian Federation. Alglucosidase alfa (ATC code: A16AB07) is a recombinant enzyme synthesized by a cell line derived from Chinese hamster ovaries. Alglucosidase alfa restores the activity of lysosomal acid alpha-glucosidase, leading to the stabilization or restoration of cardiac and skeletal muscle function, including respiratory muscles. The drug is well tolerated and has no pronounced adverse effects. It is indicated for long-term ERT in patients of all ages with a confirmed diagnosis of Pompe disease. Currently, the efficacy and safety of alglucosidase alfa have been evaluated in clinical trials in both pediatric and adult patients.

The drug is available in vials containing an amount of lyophilizate equivalent to 50 mg of the active substance. It is administered intravenously as an infusion at a dose of 20 mg/kg of the patient's weight. Early initiation of therapy is very important as it allows for better clinical outcomes. It has been proven that the use of ERT in infantile-onset disease reduces the risk of death by 99%, and the risk of death or the need for invasive mechanical ventilation by 92% [30].

Timely initiation of alglucosidase alfa therapy reverses cardiomyopathy in patients with infantile-onset Pompe disease, improves muscle strength and motor activity, and stabilizes the respiratory system in both children and adult patients. Enzyme replacement therapy with alglucosidase alfa in patients with late-onset Pompe disease slows disease progression, improves musculoskeletal status, stabilizes respiratory function, increases patient survival, and prolongs the period prior to the need for mechanical ventilation and a wheelchair. The drug is administered as an intravenous infusion at a dosage of 20 mg/kg of body weight once every two weeks. The literature contains isolated descriptions of alternative dosing regimens (higher enzyme doses administered more frequently for patients with early-onset disease).

Both drugs, alglucosidase alfa and avalglucosidase alfa, represent recombinant human acid alpha-glucosidase produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. The drugs are administered to replenish lysosomal acid alpha-glucosidase activity, leading to the stabilization or restoration of skeletal and cardiac muscle function, including respiratory muscles. Avalglucosidase alfa is characterized by an increased number of bis-M6P glycan structures at glycosylation sites, resulting in enhanced cellular uptake, a greater degree of glycogen clearance, and improved clinical outcomes compared to alglucosidase alfa. Avalglucosidase alfa contains 15 times more mannose-6-phosphate (M6P) moieties than alglucosidase alfa. Switching from one drug to the other is possible at the next scheduled infusion [49, 53].

Avalglucosidase alfa is a modified form of alglucosidase alfa in which an increased number of bisphosphorylated mannose-6-phosphate (M6P) moieties at glycosylation sites leads to enhanced cellular uptake, a greater degree of glycogen clearance, and improved clinical outcomes compared with treatment with alglucosidase alfa [49, 53].

Switching a patient—whose condition was previously stabilized on alglucosidase alfa but who now exhibits a suboptimal response or decreased treatment efficacy (negative dynamics in parameters such as a 10–15% decrease in FVC, reduced endurance on the 6-minute walk test)—to avalglucosidase alfa may provide additional clinical benefits and improve the disease prognosis [49, 53].

The first 3 infusions must be performed in a hospital setting, for the purpose of early detection and prompt management of potential adverse reactions to the drug administration. Vital signs must be monitored—including heart rate, peripheral blood pressure, and oxygen saturation (SatO₂)—during the infusion. Administration of enzyme replacement therapy (ERT) is carried out regularly when indicated: in an inpatient setting for complicated disease courses, or in a day hospital or outpatient setting once every 2 weeks when the condition is stable. The following specific features of ERT in Pompe disease must be considered:

– do not feed the child 3–4 hours prior to the infusion to prevent aspiration and potential resuscitation procedures;

– reconstitute the drug in a minimal volume;

– initial infusions of the drug should be administered via a central venous line, or if administered via a peripheral venous line, two vascular accesses must be secured; subsequently, an infusion port system should be implanted;

– infusions should be administered at a limited rate (increasing by 0.5–1 mL/h every 30–60 min), given the high risk of heart failure decompensation due to hypervolemia.

3.2 Symptomatic treatment

There are no randomized controlled trials regarding the symptomatic therapy of Pompe disease. All recommendations provided below reflect the expert opinion of specialists from various countries. Symptomatic therapy is prescribed in accordance with clinical guidelines developed for the respective pathologies [3, 15, 29, 30].

Comments: a diagnosis of Pompe disease is not a contraindication for vaccination. In addition to vaccines included in the National Immunization Schedule, patients and their close contacts should receive annual seasonal influenza vaccination; during the first 2 years of life (for infantile-onset Pompe disease), passive immunization against respiratory syncytial virus [55, 56] is indicated; patients with Pompe disease should also be vaccinated against pneumococcal infection [57, 58].

