Mucopolysaccharidosis type I: clinical guidelines

List of Abbreviations

ALT — alanine aminotransferase;

AST — aspartate aminotransferase;

VNV — nucleotide sequence variant;

GAG — glycosaminoglycans;

CT — computed tomography;

MPS — mucopolysaccharidosis;

MRI — magnetic resonance imaging;

CVS — cardiovascular system;

HSCT — hematopoietic stem cell transplantation (MMP Bone marrow transplantation);

US — ultrasound examination;

PFT — pulmonary function testing;

ERT — enzyme replacement therapy;

ECG — electrocardiography (MMP Electrocardiogram recording);

ENMG — electroneuromyography;

EchoCG — echocardiography;

EEG — electroencephalography.

Terms and Definitions

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

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

Mucopolysaccharidoses (MPS) are a group of inherited metabolic disorders associated with impaired glycosaminoglycan (GAG) metabolism, leading to organ and tissue damage. These diseases are caused by mutations in genes controlling the intra-lysosomal hydrolysis of macromolecules.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease caused by alpha-L-iduronidase deficiency, presenting with various clinical manifestations: growth retardation, intellectual disability, nervous system involvement, cardiopulmonary disorders, hepatosplenomegaly, multiple dysostoses, and corneal clouding. All of the above signs lead to disability and, in severe cases, to death [1].

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

The cause of MPS type I is a mutation in the gene encoding the lysosomal enzyme alpha-L-iduronidase. Inheritance pattern: autosomal recessive. The IDUA gene encoding alpha-L-iduronidase is located on chromosome 4p16.3.

Due to reduced enzyme activity, various types of GAGs accumulate, leading to somatic manifestations such as facial dysmorphism, hepatosplenomegaly, cardiac and respiratory involvement, skeletal changes, neurological symptoms, and hematological and ophthalmological alterations. The variability of MPS is determined by the type of accumulated substrate resulting from insufficient GAG degradation: in MPS type I, heparan sulfate and dermatan sulfate accumulate. Alpha-L-iduronidase deficiency can lead to the development of various disease phenotypes, causing differences in symptom severity. Three clinical phenotypes are distinguished [3, 4, 5]:

- Hurler syndrome (mucopolysaccharidosis I H — severe form),

- Scheie syndrome (mucopolysaccharidosis I S — mild form)

- Hurler-Scheie syndrome (mucopolysaccharidosis I H/S — intermediate form)

1.3 Epidemiology of the Disease or Condition

Mucopolysaccharidosis type I is a panethnic disease with a frequency of 1:100,000 newborns. Approximately 50%-80% of patients have the severe form of the disease. MPS I H/S Hurler-Scheie syndrome occurs with a population frequency of 1:100,000–1:500,000 newborns; MPS I S Scheie syndrome occurs in 1:500,000 newborns [6, 7]. However, it should be considered that there is a certain margin of error in estimating the prevalence of various disease phenotypes, which may be associated with more frequent detection of severe forms of MPS I.

1.4 Features of Coding the Disease or Condition

According to ICD-10, the disease belongs to Class IV, endocrine, nutritional and metabolic diseases.

E76.0 — Mucopolysaccharidosis type I.

1.5 Classification of the disease or condition

According to the deficiency/absence of lysosomal enzymes, corresponding gene defects, and the severity of clinical symptoms, 11 types of MPS are distinguished (Appendix A3.2).

1.6 Clinical presentation of the disease or condition

Currently, MPS I is considered a disease with a continuum of clinical phenotypes that differ in the age of onset, severity of clinical manifestations, and rate of disease progression in patients [1–5].

Thus, it is somewhat conventional to distinguish between the severe form of the disease (Hurler syndrome), with onset in the first year of life, progressive cardiorespiratory failure, and pronounced neurological symptoms; and the mild form (Hurler-Scheie and Scheie syndromes), in which symptoms appear at the age of 4–10 years and the disease progresses slowly, with some patients surviving into adulthood.

These clinical guidelines do not cover Hurler syndrome, as it is discussed in detail in the clinical guidelines for MPS type I in children and does not occur in adults.

Taking into account the traditionally used classification, the characteristic clinical signs for various forms of MPS I are given below.

Mucopolysaccharidosis type I S — mild form.

Synonyms: Scheie syndrome, MPS I S — mild form.

Main clinical manifestations: coarse facial features, joint stiffness, multiple dysostosis, corneal clouding [3, 4].

Appearance. The first signs of the disease appear at the age of 3–5 years. Patients are of hypersthenic build with well-developed musculature; facial features are coarse, characterized by a wide mouth with full lips and mandibular prognathism. There is a gradual limitation of movement in the upper extremity joints, as well as joint stiffness, with emerging and progressive contractures of the hand joints. All symptoms of the disease become most pronounced by puberty. Hypertrichosis and a short neck may be present.

Skeletal system: slight growth retardation may be noted. Multiple dysostosis: facial dysostosis, flat nasal bridge, widely spaced eyes, thickened lips, hypoplastic mandible, macroglossia and gingival hyperplasia, short neck, flexion contractures and joint stiffness of the extremities; with age, pain in the hands and feet joints develops, with the formation of a "claw hand" and pes cavus, and valgus deformity of the knee joints. Carpal tunnel syndrome frequently develops, which, along with stiffness, leads to restricted upper extremity function. Rarely — congenital triggering of the 1st digit (Notta's disease).

Respiratory system: frequent respiratory infections in the form of rhinitis and otitis. Obstructive airway disease and sleep apnea may develop.

Organs of vision: early uneven corneal clouding is noted. Later, usually after 30 years of age, glaucoma and pigmentary retinal dystrophy develop. Rarely — papilledema.

Central nervous system: psychomotor development is normal or slightly delayed.

Craniocervical stenosis develops in patients with MPS due to hypoplasia of the dens of the C2 vertebra, atlantoaxial instability, deposition of mucopolysaccharides in the dura mater and posterior longitudinal ligament, which subsequently leads to compression myelopathy at this level and, consequently, to bulbar disorders and central respiratory failure. Symptoms may include gait disturbance, muscle weakness, clumsiness with preserved motor skills, and bladder dysfunction.

Carpal tunnel syndrome is a common compression neuropathy in patients aged 5 to 10 years and adults. If left untreated, it can lead to irreversible contracture of the distal interphalangeal joints, as well as impaired or lost sensation in the first three digits and thenar muscleparesis. Unfortunately, patients rarely report pain until function is lost.

Cardiovascular system: aortic valve defects, aortic coarctation, and mitral stenosis are characteristic.

Gastrointestinal system: inguinal-scrotal and umbilical hernias are noted; hepatosplenomegaly is uncommon.

Mucopolysaccharidosis type I H/S — intermediate form.

Synonyms: Hurler-Scheie syndrome.

Main clinical features: facial dysmorphisms, joint stiffness, short stature, corneal clouding [1, 2, 5, 7].

Appearance: the first symptoms of the disease appear by the age of 3–8 years. Characteristic features include scaphocephaly, macrocephaly, depressed nasal bridge, full lips, corneal clouding, micrognathia, moderate hypertrichosis, and thickening of the skin.

Skeletal system: in the first year of life, growth is within the normal range, after which growth rates decline, resulting in short stature. Body proportions are disproportionate. Multiple dysostosis, scaphocephaly, macrocephaly. Valgus deformities of the lower legs are mildly pronounced. Joint mobility is moderately restricted, with dysostoses, barrel-shaped chest, kyphoscoliosis, and hyperlordosis.

Respiratory system: frequent respiratory infections in the form of rhinitis, otitis, and tonsillar hypertrophy. Airway obstructions and laryngeal stenosis may develop.

Organ of vision: corneal clouding.

