Proximal 5q spinal muscular atrophy: clinical guidelines

List of Abbreviations

BiPAP — from English Biphasic Positive Airway Pressure, BPAP, BiPAP

Borg CR10 scale — Borg category-ratio scale

URT — upper respiratory tract

RF — respiratory failure

DNA — deoxyribonucleic acid

FVC — forced vital capacity

IMV — invasive mechanical ventilation

kDa — kilodalton

CT — computed tomography

CK — creatine kinase (synonym – creatine phosphokinase)

LDH — lactate dehydrogenase

MRI — magnetic resonance imaging

NIV — non-invasive ventilation

FEV1 — forced expiratory volume in one second

ARVI — acute respiratory viral infection

MUAP — motor unit action potential

RFLP — restriction fragment length polymorphism (a method for genomic DNA analysis)

PEF — peak expiratory flow

PCF — peak cough flow

FMP — physical management program

PCR — polymerase chain reaction

RNA — ribonucleic acid

rRNA — ribosomal RNA

mRNA — messenger RNA

CPAP — from English Constant Positive Airway Pressure, CPAP

SMA — spinal muscular atrophy

SMA I — spinal muscular atrophy, type I

ATD — assistive technology devices

FVC — forced vital capacity

LeR — level of recommendation validity

LoE — level of evidence

ECG — electrocardiography

EMG — electromyography

ENMG — electroneuromyography

EchoCG — echocardiography

MLPA — Multiplex Ligation-dependent Probe Amplification

NIPPV — Noninvasive Positive Pressure Ventilation

OMIM — Online Mendelian Inheritance in Man

PtcO₂ — transcutaneous pulse oximetry

PetCO₂ — partial pressure of end-tidal CO₂

SpO₂ — arterial oxygen saturation measured noninvasively via pulse oximetry (mean nighttime oxyhemoglobin saturation)

Terms and Definitions

Auto CPAP (angl. Auto CPAP; according to medical device nomenclature — continuous positive airway pressure ventilator Auto CPAP) is a CPAP device (see below) with automatic adjustment of the delivered air pressure, which determines the required pressure level and supplies airflow only during respiratory pauses, gradually increasing it until an inhalation occurs.

BiPAP (from Eng. Biphasic Positive Airway Pressure, BPAP, BiPAP; according to medical device nomenclature — continuous positive airway pressure ventilator BPAP) — bilevel positive airway pressure ventilation — is a device that provides different levels of positive airway pressure during inhalation and exhalation.

Myocardial hypertrophy is a pathological thickening of the heart walls.

Densitometry is a non-invasive method for determining bone mineral density.

Cardiac chamber dilatation is a pathological enlargement of the volume of the heart chambers.

Myocardial dysfunction is an impairment of myocardial function; dysfunction can be systolic (reduced myocardial contractility), diastolic (slowed relaxation of the heart muscle), and electrical (impaired propagation of electrical depolarization and repolarization through the heart muscle).

Cardiomyopathy is a heterogeneous group of myocardial diseases associated with mechanical and/or electrical dysfunction, usually (but not always) leading to hypertrophy or dilatation, and having various (often genetic) causes.

Capnometry and capnography are the measurement and digital display of the concentration or partial pressure of carbon dioxide in inspired and expired gas during a patient's respiratory cycle.

Acid-base balance (acid-base state, ABS) is the ratio of hydrogen ion concentrations H⁺ and hydroxyl groups OH in the body's biological fluids.

Contracture is a limitation of passive movement in a joint.

Pathological posture of a limb or limb segment is a pathological position of a limb or its segment resulting from altered muscle tone while the range of motion in the joint(s) is preserved.

Pulse oximetry is a method that allows determining the O₂ content in the blood and the pulse rate per minute.

Heart failure is a reduction in the heart's ability to provide pumping function. It can be acute or chronic.

CPAP (from Eng. Constant Positive Airway Pressure, CPAP — constant positive airway pressure in the airways; according to medical device nomenclature — continuous positive airway pressure ventilator CPAP) is an individual medical device for automated long-term assisted intranasal continuous positive airway pressure ventilation used by a patient during night sleep. A CPAP device is a small compressor that delivers a continuous stream of air under a certain pressure into the airways through a flexible tube and a tight nasal or oro-nasal mask. Thus, it prevents the airways from collapsing and blocking the flow of air (and the oxygen necessary for the body). As a result, the risk of sudden death from lack of air in the airways is eliminated, and normal sleep is ensured.

