Mucopolysaccharidosis Type II: Clinical Guidelines

List of Abbreviations

ALT – alanine aminotransferase;

AR – allergic reaction;

AST – aspartate aminotransferase;

GAG – glycosaminoglycans;

CT – computed tomography;

MPS – mucopolysaccharidosis;

MRI – magnetic resonance imaging;

CVS – cardiovascular system;

HSCT – hematopoietic stem cell transplantation;

ultrasound – ultrasound examination;

PFT – pulmonary function testing;

ERT – enzyme replacement therapy;

ECG – electrocardiography;

ENMG – electroneuromyography;

EchoCG – echocardiography;

EEG – electroencephalography;

MPR – Merrill-Palmer-Revised Scales of Development.

Terms and Definitions

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

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

Mucopolysaccharidoses (MPS) – a group of inherited metabolic disorders associated with impaired glycosaminoglycan (GAG) metabolism, leading to organ and tissue damage. These conditions are caused by mutations in genes that control the intracellular lysosomal hydrolysis of macromolecules.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Type II MPS (Hunter syndrome) is an inherited lysosomal storage disease with an X-linked recessive inheritance pattern, characterized by decreased activity of the lysosomal enzyme iduronate-2-sulfatase (I2S) due to a mutation in the IDS gene. Enzyme deficiency leads to the accumulation of glycosaminoglycans (GAGs) in lysosomes, predominantly heparan sulfate and dermatan sulfate, and manifests as progressive neuropsychiatric disorders (in the severe form), parenchymal organ involvement, cardiopulmonary disorders, and skeletal deformities [1-3].

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

The cause of the disease is a deficiency or absence of the enzyme iduronate-2-sulfatase (I2S). The iduronate-2-sulfatase gene IDS is mapped to the long arm of the X chromosome, at locus Xq27.1-q28. The inheritance pattern of Hunter syndrome is X-linked recessive. MPS II generally affects only males, although several cases in females have been described, usually associated with chromosomal abnormalities [1-3].

Due to reduced enzyme activity, various types of GAGs accumulate, leading to somatic manifestations such as facial dysmorphism, hepatosplenomegaly, cardiac and respiratory system involvement, skeletal changes, neurological symptoms, as well as hematological and ophthalmological abnormalities. The variability of MPS is determined by the type of accumulated substrate resulting from insufficient GAG degradation: in type II MPS, heparan sulfate and dermatan sulfate accumulate.

1.3 Epidemiology of the Disease or Condition

Type II MPS occurs with a frequency of 1:140,000 to 1:156,000 live male newborns [1,4].

1.4 Features of Coding the Disease or Condition

According to ICD-10, the disease belongs to Class IV, Endocrine, nutritional and metabolic diseases, E76.1 - Mucopolysaccharidosis type II

1.5 Classification of the disease or condition

Based on the deficiency/absence of lysosomal enzymes, corresponding gene defects, and the severity of clinical symptoms, 11 types of MPS are distinguished (Appendix A3.1). Currently, severe (neuropathic) and moderately severe (non-neuropathic) forms of type II MPS are distinguished, depending on the rate of progression of organ and system involvement [1]. Approximately 75% of patients with MPS II have the severe form [52]. The first signs of the severe form of MPS II are often a delay in cognitive development, which usually begins around 1.5 years of age [53].

1.6 Clinical presentation of the disease or condition

The clinical presentation of Hunter syndrome is diverse.

Patient appearance: progressive growth retardation, macrocephaly, facial dysmorphism (flat nasal bridge, widely spaced eyes, thickened lips, hypoplastic mandible, macroglossia, and gingival hyperplasia), short neck, flexion contractures of the extremities, hypertrichosis, low anterior hairline, and long, thick eyelashes and eyebrows. Delayed tooth eruption is typical, and hernias of various localizations are common.

Skin: this form of MPS is characterized by nodulopapular skin lesions, predominantly in the scapular region and on the outer and lateral surfaces of the arms and thighs ("pebble-grain" or "shagreen" skin). These changes are caused by lipid and GAG deposits in the dermis [1,8].

Skeletal system: typically, in the severe form, growth retardation is already evident in the second year of life, and multiple dysostosis develops with joint stiffness due to developing contractures. Cranial bone deformation includes scaphocephaly and macrocephaly. As the child grows, kyphosis and scoliosis progress, and pectus carinatum/excavatum develops. Joint movement limitations arise and progress, frequently leading to a "claw hand" deformity of the hand. Valgus deformity of the lower leg and hip joint pathology sometimes occur.

Respiratory system: frequent respiratory infections (rhinitis, sinusitis), recurrent otitis media often leading to progressive hearing loss, recurrent bronchitis, obstructive bronchitis, pneumonia, and obstructive sleep apnea syndrome are characteristic [1,5,6].

Visual system: pigmentary retinal degeneration; moderate corneal clouding is rare and often detectable only by examining media transparency with a slit lamp. Patients with severe MPS II frequently exhibit retinal dystrophy leading to impaired peripheral and reduced night vision. Papilledema due to elevated intracranial pressure may occur. Glaucoma is rare [5,7].

Central nervous system: in the severe form of the disease, psychomotor and speech development delays are pronounced starting from 1.5–3 years of age. Severe intellectual disability develops by age 8. Seizures are characteristic (especially in the severe form).

Symptomatic epilepsy usually develops in the severe or moderately severe course of the disease. In patients with mild clinical signs, it is extremely rare. Seizures are characterized by a polymorphic clinical picture with various focal and secondary generalized paroxysms. Early clinical manifestations of seizure syndrome may include simple absences with brief depression or loss of consciousness accompanied by motor or autonomic disorders. In patients with mild clinical signs, seizure syndrome is much less common. The onset of seizures warrants a neurological status assessment. As the disease progresses, generalized tonic-clonic paroxysms are frequently observed, which usually respond well to antiepileptic monotherapy. Anticonvulsant therapy requires an individualized approach and sometimes prolonged dose titration. Management at lower doses of antiepileptic drugs is often necessary due to poor tolerance of high doses.

Communicating hydrocephalus and spastic para- and tetraparesis frequently develop.

Signs of hydrocephalus often appear slowly and insidiously, and may include behavioral changes, headache, and visual impairment.

Cases of spinal cord compression caused by thickening of its meninges or atlantoaxial joint instability have also been described. Craniocervical stenosis develops in MPS II patients due to hypoplasia of the odontoid process of the C2 vertebra, atlantoaxial instability, and GAG deposition in the dura mater and posterior longitudinal ligament, which subsequently leads to compression myelopathy at this level and, consequently, the development of bulbar disorders and central respiratory failure. Symptoms may include gait disturbance, muscle weakness, clumsiness despite preserved motor skills, and bladder dysfunction.

Carpal tunnel syndrome is a frequent entrapment neuropathy in patients aged 3 to 10 years. In the early stages of the disease, numbness of the affected hand, difficulty performing fine motor tasks, and decreased sensation in the fingers occur. These symptoms are rarely reported by the child and are not perceived as pathological by the parents. Later, paresthesias and a tingling sensation in the fingertips appear, and over time the process may spread to the forearm and arm. Patients often do not report pain until function is lost.

Swallowing disorders: contractures of the temporomandibular joints lead to decreased mobility of the mandible, which limits the ability to open the mouth and chew. Swallowing disorders are observed in moderate and severe courses of the disease and are associated with the functioning of the brainstem structures. When their function is impaired, signs of pseudobulbar or bulbar paralysis are observed. Symptoms debut with rare choking on solid food and hypersalivation, develop gradually, and ultimately lead to a severe impairment of the swallowing function or its complete loss. The lack of proper regulation of the swallowing act leads to the reflux of food and saliva into the trachea and bronchial tree and the development of secondary infection in the form of recurrent aspiration bronchitis and pneumonia. This exacerbates respiratory disorders, which are a consequence of GAG deposition in the upper and lower respiratory tracts.

Behavioral disorders—hyperactivity, disinhibition, aggressiveness, and stubbornness—typically occur in adult patients with moderate and severe forms of MPS II. Behavioral problems significantly affect the patient's daily life and social adaptation. Appearing in the second year of life, they persist up to 8–12 years of age. Cognitive regression, along with severe hearing loss and sleep disorders (especially those caused by obstructive sleep apnea), has a significant impact on the behavior of the child and young adult. As cognitive deficits increase, autistic features join hyperactivity and aggressiveness, and a gradual loss of expressive and receptive speech skills is noted. Pharmacological therapy aimed at controlling destructive behavior is often ineffective. Subsequently, the progression of neurodegenerative changes leads to dementia and motor disorders, which overshadow behavioral peculiarities.

Cardiovascular system: due to GAG deposition from an early age, the heart valves thicken, resulting in regurgitation or stenosis. In some cases, hypertrophy of the heart muscle, a decrease in its elasticity, conduction disturbances, and coronary artery disease may develop.

Heart valve pathology (insufficiency and/or stenosis of the mitral, aortic, tricuspid, and pulmonary valves) is more common. Coronary vessel involvement occurs. The major vessels in patients with MPS may have thickened walls, but at the same time may be narrowed or dilated. Due to arterial narrowing, such patients develop clinically significant arterial hypertension. Widening of the ascending aorta and a significant decrease in the elasticity of the aortic walls are observed. In infiltrative cardiomyopathy, myocardial hypertrophy or ventricular dilation is detected. Patients may have cardiac rhythm and conduction disorders. The course of heart failure (HF) in MPS II is progressive in nature. Difficulties in diagnosing this condition are associated with the non-specificity of clinical symptoms and the absence of complaints or characteristic signs of circulatory disorders in the early stages of its development.

Gastrointestinal system: due to limited range of motion of the mandible and difficulty in chewing food, tonsillar hypertrophy, and macroglossia, swallowing disorders and sialorrhea develop; diarrhea associated with GAG accumulation in the nerve cells of the digestive tract is possible. Constipation frequently develops with age. Hepatosplenomegaly has been noted from an early age. Umbilical and inguinal hernias are characteristic [1,5].

The severity of clinical manifestations according to age is presented in Appendix A3.2.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of MPS type II is established based on a combination of anamnesis, clinical data, and the results of laboratory tests (biochemical and molecular genetic analysis).

Differential diagnosis is carried out with other types of MPS, alpha-mannosidosis, late forms of gangliosidosis, mucolipidosis, non-infectious polyarthritis, and epiphyseal dysplasias [1,2,3,14,16].