Central nervous system: delayed psychomotor and speech development is noted. Craniovertebral stenosis and myelopathy develop in MPS patients due to hypoplasia of the dens of the C2 vertebra, atlantoaxial instability, GAG deposition in the dura mater and posterior longitudinal ligament, which subsequently leads to compressive myelopathy at this level, resulting in bulbar disorders and central respiratory failure. The development of cervical pachymeningitis is characteristic, leading to spinal cord compression and subsequent myelopathy. Symptoms may include gait disturbance, muscle weakness, clumsiness with preserved motor skills, and bladder dysfunction.

Tunnel syndrome — carpal tunnel syndrome.

Cardiovascular system: valvular heart disease.

Gastrointestinal system: hepatosplenomegaly, inguinoscrotal and umbilical hernias.

As with most recessive diseases, clinical polymorphism is determined by residual enzyme activity and affects the severity of the course and the age of onset. Depending on the age of onset, certain clinical manifestations may have varying degrees of severity. The severity of clinical manifestations of MPS I at different ages may vary (Appendix A3.3).

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of MPS type I is established based on a combination of medical history, clinical data, and laboratory test results (biochemical and molecular genetic analysis).

Differential diagnosis is carried out with other types of MPS, alpha-mannosidosis, late forms of gangliosidoses, mucolipidosis, non-infectious polyarthritides, and epiphyseal dysplasias [5, 7].

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

2.1 Complaints and Anamnesis

When taking the medical history and collecting complaints, attention should be paid to the following complaints and anamnestical events:

- burdened family history (similar symptoms in siblings of the proband, consanguineous marriage);

- short stature;

- coarse facial features;

- frequent respiratory infections;

- hearing loss;

- vision impairment;

- multiple dysostosis (deformities of the skull, chest, spine, extremities);

- posture disorders — kyphosis, scoliosis;

- recurrent hernias (more frequently bilateral);

- corneal clouding;

- decreased exercise tolerance;

- limb weakness;

- joint stiffness;

- difficulty rising from sitting and lying positions;

- gait abnormalities;

- fine motor clumsiness;

- pelvic organ function control disorders;

- sleep apnea.

Complaints and medical history 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 I:

- coarse facial features;

- short stature;

- joint stiffness;

- corneal clouding;

- hepatomegaly;

- splenomegaly;

- inguinoscrotal and umbilical hernias (bilateral).

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

2.3 Laboratory Diagnostics

The main laboratory method for confirming the diagnosis of MPS I is the test panel for the diagnosis of mucopolysaccharidosis type I (which includes determining the activity of the alpha-L-iduronidase enzyme, quantitative and qualitative analysis of urinary GAGs, and molecular genetic testing of the IDUA gene). These tests are performed in specialized genetic laboratories.

Comment: quantitative analysis (study of the urinary glycosaminoglycan spectrum by tandem mass spectrometry or spectrophotometry) reveals a total increase in urinary GAG excretion, along with increased excretion of dermatan sulfate and heparan sulfate. The GAG level is an age-dependent parameter. Furthermore, in mild MPS I, the urinary GAG concentration may be only slightly elevated. The test is performed during follow-up monitoring in patients receiving enzyme replacement therapy at least once every 6 months, and in patients not receiving enzyme replacement therapy — at least once a year.

Comments: when determining alpha-L-iduronidase activity in dried blood spots in patients with MPS type I, a decrease in alpha-L-iduronidase activity is detected. This parameter is the main laboratory criterion for MPS type I. It is also possible to determine alpha-L-iduronidase activity in fibroblast cultures, peripheral blood leukocytes, and isolated leukocytes.

Comments: the test is necessary for verifying the diagnosis at the molecular genetic level. Identification of a pathogenic/likely pathogenic nucleotide sequence variant (NSV) in the IDUA gene makes it possible to screen the proband's relatives, as well as to perform prenatal and preimplantation diagnostics. Most NSVs in patients with MPS I can be identified using Sanger sequencing of all exons and adjacent intronic regions of the gene, but in a small percentage of cases, standard diagnostic methods may be insufficient to identify the cause of the disease.

Comments: when performing a routine biochemical blood test, it is possible to determine the activity of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, gamma-glutamyl transferase in the blood, and to study the levels of total bilirubin, conjugated (direct) bilirubin, cholesterol, triglycerides, albumin, glucose, creatinine, total protein, sodium, potassium, and total calcium in the blood.

Comments: the levels of total hemoglobin, erythrocytes, leukocytes, and platelets in the blood are measured, hematocrit is assessed, erythrocyte sedimentation rate is studied, and a differential white blood cell count (leukocyte formula) is performed. Due to the high risk of intercurrent infections and aspiration pneumonia in MPS patients, this test is recommended to be performed at least 1-2 times a year.

2.4 Instrumental Diagnostics

Comments: moderate hepatomegaly or hepatosplenomegaly is detected. During therapy, the size of the liver and spleen decreases.

Comments: in some cases, spine radiography with functional tests is necessary. If diagnostic informativeness is insufficient, computed tomography of the cervical, thoracic, and lumbar spine may be performed. Multiple dysostoses are detected — scaphocephaly, hypoplasia of the dens of the C2 vertebra, thoracolumbar kyphosis resulting from platyspondyly, and lumbar hyperlordosis. Wide ribs, short curved clavicles, hypoplasia of the humeral heads and varus deformity of the proximal humeri, and distally tilted forearm bone epiphyses are determined. Delayed formation of ossification centers. The metacarpal bones of the hands are shortened and narrowed — "pointed" proximally, with "sloping" acetabulae, deformed, flattened femoral heads, and valgus deformity of the femoral necks.

Comments: nerve conduction study allows for the detection of median nerve compression even before the onset of symptoms and should be performed annually starting at the age of 4–5 years.

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

Comments: spirometry, tidal breathing flow-volume loops, and pulmonary function testing are performed.

Comments: the overall prevalence of epilepsy in mucopolysaccharidoses is approximately 30%, although figures reported by different researchers may vary.

Comments: according to experts, the diagnostic workup in patients with suspected epileptic seizures should additionally include polysomnography to rule out sleep-related breathing disorders as a cause of sleep disturbances, since nocturnal epilepsy can also cause sleep disruptions. The combined use of these research methods helps to obtain the most complete clinical picture.

Comments: regular ECG, Echo-CG, 24-hour cardiac rhythm monitoring, and ambulatory blood pressure monitoring are necessary for patients with this condition, as cardiovascular disorders are noted from an early age.

Comments: polysomnography/cardiorespiratory monitoring is performed to diagnose obstructive sleep apnea, which helps determine the nature of breathing disorders (rule out central origin, association with adenoid hypertrophy, heart failure, or a complex of causes) and cardiovascular pathology. The study is performed at least once a year.

In accordance with the Order of the Russian Ministry of Health dated October 13, 2017, No. 804n "On Approval of the Nomenclature of Medical Services", the service "Polysomnography" is absent, therefore it is possible to use a set of services: video-electroencephalography monitoring, ambulatory blood pressure monitoring, electrocardiography, electrocardiographic data monitoring, 24-hour cardiac rhythm monitoring, interpretation, description, and analysis of electrocardiographic data, surface electromyography (one anatomical region), electrooculography, determination of soft tissue oxygen partial pressure (oximetry)).

Comments: if necessary, brain magnetic resonance imaging is performed using combined inhalation anesthesia

Comments: if necessary, spine magnetic resonance imaging (one region) can be performed using combined inhalation anesthesia. Atlantoaxial instability can be detected by functional X-rays of the cervical spine, but confirmation of spinal cord compression due to dural thickening and developing vertebral anomalies requires MRI.

2.5 Other Procedures

Comment: orthopedic correction of posture disorders and joint contractures using non-surgical methods includes physical therapy and remedial gymnastics, as well as orthopedic devices. According to indications, surgical treatment of carpal tunnel syndrome is performed, along with hip or knee arthroplasty, and corrective osteotomies to correct limb axis.

Comments: additionally, an initial consultation (examination) by a prosthodontist, oral and maxillofacial surgeon, or maxillofacial surgeon may be required [1, 2, 5, 14, 18, 24].