Scoliosis is a three-plane deformity of the spine.

Submaximal exercise load regimen is a regimen characterized by the absence of shortness of breath, fatigue, and muscle pain.

Electromyography (EMG, ENMG, myography, electroneuromyography: myo — muscle and …grapho — to write) is a method for studying bioelectrical potentials arising in the skeletal muscles of humans and animals upon muscle fiber excitation; the recording of electrical activity of muscles.

Enteral nutrition is the administration of nutrients into the gastrointestinal tract (orally, via tubes and stomas) to maintain and correct nutritional status in accordance with the patient's current needs for energy, protein, vitamins, minerals, and trace elements.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Proximal 5q spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disorder characterized by progressive symptoms of flaccid paralysis and muscle atrophy due to the degeneration of α-motor neurons in the anterior horns of the spinal cord [1].

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

The development of proximal 5q spinal muscular atrophy is caused by mutations in the SMN1 (short for survival motor neuron) gene encoding the survival motor neuron protein. The SMN1 gene is mapped to chromosome 5 at locus 5q12.2-q13.3 and has a centromeric copy (SMN2). Both genes consist of nine exons (1, 2a, 2b, 3-8) and differ by five nucleotides in their DNA sequence [1, 2]. The critical point is a cytosine-to-thymine substitution in exon 7 of the SMN2 gene (c.840C > T), which creates a splicing repressor binding site. Due to this sequence difference, the major transcript of the SMN2 gene lacks exon 7 and is functionally defective [3]. However, the SMN2 gene also produces a full-length functional protein, but in relatively small amounts (up to 10%).

Proximal SMA is caused by mutations in the telomeric copy of the gene (SMN1). The main type of mutation in this gene is homozygous deletions of exons 7 or 7-8, which are detected in 95% of patients. The remaining 5% of patients are compound heterozygotes for a deletion in one copy of the SMN1 gene and a point mutation in the other, and extremely rarely, compound heterozygotes for two minor mutations [4]. Mutations in the SMN2 gene cannot cause SMA, but its copy number is currently the main disease modifier. Approximately 80% of the general population has 1-2 copies. Homozygous deletion of the SMN2 gene has been described in 5-10% of healthy individuals. In SMA patients, the variation in SMN2 copy number is much larger and can range from 1 to 6 copies. The small amount of functional protein produced by the centromeric SMN gene copy is able to mitigate the severity of the disease course in patients with an increased number of SMN2 copies [5-8].

The product of the SMN gene is the SMN protein, consisting of 294 amino acid residues with a molecular weight of 38 kDa. The protein functions in both the nucleus and the cytoplasm. In the nucleus, the SMN protein localizes to sphere-like structures called gems, associated with Cajal bodies, which are involved in RNA metabolism. The SMN protein plays an important role in pre-rRNA splicing and the biogenesis of small nuclear ribonucleoproteins, in gene expression at the transcriptional level, and also participates in axonal mRNA transport in alpha-motor neurons [9].

A decrease in SMN protein levels leads to axonal defects in motor neurons, including axonal truncation and/or excessive branching, growth retardation, abnormalities at neuromuscular synapses: accumulation of neurofilaments in presynaptic terminals, formation of immature postsynaptic terminals, functional anomalies, and impaired endocytosis [10, 11].

Modifiers of the clinical course of the disease. The clinical variability of proximal 5q SMA can be explained by the presence of modifying factors. Modifiers can be divided into two main groups: those that affect SMN protein levels and those that do not affect SMN protein levels.

Factors influencing SMN protein levels. Currently, the main modifying factor of SMA is considered to be the SMN2 gene—its copy number and various intragenic variants. There is evidence of a correlation between the severity of the disease and the number of SMN2 gene copies [12]. The higher the number of SMN2 gene copies, generally the less pronounced the clinical symptoms of SMA. However, determining the SMA type solely based on the SMN2 gene copy number is unacceptable and is performed by a physician based on all available information about the disease in a specific patient [12].