The main distinguishing features of MPS type II are: a clear cornea and the presence of skin changes resembling "pebble grain" [7,8].

Patients with a confirmed diagnosis of MPS II undergo dynamic and follow-up monitoring (the average frequency of consultations and examinations is presented in Appendix A3.3).

2.1 Complaints and Anamnesis

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

– burdened family history (similar symptoms in siblings and maternal relatives);

– short stature;

– coarse facial features;

– frequent respiratory infections;

– psychomotor developmental delay (only for the severe form of the disease);

– mental developmental delay/regression (only for the severe form of the disease);

– hearing loss;

– vision loss;

– multiple dysostosis (deformities of the skull, chest, spine, and limbs);

– posture disorders—kyphosis, scoliosis;

– recurrent hernias (more often bilateral);

– decreased exercise tolerance;

– limb weakness;

– joint stiffness;

– difficulty rising from sitting and lying positions;

– gait abnormalities;

– fine motor clumsiness;

– pelvic organ function disorders;

– sleep apnea.

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

2.2 Physical Examination

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

– coarse facial features;

– short stature;

– behavioral disorders (for the severe form of the disease);

– joint stiffness;

– corneal clouding;

– hepatomegaly;

– splenomegaly;

– inguinoscrotal and umbilical hernias (bilateral);

– heart murmurs.

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

2.3 Laboratory Diagnostics

The main laboratory methods for confirming the diagnosis of MPS II include determining the activity of the enzyme iduronate-2-sulfatase, quantitative and qualitative analysis of urinary GAGs, and molecular genetic testing of the IDS gene.

Comment: quantitative analysis (study of the urinary glycosaminoglycan spectrum by tandem mass spectrometry or spectrophotometry) reveals an increased urinary concentration of GAGs, with increased excretion of dermatan sulfate and heparan sulfate. These changes are also observed in MPS types I and VII. The GAG level is an age-dependent parameter. Also, in the mild form of MPS II, the urinary GAG concentration may be only slightly elevated. The test is performed as dynamic monitoring for patients receiving enzyme replacement therapy at least once every 6 months, and for patients not receiving enzyme replacement therapy, at least once a year.

Comment: patients with Hunter syndrome show a decrease in iduronate-2-sulfatase activity in fibroblast culture, blood plasma, or dried blood spots on filter paper. It is necessary to measure the activity of other sulfatases to exclude multiple sulfatase deficiency.

Collection of biomaterial for diagnosis using dried blood spots is described in Appendix A3.4.

Comment: identification of a familial mutation in the IDS gene makes it possible to examine relatives of the proband, identify female heterozygous carriers of MPS II, and perform prenatal and preimplantation diagnostics. Most mutations in patients with MPS II can be detected by Sanger sequencing of all exons and adjacent intron regions of the gene, but in a small percentage of cases, the mutation cannot be detected using standard methods. Approximately 20% of all mutations are large gene rearrangements, which may require additional, more complex molecular genetic tests.

In accordance with Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services," the name of the service is: A set of tests for diagnosing mucopolysaccharidosis type II.

Comments: cholesterol testing also includes, inter alia, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, total blood lipoproteins, and blood triglycerides. The test should be performed during follow-up monitoring, on average, once every 6 months.

Comments: due to the high risk of intercurrent infections and aspiration pneumonia in patients with MPS, this test is recommended to be performed, on average, twice a year.

Comments: this test is recommended to be performed at least twice a year.

Comments: testing frequency is, on average, once a year, or more frequently if clinically indicated (prior to any surgical intervention).

Comment: testing frequency: once a year.

2.4 Instrumental Diagnostics

Comments: moderate hepatomegaly or hepatosplenomegaly is detected. Liver and spleen dimensions decrease during therapy. The choice of imaging modality is determined individually based on patient availability and clinical necessity. Anesthesia/sedation is used when required. Frequency of examination is once a year, or more often if necessary.

Comments: findings include multiple dysostoses, scaphocephaly, hypoplasia of the odontoid process of the C2 vertebra, thoracolumbar kyphosis resulting from platyspondyly, and lumbar hyperlordosis. Wide ribs, short curved clavicles, hypoplasia of the humeral heads, and proximal varus deformity of the humerus are identified; the distal epiphyses of the forearm bones are inclined toward each other. Delayed appearance of ossification centers. Metacarpal bones of the hands are shortened and narrowed—"pointed" proximally; acetabular "slanting", deformed, flattened femoral heads, and valgus deformity of the femoral necks are observed. Examinations are performed at least once a year, or for mild forms—typically at least once every 2 years.

Comments: stimulation ENMG allows for the detection of median nerve compression even before the appearance of symptoms (starting from the age of 4–5 years—at least once every 12 months).

Comments: hypertrophy of the adenoids and tonsils is observed in patients from an early age. If indicated, endoscopic endonasal revision of the nasal cavity and nasopharynx, epipharyngolaryngoscopy, and video-endoscopic epipharyngoscopy are performed (on average, twice a year).

Comments: hearing loss of varying severity is characteristic of this disease. It may be conductive, sensorineural, or mixed. Early detection of hearing loss improves the patients' quality of life and ensures the possibility of communication and learning.

Comments: in accordance with Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services": Study of unforced respiratory volumes and flows, Study of respiratory volumes using medicinal products. The study is performed at least once a year.

Comments: changes in the lung tissue may also be detected during the study. This study should also be considered in the presence of auscultatory changes in the lungs due to the possibility of pneumonia development in patients with MPS II. The frequency of the study is determined individually, on average, once every 2 years.

Comments: electroencephalography with video monitoring should be chosen as the most informative method for this study. The study should be performed during initial diagnosis and subsequently on an annual basis in the absence of contraindications.

Comments: polysomnography/cardiorespiratory monitoring is performed to diagnose and assess the severity of obstructive sleep apnea, which helps determine the nature of respiratory disorders (to rule out central origin, connection with adenoid hypertrophy, heart failure, or a complex of causes) and cardiovascular pathology.

In accordance with Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services", the service "Polysomnography" is not listed; therefore, a set of services may be used: video-electroencephalography monitoring, 24-hour blood pressure monitoring, electrocardiogram recording, electrocardiographic data monitoring, Holter electrocardiographic monitoring, decoding, description and interpretation of electrocardiographic data, cutaneous electromyography (one anatomical region), electrooculography, determination of soft tissue oxygen partial pressure (oximetry)/pulse oximetry) (Appendix A3.3).

Comments: regular ECG, echocardiography, Holter ECG monitoring, and 24-hour blood pressure monitoring are necessary for patients with this pathology, as cardiovascular disorders are noted from an early age. These are performed, on average, once a year, or more frequently if necessary. In accordance with Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services": 24-hour blood pressure monitoring, electrocardiogram recording, electrocardiographic data monitoring, Holter electrocardiographic monitoring, decoding, description, and interpretation of electrocardiographic data.

Comments: atlantoaxial joint instability can be detected by radiography of the cervical spine with functional tests, but confirmation of spinal cord compression due to thickening of its membranes and developing vertebral anomalies requires MRI and/or CT. The examination(s) are also performed during patient follow-up, with the frequency determined individually (on average, once every two years). Anesthesia is performed if necessary. Anesthetic management (including early postoperative management) as clinically indicated.

Comments: the frequency of examinations is, on average, once a year. Corneal clouding is not characteristic of patients with MPS II. Some patients develop glaucoma and pigmentary retinal degeneration. Optic disc edema is rare.

Comments: the 6-minute walk test is one of the simplest and most accessible ways to assess the endurance and functional capabilities of patients with MPS with cardiac and pulmonary pathology, see Appendix A3.5.

The test is usually performed starting from 5 years of age (at least twice every 12 months). Exercise tolerance is assessed using the Borg scale (Appendix G1).

Comments: there is no evidence-based data on the optimal frequency of the examination; it is performed, on average, once every 1–2 years.

Comments: there is no evidence-based data on the optimal frequency of the examination; it is performed, on average, once every 1–2 years (if possible).

2.5 Other Procedures

Comments: diagnosis and monitoring of children with MPS II are usually carried out by a pediatrician or geneticist; consultations with the following specialists are necessary at least once every 6 months or more frequently if indicated: initial and follow-up consultation (examination) by an otolaryngologist, initial and follow-up consultation (examination) by a neurologist, medical psychologist, initial and follow-up consultation (examination) by a pediatric cardiologist, initial and follow-up consultation (examination) by a pediatric traumatologist-orthopedist, initial and follow-up consultation (examination) by an ophthalmologist with examination of the anterior segment of the eye by side illumination, measurement of intraocular pressure (ophthalmotonometry) and assessment of the fundus (ophthalmoscopy) to detect glaucoma, changes in the transparency of the optical media and the condition of the retina, pediatric dentist, physical therapy doctor, physical therapist / physical and rehabilitation medicine doctor / medical rehabilitation doctor [2,5,14,19,84].

If indicated, a consultation with an otolaryngologist-audiologist is recommended, including pure-tone audiometry, on average, once a year.

Initial and follow-up consultations (examinations) by a pediatric surgeon, initial and follow-up consultations (examinations) by a neurosurgeon, initial and follow-up consultations (examinations) by an anesthesiologist-resuscitologist (in the presence of pathology requiring surgical intervention), initial and follow-up consultations (examinations) by a pulmonologist (in the presence of respiratory system pathology) are performed [2,5,14,18,19]. The frequency of consultations is determined individually, depending on the clinical situation.

Comment: the prescription of pathogenetic treatment and monitoring of its efficacy and safety can be carried out by a geneticist or another specialist with experience in treating patients with MPS II.

Comment: the prescription of pathogenetic treatment and monitoring of its efficacy and safety can be carried out by a pediatrician or another specialist with experience in treating patients with MPS II.

Comment: pathogenetic treatment and monitoring of its efficacy and safety may be prescribed by a pediatric cardiologist or another specialist experienced in treating patients with MPS II.