Comments: ENT involvement is one of the frequent comorbidities. The onset of inflammatory diseases of the ear, nose, and throat in patients with MPS occurs in early childhood. Frequent combined manifestations are noted: hearing loss, recurrent acute otitis media, sleep apnea, persistent nasal breathing difficulties, and rhinitis. Patients with MPS may require fibrolaryngoscopy due to pathological changes in the larynx (thickening of the vocal cords, enlargement and edema of the arytenoid cartilages).

Comments: ophthalmoscopy, gonioscopy, biomicroscopy of the anterior segment of the eye and fundus, corneal pachymetry, and ophthalmotonometry should be performed. In patients with MPS I early uneven corneal clouding is observed. Glaucoma and pigmentary retinal dystrophy develop later. Rarely — optic disc edema.

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

Treatment of MPS type I includes both disease-modifying treatment, such as enzyme replacement therapy (ERT), and symptomatic treatment. The management of patients with MPS type I requires a multidisciplinary approach involving a neurologist, geneticist, cardiologist, pulmonologist, gastroenterologist, physical therapist, and other specialists with experience in treating this rare disease.

3.1 Pathogenetic treatment

Comments: prescription and adjustment of ERT can be performed by a geneticist, general practitioner (family physician), neurologist, or another specialist with experience in treating patients with MPS I. The drug for ERT is laronidase** (ATX code A16AB05). One milliliter of solution contains 100 IU (approximately 0.58 mg) of laronidase**. It is a recombinant form of human alpha-L-iduronidase produced using recombinant DNA technology in Chinese hamster ovary cell culture. ERT is intended to restore enzyme activity levels sufficient to hydrolyze accumulated GAGs and prevent their further accumulation. Following administration, laronidase** is rapidly cleared from the systemic circulation and taken up by cells, entering their lysosomes via mannose-6-phosphate receptors. The recommended dosing regimen is weekly administration at a dose of 100 IU/kg as an IV infusion. The initial infusion rate of 2 IU/kg/h may be gradually increased every 15 minutes, up to a maximum of 43 IU/kg/h, provided the infusion is well tolerated. The total required volume of the solution should be infused over approximately 3–4 hours [12, 13].

Attention should be paid to maintaining the intervals between infusions and avoiding treatment interruptions, as non-compliance with the treatment regimen carries a potential risk of patient deterioration and progression of MPS I symptoms.

Administration is carried out via a peripheral venous catheter (peripheral catheter) or a port system (implantable infusion/injection port***, placed in a central vein), which are 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 Under the State Guarantee Program for Free Medical Care to Citizens, as Well as the List of Medical Devices Dispensed on Prescription Upon Provision of a Set of Social Services."

Treatment is performed in the absence of contraindications.

Initiation of ERT in patients over 18 years of age helps reduce liver and spleen size and GAG excretion; the effect on other organ systems is insignificant.

Adult patients with MPS I need periodic assessment of clinical symptoms, monitoring of urinary GAG levels, and evaluation of alpha-L-iduronidase enzyme activity at least once a year. In adult patients with MPS I who underwent hematopoietic stem cell transplantation (HSCT) (referred to in local nomenclature as bone marrow transplantation) in childhood, in case of symptom progression, elevated urinary GAGs, or decreased enzyme activity, the initiation of ERT should be considered.

3.2 Symptomatic treatment

Treatment of chronic conditions (behavioral disorders, ophthalmological disorders, orthopedic pathology, seizure syndrome, arterial hypertension, heart failure, recurrent otitis media, frequent respiratory infections, etc.) in patients with MPS I is recommended to be carried out taking into account current clinical guidelines, the results of a comprehensive evaluation by all organs and systems, and the patient's personalized goals.

Comment: in patients with MPS receiving ERT, as with the IV administration of any other protein product, adverse reactions may occur (fever, chills, vomiting, urticaria, severe allergic-type hypersensitivity reactions) developing either during the infusion or on the day of the infusion. Systemic corticosteroids (e.g., prednisolone**) may be used when allergic reactions develop. If adverse reactions occur during or after the infusion, appropriate treatment should be administered following current standards of medical care for the respective pathologies.

Comments: it is possible to use Lactulose** (A06AD11) at 15–45 ml per day. Prescription and/or adjustment of therapy requires an examination (consultation) by a general practitioner (family physician) and/or gastroenterologist.

Comments: the overall prevalence of epilepsy in mucopolysaccharidoses is about 30%, although figures from different researchers may vary. There is likely no difference between the treatment of epilepsy in patients with mucopolysaccharidosis and other patients, therefore standard epilepsy treatment guidelines should be followed. Prescription and/or adjustment of therapy requires an examination (consultation) by a neurologist.

Comments: prescribing and/or adjusting therapy requires an appointment (examination, consultation) with a neurologist. The positive effect of pharmacotherapy for chronic pain in patients with MPS can be achieved by taking into account the medications the patient is taking and regular monitoring of treatment safety. Medications acting on the central mechanisms of chronic pain formation are effective. When treating pain syndrome in a patient, the least invasive method should be used.

Comment: for ophthalmological disorders, treatment is provided according to indications; therapy selection is carried out based on clinical guidelines for the corresponding nosologies.

Comment: recurrent otitis media and frequent upper respiratory tract infections require symptomatic and antibacterial therapy. Treatment and diagnostics are carried out based on clinical guidelines for the corresponding nosologies [1, 34].

Comment: in patients with MPS presenting with epileptic seizures, the use of medications and treatment regimens based on relevant clinical guidelines is recommended. Treatment of behavioral disorders is carried out by a neurologist; typically, hypnotics and sedatives, anxiolytics, and other antipsychotic agents are used. The choice of drug, dosage, and duration of the course are determined individually. Initiation of these drugs should be carried out under careful medical supervision in a 24-hour or day hospital setting.

Comment: orthopedic correction of posture disorders and joint contractures using non-surgical methods includes physical therapy procedures and therapeutic exercise, and the use of orthopedic devices. According to indications, surgical treatment of carpal tunnel syndrome is performed, orthopedic hip or knee arthroplasty, and corrective osteotomies to correct limb axis (femoral osteotomy, proximal femoral osteotomy, open tibial osteotomy, open fibular osteotomy, bone reconstruction using internal fixators and external fixation devices, bone reconstruction with corrective osteotomy for foot deformity, bone reconstruction with corrective femoral osteotomy, bone reconstruction with corrective lower leg osteotomy).

Comment: participation of a multidisciplinary team in the management of heart failure in patients with MPS I is recommended. In the treatment of arterial hypertension in patients with MPS I, the administration of antihypertensive therapy in accordance with the clinical guidelines "Arterial Hypertension in Adults" is recommended.

Comments: frequent upper and lower respiratory tract diseases require symptomatic and antibacterial therapy [1, 14].

3.3 Surgical treatment.

Surgical treatment of patients with MPS I should be carried out 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 recompression of the median nerve due to scarring or glycosaminoglycan deposition is possible, continued follow-up is necessary. An appointment (examination, consultation) with a surgeon and/or neurosurgeon is required to decide on the necessity and scope of possible surgical intervention.

Comment: an appointment (examination, consultation) with a neurosurgeon is required to decide on the necessity and scope of possible surgical intervention.

Comments: an appointment (examination, consultation) with a neurosurgeon is required to decide on the necessity and scope of possible surgical intervention. Spinal cord compression leads to irreversible neurological disorders, 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.

Comment: an appointment (examination, consultation) with an orthopedic traumatologist is required to decide on the necessity and scope of possible surgical intervention.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific rehabilitation is not required for patients with MPS I. Rehabilitation measures for patients with MPS I may include clinical and psychological correction, a psychological rehabilitation school for patients and relatives, stays in specialized health resorts, as well as social adaptation involving specialists and social workers, and courses of general medical massage. Specific rehabilitation methods in the presence of complications are indicated in the respective sections.