Another modifying factor of SMA, directly related to the centromeric copy of the SMN gene, is the single-nucleotide substitution c.859G > C in exon 7 of the SMN2 gene, which leads to the formation of a novel enhancer splice site, resulting in the inclusion of exon 7 into the SMN2 gene transcript. This variant is associated with an increase in blood levels of full-length SMN protein in patients with type II-III SMA [13].

Table 1. Additional factors influencing SMN protein levels

However, the effect of most of these factors was evaluated in vitro. In vivo, interaction mechanisms are much more complex and require in-depth study.

Factors not affecting SMN protein levels. There are also many modifiers not associated with the SMN gene and its product. More and more mechanisms are discovered every year. Recently, attention has focused on a number of proteins that improve the endocytosis process at synapses, since it has recently been established that endocytosis is one of the key impaired mechanisms in SMA. These proteins include plastin-3 (PLS3), coronin (CORO1C) [14], neurocalcin delta (NCALD) [15], and calcium-binding protein 1 (CHP1) [16].

Of particular interest is DNA methylation, as the most stable modification altering gene expression patterns. A correlation was revealed between the methylation of a number of genes (SLC23A2, NCOR2, DYNC1H1), which may be involved in the pathogenesis of SMA, and disease severity [17-19].

1.3 Epidemiology of the Disease or Condition

The prevalence of proximal spinal muscular atrophy is 1 in 6,000–10,000 newborns [20]. Data on the prevalence of the disease in the Russian Federation are absent. The carrier frequency of the disease is 1/40–1/50 in the general population [21, 22]. According to the Research Centre for Medical Genetics (Bochkov Medical Genetics Research Centre), the carrier frequency of the SMN1 gene mutation in Russia is 1/36 individuals, and the estimated birth incidence of a child with SMA is 1 in 5,184 newborns [23].

1.4 Features of Coding the Disease or Condition

G12.0 Infantile spinal muscular atrophy, type I [Werdnig-Hoffmann]

G12.1 Other inherited spinal muscular atrophies

1.5 Classification of the disease or condition

The clinical classification of the disease is based on the age of onset, severity of the disease course, and life expectancy [20] (Tab. 2).

Table 2. Clinical classification of proximal 5q spinal muscular atrophy.*

*type IV SMA also exists, but this type manifests in adulthood

**under the natural course of the disease

1.6 Clinical presentation of the disease or condition

Proximal spinal muscular atrophy type 0, or congenital SMA with postnatal asphyxia, is the most severe variant of the disease course. At 30–34 weeks of gestation, decreased fetal mobility is noted. After birth, movements are practically absent; contractures, swallowing, and breathing difficulties are present—without respiratory support, the child dies [24].

Proximal spinal muscular atrophy type I, or Werdnig-Hoffmann disease, occurs before the age of 6 months and is characterized by severe muscle weakness. Affected infants are unable to hold their head up, roll over, or sit without support. Proximal, symmetric muscle weakness, lack of motor development, and muscle hypotonia are the main clinical signs of type I SMA. Contractures in the knee and wrist joints are frequently noted, and less commonly in the elbow joints. In the neonatal period or during the first three months of life, children with a fatal prognosis experience difficulties with sucking and swallowing and often demonstrate diaphragmatic breathing. The diaphragm itself is not involved in the pathological process until the final stage of the disease. Swallowing disorders can lead to aspiration pneumonia and death. Patients exhibit tongue fasciculations and postural tremor of the fingers. Most affected children with type I SMA without medical management and specialized care die before the age of two [25].

Proximal spinal muscular atrophy type II, or chronic SMA (Dubowitz disease), has a later onset at 6–18 months of age and a less severe course. Such children retain the ability to sit and hold their head up independently. Patients with type II SMA exhibit tongue fasciculations, tremor of the fingers of outstretched hands, fascicular and fibrillary twitches in the proximal limb muscles, pronounced scoliosis, weakness of the intercostal muscles, and diaphragmatic breathing. Children experience difficulties with coughing and deep breathing during sleep to maintain normal oxygen and carbon dioxide levels [26, 27]. Skeletal deformities develop and progress. Poor sleep at night, fatigue after night sleep, daytime sleepiness, and potential development of morning hypertension are also characteristic (the same changes develop at an older age in type III SMA).