Other tests are performed as decided by a medical board. When assessing a child's functional developmental domains, the choice of a specific diagnostic tool should be determined by the child's age, preliminary information on the severity of social and communicative impairments, the presence or absence of suspected intellectual and speech delays, as well as a number of additional parameters, such as the availability of the methodology, the required qualifications of the specialist, and the time resources available for diagnostic assessment. Among standard tools for assessing the cognitive sphere in children with MPS II, the most widely used in clinical and research practice are:

√ To verify the state of cognitive/intellectual development of children with MPS II in the absence of hearing impairment, the following are used, for example:

- at the age of 1 month to 6.5 years – assessment using the Merrill-Palmer-Revised Scales of Development (MPR) [55, 88] (Appendix G2),

- over the age of 5 years – assessment using the Wechsler Intelligence Scale for Children (WISC) [57] (Appendix G3).

√ To verify the state of non-verbal intelligence and cognitive functions in cases of hearing impairment / suspected hearing impairment, for example:

- in children older than 3 years, assessment is performed using the Leiter International Performance Scale, Third Edition (Leiter-3) [54, 88] (Appendix G4).

Note: other interchangeable methods may also be used in clinical practice.

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

Treatment of MPS type II includes both pathogenetic treatment—enzyme replacement therapy (ERT)—and symptomatic therapy. Management of patients with MPS type II involves a multidisciplinary approach with the participation of a pediatrician / general practitioner (family doctor), neurologist, medical psychologist, otorhinolaryngologist, geneticist, pediatric cardiologist, pulmonologist, gastroenterologist, pediatric dentist, maxillofacial surgeon, neurosurgeon, anesthesiologist-resuscitologist, exercise therapy doctor, physical therapy and rehabilitation doctor / physical medicine and rehabilitation physician and, if necessary, other specialists with experience in treating this rare disease, as well as medical psychologists.

3.1 Pathogenetic treatment

Comments: for ERT in MPS type II, idursulfase**, idursulfase beta** (for intravenous infusion), and idursulfase beta (for intracerebroventricular administration) (in children aged 1 year and older) are used.

ERT significantly improves patients' condition, reduces spleen and liver size, increases pulmonary function parameters, and lowers urinary GAG levels. Intravenously administered medication does not cross the blood-brain barrier (BBB) and therefore cannot correct neurological impairments. Intracerebroventricular ERT ensures direct delivery of the drug into the cerebral ventricles, leading to a decrease in GAG concentration in the cerebrospinal fluid, thereby helping to stabilize and slow the progression of neurological symptoms in patients with MPS II [62].

One of the latest analyses from the Hunter Outcome Survey (HOS) has convincingly demonstrated an increase in the life expectancy and quality of life of patients with MPS II receiving ERT.

ERT with idursulfase** or idursulfase beta** (for intravenous infusion) is prescribed lifelong and continuously at a dose of 0.5 mg/kg once a week as an intravenous infusion lasting 3 hours with a maximum infusion rate of up to 40 mL/h on an outpatient basis or in a day/24-hour hospital setting. The entire volume of the drug must be diluted in 100 mL of sodium chloride** 9 mg/mL (0.9%) solution. The infusion time can be gradually reduced to 1 hour if no adverse reactions develop during the infusion.

The infusion is administered via peripheral or central venous access and is monitored by medical personnel.

If allergic reactions occur in response to the infusion, patients may be prescribed systemic antihistamines (orally or intramuscularly) and/or low doses of systemic corticosteroids, selective beta-2 agonists (for inhalation); for fever and headache management, antipyretic therapy (with paracetamol** (from the age of 1 month) or ibuprofen** (from the age of 3 months) orally) [42]. If an adverse reaction occurs, the infusion must be stopped until symptoms resolve and then resumed at half the rate at which it was being administered. If an anaphylactoid/anaphylactic reaction develops, the infusion should be stopped immediately, appropriate treatment and monitoring initiated. Modern emergency care standards [29, 30] and relevant clinical guidelines should be followed, see Appendix A3.6 and Appendix A3.7.

Abrupt discontinuation of ERT or interruptions in ERT are undesirable and may lead to clinical deterioration in patients [20].

Severe or life-threatening hypersensitivity reactions that cannot be controlled are a contraindication to re-administration of the drug (data from the package leaflets for idursulfase**, idursulfase beta** (for intravenous infusion), and the package leaflet for idursulfase beta for intracerebroventricular administration (in children aged 1 year and older)).

Idursulfase** is a purified recombinant form of the enzyme iduronate-2-sulfatase produced in a human cell line, capable of providing a glycosylation profile similar to the native enzyme.

Idursulfase beta** (for intravenous infusion) is produced from recombinant Chinese hamster ovary (CHO) cells transfected with a plasmid encoding a 550-amino acid human iduronate-2-sulfatase protein, including a 25-amino acid signal sequence.

Idursulfase beta** for intravenous infusion is indicated for patients aged 0 months and older [63, 64]. In 2018, this medicinal product was approved for use in the Russian Federation. The production of proteins in the CHO line does not require the use of serum, therefore products manufactured using this line have a lower risk of allergic complications due to the fact that anti-drug antibodies may develop less frequently than with the administration of idursulfase** [10, 65].

Idursulfase beta for intracerebroventricular administration is indicated for the long-term treatment of adults and children aged 1 year and older. Idursulfase beta for intracerebroventricular administration should be used in patients who are already receiving intravenous ERT (idursulfase beta** (for intravenous infusion) or idursulfase**) and tolerate it well. Prescription of the drug should be considered to ameliorate central nervous system symptoms.

Administration of the medicinal product requires the implantation of an intracerebroventricular access device (ventricular reservoir). To prevent fluctuations in intraventricular pressure, cerebrospinal fluid (2 mL)—equal in volume to the dose to be administered—is withdrawn prior to drug administration. Idursulfase beta for intracerebroventricular administration is given undiluted over at least 1 min. Idursulfase beta should be administered intracerebroventricularly at a dose of 30 mg (2 mL) once every 4 weeks (in children aged 1 year and older) [62]. Currently, there is a limited number of publications comparing the efficacy of the two ERT products for Hunter syndrome and their use in different patient populations.

The evidence base for the efficacy and safety of idursulfase beta** (for intravenous infusion) is based on data from 4 clinical studies involving 61 patients with Hunter syndrome. These include the phase I/II study NCT01301898 (31 patients) [79] and the phase III study NCT01645189 (6 children under 6 years of age) [10,80].

The evidence base for idursulfase beta (for intracerebroventricular administration) includes the phase I/II study JPRN-JMA-IIA00350 (6 patients) [81] and the phase III study NCT03920540 (29 patients) [65].

The medicinal products idursulfase** and idursulfase beta** (for intravenous infusion) have identical amino acid sequences, but are produced in different cell lines, have different INNs, and are not interchangeable. Switching from one product to another is possible either in the event of uncontrolled serious adverse events (AEs) recurring despite adequate pre-infusion premedication, or in the case of inefficacy of the drug used for enzyme replacement therapy (ERT), confirmed by laboratory data (no dynamics in GAG reduction) and instrumental studies (no dynamics in liver/spleen size reduction). The decision to switch must be made solely upon the conclusion of a medical board of a Federal Center.

Administration of idursulfase** and idursulfase beta** (for intravenous infusion) is performed via a peripheral venous catheter (peripheral catheter) or a port system (implantable infusion/injection port***) installed in accordance with the guidelines "Venous Access, 2019" (https://msestra.ru/download/file.php?id=4763) using necessary medications. Port systems are installed in accordance with Decree of the Government of the Russian Federation No. 3053-r dated December 31, 2018, "On approval of the list 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, as well as the list of medical devices dispensed on prescription for medical devices when providing a set of social services."

Treatment is performed in the absence of contraindications.

Pathogenetic treatment and monitoring of its efficacy and safety may be prescribed by a medical geneticist or another specialist with experience in treating patients with MPS II.

3.2 Symptomatic treatment

Comments: in MPS patients receiving ERT, as with the IV administration of any other protein drug, adverse reactions (fever, chills, vomiting, urticaria, severe allergic-type hypersensitivity reactions) may develop either during the infusion or on the day of the infusion. If adverse reactions occur during/after the infusion, appropriate treatment is recommended, following current standards of medical care (see Appendix A3.6, Appendix A3.7 )).

Comment: treatment of behavioral disorders is carried out by a neurologist; medications from the group of "Hypnotics and sedatives", anxiolytics, and others are usually used. The choice of drug, dosage, and duration of the course are determined individually. Administration of these drugs is initiated under close medical supervision in an inpatient/day-care setting [2,12,14,16,43]. Level of recommendation C (level of evidence – 5).

Comments: are carried out in accordance with relevant guidelines, taking into account the specifics of the underlying disease.

Non-surgical methods: physical therapy procedures (e.g., transcutaneous electrical nerve stimulation for diseases of the peripheral nervous system, etc.) and therapeutic exercise (exercise therapy for diseases and injuries of joints), and the use of orthopedic devices (e.g., orthoses).

According to indications (in accordance with relevant clinical guidelines) - surgical treatment of carpal tunnel syndrome, hip or knee arthroplasty (Orthopedic hip arthroplasty, Orthopedic hip arthroplasty (resection of the proximal femur), Orthopedic knee arthroplasty (resection of the distal femur), Orthopedic knee arthroplasty), corrective osteotomies (Bone reconstruction. Bone osteotomy using biodegradable materials, Bone reconstruction. Corrective osteotomy for foot deformity, Bone reconstruction. Corrective femoral osteotomy, Bone reconstruction. Corrective tibial osteotomy, Bone reconstruction. Bone osteotomy using internal fixators and external fixation devices).

Comments: drugs are prescribed in accordance with relevant guidelines.

Comments: the off-label use of medicinal products in children—outside the indications approved in the drug's instructions—is carried out by decision of a medical commission subject to signed informed consent.

Comments: a positive effect of chronic pain pharmacotherapy in patients with MPS can be achieved by taking into account the medications the patient is already taking and through regular monitoring of treatment safety. The least invasive method should be used when treating pain syndrome in a patient.

3.3 Surgical Treatment

Surgical treatment of patients with MPS II should be performed with the participation of a multidisciplinary team in accordance with current clinical guidelines.

Comments: the recurrence rate of carpal tunnel syndrome in patients with various types of MPS is unknown. Since recurrent compression of the median nerve due to scarring or glycosaminoglycan deposition is possible, follow-up monitoring must be continued.

Comments: spinal cord compression leads to irreversible neurological deficits, surgery should be considered even in patients without neurological symptoms if the sagittal diameter of the spinal canal is narrowed by more than 50%. Surgical intervention should be performed before the development of neurological manifestations.