5. Prevention and Dispensary Observation

Comment: medical genetic counseling is recommended for families with affected children to determine genetic risks. As with other autosomal recessive disorders, the risk of having a child with MPS type I is 25% for each pregnancy. In families with an affected child, prenatal and preimplantation genetic diagnosis is available. To do this, parents need to contact specialized diagnostic laboratories and medical centers. Prenatal diagnosis is carried out using molecular genetic or biochemical methods by analyzing DNA extracted from chorionic villus sampling at 9–11 weeks of gestation and/or amniotic fluid cells, fetal blood at 20–22 weeks of gestation.

5.1 Prenatal diagnosis

5.2 Dispensary monitoring

Comments: the assessment includes total hemoglobin, red blood cells, white blood cells, platelets, hematocrit, erythrocyte sedimentation rate, and differential leukocyte count (leukocyte formula) due to the high risk of intercurrent infections and aspiration pneumonia in patients with MPS, this test is recommended at least 1–2 times a year.

Comments: the evaluation includes measuring the activity of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, gamma-glutamyl transferase in the blood, as well as total bilirubin, conjugated (direct) bilirubin, cholesterol, triglycerides, albumin, glucose, creatinine, total protein, sodium, potassium, and total calcium in the blood. The test is performed every 6 months.

Comments: moderate hepatomegaly or hepatosplenomegaly is detected. During therapy, the size of the liver and spleen decreases.

Comments: if necessary, magnetic resonance imaging of the spine (one segment) is performed using combined inhalation anesthesia. Atlantoaxial instability can be detected by radiography of the cervical spine with functional tests, but MRI is required to confirm spinal cord compression caused by thickening of its membranes and developing vertebral anomalies.

Comments: in some cases, radiography of the spine with functional tests is necessary. If diagnostic yield is insufficient, computed tomography of the cervical, thoracic, and lumbar spine may be performed. Multiple dysostoses are detected: scaphocephaly, hypoplasia of the dens of the axis (C2 vertebra), dorsolumbar kyphosis resulting from platyspondyly, and lumbar hyperlordosis. Wide ribs, short curved clavicles, hypoplasia of the humeral heads and varus deformity of the proximal humerus, and convergent sloping distal epiphyses of the forearm bones are observed. Delayed appearance of ossification centers. Metacarpal bones of the hands are shortened and narrowed—"pointed" proximally, with acetabular "slanting", deformed, flattened femoral heads, and valgus deformity of the femoral necks.

Comments: if necessary, magnetic resonance imaging of the spine (one segment) is performed using combined inhalation anesthesia. Atlantoaxial instability can be detected by radiography of the cervical spine with functional tests, but MRI is required to confirm spinal cord compression caused by thickening of its membranes and developing vertebral anomalies.

Comments: stimulation ENMG allows detection of median nerve compression even before symptoms appear and should be performed annually starting at 4–5 years of age.

Comments: spirometry, tidal breathing flowmetry, and pulmonary function testing are performed.

Comments: regular ECG, echocardiography, Holter ECG monitoring, and 24-hour ambulatory blood pressure monitoring are necessary for patients with this condition, as cardiovascular disorders manifest at an early age.

Comments: ENT involvement is one of the frequent comorbidities. The onset of inflammatory diseases of the ear, nose, and throat in patients with MPS occurs in early childhood. Frequent combined manifestations are noted: hearing loss, recurrent acute otitis media, sleep apnea, persistent nasal breathing difficulties, and rhinitis. Patients with MPS may require fibrolaryngoscopy due to pathological changes in the larynx (thickening of the vocal cords, enlargement and edema of the arytenoid cartilages).

Comment: orthopedic correction of posture disorders and joint contractures using non-surgical methods includes physical therapy and remedial gymnastics, as well as orthopedic devices. According to indications, surgical treatment of carpal tunnel syndrome is performed, along with hip or knee arthroplasty, and corrective osteotomies to correct limb axis.

Comments: additionally, consultation (examination) with an orthodontic dentist, dental surgeon, or maxillofacial surgeon may be required [2, 18, 24].

6. Organization of Medical Care

6.1 Organization of parenteral administration

This section focuses on the organization of long-term pathogenetic enzyme replacement therapy using the pharmaceutical form "concentrate for solution for infusion" administered via intravenous infusion:

1) administering infusions via permanent venous access, if possible [38];

2) venous access can be provided by small catheters placed in peripheral veins, central veins, and semi-permanent central venous access devices with subcutaneous ports [38];

3) the use of central venous access is preferable: peripheral veins with relatively slow blood flow will be irritated by the high osmotic load, extreme pH values, and the chemical nature of certain active and excipient substances. Phlebitis, thrombophlebitis, or tissue infiltration can lead to the loss of the vein for treatment and potential tissue damage. The blood flow velocity in central veins ensures rapid dilution of the administered substances, eliminating the need for strict control of the administered substance concentration when using central venous access for infusion. With rapid natural dilution by the blood flow, additional volumes of infusion media are unnecessary, which may be important for individual patients [38];

4) when infusing via central venous access, attention should be paid to the selection of the infusion rate and the potential for increased toxicity and side effects with its increase [38].

6.2 Organization of patient routing and logistics for the medicinal product intended for pathogenetic enzyme replacement therapy.

This section focuses on organizing the patient routing scheme, as well as including all municipalities of the constituent entity of the Russian Federation in the routing schemes.

1) for each constituent entity of the Russian Federation, patient routing schemes for MPS should be developed and approved by an order of the head of the Territorial Healthcare Management Authority.

2) the use of the pathogenetic enzyme replacement therapy medicinal product procured under the preferential drug provision program in the pharmaceutical form of "concentrate for solution for infusion" should be organized in a medical organization licensed for medical activities in any profile within a day-care hospital or inpatient setting [39].

3) when approving patient routing schemes, provision should be made for the logistics of the medicinal product itself using temperature indicators to monitor the temperature regime of storage and transportation of medical immunobiological drugs within the "cold chain" system [40], which is necessary to ensure the continuity of pathogenetic enzyme replacement therapy in the pharmaceutical form of "concentrate for solution for infusion" to the point of drug administration directly to the patient in the medical organization.

Indications for hospitalization in a medical organization:

Indications for planned hospitalization:

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

- a condition requiring active treatment and round-the-clock medical observation (herniotomy, surgical treatment of joint and spinal lesions, scoliosis, adenoidectomy, tonsillectomy, neurosurgical decompression for carpal tunnel syndrome, placement of transtympanic ventilation tube for otitis media, surgical correction of cardiovascular system (CVS) pathology, and others);

- a condition requiring high-tech treatment methods (including monitoring the efficacy of HSCT);

- impossibility of providing ERT in outpatient and day-care settings;

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

Indications for emergency hospitalization:

- acute diseases;

- exacerbations of chronic diseases;

- poisoning and trauma, 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 diagnostic and treatment procedures.

Indications for patient discharge from a medical organization:

- absence of threat to the patient's life;

- absence of risk of developing complications requiring urgent treatment;

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

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

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

7. Additional Information

When administering 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, marked hypertrophy of the adenoids and tonsils pose challenges during anesthesia management; therefore, local or regional anesthesia should be preferred. The patient is pre-evaluated by a cardiologist, otorhinolaryngologist, anesthesiologist, and neurologist. A full cardiological examination and polysomnography (to assess the severity of respiratory disorders) are mandatory, along with nasopharyngoscopy and computed tomography of the lungs, if indicated. 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 [1-3].