Pompe disease is not a contraindication for vaccination against the novel coronavirus infection (COVID-19) [59], which is performed according to epidemiological indications. Contraindications are in accordance with the product instructions for the respective vaccines.

Comments: decreased bone mineral density is a frequent finding in patients with Pompe disease, reaching 67% of cases according to recent studies [32]. Osteopenia and osteoporosis are detected in both infantile-onset and late-onset Pompe disease. Instability during walking and difficulty maintaining balance resulting from muscle weakness, combined with osteoporosis, pose a risk of bone and vertebral fractures. All patients with late-onset Pompe disease, regardless of their degree of immobility (e.g., wheelchair-bound), must be instructed in all precautions to prevent falls and household fractures.

3.3 Other Treatment

Comments: anti-reflux formulas are also used to prevent aspiration.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Depending on the leading clinical symptoms, patients with Pompe disease may be prescribed various rehabilitation programs:

- Oral stimulation, pacifier sucking, and exercises should be performed in all patients to support the normal development of swallowing and speech skills.

- Avoid excessive (maximal) physical exertion during rehabilitation activities.

- Regularly: physiotherapy, massage, exercise therapy (physical therapy), speech therapy, respiratory therapy (breathing exercises), and training in self-care and the use of assistive devices (depending on the child's age).

- As indicated—development of an individual speech therapy rehabilitation program, development of an individual defectology rehabilitation program.

- Non-invasive oxygen support (positive pressure ventilation) in the event of hypoxemia or obstructive syndrome.

- Instruction of parents on the use of a nebulizer and suction device.

A proper lifestyle with adequate distribution of physical activity and supervised exercise therapy under the guidance of an informed instructor is of great importance.

Patients with gait and balance disturbances should be strongly advised to use assistive devices such as a cane or walker, and mechanical mobility aids (such as a wheelchair) when necessary.

Comments: Patients with Pompe disease need support for the maximum level of musculoskeletal function to prevent and minimize secondary complications (development of contractures, muscle atrophy, compensatory skeletal deformity, osteopenia, osteoporosis). During rehabilitation measures, excessive (maximum) loads should be avoided. When indicated, the following are appropriate: initial/follow-up appointment (consultation) with a medical speech therapist, initial and follow-up appointment (examination, consultation) with an otorhinolaryngologist/audiologist-otorhinolaryngologist.

5. Prevention and Dispensary Observation

5.1 Prevention

Comments: For families with children with Pompe disease, it is important to conduct medical genetic counseling to determine the genetic risk. As with other autosomal recessive diseases, the risk of having a child with Pompe disease for each pregnancy is 25%. In families with a child affected by Pompe disease, prenatal and preimplantation diagnostics are possible. To do this, parents need to contact specialized diagnostic laboratories and medical centers.

Prenatal diagnostics is carried out using molecular genetic or biochemical methods by examining DNA extracted from a chorionic villus biopsy sample at 9-12 weeks of gestation and/or amniotic fluid cells at 16-20 weeks, and fetal blood at 20-22 weeks of gestation.

5.2 Dispensary monitoring

Comments: the geneticist carries out dispensary observation of patients with congenital and (or) hereditary diseases, determines the plan of laboratory and instrumental studies, and consultations with other specialists.

Comments: in the infantile-onset form of Pompe disease, along with muscular hypotonia, hepatomegaly, and macroglossia, cardiomyopathy and conduction disturbances are observed. Cardiomyopathy is predominantly hypertrophic with marked thickening of the interventricular septum (asymmetric hypertrophy) or of both the septum and the free walls of the left and right ventricles (concentric hypertrophy). With marked hypertrophy, left ventricular outflow tract obstruction may occur (observed in 30% of cases). During enzyme replacement therapy (ERT), rapid regression of left ventricular hypertrophy is noted [38]. Descriptions of cardiac anomalies in adults with Pompe disease are few. According to a study (87 patients, mean age 44 years), PR interval shortening was observed in 10%, 7% showed decreased left ventricular systolic function, and 5% had increased left ventricular mass on echocardiography. No cardiovascular changes associated with enzyme replacement therapy (ERT) were observed [44]. There are assumptions about increased aortic wall thickness in patients with Pompe disease, which requires increased attention from cardiologists [45].

Patients with Pompe disease may experience pulmonary impairment. Patients with LOPD must undergo annual pulmonary function monitoring.

Dispensary monitoring of a patient with Pompe disease

* Blood tests should include: AST, ALT, LDH, CK (MB fraction), serum albumin, prothrombin time, partial thromboplastin time, total bilirubin, serum creatinine.