Comments: the following may be performed: surgical replacement of the hip or knee joint (orthopedic hip replacement, orthopedic hip replacement (proximal femur resection), orthopedic knee replacement (distal femur resection), orthopedic knee replacement), corrective osteotomies of the limb bones (bone reconstruction using biodegradable materials, corrective osteotomy for foot deformity, corrective femoral osteotomy, corrective lower leg osteotomy, bone reconstruction using internal fixators and external fixation devices).

Comments: these interventions are used in patients with MPS type II, as in the general population, for obstructive sleep apnea syndrome, secretory otitis media, nasal breathing difficulty, and recurrent upper respiratory tract infections. However, it should be taken into account that in MPS type II, surgical intervention is required more frequently than in typically developing children. Patients with MPS type II should be offered the most gentle and effective techniques, favoring endoscopic interventions [48,49,50].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: rehabilitation measures for patients with MPS II may include sessions with a medical psychologist, stays in specialized sanatoriums, as well as social adaptation involving specialists and social workers, massage courses (general medical massage, massage for peripheral nervous system disorders), yoga, physical therapy for joint diseases and injuries, and the application of heat and cold.

It is important to train the patient to facilitate mobility and posture alignment, as well as to prevent contracture formation and scoliosis progression.

If the disease causes kyphotic deformity or a spinal anomaly, orthoses are used as supportive treatment (provided that high cervical spinal cord compression is absent). The necessary methods are determined by an orthopedic traumatologist.

Percutaneous electrical nerve stimulation may be performed for peripheral nervous system disorders to control hyperalgesia and allodynia.

It is possible to consider the application of impact on acupuncture points using other physical factors (acupuncture and acupressure) for analgesia (the evidence base is limited).

Since MPS II can lead to neurocognitive changes such as behavioral disorders, sleep problems, etc., comprehensive psychological approaches are used, which include educational and behavioral programs, mindfulness and relaxation exercises, and may also serve as an appropriate strategy to manage stress levels in these patients and prevent symptom exacerbation. They can also be applied to family members of patients with MPS II to provide support and alleviate the burden of the disease. There are reports of animal-assisted therapy and music therapy in comprehensive rehabilitation regarding pain syndrome, but currently, evidence of the efficacy of these methods is insufficient.

5. Prevention and Dispensary Observation

Patients with MPS II are at risk for infectious diseases, including due to a high risk of intercurrent infections and aspiration pneumonia [66,67]. There is no data on contraindications for routine vaccination according to the National Immunization Schedule in patients with MPS II [66,68,69].

Comments: patients with MPS II should be administered vaccines [68]. Despite the rarity and severity of the disease, it should be remembered that vaccinating patients with MPS II is mandatory, as immunizations help prevent acute respiratory infections; first and foremost, vaccination against pneumococcal infection and influenza is necessary [69].

5.1 Prenatal Diagnostics of MPS II

Comments: hemizygous males carry a single mutant X chromosome, which they transmit only to their daughters, but not to their sons.

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

○ for a female carrier of the mutation, the risk of having a boy with MPS II is 50%, and the risk of having a female carrier is 50%;

○ for a man with MPS II, the risk of having a female carrier of the mutation is 100%.

5.2 Dispensary Follow-up of Children with MPS II

Patient follow-up at the place of residence (outpatient clinic settings) must be carried out continuously. Laboratory and instrumental examinations and their recommended frequency are presented in Appendix A3.3. The disease has a multisystem nature and irreversible, progressive clinical manifestations, which necessitates ongoing follow-up/dispensary monitoring not only by subspecialists (otorhinolaryngologists, pediatric surgeons / orthopedic traumatologists, neurosurgeons, maxillofacial surgeons, anesthesiologists-resuscitologists, ophthalmologists, pediatric cardiologists, pulmonologists, neurologists, pediatric dentists), but also by physical therapists, exercise therapy physicians, medical speech therapists, medical psychologists, and palliative care staff, as needed (initial palliative care consultation / follow-up palliative care consultation, etc.) [2,14,20].

Patients with MPS II must be under continuous supervision, undergoing dynamic evaluation in multidisciplinary inpatient facilities every 6 months, including necessary specialist examinations, laboratory and instrumental tests (see Section 2).

Comments: due to the high risk of intercurrent infections and aspiration pneumonia in patients with MPS, this test should be performed, on average, twice a year.

Comments: this study should be performed at least twice a year.

Comments: moderate hepatomegaly or hepatosplenomegaly is detected. With therapy, the size of the liver and spleen decreases. Frequency of the examination: once a year, or more often if necessary.

Comments: regular ECGs, and when necessary – echocardiography, Holter heart rhythm monitoring, and 24-hour blood pressure monitoring are required for patients with this condition, as cardiovascular disorders are noted from an early age. These are performed, on average, once a year, or more often if necessary.

Comments: patients exhibit adenoid and tonsillar hypertrophy from an early age.

If indications are present, endoscopic endonasal revision of the nasal cavity and nasopharynx, epipharyngolaryngoscopy, and video-endoscopic epipharyngoscopy are performed (on average, twice a year).

6. Organization of Medical Care

6.1 Indications for hospital admission:

6.1.1 Indications for elective hospitalization

– provision of diagnostics and treatment requiring round-the-clock medical supervision;

– condition requiring active treatment and round-the-clock medical supervision (herniorrhaphy, surgical treatment of joint and spinal lesions, scoliosis, adenoidectomy, tonsillectomy, neurosurgical decompression of carpal tunnel syndrome, tympanostomy tube placement (transtympanic drainage) for otitis media, surgical correction of cardiovascular system pathology, and others);

– inability to provide ERT in outpatient and day-care settings;

– necessity of performing various types of examinations or evaluations in a medical organization when outpatient implementation is impossible, requiring dynamic monitoring (including issuing a federal concilium opinion);

– decision to replace the drug for enzyme replacement therapy (idursulfase** and idursulfase beta**).

6.1.2 Indications for Emergency Hospitalization

– acute illnesses;

– exacerbations of chronic diseases;

– poisoning and injuries, conditions requiring intensive care and transfer to intensive care units or critical care units (including adverse reactions occurring during the infusion or on the day of the ERT infusion, cervical stenosis with spinal cord compression, and other life-threatening acute conditions), as well as round-the-clock medical observation and special types of examination and treatment.

6.2 Indications for Discharge from the Inpatient Facility

1) absence of a threat to the patient's life;

2) absence of a threat of complications requiring urgent treatment;

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

4) absence of the need for continuous medical and round-the-clock observation for the underlying disease;

5) the need to transfer the patient to another hospital or social welfare institution.

7. Additional Information

During anesthesia and intubation, one must remember the high risk of spinal cord compression due to atlantoaxial joint instability. A short neck, restricted mobility of the lower jaw, macroglossia, and marked adenoid and tonsillar hypertrophy create difficulties during anesthetic management; therefore, preference should be given to local or regional anesthesia. The patient is pre-consulted by a pediatric cardiologist, otorhinolaryngologist, anesthesiologist-resuscitologist, and neurologist. A full cardiological examination and polysomnography (to detect the severity of respiratory disorders) are mandatory, along with nasopharyngeal endoscopy and computed tomography of the lungs if necessary. Surgical intervention with anesthesia should be performed in large medical centers equipped with an intensive care unit (ICU), as intubation and subsequent extubation in such patients can be difficult [2,14,20].

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for primary health care provided to children with mucopolysaccharidosis type II (ICD-10 codes: E76.1)

Quality assessment criteria for specialized medical care provided to children with mucopolysaccharidosis type II (ICD-10 codes: E76.1)

References

Appendix A1. Working Group Composition

1. Baranov Alexander Alexandrovich – Academician of the RAS, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pediatricians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the Academician V.I. Petrovsky National Medical Research Center of Surgery, Professor of the Department of Pediatrics and Pediatric Rheumatology at the I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Chief freelance pediatric specialist of the Russian Ministry of Health.

2. Kutsev Sergey Ivanovich – Academician of the RAS, Doctor of Medical Sciences, Director of the Research Centre for Medical Genetics, President of the Association of Medical Geneticists (AMG).

3. Namazova-Baranova Leyla Seymurovna – Academician of the RAS, Professor, Doctor of Medical Sciences, President of the Union of Pediatricians of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health of the Academician V.I. Petrovsky National Medical Research Center of Surgery, Head of the Department of Faculty Pediatrics at the Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University), Chief freelance pediatric specialist in preventive medicine of the Russian Ministry of Health.

4. Inha V. Anisimova — Cand. of Sci. (Med.), Head of the Medical Care Organization Department, Geneticist at the Research Centre for Medical Genetics (Bochkov Research Centre for Medical Genetics), Member of the Association of Medical Geneticists.

5. Galina V. Baidakova — Cand. of Sci. (Biol.), Leading Researcher at the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics (Bochkov Research Centre for Medical Genetics).

6. Irina V. Vakhlova — Dr. of Sci. (Med.), Professor, Head of the Department of Hospital Pediatrics, Faculty of Pediatrics, Ural State Medical University.

7. Nato D. Vashakmadze — Dr. of Sci. (Med.), 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 of the Department of Faculty Pediatrics, Faculty of Maternal and Child Health, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Member of the Union of Pedatricians of Russia.

8. Elena A. Vishneva — Dr. of Sci. (Med.), Professor of the Russian Academy of Sciences, Deputy Head for Research at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery of the Ministry of Science and Higher Education of the Russian Federation; Professor of the Department of Faculty Pediatrics, Faculty of Maternal and Child Health, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Member of the Union of Pediatricians of Russia.

9. Elena Yu. Voskoboeva — Cand. of Sci. (Med.), Leading Researcher at the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics.

10. Natalia V. Zhurkova — Cand. of Sci. (Med.), Leading Researcher at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Member of the Union of Pediatricians of Russia, Member of the Association of Medical Geneticists.

11. Ekaterina Yu. Zakharova — Dr. of Sci. (Med.), Head of the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics (Bochkov Research Centre for Medical Genetics); Member of the Russian Society of Medical Geneticists, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

12. Irina V. Zelenkova — Cand. of Sci. (Med.), Leading Researcher at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery.

13. Georgy A. Karkashadze — Cand. of Sci. (Med.), Head of the Department of Ontogenetic Brain Development, Cognitive Function Formation and Neurobiology, Neurologist at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Member of the Union of Pediatricians of Russia.