The onset of proximal spinal muscular atrophy type III (juvenile form), or Kugelberg-Welander disease, varies from 18 months of age up to adolescence. Patients with type III SMA retain the ability to move independently, but may frequently fall or experience difficulty climbing and descending stairs, running, bending over, or rising from a sitting position. The lower limbs are more severely affected than the upper limbs in this type of disease. Patients with type III SMA also retain tremor of the fingers of outstretched hands [26-28].

In all types of SMA, the main groups of respiratory muscles can be affected, including inspiratory and expiratory muscles and bulbar musculature, while the degree of involvement and the mechanisms leading to respiratory impairment may vary depending on the SMA type and disease stage. Initially, hypoventilation due to respiratory impairment develops during sleep, and subsequently during the daytime as well. Hypoventilation during sleep leads to apnea. Respiratory disorders are the main cause of complications and mortality in patients with type I and type II SMA; in addition, they can also develop in a small proportion of patients with type III SMA.

Cardiological pathology (cardiac arrhythmias, cardiomyopathy, etc.) may be detected in all types of SMA.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition: results of molecular genetic testing (detection of homozygous deletions of exons 7 or 7–8 (i.e., in both gene copies) or homozygous point mutations in the SMN1 gene, or a point mutation and an exon deletion in a compound heterozygous state).

2.1 Complaints and Anamnesis

The main complaints and anamnesis are described in the section "Clinical presentation of the disease or condition (groups of diseases or conditions)". Complaints requiring separate clarification are listed below:

2.2 Physical Examination

Clinical evaluation of SMA includes a physical examination focusing on the musculoskeletal system and associated functional impairments. The choice of examinations used will depend on the aspects most relevant to each severity grade. Physical examination findings are described in the section "Clinical picture of the disease or condition (group of diseases or conditions)". The specific features of the physical examination are outlined below:

Comments: changes in nutritional status are frequently observed in SMA patients. Non-ambulatory patients and those with dysphagia are at an increased risk of malnutrition. Sitting and ambulatory patients are at risk of overweight/obesity due to reduced energy expenditure caused by decreased activity upon loss of the ability to walk. Following an SMA diagnosis, all patients must undergo height and weight measurements at least once every 3–6 months in children under 7 years of age, and annually in children over seven years of age, or more frequently as clinically indicated.

Comments: special attention during the examination is paid to potential swallowing disorders during feeding — decreased or absent pharyngeal and palatal reflexes, weakened sucking in young infants, difficulties with chewing and swallowing food, prolonged meal times, and the presence of temporomandibular joint contractures.

Comments: the frequency of respiratory function assessment and monitoring depends on the clinical status and rate of disease progression in each individual patient. The frequency of assessment averages once every 3–6 months in mild-to-moderate SMA II and SMA III patients. Respiratory functions are assessed less frequently in ambulatory patients in a stable condition, and more frequently in non-ambulatory patients with an unstable disease course. Respiratory assessments can be performed once every 3 months in patients receiving invasive mechanical ventilation. For children on non-invasive positive pressure ventilation (NIPPV), it is advisable to perform the assessment once a month. In SMA I, if the child is not on NIPPV, respiratory disorders can progress very rapidly, sometimes necessitating even more frequent evaluation.

Comments: skeletal deformations develop in all forms of SMA. Spinal curvature, associated with reduced muscle tone, progressively worsens throughout life. In addition, the majority of patients develop varying degrees of thoracic kyphosis.

Comments: the scales are provided in Appendices G1-G5. Assessments using these scales should preferably be performed by certified specialists on a regular basis every six months, unless specific circumstances dictate a different observation frequency. Serial evaluation of a child using special scales is particularly important when assessing the efficacy of targeted therapy. In the absence of a certified specialist, it is advisable to refer the patient to a center where such specialists are available.

Comments: for 5q SMA types (SMA type 1, SMA type 2, and SMA type 3), see Section 1.5 "Classification of the disease or condition (group of diseases or conditions)".