** Urine tests should include: urinary creatinine, protein, GFR

*** Scales used:

Alberta Infant Motor Scale (AIMS) (Appendix G1)

Muscle strength according to the Medical Research Council scale (Appendix G2)

6MWT – 6-minute walk test (Appendix G3) [1]

To monitor the condition of patients receiving pathogenetic therapy, they must be observed at least once a year in specialized centers capable of providing medical care in accordance with these clinical guidelines.

6. Organization of Medical Care

Patients with Pompe disease, depending on necessity, may be provided with any type, conditions, and forms of medical care stipulated by the legislation of the Russian Federation.

Indications for elective hospitalization:

- Provision of diagnostics and treatment requiring round-the-clock medical supervision.

- a condition requiring active treatment and round-the-clock medical supervision (progressive respiratory failure, cardiac rhythm disturbances);

- a condition requiring high-tech treatment methods

- lack of opportunity to provide ERT in outpatient and day-care settings;

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

Indications for emergency hospitalization:

Acute illnesses, exacerbations of chronic diseases, poisoning and trauma, conditions requiring intensive care and transfer to intensive care units or critical care departments, as well as round-the-clock medical supervision and special types of examination and treatment.

Indications for patient discharge from the hospital:

- absence of threat to the patient's life;

- absence of risk of developing complications requiring urgent treatment;

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

- no need for constant physician and round-the-clock medical supervision regarding the underlying disease;

- the need to transfer the patient to another medical organization or social welfare institution

7. Additional Information

Early diagnosis of Pompe disease and the prescription of ERT can improve prognosis and slow disease progression. In some countries, the inclusion of Pompe disease in mass newborn screening programs is being considered [13, 30].

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for primary health care provided to adults and children with Pompe disease

Criteria for assessing the quality of specialized medical care for adults and children with Pompe disease

References

Appendix A1. Working Group Composition

1. Inga V. Anisimova — Cand. of Sci. (Med.), Head of the Medical Care Organization Department, Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

2. Svetlana B. Artemyeva — MD, PhD, Head of the Psychoneurological Department No. 2, Academician Yu.E. Veltischev Research Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University of the Russian Ministry of Health

3. Elena N. Arkhipova — PhD, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

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

5. Elena N. Basargina — MD, Head of the Cardiology Department, Chief Researcher at the National Medical Research Center for Children's Health of the Russian Ministry of Health

6. Nato D. Vashakmadze — MD, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

7. Natalia V. Zhurkova — PhD, Leading Researcher, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Member of the Union of Pediatricians of Russia, Member of the Association of Medical Geneticists

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

9. Sergey A. Klyushnikov — PhD, Leading Researcher at the 5th Neurological Department, Research Center of Neurology, Highest Category Neurologist, Member of the Russian Societies of Neurologists and Medical Geneticists, National Society for the Study of Parkinson's Disease and Movement Disorders, Movement Disorder Society

10. Natalia P. Kotlukova — MD, Consultant Physician, Pediatric Cardiologist, Z.A. Bashlyaeva City Children's Clinical Hospital of the Moscow Healthcare Department, Professor at the Department of Hospital Pediatrics No. 1, Pediatric Faculty, Pirogov Russian National Research Medical University

11. Sergey I. Kutsev — Academician of the RAS, MD, Director of the Academician N.P. Bochkov Research Centre for Medical Genetics, President of the Association of Medical Geneticists (AMG)

12. Larionova Valentina Ilyinichna — Doctor of Medical Sciences, Institute of Experimental Medicine, Member of the Russian Society of Medical Geneticists

13. Mikhailova Svetlana Vitalievna — Doctor of Medical Sciences, Head of the Department of Medical Genetics, Russian Children's Clinical Hospital of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia

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

15. Sergey S. Nikitin — Dr. of Sci. (Med.), Professor, Chairman of the Society of Neuromuscular Disease Specialists

16. Liliya R. Selimzyanova — PhD, Leading Researcher, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

17. Semyachkina Alla Nikolaevna — Doctor of Medical Sciences, Chief Research Fellow at the Department of Clinical Genetics, Moscow Research Institute of Pediatrics and Pediatric Surgery of the Ministry of Health of Russia, Member of the Association of Medical Geneticists (AMG)

18. Olga Ya. Smirnova — Geneticist, Senior Researcher at the Department of Standardization and Study of Evidence-Based Medicine Fundamentals, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Member of the Union of Pediatricians of Russia

19. Dmitry M. Subbotin — Geneticist, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Association of Medical Geneticists (AMG)

20. Marina V. Fedoseenko — PhD, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Deviations and Chronic Diseases, Leading Researcher, Pediatrician, 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 Pediatricians of Russia

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

Appendix A2. Methodology for Developing Clinical Guidelines

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

These guidelines establish the types, scope, and quality indicators of medical care for patients with Pompe disease and were reviewed at the 3rd All-Russian Scientific and Practical Congress with international participation "Orphan Diseases" (May 31, 2018 – June 2, 2018) and at the 21st Congress of Pediatricians of Russia with international participation "Current Problems of Pediatrics" on February 15–17, 2019.