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for primary health care

Quality assessment criteria for specialized medical care

References

Appendix A1. Working Group Composition

1. Anisimova Inga Vadimovna — Candidate of Medical Sciences, Head of the Department of Medical Care Organization, Medical Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

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

3. Baranov Alexander Alexandrovich — Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Honorary Chairman of the Executive Committee of the Union of Pediatricians of Russia. Awards: Order of the Red Banner of Labour, Order of Honour, Order "For Merit to the Fatherland" IV degree, Order "For Merit to the Fatherland" III degree

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

5. Voskoboeva Elena Yuryevna — Candidate of Medical Sciences, Leading Research Fellow at the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics named after Academician N.P. Bochkov

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

7. Kuzenkova Lyudmila Mikhailovna — Doctor of Medical Sciences, Head of the Department of Psychoneurology and Psychosomatic Pathology, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Member of the Union of Pediatricians of Russia

8. Kutsev Sergey Ivanovich — Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, President of the Association of Medical Geneticists (AMG)

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

10. Lobzhanidze Tina Viktorovna — Candidate of Medical Sciences, Head of the Day Hospital and Palliative Medicine Department, City Clinical Hospital № 64 of the Moscow Healthcare Department

11. Mikhailova Lyudmila Konstantinovna — Doctor of Medical Sciences, Professor, Academic Secretary of the National Medical Research Center of Traumatology and Orthopedics named after N.N. Priorov of the Ministry of Health of the Russian Federation

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

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

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

15. Nikitin Sergey Sergeevich — Doctor of Medical Sciences, Professor, Chairman of the "Society of Neuromuscular Disease Specialists", Head of the Department of Genetics of Neurological Diseases, Institute of Postgraduate Professional Education, Research Centre for Medical Genetics named after Academician N.P. Bochkov

16. Podkletnova Tatyana Vladimirovna — Candidate of Medical Sciences, Senior Research Fellow at the Laboratory of Rare Hereditary Diseases in Children, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Member of the Union of Pediatricians of Russia

17. Polyakova Olga Alexandrovna — Pediatric Orthopedist, Traumatologist at the National Medical Research Center of Traumatology and Orthopedics named after N.N. Priorov of the Ministry of Health of the Russian Federation

18. Repina Svetlana Afanasievna — Candidate of Medical Sciences, Medical Geneticist at the Department of Medical Care Organization, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

19. Sviridova Valeria Valerievna — Medical Geneticist at the Department of Medical Care Organization, Junior Research Fellow at the Laboratory of Mutagenesis, Research Centre for Medical Genetics named after Academician N.P. Bochkov

20. Selimzyanova Lilia Robertovna — Candidate of Medical Sciences, Leading Research Fellow at the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Centre of Surgery, Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Ministry of Health of Russia, Associate Professor at the Department of Faculty Pediatrics, Faculty of Pediatrics, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Member of the Union of Pediatricians of Russia

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

22. Subbotin Dmitry Mikhailovich — Medical Geneticist, Research Fellow at the Laboratory of Neurogenetics, Research Centre for Medical Genetics

23. Udalova Olga Vasilievna — Candidate of Medical Sciences, "Genome Medical Genetic Center" LLC, Chairman of the Nizhny Novgorod Branch of the RSSM, Head of the Center for Medical Genetics, Privolzhsky Research Medical University of the Ministry of Health of Russia, Nizhny Novgorod

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

Appendix A2. Methodology for Developing Clinical Guidelines

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

These recommendations establish the types, scope, and quality indicators of medical care for patients with MPS I and were reviewed on June 1-2, 2018, at the Scientific and Practical Congress "Orphan Diseases" in Moscow.

The clinical recommendations were developed based on a systematic review of the literature from 1992–2013 in Medline (Pubmed version), Embase (Dialog version), and Cochrane Library databases, using established protocols (Muenzer J, Wraith J.E., Clarke L.A. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. 2009; 123(1):19-29; Martins AM, Dualibi AP, Norato D et al. Guidelines for the Management of Mucopolysaccharidosis Type I. J Pediatr. 2009; 155(4); (2):32-46) and modern international clinical guidelines for the diagnosis, treatment, and management of patients with metabolic diseases.

Mucopolysaccharidoses belong to rare hereditary diseases, which excludes the possibility of conducting large cohort and randomized controlled trials; therefore, only expert case studies published over the past two decades are used to create diagnostic and therapeutic protocols.

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

Target audience for these clinical guidelines:

1. General practitioners (family physicians);

2. Pediatricians;

3. General practitioners;

4. Medical geneticists;

5. Laboratory geneticists;

6. Cardiologists;

7. Pediatric cardiologists;

8. Neurologists;

9. Radiologists;

10. Functional diagnostics physicians;

11. Otorhinolaryngologists;

12. Clinical laboratory diagnostics physicians;

13. Medical psychologists;

14. Medical students;

15. Residents and interns.

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

Table 2. Scale for assessing levels of reliable evidence (LRE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

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

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

Appendix A3.1 Regulatory and legal documents

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

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

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

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

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

6. Order of the Ministry of Health of the Russian Federation No. 1051n dated November 12, 2021 "On Approval of the Procedure for Giving Informed Voluntary Consent to Medical Intervention and Refusal of Medical Intervention, the Form of Informed Voluntary Consent to Medical Intervention and the Form of Refusal of Medical Intervention"

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

8. Federal Law No. 18-FZ dated March 6, 2019, "On Amendments to the Federal Law 'On the Basics of Protecting the Health of Citizens in the Russian Federation' Regarding the Provision of Palliative Medical Care."

9. Order of the Russian Ministry of Health No. 345n, Russian Ministry of Labor No. 372n dated May 31, 2019, "On approval of the Regulations on the organization of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations, and other non-profit organizations operating in the field of health protection."

10. Order of the Russian Ministry of Health No. 348n dated May 31, 2019 (as amended on November 2, 2020) "On Approval of the List of Medical Devices Intended to Maintain Human Organ and Body Systems, Provided for Home Use."

11. 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."

Drug information: https://grls.rosminzdrav.ru/

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

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

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

3. 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."

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

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

6. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 "On approval of the nomenclature of medical services".

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

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

9. Information Letter of the Russian Ministry of Health No. 3175/25-2 dated 17.12.2019 on specific aspects of pharmaceutical procurement (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu);

Appendix A3.2 Classification of mucopolysaccharidoses

Appendix A3.3 Severity of clinical manifestations of MPS I at different ages

Appendix A3.4 Frequency of examinations in patients with MPS type I

1 - For children over 3 years of age; distance walked in 6 minutes (the preferred time interval is the same as in this patient's previous tests); number of steps climbed upward in 3 minutes. SpO2 saturation, respiratory rate (RR), and heart rate (HR) are assessed before and after exercise.

2 - DQ or Developmental Quotient is a method of comparing mental development typical for a given age (a child's mental abilities relative to their peers) with 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 A3.5 Collection of biomaterial for dry blood spot diagnostics

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

Figure 1. Sample of correct blood application to the Card for collection and transportation of biological material (filter card) Figure 2. Sample of the Card for collection and transportation of biological material (filter card)

Algorithm of actions for medical personnel during blood sample collection

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

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

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

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

• gently press to obtain a second drop of blood;

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

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

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

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

Specifics during infusion therapy

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

Blood sampling is not permitted

• immediately after the patient undergoes infusion therapy;

• immediately after an exchange blood transfusion.

Storage and transportation of biological material

Dried blood spot samples can be stored in a standard refrigerator chamber at +4°C until shipment. Storage time prior to 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 B. Physician Action Algorithms

Appendix C. Patient Information

Hurler, Scheie, and Hurler-Scheie syndromes

Hurler syndrome, or mucopolysaccharidosis type I (MPS I), is one of the earliest described forms of mucopolysaccharidoses (MPS). Originally named Pfaundler-Hurler disease, it was first described by two pediatricians: Austrian Gertrud Hurler (1889–1965) and German Meinhard Pfaundler (1872–1947). Later, American ophthalmologist Harold Scheie (1909–1990) described a second form of the disease with a later onset and milder course, termed Scheie syndrome. Subsequently, an intermediate form of the disease, termed Hurler-Scheie syndrome, was described. MPS I is a very rare disease, estimated to occur in approximately 1 in 100,000 newborns.