14. Lyudmila M. Kuzenkova — Dr. of Sci. (Med.), National Medical Research Center for Children's Health of the Russian Ministry of Health; Professor of the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University).

15. Valentina I. Larionova — Dr. of Sci. (Med.), Institute of Experimental Medicine.

16. Yulia G. Levina — Dr. of Sci. (Med.), Head of the Department of Clinical Immunology and Allergology, Allergist-Immunologist at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery of the Ministry of Science and Higher Education of the Russian Federation; Associate Professor of the Department of Faculty Pediatrics, Faculty of Maternal and Child Health, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Member of the Union of Pediatricians of Russia.

17. Lyudmila K. Mikhailova — Dr. of Sci. (Med.), Professor, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Scientific Secretary, National Medical Research Center of Traumatology and Orthopedics named after N.N. Priorov of the Russian Ministry of Health.

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

19. Sergey V. Moiseev — Dr. of Sci. (Med.), Head of the Department of Internal, Occupational Diseases and Rheumatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

20. Lyudmila P. Nazarenko — Dr. of Sci. (Med.), Professor, Honored Doctor of the Russian Federation, Head of the Laboratory of Hereditary Pathology, Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences; Member of the Russian Society of Medical Geneticists, Member of the Association of Medical Geneticists, Member of the European Society of Human Genetics.

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

22. Aleksandr V. Pashkov — Dr. of Sci. (Med.), Head of the Department of Otorhinolaryngology and Audiology, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery.

23. Tatiana A. Polunina — Cand. of Sci. (Med.), Otorhinolaryngologist, Member of the Union of Pediatricians of Russia.

24. Olga A. Polyakova — Trauma and Orthopedic Surgeon, National Medical Research Center of Traumatology and Orthopedics named after N.N. Priorov of the Ministry of Health of the Russian Federation.

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

26. Alla N. Semyachkina — Dr. of Sci. (Med.), Chief Researcher, Department of Clinical Genetics, Academician Yu.E. Veltiščev Research Institute of Pediatrics, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Member of the Association of Medical Geneticists (AMG).

27. Olga Ya. Smirnova — Geneticist, Senior Researcher at the Department of Standardization and Study of Evidence-Based Medicine Foundations, 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.

28. Olga V. Udalova — Cand. of Sci. (Med.), Medical Genetics Center "Genom LLC", Chairperson of the Nizhny Novgorod Branch of the Russian Society of Medical Geneticists, Head of the Center for Medical Genetics, Privolzhsky Research Medical University of the Russian Ministry of Health, Nizhny Novgorod.

29. Marina V. Fedoseenko — Cand. of Sci. (Med.), Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Status Deviations and Chronic Diseases, Leading Researcher, Pediatrician at the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Associate Professor of the Department of Faculty Pediatrics, Faculty of Maternal and Child Health, Pirogov Russian National Research Medical University (Pirogov 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.

Mucopolysaccharidoses are rare genetic disorders, which precludes large cohort and randomized controlled trials; therefore, diagnostic and therapeutic protocols are based exclusively on expert case studies published over the past two decades.

The evaluation of the levels of evidence and the grades of recommendation for medical technologies was carried out 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. Trauma and orthopedic surgeons;

10. Otorhinolaryngologists;

11. Otorhinolaryngologist-audiologists;

12. Radiologists;

13. Rheumatologists;

14. Pediatric endocrinologists;

15. Functional diagnostics physicians;

16. Medical psychologists;

17. Psychiatrists / Child psychiatrists;

18. Medical students;

19. Residents, postgraduate students.

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

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

Table 3. Scale for grading grades of recommendation (GoR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• External peer review;

• Internal expert review.

Description of the guideline validation method:

The preliminary version of these guidelines was reviewed by independent experts, who were asked to comment primarily on how accessible the interpretation of the evidence underlying the recommendations is for understanding.

Feedback was received from primary care physicians regarding the clarity of the presentation and the assessment of the recommendations as a working tool for daily practice.

The preliminary version was also sent to a non-medical reviewer for comments from the patients' perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and the resulting changes made to the recommendations were logged. If no changes were made, the reasons for refusing to make changes were logged.

Consultation and peer review:

The draft guidelines were reviewed by independent experts, who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

Working Group:

For the final edition and quality control, the recommendations were re-analyzed by the working group members, who concluded that all remarks and comments from the experts had been taken into account, and the risk of systematic bias in the development of the recommendations was minimized.

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. Information on medicinal products: State Register of Medicines: https://grls.rosminzdrav.ru

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

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

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

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

7. 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 Protection in the Russian Federation' Regarding Clinical Guidelines."

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

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

10. Order of the Ministry of Labor of the Russian Federation No. 374n dated July 26, 2024, "On Approval of Classifications and Criteria Used in the Implementation of Medical and Social Expertise of Citizens by Federal Medical and Social Expertise Institutions."

11. Order of the Russian Ministry of Health (Ministry of Health of the RF) No. 1094n dated November 24, 2021, "On Approval of the Procedure for Prescribing Medicinal Products, Forms of Prescription Blanks for Medicinal Products, the Procedure for Issuing Said Blanks, Their Accounting and Storage, Forms of Prescription Blanks 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 Blanks, Including in the Form of Electronic Documents."

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

13. Information Letter of the Ministry of Health of Russia 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).

Main regulatory legal acts governing the provision of palliative medical care

1. Federal Law "On Amendments to the Federal Law 'The Fundamentals of Healthcare Legislation in the Russian Federation' Regarding the Provision of Palliative Medical Care" No. 18-FZ dated March 6, 2019.

2. Order of the Ministry of Health of the Russian Federation No. 345n, 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, Other Non-Profit Organizations Operating in the Sphere of Health Protection".

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

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

Appendix A3.1 Classification of Mucopolysaccharidoses [1]

Classification of mucopolysaccharidoses.

Appendix A3.2 Severity of MPS II clinical manifestations at different ages

Appendix A3.3 Frequency of examinations in patients with type II MPS

¹-For children older than 5 years; distance walked in 6 minutes (the preferred time interval is the same as in the patient's previous tests); number of steps climbed up in 3 minutes. SpO₂ saturation, respiratory rate (RR), and heart rate (HR) are evaluated before and after exertion.

²-DQ or Developmental Quotient (DQ) is a method for comparing the intellectual development appropriate for a given age (a child's mental abilities relative to their peers) with their chronological age (the child's actual age).

DQ is calculated by dividing mental age by chronological age and multiplying by 100 to obtain a whole number. The average developmental quotient for any age is considered to be 100.

Appendix A3.4 Sampling of biological material for diagnostics using 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 infant's heel, if blood is collected from the heel);

• - wipe the puncture site with a sterile gauze pad moistened with 70% alcohol, blot with a dry sterile gauze pad; - 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 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 collection 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^oC until shipment. The storage period before shipment should not exceed 7 days. Storing them longer and at a higher temperature may reduce enzyme activity even in normal conditions, leading to false-positive results.

Appendix A3.5 6-minute walk test (6MWT) [28]

It should be remembered that the 6-minute walk test has the following absolute contraindications: acute chest pain, decompensated heart and respiratory failure, acute illnesses, fever, musculoskeletal disorders that prevent performance of the test.

Relative contraindications include marked brady-tachycardia, severe arterial hypertension, and the child's age. Young children find it difficult to understand and follow all the rules of the test; therefore, it is recommended for children aged 5 years and older.

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 in the event of chest pain, severe shortness of breath, leg cramps, dizziness, loss of balance, increasing weakness, and obvious pallor.

The 6MWT is performed in an environment familiar to the patient, featuring a sufficiently long corridor with a hard surface. The walking track length must be at least 30 meters with markings every 5–10 meters, as well as turn-around points. Chairs for patient preparation and rest should be set up at both ends of the track. In addition, an oxygen source and a defibrillator must be available.

You will also need a blood pressure monitor, a stopwatch with a second hand, a pulse oximeter, and a phone for the test. The test is recommended to be performed in the morning hours after a light breakfast. The patient should wear comfortable clothing and appropriate walking shoes. Intensive physical exertion is prohibited less than two hours before the test. The patient's treatment continues as usual. If the child uses a cane, crutches, or a walker for walking in everyday life, they should be used for the test as well. Before starting the test, the patient's blood pressure, heart rate, respiratory rate, and pulse oximetry must be measured.

The 6-minute walk test involves the child walking the maximum possible distance for themselves along the track at a comfortable pace within 6 minutes. Running or jumping is prohibited, but the patient may slow down or stop if the need arises.

Appendix A3.6 Basic measures for managing patients with an allergic reaction to a drug

¹ For basic measures in managing patients with an anaphylactic reaction, see Appendix A3.7

Appendix A3.7 Basic measures for managing patients with anaphylaxis / anaphylactic shock (AS) [30, 31]

Appendix A3.8 Notes Legend

** — the drug is included in the list of vital and essential drugs (Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019) as amended;

# — The use of a medicinal product in accordance with indications (characteristics) not specified in its instructions for use (off-label) is carried out by decision of the medical commission subject to a signed informed voluntary consent (pursuant to Federal Law No. 323-FZ dated November 21, 2011, as amended);

*** – a medical device implanted into the human body during the provision of medical care under the state guarantee program for free medical care to citizens.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Hunter syndrome

Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is one of the most common forms of mucopolysaccharidoses (MPS). The disease was first described by the Canadian physician Charles Hunter in 1917 in two brothers. MPS II is a very diverse disease, encompassing both very severe and milder forms of the condition.

Unfortunately, this disease cannot be cured, but there are many supportive care approaches that can significantly improve patients' quality of life. Since 2006, a drug has been available that helps slow down disease progression and alleviate some of its manifestations. In addition to medication, one must not forget about symptomatic therapy, physiotherapy, rehabilitation, and a positive attitude toward life from family members.

Pathogenesis

In all mucopolysaccharidoses, the metabolism (breakdown) of glycosaminoglycans (GAGs)—special structural components of connective tissue—is impaired. GAGs are long chains of sugar molecules that bind to proteins and serve as an important building block for bones, cartilage, skin, tendons, heart valves, and many other tissues. GAGs are found in the viscous synovial fluid that lubricates joints, and are part of joints, tendons, and heart valves. Normally, there is a continuous process of "new" GAG formation and "old" GAG breakdown. The process of breaking down and processing GAGs requires a group of special proteins called enzymes. To break down GAGs, enzymes work sequentially, one after another, breaking the long GAG molecule into pieces. Patients with MPS lack an enzyme (specific to each type of MPS) that is necessary to break down a specific GAG.