2.3 Laboratory Diagnostics

Comments: the “gold standard” of molecular genetic testing for SMA 5q is quantitative analysis — analysis of the copy number of the SMN1 and SMN2 genes. This testing is performed using real-time PCR or quantitative MLPA analysis. The diagnosis is confirmed when deletion of exons 7 or 7-8 is detected in the homozygous state (i.e., in both copies of the gene). Molecular genetic testing for deletion of exon 7 and/or exon 8 of the SMN1 gene (real-time PCR or MLPA analysis) is also indicated for the parents of a patient, or the parents of a deceased child with a presumptive diagnosis of SMA in the absence of their biological material for DNA diagnosis, in subsequent marriages of parents of affected children — their new spouses (if childbearing is planned), spouses of adult SMA patients when planning childbearing; close relatives (siblings of patients and siblings of patients' parents) for prognosis regarding their offspring; sperm and egg donors in in vitro fertilization. Molecular genetic testing for deletion of exon 7 and/or exon 8 of the SMN1 gene, as with a number of other common autosomal recessive diseases, is necessary when planning pregnancy in consanguineous marriages. Parents of children with a molecularly verified diagnosis, as well as couples in which each partner is a confirmed heterozygous carrier of a deletion of exon 7 or 7-8 of the SMN1 gene, should be informed about the possibility of prenatal (during pregnancy) or preimplantation (using in vitro fertilization) DNA diagnosis [44]. It is also possible to perform molecular genetic testing for mutations in the SMN1 gene in the fetus and preimplantation genetic diagnosis of the embryo (using in vitro fertilization) for parents of a patient with SMA 5q, as well as for couples in which each partner is a confirmed heterozygous carrier of a deletion of exon 7 or 7-8 of the SMN1 gene, in order to prevent the recurrent birth of a child with SMA in the family [27]. Prenatal DNA diagnosis can be performed at various stages of pregnancy: 8-12 weeks (chorionic villi), 15-18 weeks (amniotic fluid), 20-24 weeks (cord blood). Testing of a chorionic villus biopsy sample is optimal: in case of an unfavorable prognosis, the pregnancy can be terminated within the time frame of a standard medical abortion.

Comments: the presence of a heterozygous deletion is defined as the presence of a single copy of the SMN1 gene. Detection of a pathogenic mutation in the second copy of the SMN1 gene confirms the diagnosis of SMA.

Comments: the absence of exon 7 or exons 7–8 deletion of the SMN1 gene is defined as the presence of 2 or more copies of the SMN1 gene detected by real-time PCR or quantitative MLPA analysis. In cases of consanguineous marriages, it is mandatory to screen for point mutations in the SMN1 gene using direct automated Sanger sequencing, even if exon 7 or exons 7–8 deletions of the SMN1 gene are absent.

Comments: it should be borne in mind that the type of SMA in a particular patient cannot be established by the SMN2 copy number; it is determined solely on a clinical basis. The SMN2 copy number must be taken into account when predicting the course of the disease, as it is an important factor determining the severity of the clinical picture. Patients and their families should be advised during counseling that despite the strong correlation between the SMN2 copy number and prognosis, exceptions do exist.

Comments: this test is monitored dynamically depending on the disease-modifying therapy, but at least twice a year [101, 105–107].

Comments: this test is monitored dynamically depending on the disease-modifying therapy, but at least once a year [101, 105–107].

Comments: this test is monitored dynamically as clinically indicated.

Comments: this test is monitored dynamically twice a year.

Comments: creatine kinase (CK, CPK) levels are usually normal or slightly elevated; however, isolated cases with a high (10-fold) increase in enzyme activity have been described. Thus, an elevated enzyme level does not necessarily rule out a diagnosis of SMA.

Comments: changes in acid-base balance occur at advanced stages of respiratory failure. For timely diagnosis, it is advisable to use more informative instrumental methods (capnometry, etc. — see below). Decompensation of respiratory disorders is diagnosed in the presence of hypercapnia and acidosis.

Comments: there is a consensus on the need to perform this test at least once a year.