Over the years, a specific drug has been developed that helps slow disease progression and mitigate some of its manifestations. However, along with using this medication, one must not forget about symptomatic therapy, physical therapy, rehabilitation, and above all, a positive attitude toward life for the patient and their family members.

Pathogenesis.

In all mucopolysaccharidoses, the metabolism (breakdown) of GAGs—special structural components of connective tissue—is impaired.

GAGs are long chains of sugar molecules bound to proteins, serving as an essential building material for bones, cartilage, skin, tendons, heart valves, and many other tissues. GAGs are contained in the viscous synovial fluid that lubricates joints and are part of heart valves, joints, and tendons. Normally, there is a continuous process of "new" GAG formation and "old" GAG breakdown. This breakdown and processing of GAGs requires a group of special enzymes (proteins). To break down GAGs, enzymes work sequentially, one after another, breaking the long GAG molecule into pieces.

All patients with MPS lack a specific enzyme (unique to each type of MPS) required to break down a specific glycosaminoglycan (Fig. 1). Patients with MPS type I lack the enzyme alpha-L-iduronidase, which is required to break down the GAGs heparan sulfate and dermatan sulfate. Unbroken-down GAGs accumulate in cells, disrupting their function. Dermatan sulfate is found primarily in bones and connective tissue, and its accumulation causes numerous skeletal-related problems. Heparan sulfate is located predominantly in nervous system cells, leading to brain damage.

MPS type I belongs to lysosomal storage diseases. Lysosomes (cell organelles) are responsible for breaking down large molecules (macromolecules) such as fats, proteins, glycosaminoglycans, and glycogen. Different stages of macromolecule breakdown are impaired in various forms of the disease.

Inheritance of Hurler, Scheie, and Hurler-Scheie syndromes

Mucopolysaccharidosis type I is a hereditary disorder inherited in an autosomal recessive manner. This means the disease manifests only if both parents are carriers; although unaffected themselves, they pass on two mutated genes to the child. Most families with a child affected by this disorder have not previously encountered such a problem. The recurrence risk for having an affected child in a family that already has affected children is 25% for each pregnancy.

All families with MPS I must undergo genetic counseling and receive complete information from a geneticist regarding the recurrence risk of this disease in the family, as well as discuss all aspects of the disease's inheritance with a specialist. In Russia, medical genetics services operate in every region.

How is the diagnosis established?

Physicians may suspect the disease based on clinical symptoms. Subsequently, laboratory tests and instrumental examinations are performed. Because different types of MPS are very similar in their clinical manifestations, it is necessary to confirm the diagnosis using laboratory methods. Confirmatory diagnosis of MPS involves determining the level of urinary GAG excretion and measuring enzyme activity in blood cells, dried blood spots, or cultured skin fibroblasts. For MPS I, alpha-L-iduronidase enzyme activity is measured. Further DNA testing is subsequently recommended (if enzyme activity was reduced).

Clinical manifestations of mucopolysaccharidosis type I

Hurler syndrome (as well as Scheie and Hurler-Scheie) is a progressive multisystem disorder affecting not only the skeleton and joints, but also the nervous system, eyes, ears, cardiovascular system, and bronchopulmonary system (Fig. 2).

There are three clinical forms of MPS type I:

- Hurler syndrome (mucopolysaccharidosis I H — severe form),

- Hurler-Scheie syndrome (mucopolysaccharidosis I H/S — intermediate form).

- Scheie syndrome (mucopolysaccharidosis I S — mild form)

The severity of clinical manifestations in this syndrome varies. Both extremely severe forms of the disease—Hurler syndrome, which manifests in early childhood—and relatively mild forms—Scheie syndrome—are known. Accordingly, there is an intermediate form—Hurler-Scheie syndrome. In some cases, the presence of the syndrome does not affect the patient's life expectancy, but the quality of life is certainly impaired across all forms of the disease.

The main task for physicians, relatives, and the patient with mucopolysaccharidosis type I is to make life as comfortable as possible, reduce the risk of severe complications, slow down disease progression, and alleviate the core symptoms of the condition.

Below we describe the main problems faced by patients with Hurler, Scheie, and Hurler-Scheie syndromes, but this does not mean that every patient will experience all of them. The disease course varies significantly, even within the same family.

Early development and growth

It is practically impossible to diagnose Hurler-Scheie syndrome in a newborn, as our patients are born full-term with normal height and weight parameters. However, in Hurler syndrome—a more severe form—the first clinical signs of the disease appear during the first year of life. In some cases, a slight enlargement of the liver, umbilical or inguinal-scrotal hernias are observed right from birth. Growth slows down when the toddlers reach one to two years of age. Patients with the severe form of the disease usually almost stop growing by the age of eight, and their height typically does not exceed 110 cm. Other patients continue to grow into adolescence and reach 152–160 cm. In the mild form, patients' height is generally lower than that of healthy peers, but it can also be nearly normal.

Fig. 2 Multisystem involvement in mucopolysaccharidoses

Figure 2 Multisystem involvement in mucopolysaccharidoses

Note: intellectual disability is not observed in Hurler-Scheie and Scheie syndromes

External features

The appearance of patients with the severe form of Hurler syndrome is unusual—they resemble each other more than they resemble their parents and healthy brothers and sisters. Changes in their facial structure are denoted by the special term facial dysmorphism (coarse facial features): a large head, short neck, round face, and a wide nose with a broad and flat bridge.

In the mild and intermediate forms of the disease, the patient's external features are so subtle that only doctors notice them, while relatives and acquaintances see nothing unusual.

In patients with MPS I, due to the deposition of mucopolysaccharides, the skin is "thick" and rigid, which complicates blood collection and the use of intravenous catheters.

Patient photographs

Skeleton, musculoskeletal, and osteoarticular system

In patients with MPS type I, as with all other forms of mucopolysaccharidoses, there are problems with bone formation and growth. Alterations in bones accompanied by shape abnormalities are referred to as multiple dysostosis. In the severe form of the syndrome—Hurler syndrome—the structure of the vertebrae changes. One or two vertebrae in the middle of the back are flattened more than the others and slightly displaced. Such displacement of the vertebrae sometimes causes the development of spinal curvature (kyphosis, scoliosis). If spinal curvature or scoliosis progresses, medical assistance is required. In Scheie syndrome, spinal curvature is rather mild and does not require surgical treatment.

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 body parts will be disrupted, leading to muscle weakness (flaccid paresis), walking difficulties, and sometimes even breathing difficulties. In the severe form of the disease, weakness in the arms and legs can develop during the first year of life, leading to delayed motor development in the child.

Joint stiffness is characteristic of all forms of mucopolysaccharidoses. Over the years, joint stiffness may progress and become a cause of pain.

Due to restricted joint mobility and the structural features of the small bones of the hand, the fingers become rigid and deformed, forming the so-called "claw hand".

Due to the stiffness of large joints and bone structural features, patients walk with slightly bent knees and hips. Some patients develop valgus deformity of the lower extremities (knock-knees). Most physicians believe that this deformity is compensatory, helping the patient distribute weight, so surgical correction at an early age is in most cases best avoided. Furthermore, due to ligamentous laxity and altered bone structure, surgery does not always lead to the expected result—the deformity returns after some time.

Respiratory organs

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

It is important to understand that inadequate oxygen supply to tissues (hypoxia) affects the function of all organs; therefore, improving respiratory function is one of the primary tasks.

Breathing problems are exacerbated by the altered structure of the chest: the rib cage is "rigid" and cannot move freely, preventing the lungs from expanding to a large volume. These features lead to patients tolerating upper respiratory tract and lung infections more poorly.