The clinical guidelines are based on a systematic review of the 1992–2019 literature from the Medline (Pubmed version), Embase (Dialog version), and Cochrane Library databases, using established protocols (Bembi B., Cerini E., Danesino C. et al. Management and treatment of glycogenosis type II. Neurology 71(Suppl 2) December 2, 2008. 12 – 36, Barba-Romero M.A., Barrot E., Bautista-Lorite J. et al. Clinical guidelines for late-onset Pompe disease. Rev Neurol 2012; 54 (8): 497-507, Cupler E., Berger K., Leshner R. et al. Consensus treatment recommendations for late-onset Pompe Disease. Muscle and Nerve. 2012. 319-333.) and modern international clinical guidelines for the diagnosis, treatment, and management of patients with metabolic disorders.

Pompe disease is a rare hereditary disorder, which precludes large cohort and randomized controlled trials; therefore, the creation of diagnostic and therapeutic protocols relies solely on expert case studies published over the past two decades.

The evaluation of the quality of evidence and the strength of recommendations for the application of medical technologies was performed in accordance with the standardized scale presented in Tables 1–3.

Target audience for these clinical guidelines:

1. General practitioners (family physicians);

2. Pediatricians;

3. General practitioners;

4. Medical geneticists;

5. Laboratory geneticists;

6. Cardiologists;

7. Pediatric cardiologists;

8. Neurologists;

9. Radiologists;

10. Functional diagnostics physicians;

11. Otorhinolaryngologists;

12. Medical psychologists;

13. Medical students;

14. Residents and interns.

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

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

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

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

Appendix A3.1. Key regulatory legal documents used in drafting the clinical guidelines

1. Federal Law "On the Basics of Protecting Health of Citizens in the Russian Federation" (№ 323-FZ of November 21, 2011).

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

3. Order of the Ministry of Health of the Russian Federation dated April 21, 2022, No. 274n, "On approval of the Procedure for Medical Care Delivery to Patients with Congenital and/or Hereditary Diseases"

4. Government Decree No. 403 dated April 26, 2012, "On the Procedure for Maintaining the Federal Register of Persons Suffering from Life-Threatening and Chronically Progressive Rare Orphan Diseases Leading to Reduced Life Expectancy or Disability of Citizens, and Its Regional Segment."

5. Criteria for Assessing the Quality of Medical Care (Order of the Ministry of Health of the Russian Federation No. 203n of May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care").

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

7. Order of the Ministry of Health of the Russian Federation No. 1177n dated December 20, 2012, "On Approval of the Procedure for Giving Informed Voluntary Consent to Medical Intervention and Refusal of Medical Intervention with Respect to Certain Types of Medical Interventions, Forms of Informed Voluntary Consent to Medical Intervention, and Forms of Refusal of Medical Intervention."

8. 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 Form Templates for Medicinal Products, the Procedure for Issuing, Recording, and Storing Said Forms, Templates of Prescription Forms Containing Prescriptions for Narcotic Drugs or Psychotropic Substances, the Procedure for Their Manufacture, Distribution, Registration, Accounting, and Storage, as well as the Rules for Issuing Prescription Forms, Including in the Form of Electronic Documents"

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

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

11. Order of the Ministry of Health of the Russian Federation No. 354n dated June 6, 2013, "On the Procedure for Conducting Pathological Autopsies" (registered by the Ministry of Justice of the Russian Federation on December 16, 2013, registration No. 30612).

Drug information: 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 Amending the Federal Law 'On the Fundamentals of Protecting Citizens' Health in the Russian Federation' Regarding the Provision of Palliative Medical Care."

2. Order of the Ministry of Health No. 345n and the Ministry of Labor of the Russian Federation 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 Welfare Organizations, and Public Associations and Other Non-Profit Organizations Operating in Healthcare."

3. Order of the Russian Ministry of Health No. 348n of May 31, 2019, "On Approval of the List of Medical Devices Intended to Maintain Organs and Systems of the Human Body Provided for Home Use."

4. Order of the Russian Ministry of Health No. 505n of July 10, 2019, "On Approval of the Procedure for Transferring Medical Devices Intended to Maintain Functions of Organs and Systems of the Human Body from a Medical Organization to a Patient (Their Legal Representative) for Home Use in the Provision of Palliative Medical Care."

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

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

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

7. Order of the Ministry of Health of the Russian Federation of December 20, 2012, No. 1183n, "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers."