2.4 Instrumental Diagnostics

2.4.1 Instrumental diagnostics for 5q SMA

Comments: when examining patients with SMA, needle electromyography (one muscle) (EMG) and stimulation electroneuromyography of a single nerve (ENMG) should be used. Stimulation electroneuromyography of a single nerve allows assessment of the response of spinal motor neurons by examining F-waves. Stimulation electroneuromyography of a single nerve reveals F-wave abnormalities: the appearance of giant F-waves, paired and repeated F-waves, scattered F-waves, or their absence (F-wave blocks). Conduction velocities and M-wave amplitudes along peripheral motor fibers can be either normal or slightly reduced due to secondary axonal changes. Needle electromyography (one muscle) makes it possible to examine a specific muscle and determine the degree of denervation activity. Findings characteristic of needle electromyography (one muscle) include: increased amplitude of the interference pattern, rarefaction of the interference pattern, and the appearance of various spontaneous activity potentials forming a so-called "fence rhythm" [49].

Comments: MRI of the muscular system reveals fatty replacement of muscle tissue. A characteristic pattern of involvement is visualized—hypertrophy and relative sparing of the long head of the adductor magnus/longus muscle (m. adductor longus), which is quite specific for spinal muscular atrophy. However, this specific pattern of involvement appears at a late stage of the disease, and it is quite difficult to detect at the very onset of the disease and in young children.

Comments: pathomorphological examination of muscle biopsy (surgical) material in patients with spinal muscular atrophy reveals non-specific signs of fascicular atrophy and muscle fiber grouping. Most hypertrophied muscle fibers belong to type I. All immunohistochemical markers will be normal. Ultrastructural changes will also be non-specific.

2.4.2 Instrumental diagnostics for cardiac complications of 5q SMA

Comments: congenital structural abnormalities (septal defects, outflow tract defects) predominate in patients with type I SMA. In patients with less severe forms of SMA, acquired arrhythmias predominate, most frequently — rhythm initiation disorders. If complaints or clinical symptoms of cardiovascular involvement appear, the frequency of follow-up examinations is determined individually for each patient. The test should be performed at least once a year, as well as prior to orthopedic surgery.

Comments: congenital heart defects are occasionally seen in SMA type I. Cardiomyopathy is more commonly observed in patients with spinal muscular atrophy types 1 and 2 and typically presents as dilated cardiomyopathy. In severe cases, a classic presentation of pulmonary hypertension may develop (dyspnea, cyanosis, hemodynamic disturbances up to pulmonary edema due to compression of the left ventricle by enlarged right chambers and reduced ejection capacity of the left ventricle). Echocardiography should be performed in patients with less severe forms of 5q SMA who present with clinical symptoms, as well as in all 5q SMA patients as a preoperative assessment.

2.4.3 Instrumental diagnostic tests for musculoskeletal complications of 5q SMA

Comments: patients with SMA are characterized by a high frequency of fractures and osteopenia. These risks are driven not only by muscle weakness and low mobility, but also by the fact that the SMN gene plays a role in bone tissue metabolism [54].

Comments: spinal radiography (spine radiography, special examinations and projections, cervical spine radiography, thoracic spine radiography, thoracolumbar spine radiography, lumbar spine radiography, pelvic radiography) is performed in anteroposterior and lateral projections. The study is conducted in the most upright position achievable by the patient, regardless of assistive devices (i.e., sitting in children who can sit independently, standing in SMA III, supine in non-ambulatory patients) to determine and quantify the degree of spinal deformity in both the frontal and sagittal planes. Radiography is performed in patients with SMA I and SMA II with scoliosis > 20° (anteroposterior spine radiography in sitting and supine positions) every 6 months, and then annually after skeletal maturity to monitor the progression of kyphoscoliosis and determine further orthopedic management. In specific clinical scenarios (appearance of new clinical symptoms of the pathology and their worsening), the study is performed more frequently. The frequency of evaluations should be determined by the relevant specialist or a multidisciplinary team.

For computed tomography of the spine (one segment), Level of Recommendations C (Level of Evidence – 3)

For magnetic resonance imaging of the spine (one segment) and ultrasound examination of the spine. Level of recommendation C (level of evidence – 4)

Comments: conducting additional studies is especially indicated in the case of administration of nusinersen**, if a lumbar puncture at the C1-C2 level is being considered.