The initial symptoms of upper respiratory tract dysfunction can include nocturnal snoring, noisy breathing, and obstructive sleep apnea (brief breathing pauses lasting up to several seconds during night sleep). Such manifestations should be alarming, as they may subsequently progress and lead to the development of complications involving 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 of MPS patients is mandatory, as immunizations help prevent the development of lung-affecting diseases. Notably, it is important not to miss vaccination against pneumococcal infection.

Oral cavity and teeth

In patients with MPS I, teeth are covered with brittle enamel, which leads to the rapid development of dental caries.

Cardiovascular system

Virtually all patients with MPS I exhibit cardiovascular system pathology: thickening of the heart walls, decreased myocardial contractility, and changes in the valvular apparatus (thickening of valve leaflets and chordae).

Upon examining patients with MPS I, a physician may note the presence of heart "murmurs". As a rule, this is associated with valvular damage: the damaged valve does not close tightly, and during heart contraction, a small amount of blood moves in the reverse direction, causing the murmur heard by the doctor. The aortic and mitral valves are most frequently affected.

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

Cardiovascular system

Cardiovascular pathology in MPS patients manifests as: thickening of the heart walls, changes in the valvular apparatus (thickening of valve leaflets and chordae), and the development of heart failure with both preserved and reduced myocardial contractility.

Characteristic signs of cardiovascular involvement in MPS include valve dysfunctions (mainly of the mitral and aortic valves), myocardial hypertrophy, and rhythm and conduction disturbances. Valve function, despite thickening resulting from mucopolysaccharide deposition, may remain unimpaired for some time. Subsequently, murmurs characteristic of mitral (systolic) and aortic (diastolic) regurgitation appear, developing as a result of valve incompetence. Later, shortening of the chordae and fibrosis of the left atrioventricular ring lead to stenosis of the mitral orifice. Tricuspid and pulmonic valve regurgitation are usually not clinically diagnosed.

The most frequent cause of heart failure with a preserved left ventricular ejection fraction in these patients is an increase in myocardial stiffness resulting from mucopolysaccharide deposition (akin to restrictive cardiomyopathy). In rare cases, a decrease in contractility due to chamber dilatation may be observed.

Furthermore, heart failure may develop with involvement of the right heart chambers, resembling chronic cor pulmonale, as a result of chest deformity, pulmonary involvement due to mucopolysaccharide deposition (stiff lungs), impaired drainage of the bronchial tree due to bronchial narrowing and developing tracheomalacia, and the development of chronic hypoxia.

Abdominal cavity

In Hurler syndrome, the liver and spleen are enlarged due to GAG accumulation (hepatosplenomegaly). Hepatomegaly usually does not lead to impaired liver function, but may affect the tolerance of certain foods.

In mucopolysaccharidoses, the abdomen is generally enlarged due to hepatosplenomegaly and weakness of the rectus abdominis muscles. Combined or isolated hernias (umbilical, inguinal, inguinoscrotal, and ventral midline) also frequently occur. The decision on the need for surgical treatment should be made jointly with the attending physician: an indication for emergency surgery is the strangulation of a hernia protrusion.

Patients with MPS I often experience irregular bowel movements (constipation or diarrhea). The cause of this is not fully understood. It is possible that autonomic nervous system function is impaired because GAGs accumulate in the enteric nerve cells. Diarrhea may disappear with age, but reappear during antibiotic therapy. If diarrhea is caused by antibiotics, physicians may prescribe medications to help normalize intestinal microflora. If the patient is physically inactive, constipation may develop. In this case, increasing the amount of roughage (dietary fiber) in the diet is effective.

Nervous system

In Hurler syndrome, children exhibit delayed speech development, impaired intellect, and behavioral disturbances. As cognitive impairments progress, autistic features are added to hyperactivity and aggressiveness. In milder forms—Hurler-Scheie and Scheie syndromes—intellect is not impaired, and development is slightly delayed.

In severe forms, cerebrospinal fluid circulation disorders may also occur. In this case, patients complain of headaches, while in children, anxiety, vomiting, and developmental delay draw attention. Consultation with a neurosurgeon is necessary to decide on the need for surgical or medical treatment of this complication. Progressive communicating hydrocephalus is the most frequent symptom of Hurler syndrome and is rare in mild forms of MPS type I (Hurler-Scheie and Scheie syndromes).

If hydrocephalus is suspected, computed tomography or MRI must be performed. A fundus examination by an ophthalmologist is insufficient for diagnosis, as hydrocephalus in children with MPS I can occur without papilledema.

Spinal cord compression leads to irreversible neurological deficits; therefore, decompressive surgical treatment should be considered even in patients without neurological symptoms, and surgical intervention should often be performed before the development of neurological manifestations.

Upon the onset of neurological deficit, the patient may already be at the threshold of treatability; therefore, the question of urgent surgical intervention is considered at the appearance of the first symptoms.

Surgical hip or knee replacement, limb axis correction, and carpal tunnel release are indicated for marked functional impairment and in the absence of a response to conservative therapy.

Carpal tunnel syndrome is a common problem in patients with MPS. 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 is why corneal clouding may be observed. One sign of corneal changes is photophobia, as clouding 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"). In this situation, the child becomes frightened and refuses to walk in the dark. It is advisable to leave a nightlight on in the bedroom and hallway. Sometimes vision problems caused by retinal changes or glaucoma (increased intraocular pressure) may occur, so regular ophthalmological examinations are necessary.

Using special examinations, a specialist will determine the cause of vision deterioration.

Organs of hearing

In MPS, hearing loss can be sensorineural (associated with damage to sensory (hair) cells in the cochlea), conductive (associated with impairment of the sound-conducting pathways), or mixed (a combination of both types). In Hurler syndrome, hearing loss is more frequently of a mixed 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 methods are used. It is important to notice signs of hearing loss as early as possible, because without correction, hearing loss will hinder the normal development and education of patients. A factor aggravating 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 I. And we will briefly discuss them.

Monitoring, scheduled examinations, and tests

To assess the patient's condition and the effect 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 assess the patient's condition, substantiate treatment, and introduce changes into rehabilitation and habilitation programs.

The most well-known is the 6-minute walk test. Its essence is very simple: to assess the patient's endurance. The patient is asked to walk down a long hallway for 6 minutes. The number of steps taken is evaluated. When initial clinical trials of the drug for treating various types of MPS were conducted, researchers performed such testing before and after the initiation of enzyme replacement therapy, and compared the results of the patient group receiving the drug with those receiving a placebo. This very test proved 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 quickly gas exchange occurs. These tests can detect lung diseases, determine the degree of their involvement, and evaluate treatment efficacy. Tests are usually performed using specialized equipment. During the test, the patient must inhale, hold their breath, and exhale on command. Pulmonary function testing presents no health risks.

To diagnose lung and bronchial diseases, pulmonary function testing (PFT) must be performed. PFT determines the maximum volume of air the patient can inhale and how quickly gas exchange occurs. These tests can detect lung diseases, determine the degree of their involvement, and evaluate treatment efficacy. Tests are usually performed using specialized equipment—a spirometer. During the test, the patient must inhale, hold their breath, and exhale on command. Pulmonary function testing presents no health risks.

Heart auscultation should be a mandatory and regular examination for patients with mucopolysaccharidoses. An important method for studying the heart is ultrasound—echocardiography (EchoCG); it is safe, painless, and highly informative. Modern devices allow for one-, two-, and three-dimensional imaging of the heart, determination of blood flow velocity and pressure in various chambers, and determination of the direction and turbulent nature of blood flow. EchoCG is recommended as indicated, but at least once a year. This examination is necessary to detect any heart problems (chamber enlargement, left ventricular mass index, impaired contractility (ejection fraction) as well as diastolic function, evaluation of heart valves, and motion of the interventricular septum).

If necessary, contrast-enhanced cardiac MRI can be performed for a more detailed study of the structure and function of the ventricles, great vessels, and coronary arteries.

In addition, to detect cardiac rhythm and conduction disorders, Holter ECG monitoring should be performed at least once a year. To detect arterial hypertension, 24-hour ambulatory blood pressure monitoring should be performed.