In patients with type II MPS, there is a functional impairment of a specific enzyme called iduronate-2-sulfatase, which is necessary to break down two GAGs—dermatan sulfate and heparan sulfate—in specialized cell structures called lysosomes. In MPS II, the enzyme is either completely absent or its activity is reduced.

Undegraded dermatan sulfate and heparan sulfate are not toxic in themselves, but as they gradually accumulate in cells, they cause cellular dysfunction.

The severity of the disease is determined by the activity level of the enzyme iduronate sulfatase. Studies have shown that in milder forms of the disease, the active enzyme is present in the body in small amounts. Unfortunately, there is currently no way to predict whether the disease will be severe or mild. The form of the disease is determined clinically by a physician based on the combination of symptoms and the rate of disease progression.

MPS II is a very rare disease. According to expert estimates, its incidence is approximately 1:140,000 to 1:156,000 live births.

Inheritance of Hunter syndrome

Hunter syndrome has an X-linked recessive inheritance pattern. This means that the disease gene is located on the X chromosome. To understand how the disease is inherited, it is necessary to explain basic genetic concepts. Every human has a double set of genes, one of which is received from the mother and the other from the father. The X and Y chromosomes determine a person's sex. Males have one X chromosome inherited from the mother and one Y chromosome from the father. Females have two X chromosomes, inherited from the mother and father. Thus, only boys are affected by MPS II, while girls, with rare casuistic exceptions, do not have symptoms of the disease. If a woman is a carrier of MPS II, there is a 50% risk that she will pass the disease on to her son along with the MPS II gene located on the X chromosome. However, if the child receives the "healthy" X chromosome, the disease will not develop. There is also a 50% probability that the daughter of a carrier female will also be a carrier of the disease and in the future could pass the disease on to her grandson. The mother's sisters can also be carriers of the disease, so it is very important to clarify whether the child's mother is a carrier of the disease and, if necessary, to screen female relatives on the mother's side of the family.

If carrier status is confirmed, prenatal diagnosis can be performed—i.e., determining early in pregnancy whether the child will be affected or healthy.

It should also be noted that in some cases, the mother of a child with MPS II may not be a carrier of the disease, and the risk of having another affected child in the family is minimal.

DNA analysis is used to determine MPS II carrier status. Enzyme activity testing is not always a reliable method.

All families with MPS II must undergo medical genetic counseling and receive complete information from a medical geneticist regarding the risk of recurrence of this disease in the family or discuss other issues related to the inheritance of the disease. In Russia, medical genetic clinics operate in every region.

How is the diagnosis established?

Physicians may suspect the disease based on clinical symptoms. Laboratory tests and instrumental examinations are then performed. Since different types of MPS are very similar in their clinical manifestations, it is necessary to confirm the diagnosis using laboratory methods. The first stage involves determining the level of GAG excretion in the urine, which is higher in MPS patients than in healthy individuals. The second stage involves measuring the activity of the enzyme iduronate sulfatase in blood cells, dried blood spots, or cultured skin fibroblasts. Subsequently, DNA diagnostics is recommended (if enzyme activity was reduced) in the child, and then in the mother to clarify whether she is a carrier of the disease.

Clinical manifestations of Hunter syndrome

The severity of clinical manifestations in Hunter syndrome varies. Extremely severe forms of the disease that manifest in early childhood are known, as well as rather mild forms. In some cases, the presence of Hunter syndrome does not affect the patient's life expectancy, but the quality of life is certainly impaired in all forms of the disease.

The main objective for doctors, loved ones, and the patient themselves is to make life with Hunter syndrome as comfortable as possible, reduce the risk of severe complications, slow down disease progression, and alleviate the main symptoms of the disease.

The following describes potential problems that may arise in patients with Hunter syndrome. However, given the high variability of clinical manifestations, they may not occur in every patient, even within the same family.

It must be understood that Hunter syndrome is a progressive multisystemic disease, and patients' problems are not limited to skeletal and joint involvement—the nervous system, organs of vision and hearing, as well as the cardiovascular and bronchopulmonary systems are also affected.

Early development and growth

Children with severe forms of Hunter syndrome are typically born large and gain height and weight faster than normal children up to the age of 2. At an older age, weight and height growth slows down, and patients with MPS II have a lower height compared to healthy peers. In milder forms, growth may be normal.

Mental development

The mental development of children with Hunter syndrome depends on the form of the disease. In severe cases of the disease, due to the accumulation of glycosaminoglycans (GAGs) in the brain, psychomotor and speech delay is gradually observed between the ages of 2 and 4, and subsequently children lose previously acquired skills. The degree of intellectual deficit varies among patients: some boys with Hunter syndrome are able to pronounce only a few words, while others can speak in full sentences, read, and recite poetry. Many parents note that it is very important to work with the child as much as possible, especially at an early age before the disease affects intellectual functions. Even after the loss of speech, children retain the ability to experience emotions, understand their loved ones, and feel joy and sorrow.

In patients with the mild form of Hunter syndrome, intelligence may be within the normal range. Some adult patients have higher education and high social status.

External features

The appearance of patients with the severe form of Hunter syndrome is unusual, and they resemble each other more than they resemble their parents and healthy brothers and sisters. Structural changes in the face are designated by the special term facial dysmorphism, or coarse facial features. Patients have a large head, short neck, round face, and a broad nose with a wide nasal bridge. This is more characteristic of the severe form of the disease. In mild and intermediate forms of the disease, facial features are so subtle that they may only be visible to doctors, while family and friends may not notice them at all.

In MPS II, the skin is thick and tough, which complicates blood collection and the use of intravenous catheters.

Skeleton, musculoskeletal, and osteoarticular systems

In MPS type II, as in all other forms of mucopolysaccharidosis, there are problems with bone formation and growth. Damage to multiple bones, altering their shape, is called dysostosis multiplex. In the severe form of Hunter syndrome, the structure of the vertebrae changes. One or two vertebrae in the middle of the back are sometimes flattened more than the others and slightly displaced. Such vertebral displacement can cause spinal curvature (kyphosis, scoliosis). Usually, in this disease, the spinal curvature is mild and rarely requires surgical treatment. If the spinal curvature or scoliosis progresses, surgical treatment is required.

The most serious, dangerous, and life-threatening problems are associated with the deformity and structural features of the cervical spine. If the spinal cord is compressed or damaged (cervical myelopathy), the innervation of all parts of the body is disrupted, leading to limb weakness (paresis), gait disturbances, impaired control over pelvic functions (urination and defecation), and sometimes even breathing difficulties.

Joint stiffness is characteristic of all forms of mucopolysaccharidosis. Over the years, joint stiffness can progress and cause pain. Due to restricted joint mobility and the structural features of the small bones of the hand, the fingers become stiff and deformed, forming the so-called "claw hand". Due to stiffness of the large joints and bone structural features, patients walk with slightly flexed knees and hips. Some patients develop valgus deformity (knock-knees) of the lower extremities. Most physicians believe that this deformity is compensatory, helping the patient distribute weight, so surgical correction at an early age is best avoided. Furthermore, due to ligamentous laxity and impaired bone structure, surgery may be ineffective, and the deformity will return after some time.

In some cases, lesions of the femoral heads occur (aseptic necrosis), which can lead to pain syndrome and a waddling gait.

Respiratory organs

Respiratory system impairment in patients with MPS is associated both with the structural features of the skeleton, tracheal cartilage, and ribs, and with the accumulation of GAGs in soft tissues (adenoids enlarge, and the mucous membranes lining the respiratory tracts become loose and hypertrophied, resulting in a narrowed airway lumen).

The trachea in patients with MPS is more flexible and soft due to the abnormal structure of its constituent cartilaginous rings; in addition, it narrows due to mucus accumulation. The breathing process in patients with MPS is impaired. It is important to understand that insufficient oxygen supply to tissues (hypoxia) affects the function of all organs, so improving respiratory function is one of the primary tasks.

Breathing problems are exacerbated by the altered structure of the chest: due to impaired articulation between the ribs and the sternum, the chest is "stiff" and cannot move freely, preventing the lungs from expanding to a large volume. The problem is further aggravated by the fact that enlarged liver and spleen "push" on the diaphragm and impede normal excursion of the lungs. These features result in patients tolerating upper respiratory and pulmonary infections much worse.

The first symptoms of upper respiratory tract dysfunction can include nocturnal snoring, noisy breathing, and obstructive sleep apnea (brief, up to several seconds, cessations of breathing during night sleep). Such manifestations should be alarming, as they can progress further and lead to complications affecting other organs (heart, brain).

MPS patients are prone to developing otitis media, rhinitis, and pneumonia; therefore, antibacterial therapy should be initiated in the early stages of the disease. Undoubtedly, one must consult specialists rather than engage in self-medication.

Despite the rarity and severity of the disease, it should be remembered that vaccination is mandatory for patients with MPS, as it helps prevent the development of pulmonary diseases, and it is especially important not to miss vaccination against pneumococcal infection.

Oral cavity and teeth

In patients with MPS II, teeth are covered with fragile enamel, which leads to the rapid development of caries. Thorough dental care and regular brushing are very important.

Cardiovascular system

Almost all patients with MPS II exhibit changes in the valvular apparatus of the heart (thickening of valve leaflets and chordae).

During the examination of patients with Hunter syndrome, a physician may note the presence of heart murmurs. As a rule, this is associated with valve damage: the damaged valve does not close tightly, and during heart contraction, a small amount of blood moves in the reverse direction, which causes the murmur heard by the doctor. The aortic and mitral valves are most frequently affected.

The pulmonary damage described above can also cause cardiac changes. "Pumping" blood through altered lungs leads to an overload of the right heart chambers, and right-sided heart failure develops.

In the severe form of Hunter syndrome, cardiomyopathy may develop due to the accumulation of glycosaminoglycans directly within the heart muscle.

Abdominal cavity

In Hunter syndrome, the liver and spleen are enlarged due to GAG accumulation (hepatosplenomegaly). Liver enlargement usually does not impair its function, but it can affect the tolerance of certain foods and exacerbate respiratory problems.