Comments: radiography of the hip joint (hip joints) is performed in the anteroposterior view with evaluation of the femoral head migration index and the vertical center-edge angle. In the presence of signs of femoral head migration, radiography is performed in the anteroposterior view with maximum possible hip abduction to clarify the degree of femoral head centration upon abduction. If the patient has pronounced hyperlordosis or flexion contractures in the hip joints, positioning correction is required to eliminate lordosis by placing a bolster under the popolar region or by changing the centration of the X-ray tube taking into account the pelvic tilt. Radiography of the hip joint (hip joints) is performed for all patients in the "non-ambulatory" and "sitter" categories every 6 months if there are radiological signs of femoral head migration. For patients in the "walker" category, radiography is performed once at the time of diagnosis and is repeated only in the presence of clinical or radiological signs of joint changes. For specific indications (appearance of new clinical manifestations of pathology and their negative dynamics), the examination is performed more frequently. In this case, the frequency of examinations must be determined by a specialized physician or a multidisciplinary medical board.

2.4.4 Instrumental examinations for the diagnosis of respiratory complications of 5q SMA

Comment: this examination is performed at least once every 2 years.

Comments: for non-ambulatory patients, this examination should be performed every 3 months; for less severe patients, less frequently.

Comments: normally, saturation values are within 95-100%. If SpO₂ is below 90%, emergency measures must be taken. Saturation between 94-90% is considered borderline. Patients with hypoventilation must have a pulse oximeter at home.

Comments: unprovoked respiratory volumes and flows testing should be performed in patients with SMA older than 5 years who are able to perform the test, once every 6 months for type II SMA and once every 12 months for type III SMA. The best and simplest parameter for monitoring respiratory muscle strength in pediatric patients with SMA (capable of performing the test) is forced vital capacity (FVC). Patients with an FVC reduction of 20% to 50% of predicted are at increased risk of pulmonary complications, and patients with FVC < 20% are at an even higher risk. Patients with FVC > 60% have a low risk of nocturnal hypoventilation. Assessment of respiratory muscle function effects, including maximal inspiratory pressure, nasal respiratory pressure, or maximal expiratory pressure, does not provide sufficient or additional information when compared to FVC in patients with SMA.

Comments: the study is performed for patients with a decrease in forced expiration by 45% or more once every 6 months. As of the end of 2019, the study is available for patients in neurological departments specialized in neuromuscular diseases. Of course, it is desirable to introduce this method in other neurological departments as well as for home care support.

Comments: patients with SMA are susceptible to sleep-related breathing disorders, most commonly — hypoventilation due to decreased tidal volume, impaired diaphragmatic function, and reduced function of intercostal and accessory muscles. Obstructive syndrome is also observed due to weakness of the laryngeal and pharyngeal muscles, causing a predisposition to airway collapse. In accordance with Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services," there is no service named "Polysomnography," therefore the use of a set of services is possible.

2.5 Other Procedures

Specialist consultations can be provided to patients at various stages of medical care, including during the disease diagnosis period.

Comments: if the neurologist confirms the likelihood of the disease, they must refer the child for genetic testing.

Comments: subsequent follow-up of the child depending on the patient's functional status (for non-ambulatory patients at least once every 3 months, for sitting patients — once every 6 months, for ambulatory patients — once every 12 months). During the examination, it is necessary to assess the range of active and passive movements in combination with functional tests (Medical Research Council scale, Hamstring test, Silverstein test) and record the data in the patient's medical history in comparison with the previous study. Frequency of the study is once every 6 months [20, 83].

Comments: the first specialist to whom the pediatrician refers the patient may not be a neurologist, but specifically a geneticist.

Comments: specialist examination includes determining the range of passive and/or active motion of a single joint in a single plane and the presence of spinal curvatures, as well as determining the static and/or dynamic strength of a single muscle, and the functional capabilities of each limb and joint. Issues regarding necessary orthotics are addressed.

Comments: the pulmonologist determines whether the patient needs additional examinations and which ones (determination of partial pressure of oxygen in soft tissues (oximetry), study of acid-base balance and blood gases, targeted chest X-ray, cardiorespiratory monitoring, unprovoked respiratory volumes and flows testing).

Comments: palliative care consultation can be provided at all stages of SMA patient management: at diagnosis, during key therapeutic decision-making, in the event of life-threatening conditions, and in the terminal phase of the disease.