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

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

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

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

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

13. 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" of August 9, 2005, No. 494

14. Information Letter of the Russian Ministry of Health on the Possibility of Procuring a Medicinal Product by Trade Name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu);

Appendix A3.2. Main diseases for the differential diagnosis of LOPD

Appendix A3.3. Biological material sampling for diagnostics using dried blood spots

Blood is collected on a standard filter paper card (No. 903) used for newborn screening in the Russian Federation or a similar one to obtain a dried blood spot. Blood can be either capillary (from a finger or heel) or venous. Venous blood is collected into a collection tube, mixed gently, and then quickly applied to the filter paper using a pipette, with 25–50 µl of blood per designated area. The designated area on the filter paper must be thoroughly saturated (Fig. 1). It is preferable to collect samples postprandially, 40 minutes to 1 hour after a meal. Blood collection is also possible while fasting. The filter paper card must clearly indicate the patient's full name, the name and department of the referring physician, date of birth, and the attending physician's phone number (Figure 2). The dried blood spot sample is placed in a clean envelope or a clean file folder. The filter paper card must not come into contact with dirty surfaces or samples from other patients. Informed consents from the patient or their legal representatives for laboratory testing must be attached to the samples.

Figure 1. Example of correct blood application to the filter paper card Figure 2. Example of a filter paper card

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 alcohol swab (70% ethanol), blot with a dry sterile swab; 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;

• apply 6–8 drops to the test form in a similar manner; the appearance of the blood spots should be identical on both sides.

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

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

Specifics during infusion therapy

Some patients may receive infusion therapy or blood component transfusions, which can affect test results. For example, blood plasma transfusions may yield false-negative results because the enzymes being measured are present in plasma and blood cells. Blood collection for enzyme and DNA diagnostics should be performed 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 chamber at +4 °C prior to shipment. The storage period prior to shipment must not exceed 7 days. Storing them longer or at a higher temperature may reduce enzyme activity even within the normal range, leading to false-positive results.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What is Pompe disease?

Pompe disease is one of 50 inherited disorders belonging to the group of lysosomal storage diseases. Lysosomes (cellular organelles) break down large molecules (macromolecules) such as fats, proteins, glycosaminoglycans, and glycogen. In various diseases, a specific stage of the breakdown of these macromolecules is impaired. The incidence of Pompe disease (type II glycogen storage disease) is approximately 1 in 140,000 (classic infantile form) and 1 in 60,000 for the adult-onset form. The disease occurs in virtually all ethnic groups.

Pompe disease is a rare inherited disorder in which the body lacks a specific enzyme, alpha-glucosidase (synonym: acid maltase). As a result of a mutation in the GAA gene encoding this enzyme, a specific substance—glycogen—accumulates within cells. This occurs in the muscles and the heart. If treatment is not initiated, the muscle tissue changes its structure and becomes unable to perform its function.

How does Pompe disease manifest?

Pompe disease is a progressive neuromuscular disorder. Over time, symptoms worsen and new muscle groups become affected. Many patients lose the ability to walk independently and become dependent on mechanical ventilation due to involvement of the respiratory muscles. There are several forms of the disease that vary in severity and age of onset: early-onset (infantile), late-onset (childhood), and adult. They differ in symptoms and progression rate. Pompe disease manifests as muscle weakness and muscle atrophy across all forms. The infantile form is also characterized by cardiac muscle involvement. The heart size increases significantly, and heart failure can develop rapidly.

Children may sometimes have difficulty speaking because all muscle groups are affected; speech becomes slurred and indistinct. Muscle weakness may manifest as clumsiness; patients stumble and have difficulty climbing stairs. The gait of adult patients with Pompe disease is peculiar, as they try to compensate for the defect by shifting their center of gravity. The less a patient moves, the higher the likelihood of developing spinal curvature and contractures.

How is Pompe disease inherited?

Pompe disease is inherited in an autosomal recessive manner. A child with Pompe disease inherits one altered gene (a gene with a mutation in its sequence) from each parent. In families where both parents are carriers of Pompe disease, the risk of having a child with the disease is 25% for each pregnancy. Therefore, having a child with Pompe disease does not mean that all subsequent children will be ill. There is a chance of having a healthy child.

How is the diagnosis established?

Physicians may suspect the disease based on clinical symptoms. Subsequently, laboratory tests and instrumental examinations are performed. In almost all patients with Pompe disease, blood biochemistry reveals elevated activity of the enzymes creatine phosphokinase, ALT, and AST. Electroneuromyography determines the primarily myopathic nature of the disorder. However, these symptoms can also occur in other hereditary forms of muscular dystrophy. To definitively confirm the diagnosis, measuring alpha-glucosidase activity in the blood is necessary. If enzyme activity is reduced, DNA diagnostics are performed.