In mucopolysaccharidoses, the abdomen is generally enlarged due to hepatosplenomegaly and weakness of the rectus abdominis muscles. Combined or isolated hernias (umbilical, inguinal, inguinal-scrotal, and midline abdominal) also frequently occur. As a rule, elective surgical treatment is required for inguinal hernias, but hernias can recur. Small umbilical hernias usually do not require surgical treatment. The decision on the need for surgery should be made jointly with the attending physician; an absolute indication for emergency surgery is the strangulation of a hernia sac.

Patients with MPS II often experience unstable stools (constipation or diarrhea). The reason for this is not fully understood. It is possible that autonomic nervous system function is impaired because GAGs accumulate in the nerve cells of the intestine. Diarrhea may disappear with age, but it can reappear during antibiotic therapy. If diarrhea is caused by antibiotics, doctors may prescribe medications to restore intestinal microflora. If the patient is sedentary, constipation may develop. In this case, increasing the amount of roughage (dietary fiber) in the diet is effective.

Nervous system

Psychomotor development delay and regression in MPS II are associated with the direct accumulation of GAGs in brain cells. Inadequate ventilation and cerebral hypoxia, elevated intracranial pressure due to hydrocephalus, and cognitive impairment caused by vision and hearing loss also contribute. A formidable complication in severe forms of MPS II is the disruption of cerebrospinal fluid circulation with the development of hydrocephalus. In this case, patients complain of headaches; in children, restlessness, vomiting, and developmental delay draw attention. Consultation with a neurosurgeon is necessary to resolve the issue of surgical or medical treatment for this complication.

If hydrocephalus is suspected, computed tomography or MRI must be performed. Funduscopic examination by an ophthalmologist is not sufficient for diagnosis, as hydrocephalus in children with MPS II can occur without papilledema.

Surgical treatment of hydrocephalus involves inserting a thin tube (shunt) into the cerebral ventricles, which drains excess fluid into the abdominal cavity. Such a shunt has a pressure-sensitive valve that allows cerebrospinal fluid to be drained when the cerebrospinal fluid pressure becomes too high.

An equally formidable complication of MPS is spinal cord compression within the spinal canal due to thickening of the spinal meninges combined with vertebral instability, most frequently in the upper cervical spine. Compression leads to severe neurological complications, often irreversible—gait disturbance, restricted limb movement, loss of control over urination and defecation, and respiratory impairment. Early surgical intervention is crucial in relieving stenosis.

Another complication involving the nervous system can be carpal tunnel syndrome—a common problem in MPS patients. Nerves pass through the wrist between the carpal bones and ligaments. Thickening of the ligaments due to GAG accumulation exerts pressure on the nerves. Manifestations of this syndrome may include pain and numbness in the fingers and difficulty grasping objects.

For diagnosis, nerve conduction velocity in the hand is measured. This is a simple procedure that establishes the presence or absence of nerve damage.

Some nervous system disorders (movement disorders) are secondary and largely related to skeletal involvement.

Organ of vision

GAG accumulation occurs in many tissues, including the cornea, which can lead to corneal clouding. One of the signs of corneal changes is intolerance to bright light, as the opacity causes improper light refraction. Sunglasses can help in this case. If corneal clouding is severe, vision deteriorates, especially in dim light.

GAG deposition in the retina can lead to peripheral vision loss and nyctalopia ("night blindness"). The child may become frightened and refuse to walk in the dark. It is advisable to leave a nightlight on in the bedroom and hallway. Sometimes vision problems may occur due to changes in the retina or glaucoma (elevated intraocular pressure), so regular examinations by an ophthalmologist are necessary. Using special tests, the ophthalmologist will help determine the cause of visual impairment.

Hearing organ

In mucopolysaccharidoses, hearing loss can be sensorineural (associated with damage to sensory (hair) cells in the cochlea), conductive (associated with impaired sound-conducting pathways), or mixed (a combination of both types). In Hunter syndrome, hearing loss is most commonly mixed in nature and progresses with age. There are 3 degrees of hearing loss: mild, moderate, and severe. Depending on the type and severity of hearing impairment, various correction approaches are applied. It is extremely crucial to notice signs of hearing loss as early as possible, because without correction, hearing loss hinders normal development and learning in patients. A factor that exacerbates hearing impairment is frequent middle ear infections (otitis media).

Treatment, monitoring, and scheduled examinations

Expert physicians from various countries have created guidelines for the monitoring, diagnosis, and treatment of patients with MPS type II. In this section, we will briefly review them.

Monitoring, scheduled examinations, and tests

To assess the patient's condition and the efficacy of enzyme therapy and physical therapy, various tests and scales exist. It is very important not to refuse these examinations, because they help physicians objectively evaluate the patient's condition, justify treatment, or introduce changes to rehabilitation and habilitation programs.

The most well-known is the 6-minute walk test. The essence of this test is very simple: to assess the patient's endurance. The patient is asked to walk down a long corridor for 6 minutes. The test is evaluated by the number of steps taken during this time. When conducting the first clinical trials of a drug for the treatment of various types of MPS, researchers evaluated this parameter before and after the initiation of enzyme therapy and compared it with a group of patients receiving placebo. It was this test that demonstrated that enzyme replacement therapy improves patients' endurance and physical activity.

To assess the degree of respiratory limitation, the physician may perform pulmonary function tests. Pulmonary function tests determine the maximum volume of air the patient can inhale and how rapidly gas exchange occurs. These tests can detect lung diseases, determine the extent of damage, and evaluate treatment efficacy. Tests are usually performed using specialized equipment. During the examination, you need to inhale, hold your breath, and exhale on command. Pulmonary function testing poses no health risks.

Cardiac auscultation must be a mandatory and regular examination for patients with mucopolysaccharidoses. An important imaging method for the heart is ultrasound—echocardiography (EchoCG), which is safe, painless, and highly informative. Modern devices make it possible to obtain one-, two-, and three-dimensional images of the heart, determine blood flow velocity and pressure in its various chambers, and determine the direction and turbulent nature of blood flow. EchoCG is recommended as clinically indicated, but at least once a year. This examination is necessary to detect any heart problems (enlargement, impaired contractile function, valve involvement).

It is necessary to check hearing regularly (twice a year) in order to start treatment immediately and preserve the ability to learn and communicate to the maximum extent possible.

Magnetic resonance imaging

Spine MRI should be performed annually, with a particular focus on areas where spinal cord compression may develop: the cervical, thoracic, and thoracolumbar regions. Patients with Hunter syndrome must be monitored by a pediatric surgeon / pediatric traumatologist-orthopedist to monitor the condition of the cervical spine. It is important to evaluate examination results dynamically, so all scans should be saved and provided to doctors at every subsequent examination. Spine computed tomography is usually performed prior to planned surgical treatment.

Radiography

X-rays of the cervical and thoracolumbar spine in two projections should be performed every 1–3 years. This examination is often technically easier to perform than MRI; furthermore, radiography provides more information on the structure of the vertebrae.

Symptomatic treatment

The main goal of symptomatic treatment is to correct the changes caused by the disease.

Skeleton and musculoskeletal system

It is important to strike a balance between living as full a life as possible and preventing complications of the disease associated with skeletal structure. On the one hand, the patient should not be overly restricted and overprotected, but it is important to remember that certain types of physical activity, such as tumbling, headstands, and diving, must be completely excluded due to cervical spine instability. Light jumping is permitted, but independent jumping on both feet should be avoided because the patients' support and coordination systems are not fully developed. Parents of schoolchildren must inform the physical education teacher about this.

Patients with Hunter syndrome should lead an active lifestyle to maintain joint function and improve overall health. A physical therapist can advise on various combinations of daily exercises.

Intensive therapy to improve joint and spinal mobility, as well as to strengthen the back and abdominal muscles, is recommended for all patients. To reduce the effects of hyperlordosis, it is necessary to strengthen all groups of chest muscles, while also conducting therapy aimed at developing the lumbosacral region. It is necessary to ensure that the patient does not overexert or fatigue excessively, so it is recommended to carefully study their physical condition and conduct therapy accordingly.

Parents are advised to conduct such sessions at home, combining active and passive exercises. The exercise regimen should include:

- posture and balance training exercises;

- stretching exercises;

- water procedures and aquatic sports, especially for elderly patients. Relaxing massage and underwater massage have a very beneficial effect.

Deformed feet and hands require special attention.

To maintain foot mobility, gymnastics should be performed, preferably at home or during play. To relieve excessive muscle tension, orthopedic shoes, insoles, and inserts that perform a supportive function are necessary; in some cases, orthoses, foot baths, and foot massage are also required.

It is important to perform stretching exercises for the muscles of the posterior thigh and lower leg.

To improve fine motor skills of the hands, intensive finger and palm gymnastics is recommended, which parents can perform at home. It is best to incorporate it into everyday home routines, such as during meals at the table. Hand and finger games are very appealing to children, but during stretching exercises, complaints of pain and discomfort may arise. In this case, warm hand baths, or pads filled with heated grains, moss, or peat that the patient holds in their hands during play, are very helpful.

Following intensive training, electrotherapy, manual massage, underwater massage, peloid therapy (mud therapy), and water exercise equipment help relieve pain and provide relief.

During all active therapies, special attention should be paid to the breathing rhythm and sufficient rest breaks should be provided to recover breathing.

Surgical treatment

There are various opinions on the necessity of surgical intervention. However, surgery carries certain risks and should be performed in cases of urgent necessity. One of the major difficulties in MPS is anesthesia management. Intubation in individuals with MPS requires specific skill and must be performed by an experienced physician. Cervical spine instability in patients with MPS increases the risk of traumatic injury, including to the cervical spinal cord, during anesthesia management, since many anesthetic procedures involve maximal neck extension. In this case, special precautions must be taken. If a patient is admitted to the hospital in critical condition, the anesthesiologist-resuscitator must be informed that neck and intubation problems may occur. The airways are typically narrowed, so an endotracheal tube of a smaller diameter may be required. The placement of such a tube itself is a very difficult process, and the use of a flexible bronchoscope may be necessary to do it safely.

Cervical spine instability is corrected surgically (cervical spine fusion). Using bone fragments or artificial materials, a support is formed connecting the top two vertebrae and the base of the skull.

Hearing organ

Sensorineural and conductive hearing loss can in most cases be compensated for by fitting hearing aids (Implantable bone conduction hearing aid***, Head-band bone conduction hearing aid***, Fully implantable middle ear implant system***, Implantable vibrator bone conduction hearing aid***).