Hearing checks must be carried out regularly (twice a year) in order to start treatment immediately if necessary and maximize the ability to learn and communicate.

Magnetic resonance imaging

Spinal MRI should be performed annually, with a special focus on areas where spinal cord compression may develop: cervical, thoracic, and thoracolumbar regions. Patients with type I mucopolysaccharidosis should be followed by an orthopedic surgeon to monitor the state of the cervical spine. It is important to evaluate study results over time, so all scans should be saved and provided to physicians at each subsequent imaging session. Spinal computed tomography is usually performed prior to planned surgical treatment.

Radiography of the cervical, thoracic, and lumbar spine. Radiography of the cervical and thoracolumbar spine in two projections should be performed every 1–3 years. This study is technically simpler than MRI, and radiography also provides more information about vertebral structure.

A list of recommended examinations is given in Table 1.

Symptomatic treatment

The main goal of symptomatic treatment is to correct disease-induced changes.

Skeleton and musculoskeletal system, osteoarticular system

It is important to find a balance between the opportunity to live as full a life as possible and minimizing complications associated with the patients' skeletal structure. On the one hand, children should not be overly restricted and overprotected; physical therapy is necessary, but certain physical activities such as tumbling, headstands, and diving must be completely excluded due to cervical instability. Light hopping is permitted, but the patient should not jump independently on both feet because their support and motor coordination system is poorly developed. Parents of school-aged children must inform the physical education teacher about the student's specific needs.

Patients with Hurler-Scheie syndrome should lead an active lifestyle to maintain joint function and improve overall health. A pediatrician or 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 consequences of hyperlordosis, it is necessary to strengthen the chest muscles while carrying out therapy aimed at developing the lumbosacral region. It is important to ensure that the patient does not overexert or become excessively fatigued, so it is recommended to thoroughly evaluate their physical condition and develop individualized recommendations.

- 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, it is necessary to perform special exercises, preferably at home or during play. To relieve excessive muscle tension, orthopedic shoes, insoles, and inserts that provide support are needed, and in some cases orthoses. Foot baths and leg massages are also necessary.

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 and patients can perform at home.

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 regarding the necessity of surgical intervention. However, surgery is always a risk and should be resorted to only in cases of acute necessity. A major challenge in MPS is anesthesia administration. Cervical spine instability, difficulty opening the mouth, a large tongue, and enlarged tonsils in patients with MPS increase the risk of traumatic injury during anesthesia management, as many anesthetic techniques involve maximal neck extension. In this case, special precautions must be taken. Intubation of individuals with MPS must be performed by an experienced physician with specific skills. If a patient is admitted to the hospital in critical condition, the anesthesiologist must be informed of potential neck and intubation issues. The airways are typically narrowed, so a smaller endotracheal tube 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.

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.

Organs of hearing

Sensorineural and conductive hearing loss can in most cases be compensated by fitting hearing aids or, if necessary, middle ear implants (partially implantable middle ear implant system). In case of frequent otitis media, tympanostomy tube placement is performed for fluid drainage.

Cardiovascular system

Due to the development of valve dysfunctions, a consultation with a cardiac surgeon is often recommended to address the need for heart valve replacement. Due to frequently developing rhythm disorders, the issue of implanting a cardioverter-defibrillator is raised (single-chamber implantable pacemaker, fixed-rate without rate response).

Infectious Diseases

It is important to ensure good dental care, as 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 meticulous dental care, inflammatory processes can develop. Irritability, crying, and restlessness may sometimes be the only symptoms of dental problems. Prior to dental surgery, patients already diagnosed with heart valve disease require prophylactic antibiotic therapy before and after treatment. This is because certain bacteria from the oral cavity can enter the bloodstream and cause an infectious process on the damaged valve. If tooth extraction under anesthesia is necessary, it must be performed in a hospital rather than a dental clinic, under the supervision of an experienced anesthesiologist and dentist.

Treatment of ordinary ARVI in patients with MPS is also best carried out under close medical supervision. The specific considerations of using standard medications in this group of patients should be kept in mind. For example, drugs such as R06 antihistamines may dry out the mucosa, making it thicker, while decongestants or vasoconstrictors may raise blood pressure and narrow blood vessels, which is undesirable in MPS.

Due to the specific structure of the spine and chest, patients with type I mucopolysaccharidosis find it more difficult to cope with infection if it affects the lungs, which is why doctors may prescribe antibiotics even for a minor infection.

To normalize air circulation in the lungs, it is recommended, both preventively and during illness, to play games with soap bubbles, cotton wool, drinking straws, paper bags, and other objects (balloons, balls) that require active work of the respiratory system. For older children and adolescents, chest muscle stretching exercises can be developed so that parents can work with the children 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.

Diet therapy

A special diet cannot prevent the accumulation of GAGs, as they are synthesized in cells rather than obtained from food. Therefore, dietary restrictions are not needed for patients with MPS; children should eat according to their age-related needs.

Pathogenetic therapy

For MPS type I, a specific enzyme replacement therapy has been developed

The therapeutic effect largely depends on when treatment is initiated. Before starting enzyme replacement therapy, it is essential to discuss all potential risks, side effects, and, most importantly, treatment expectations with your physician. It is important to understand that enzyme administration will not cure the disease; the goal of therapy is to slow disease progression. Therapy will not correct skeletal deformations that have already developed, nor will infusion therapy replace necessary surgical interventions.

Bone Marrow / Hematopoietic Stem Cell Transplantation

It should be noted that the transplantation procedure itself carries a significant risk for the patient due to frequent complications caused by graft "rejection" by the patient's body.

Puberty and Marriage

Adolescents with Hurler-Scheie and Scheie syndromes go through normal stages of puberty, although it starts somewhat later.

Table 1 - Monitoring plan for patients with MPS I

The disease does not affect fertility, but women with the severe form of the disease sometimes find it difficult to carry a pregnancy to term due to severe cardiac and skeletal impairments. Worldwide and in Russia, there are families where mothers have given birth to several healthy children. Therefore, all issues related to pregnancy and childbirth must be addressed on an individual basis.

All children born to parents with Hurler-Scheie and Scheie syndromes are carriers of the disease, but will not be affected if the second parent is healthy.

Recreation

Patients with the mild form of the disease need to learn to be independent from their families. Do not allow a child or adolescent to become withdrawn. They need friends, social interaction, and independent living skills.

Since children with the mild form of the syndrome have normal intelligence, every effort must be made to ensure they receive a good education.

Healthcare facilities have been designated in each region where patients receive pathogenetic treatment and undergo all necessary diagnostic evaluations.

Learn more

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

International Mucopolysaccharidosis Society: www.mpssociety.org

International Rare Diseases Portal www.orpha.net

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

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

Russian Public Organizations and Foundations

MPS type I is included in the list of orphan diseases funded by the state. Public organizations can help patients receive treatment, raise public awareness about rare diseases, and advocate for legislative initiatives in the field of orphan diseases. On the internet, you can find information about several public organizations that assist families affected by mucopolysaccharidoses.

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

Appendix G1. 6-Minute Walk Test (6MWT)

Russian title: 6-minute walk test

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

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

Type (underline):

rating scale

index

questionnaire

other

Purpose: determination of patient endurance to assess treatment efficacy

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

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

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

It should be remembered that this test has the following absolute contraindications: unstable angina pectoris and myocardial infarction within the last 1 month. Relative contraindications include: resting heart rate above 120 bpm, systolic BP >180 mmHg and diastolic BP >100 mmHg. Stable angina is not an absolute contraindication to the test, but it should be performed with caution, against the background of antianginal drugs as indicated.

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

The test must be stopped immediately if the following occur:

1) Chest pain;

2) Intolerable dyspnea;

3) Leg cramps;

4) Severe instability and swaying while walking;

5) Excessive sweating;

6) Sharp change in skin color (pallor).

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

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

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