How is Pompe disease treated?

A specific enzyme replacement therapy has been developed for the treatment of Pompe disease. The principle of therapy is that the missing enzyme is administered intravenously to the patient every two weeks. The drug used for enzyme replacement therapy is called alglucosidase alfa. There is nothing complicated or frightening about the intravenous enzyme administration procedure itself. With proper training, this can be performed in any hospital.

The efficacy of therapy largely depends on when treatment is initiated. If the degenerative process in the muscle tissue has reached a certain stage, restoring lost muscle function is impossible.

Medical genetic counseling in Pompe disease

It is very important for families to consult a medical geneticist. A geneticist can determine the risk of having a child with Pompe disease in a given family, arrange for relatives to be screened if necessary, and discuss prenatal and preimplantation diagnostics.

Prenatal diagnostics are performed at 9–11 weeks of gestation. Enzyme activity is measured and testing is performed to detect mutations in the GAA gene using chorionic villus sampling (the tissue from which the placenta subsequently develops). Based on the analysis, a conclusion is made whether the fetus is affected or healthy. Modern technologies also allow for preimplantation genetic diagnosis. Fertilization is carried out in vitro, after which only those fertilized embryos at the multi-blastomere stage that lack the familial mutation are selected and implanted into the mother's body. This procedure carries its own risks, which the geneticist can explain.

Pompe disease is not included in the list of orphan diseases whose treatment is funded by regional budgets; however, patients have the opportunity to receive treatment in Russia.

Family support

Remember: the success of treatment depends just as much on the family as it does on the physician. It is essential to follow recommendations and never lose hope under any circumstances. Even if you cannot completely defeat the disease, you can change life for the better and make your loved one happy—this is within your power.

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

Appendix G1. Alberta Infant Motor Scale

Russian title: Alberta Infant Motor Scale

Original title (if applicable): Alberta Infant Motor Scale (AIMS)

Source (official developer website, validation publication): Piper MC, Pinnell LE, Darrah J, Maguire T, Byrne PJ. Construction and validation of the Alberta Infant Motor Scale (AIMS). Can J Public Health. 1992;83:S46-50.

Type (underline):

rating scale

index

questionnaire

other

Purpose: The Alberta Infant Motor Scale (AIMS), an observational assessment scale, was designed to measure gross motor maturation in infants from birth until independent walking.

Content (template): Based on the literature, 58 items were generated and distributed across four positions: prone, supine, sit, and stand. Each item is assigned a specific score

Key (interpretation): Scores are summed to provide an overall assessment of motor development and deviation/conformity to normal development in percentiles

Alberta Infant Motor Scale

day/month/year

Last name, first name____________________________ Assessment date: _____/_____/____

Identification number________________ Date of birth: _____/_____/____

Examiner___________________________ Chronological age: _____/_____/____

Location of assessment____________ Corrected age: ____/____/____

Total score: ______   percentile: ______

Notes/Recommendations:

INFANT MOTOR DEVELOPMENT RATING SCALE

Study No.
Prone position		Prone lying position (1) Physiological flexion. Turns head to clear airway, nose from surface.
		Prone lying position (2) Symmetrically lifts head at a 45º angle. Unable to hold head in line with the trunk.
		Prone position with support Elbows are behind the shoulders. Lifts head at a 45º angle without support.
		Forearm support (1) Lifts and holds head at an angle greater than 45º. Elbows in line with shoulders. Chest is centered.
		Mobility in prone position Lifts head up to a 90º angle. Uncontrolled weight-shifting attempts.
		Forearm support (2) Elbows are in front of the shoulders. Active chin tuck with neck elongation.
Supine position		Supine lying position (1) Physiological flexion. Head turn; brings mouth to hand. Random movements of arms and legs.
		Supine lying position (2) Head turn to the midline. Optional asymmetric tonic neck reflex (ATNR).
		Supine lying position (3) Head in line with the trunk. Moves arms, but unable to bring hands to the midline.
		Supine lying position (4) Neck flexor activity with chin tuck. Brings hands to the midline.
		Bringing hands to knees Chin tuck. Reaches knees with hands. Abdominal muscle activity.
Sitting		Supported sitting Lifts and briefly holds the head in line with the trunk.
		Sitting with arm support Holds the head in line with the trunk. Briefly bears weight on the arms.
		Pull-to-sit Tucks the chin; head is in line with the trunk or forward.
Standing		Supported weight-bearing on lower extremities (1) Alternating hip and knee flexion may occur.
		Supported weight-bearing on lower extremities (2) Head in line with the trunk. Hips are positioned behind the shoulders. Varied leg movements.