Cardiovascular system

In some cases, surgery may be required to replace damaged valves.

Infections

Good dental care is important because decayed teeth cause severe discomfort and serve as sources of infection. It is necessary to brush teeth regularly and use mouthwashes. However, even with the most thorough dental care, inflammatory processes can develop. Irritability, crying, and restlessness may sometimes be the only symptoms of dental problems. Before dental surgery, patients who have already been diagnosed with heart valve disease require prophylactic antibiotics before and after treatment. This is because certain bacteria from the oral cavity can enter the bloodstream and cause an infection on the affected valve. If a tooth extraction under anesthesia is necessary, it must be performed in a hospital setting rather than a dental clinic, under the supervision of an experienced critical care anesthesiologist and a dentist/pediatric dentist.

Treatment of acute respiratory viral infections (ARVI) in patients with MPS should also be carried out under the close supervision of a physician. It is important to remember the specific considerations for using standard medications in this group of patients. For example, drugs such as antihistamines can dry out the mucous membranes, making them thicker, while decongestants or vasoconstrictors can raise blood pressure and constrict blood vessels, which is undesirable in MPS.

Due to the structural characteristics of the spine and chest cage, patients with Hunter syndrome have a harder time coping with infections affecting the lungs; therefore, physicians may prescribe antibiotics even for minor infections.

To normalize airflow circulation in the lungs, it is recommended to engage in activities such as blowing soap bubbles, moving cotton balls, using drinking straws, paper bags, and other items that require activation of the respiratory system. Playing with balloons or balls is also an option. For older children or adolescents, a chest muscle-stretching exercise routine can be developed for parents to conduct independently.

Passive chest exercises are used for patients with acute respiratory infections or for patients who cannot move independently. The exercises help with more effective mucus clearance. These include stretches, pulls, shakes, massage, and vibrations.

All patients must receive routine vaccinations!

Medical Nutrition Therapy

A special diet cannot prevent the accumulation of GAGs because they are synthesized within cells rather than ingested through food. Therefore, dietary restrictions are not necessary for patients with MPS; they should eat a normal diet suited to their age requirements.

Where to receive diagnosis and treatment in Russia

Healthcare institutions have been designated in each region where patients receive both disease-modifying treatment and all necessary examinations.

Learn more

There are many organizations worldwide that can help you find answers to any questions related to mucopolysaccharidoses:

International Mucopolysaccharidosis Organization: www.mpssociety.org

International rare disease portal: www.orpha.net

EURORDIS, the European organization representing patients with various rare diseases: www.eurordis.org

Remember that an active stance by the patients themselves is the key to a successful and happy life!

Public organizations and foundations in Russia

MPS type II is included in the list of orphan diseases, the treatment of which is state-funded. Public organizations can help patients access treatment, raise public awareness about rare diseases, and advocate for legislative initiatives in the field of orphan diseases.

Family support 

Of course, much depends on the doctor—how much they know about your disease, how correctly they prescribe treatment, and how well they explain the principles of therapy. Do not forget that the success of treatment depends equally on the family. It is essential to follow recommendations, under no circumstances lose hope, and become an expert in your own disease. Read literature, communicate with other families, and do not hesitate to ask questions. Even if you do not fully conquer the disease, you have the power to change life for the better and make your loved one happy!

Caring for a patient with a severe illness is a very difficult task. Parents also need adequate rest, which is not always possible. If there are other children growing up in the family, they also require parental attention. Many parents turn to volunteers or social workers for help. If such support is available in your city, be sure to take advantage of it.

Patients with MPS II can help their relatives simply by informing them of the need for screening. If a diagnosis is established early—before irreversible internal organ damage occurs—treatment will be much more effective. Testing is also necessary to identify female carriers, as they are at high risk of passing the disease on to their sons and need to have this information. The attending physician or geneticist is not authorized to disclose medical information, so the fate of relatives lies entirely in the hands of the patients themselves.

Siblings and all maternal relatives—uncles, aunts, and first cousins—must be informed of the need for testing.

Molecular genetic testing aimed at identifying a familial IDS gene mutation is indicated for the following relatives of the patient:

• mother,

• siblings,

• maternal half-siblings,

• daughters of daughters,

• maternal aunts and uncles,

• children of sisters,

• children of nieces,

• maternal first cousins,

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

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

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

Appendix G1 Subjective Exercise 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.

Notes: -

Appendix G2 Merrill-Palmer-Revised Scales of Development (MPR)

Russian title: Merrill-Palmer Scales of Development.

Original title: Merrill-Palmer-Revised Scales of Development - MPR.

Source (official developer website): Roid G. H., Sampers J. L. Merrill-Palmer-revised scales of development //Assessment. – 2004. Type: rating scale [55].

Type (underline):

• other (specify): technique.

Purpose: to verify the state of cognitive/intellectual development in the absence of hearing impairment in children aged 1 month to 6.5 years.

Content and Key: Descriptive classification designations for the development index and domain scores of the MPR Cognitive Battery.

Notes: The MPR technique (Merrill-Palmer-Revised Scales of Development) identifies any developmental delays or specific functional profiles at an earlier stage and across a broader age group than ever before: from 1 month to 6.5 years. It is used to assess children's cognitive and general psychological development. MPR allows for the evaluation of several clinical groups of children: those with potential psychomotor developmental delay; mild and severe intellectual disability; and language difficulties.

The technique assesses 5 domains: cognitive development, language proficiency and communication, physical culture level, socio-emotional and personal autonomy, and adaptive behavior. The stimulus material set contains no cultural biases and is made of durable, lightweight, and safe materials. Simple, quick, and standardized instructions are provided for the items. Based on the test results across all scales, normative scores relative to the child's age (standard scores) and growth scores derived using IRT methodology are generated. These normative indicators contain important supplementary information. The former allow us to determine whether a child's performance in a given area corresponds to that of their peers or falls outside the typical range. Meanwhile, growth scores allow you to determine individual strengths and weaknesses, gain insight into the child's functioning in terms of specific skills, and plan targeted interventions (to improve existing skills and/or address behaviors that are not yet emerging). Standard scores for assessing children's memory can also be obtained. Children can be repeatedly assessed longitudinally to track even the most minor gains. For example, in the case of children with neuropsychiatric disabilities, other diagnostic methods fail to capture the child's evolution after treatment because the child's developmental indicators are initially below normal. MPR growth scores overcome this obstacle and allow tracking of a child's progress over time.

Appendix G3 Wechsler Intelligence Scale for Children

Russian title: Wechsler Intelligence Scale for Children (children's version).

Original title: Wechsler Intelligence Scale for Children, WISC / Wechsler Intelligence Scale. Assessment of the level of intellectual development (children's version).

Source (official developer website): Wechsler Intelligence Scale. Assessment of the level of intellectual development (children's version): methodological guide / Yu.I. Filimonenko, V.I. Timofeev. – St. Petersburg: IMATON, 2012. – 112 p. ISBN 5-7822-0037-5

Type (underline):

• other (specify): technique.

Purpose: to verify the state of cognitive/intellectual development in the absence of hearing impairment in children over 5 years of age.

Content, Key:

Explanations: the test is administered by a certified medical psychologist. The Wechsler test consists of 12 subtests. The subtests form verbal and non-verbal groups. The examinee is asked to complete all verbal and then non-verbal subtests in the order of their numbers indicated on the registration sheet. Verbal subtests include tasks assessing general information, general comprehension, abilities, similarities, digit span reproduction, etc. Non-verbal subtests include the following: digit symbol, picture completion, picture arrangement, and block design. The examinee's answers to the subtest tasks are scored numerically according to content criteria for verbal subtests, and content and speed criteria for non-verbal subtests. Performance on each subtest is scored in points, which are then converted to standardized scaled scores that allow for scatter analysis. The overall intelligence quotient (IQ), the ratio of "verbal to non-verbal" intelligence are assessed, and performance on each task is analyzed. Quantitative and qualitative assessments of the examinee's task performance make it possible to determine which aspects of intellectual activity are less developed and how they can be compensated for. A low quantitative score on one or more subtests indicates a specific type of impairment. The examinee's final intellectual indices are calculated using normative tables derived from testing 2,200 children with equal representation of boys and girls. The test is designed to assess intellectual development from 5 to 16 years of age, though there is evidence that results become more informative and reliable starting from 7–8 years of age. If the child stops cooperating during the test due to emotional state or exhaustion, testing should be interrupted and resumed at another time when well-being and behavior are more favorable.

Appendix G4 Leiter International Performance Scale – 3rd Edition (Leiter-3)

Russian name: Leiter-3 (Leiter International Performance Scale–Third Edition).

Original name: Leiter-3.

Source (official developers' website): [54]

Type (underline):

• other (specify): test

Purpose: to verify the status of non-verbal intelligence and cognitive functions in case of hearing impairment / suspected hearing impairment in children over 3 years of age.

Content and Key:

Explanations: - Leiter-3 is an individual test designed to assess non-verbal intelligence in children, adolescents, and adults aged 3 to 75 years and older. During testing with this method, all tasks are presented without the use of speech. This makes Leiter-3 an appropriate assessment tool for those groups of examinees for whom verbal instructions are too difficult to follow. Leiter-3 consists of two batteries of subtests. The Cognitive Subtest Battery (Battery C) consists of five subtests of non-verbal intellectual abilities related to visual information processing and logical reasoning. Four of these five subtests are required to determine the non-verbal intelligence quotient (IQ). The Attention and Memory Subtest Battery (Battery A/M) also contains five subtests (two for assessing non-verbal attention, two for memory assessment, and one subtest for investigating Stroop cognitive interference). The A/M battery subtests can be used either independently or together with the C battery subtests. Together, they constitute a non-verbal tool for identifying cognitive deficits in clinical and neuropsychological diagnostics. In addition, the kit includes an expert rating scale used to assess behavior during testing. Raw scores for all 10 subtests, as well as for the rating scales, are converted into scaled scores. A single intelligence quotient is calculated based on the non-verbal intelligence scale, which includes four subtests. The intelligence quotient is calculated from the sum of scaled scores for the subtests, which are then converted into standard IQ scores. If the child stops cooperating during the test due to emotional state or exhaustion, testing should be interrupted and resumed at another time when well-being and behavior are more favorable.