Prone on extended arms	Rolling from prone to supine without rotation	Swimming
Arms extended. Chin tuck with chest elevation. Lateral weight shift.	Movement is initiated by the head. Trunk moves as a single unit.	Extensor activity pattern.
Reaching in forearm support	Rolling	Rolling from prone to supine with rotation
Active weight shift to one side. Controlled reach with the free hand.	Rolling movements. Upper and lower extremity movements. Lateral trunk flexion.	Trunk rotation
Quadruped position (1)	Bringing hands to feet	Rolling from supine to prone without rotation
Hips flexed, abducted, and externally rotated. Lumbar lordosis. Maintains the position.	Able to maintain legs in the midline. Pelvic mobility is present.	Lateral head righting. Trunk moves as a single unit.

Rolling from supine to prone with rotation	Active extension	Unsupported sitting
Trunk rotation.	Extends by pushing off with the lower extremities.	Scapular adduction and shoulder extension. Unable to maintain the position.
Sitting with arm support	Unsupported sitting without arm support	Weight shifting in unsupported sitting
Thoracic spine extension. Head movements independent of the trunk; bears weight on extended arms.	Cannot remain unattended in a sitting position indefinitely.	Weight shift forward, backward, or laterally. Cannot remain unattended in a sitting position.
Sitting without arm support (1)	Reaching with rotation in sitting	Supported standing (3)
Arms are not pressed against the body. Able to play with a toy. Can remain unattended in a sitting position.	Sits independently. Reaches for a toy with trunk rotation.	Hips are in line with the shoulders. Active trunk control.
Supported side-lying	Reciprocal crawling	Transitioning from quadruped to sitting or semi-sitting
Lower extremity dissociation. Shoulder immobility. Rotation within the body axis.	Reciprocal arm and leg movements with trunk rotation.	Moves into and out of this position. Able to assume a sitting position.
Reciprocal quadruped crawling (1)	Reaching from extended arm support	Quadruped position (2)
Hips abducted and externally rotated. Lumbar lordosis; weight shift from side to side with lateral trunk flexion.	Reaches for an object with an outstretched arm. Trunk rotation.	Hips aligned under the pelvis. Flattening of the lumbar spine.
Modified quadruped position	Transition from sitting to prone position	Transition from sitting to quadruped position
Moves into this position. Forward progression is possible.	Moves from a sitting position to lie prone. Pulls up with arms, legs are inactive.	Actively elevates the pelvis, buttocks, and unloaded leg to come to a quadruped position.
Independent standing	First steps	Rising from a modified squatting position
Stands independently for a short time. Righting reactions in the feet.	Walks independently; moves quickly with small steps.	Transitions from a squatting position to standing with controlled flexion and extension of the hips and knees.
Rising from all-fours support	Independent walking	Sitting in a squat
Pushes off quickly with palms to stand.	Walks independently.	Maintains position by balancing reactions in the feet and trunk alignment.
Sitting without arm support (2)	Pulls to stand with support	Pulls to stand / stands
Leg position varies. The infant easily transitions from one position to another.	Pushes off with arms and straightens knees.	Pulls up to stand; shifts weight from one side to the other
Rising with support and rotation	Walking with support without rotation	Half-kneeling position
Trunk and pelvic rotation.	Walks sideways with support without rotation.	Can stand up or move into this position.
Controlled lowering from standing	Reciprocal quadruped crawling (2)	Walking with support with rotation
Controlled lowering from standing.	Flat lumbar spine. Moves with trunk rotation.	Walks with support with rotation.

Evaluation of Alberta Infant Motor Scale results

Percentile values

Appendix G2. Medical Research Council muscle scale

Title in Russian: MRC

Original title (if any): RESEARCH COUNCIL SCALE

Source (official developer website, validation publication): van der Ploeg, R.J.O., Oosterhuis, H.J.G.H. & Reuvekamp, J. Measuring muscle strength J Neurol (1984) 231: 200. https://doi.org/10.1007/BF00313939

Type (underline):

rating scale

index

questionnaire

other

Purpose: This scale allows assessment of:

- muscle strength of the tested muscles at the time of examination in points;

- dynamics of involvement of specific muscles and entire muscle groups;

- rate of progression of the myopathic process.

Content (template): the scale presents muscle strength in points

Key (interpretation): the higher the score, the greater the muscle strength

Muscle strength according to the Medical Research Council scale

Appendix G3. 6MWT – 6-minute walk test

Russian title: 6-minute walk test

Original title (if applicable): The six-minute walk test (6MWT)

Source (official developer website, validation publication): Laboratories, A. T. S. C. o. P. S. f. C. P. F. (2002). "ATS statement: guidelines for the six-minute walk test." Am J Respir Crit Care Med 166(1): 111-117.

Type (underline):

rating scale

index

questionnaire

other

Purpose: determination of patient endurance to assess treatment efficacy

Content (template): The test evaluates the distance in meters walked by the patient in 6 minutes without forced stops.

Key (interpretation): compared with the results of a test performed previously (before therapy, during therapy, etc.)

6MWT – 6-minute walk test (6 minutes walking test, 6MWT)

It should be remembered that this test has the following absolute contraindications: unstable exertional angina and myocardial infarction within the last month. Relative contraindications include: heart rate >120/min at rest, systolic BP >180 mmHg, and diastolic BP >100 mmHg. Stable angina is not an absolute contraindication for the test, but it should be performed with caution, against the background of antianginal therapy as indicated.

If the patient is on continuous oxygen support, the oxygen flow rate during the test should be maintained in accordance with the prescription of the physician who prescribed and monitors the therapy.

The test must be stopped immediately if the following occur:

1) Chest pain;

2) Intolerable dyspnea;

3) Leg cramps;

4) Marked instability and staggering when walking;

5) Excessive sweating;

6) Sharp change in skin color (pallor).

The 6MWT is performed in a room familiar to the patient, featuring a sufficiently long corridor with a hard surface. The path length should be at least 30 meters with markings every 3 meters, as well as turnaround points.

The patient is instructed to walk as fast as possible (but not run) for 6 minutes.

The test evaluates the distance in meters covered by the patient in 6 minutes without forced stops.

Appendix G4. SF-36 Quality of Life Questionnaire

Russian title: SF-36 Quality of Life Questionnaire

Original title (if applicable): "SF-36 Health Status Survey"

Source (official developer website, publication with

validation): Ware J.E., Snow K.K., Kosinski M., Gandek B. SF-36 Health Survey. Manual and interpretation guide //The Health Institute, New England Medical Center. Boston, Mass.-1993.

Type (underline):

- rating scale

- score

- questionnaire

- other (specify):_____________________________________________________

Purpose: The SF-36 is a generic questionnaire for assessing quality of life. The Russian translation and validation of the methodology were carried out by the Institute of Clinical Pharmacology Research.

Content (template): The 36 items of the questionnaire are grouped into eight scales: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Each scale score ranges between 0 and 100, where 100 represents full health; all scales form two summary measures: mental and physical component summaries.

Key (interpretation): Results are presented as scores across 8 scales, constructed such that a higher score indicates a higher level of QoL

SF-36 Quality of Life Questionnaire

This questionnaire asks for your views about your health at the present time and over the past 4 weeks. We would like to get a more complete picture of how you feel, how well you are able to do your usual daily activities, and what you think about your own health.

In this questionnaire, the word "health" refers to your general state of health. Thus, this term applies not only to aspects directly related to Pompe disease, but also to your general well-being.

Please answer all the questions, choosing only one answer for each question. Please choose the answers that best match your own feelings. If you are not sure which answer you should choose, please select the most appropriate of the possible answers. For example: to answer question 3, you can choose between "yes, limited a lot", "yes, limited a little", and "no, not limited at all". However, you may not be able to perform some activities at all (anymore). In such cases, you should choose the number in the "yes, limited a lot" column.

1. In general, would you say your health is:

1 = excellent

2 = very good

3 = good

4 = fair

5 = poor

2. Compared to one year ago, how would you rate your health in general now?

1 = much better now than one year ago

2 = somewhat better now than one year ago

3 = about the same as one year ago

4 = somewhat worse now than one year ago

5 = much worse now than one year ago

3. The following questions are about activities you might do during a typical day. Does your health now limit you in these activities? If so, how much?

4. During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a result of your physical health?

5. During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a result of any emotional problems (such as feeling depressed or anxious)?

6. During the past 4 weeks, to what extent has your physical health or emotional problems interfered with your normal social activities with family, friends, neighbors, or groups?

1 = not at all

2 = slightly

3 = moderately

4 = quite a bit

5 = extremely

7. How much bodily pain have you had during the past 4 weeks? (pain localization does not matter)

1 = none

2 = very mild

3 = mild

4 = moderate

5 = severe

6 = very severe

8. During the past 4 weeks, to what extent did pain interfere with your normal work (including both work outside the home and housework)?

(pain localization does not matter)

1 = not at all

2 = slightly

3 = moderately

4 = quite a bit

5 = extremely

9. The questions below concern your well-being and general health over the past 4 weeks. For each question, please give one answer that best reflects how you have been feeling. How much of the time during the past 4 weeks:

10. During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with your social activities (like visiting friends, relatives, etc.)?

1 = all of the time

2 = most of the time

3 = some of the time

4 = a little of the time

5 = none of the time

11. How TRUE or FALSE is each of the following statements for you?

This questionnaire is authorized for use by the IQOLA group (International Quality of Life Assessment Project).