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

3.1 Pharmacotherapy

Pharmacotherapy for 5q SMA is categorized into disease-modifying therapy—aimed at correcting SMN protein deficiency using drugs with different mechanisms of action—and symptomatic therapy (management of individual disease symptoms).

3.1.1 Disease-modifying pharmacotherapy

There are several approaches to disease-modifying therapy. Gene replacement therapy, administered as a single dose, uses onasemnogene abeparvovec. The mechanism of action of this therapy is based on the delivery of a functional copy of a gene (transgene), which replaces the defective SMN1 gene function and restores SMN protein production. The use of SMN2 gene splicing modifiers (genetic modification) increases the expression of full-length functional proteins [56-58].

The antisense oligonucleotide drug nusinersen** was approved for the treatment of all SMA types in the USA in December 2016, approved for use in Europe in May 2017, and registered in the Russian Federation in 2019 [58, 59]. The small-molecule drug risdiplam** (administered orally) was approved in the USA in August 2020 and in Russia in December 2020. Onasemnogene abeparvovec, which is a non-replicating recombinant adeno-associated viral (AAV) vector utilizing the adeno-associated virus serotype 9 (AAV9) capsid to deliver a stable, fully functional SMN1 transgene, was approved in the USA in May 2019, approved for use in Europe in May 2019, and registered in the Russian Federation in December 2021 [101-104].

Direct comparative studies of the medicinal products do not exist due to the complexity of forming comparison groups. The choice of drug should be determined by the attending neurologist, taking into account the number of SMN2 copies, the patient's baseline functional status, the route of administration, dosing frequency, and pharmacoeconomic data.

The use of nusinersen** was studied in patients with type 1 5q SMA aged 1.7 to 6 months at the time of the first administration in the ENDEAR study; the study demonstrated convincing efficacy and safety of the drug in this age group [61]. The use of nusinersen** was studied in patients with type 2 or 3 SMA aged 2 to 9 years at the time of the first administration in the CHERISH study; the study demonstrated convincing efficacy and safety of the drug in this age group [63]. The use of nusinersen** was studied in patients with type 2 or 3 SMA aged 2 to 15 years at the time of the first administration in the CS2/12 study; the study demonstrated the efficacy and safety of the drug in this age group.

Upon completion of the 5-year FIREFISH study, type 1 SMA children treated with risdiplam** demonstrated improvement or stabilization of disease-related outcomes; specifically, the majority of children achieved key motor milestones that would not be observed in the natural history of the disease. Furthermore, 91% of the children were alive, and 81% achieved event-free survival; the majority of children maintained the ability to swallow and feed orally. It was noted that no treatment-related adverse events with risdiplam** led to treatment discontinuation or cessation, and the frequency of adverse events and serious adverse events decreased after the first year of risdiplam** use. The use of risdiplam** was evaluated in patients with type 2 or 3 SMA aged 2 to 25 years at screening in the international (including patients from Russia) clinical study SUNFISH. The study demonstrated statistically significant clinical improvements over 24 months of therapy as assessed by the MFM-32 (Appendix G5) and RULM (Appendix G3) scales. The most common adverse effects of risdiplam** may include upper respiratory tract infections, pneumonia, pyrexia, constipation, and nasopharyngitis. It was shown that the improvements in motor function scores observed during the first year of risdiplam** treatment were sustained at 4 years. Patients and caregivers reported a continued reduction or stabilization in the level of assistance required for daily living activities. Adverse events and serious adverse events reflected the underlying disease, while the overall incidence of adverse events decreased over the 4-year period.

The use of onasemnogene abeparvovec was studied in the completed clinical trials START [104], STRIVE-EU [101], and STRIVE-US [106] in patients with type 1 SMA under 9 months of age, as well as in the SMART study in children weighing between 8.5 kg and 21 kg with a confirmed diagnosis of SMA who had previously received other disease-modifying therapies (nusinersen** or risdiplam**) [140]. Convincing efficacy and safety of the drug were demonstrated in these patient populations. The use of onasemnogene abeparvovec was also evaluated in the SPRINT study in pre-symptomatic (presymptomatic stage) SMA patients under 6 weeks of age [132, 133]. The results of clinical trials and systematic reviews with meta-analyses indicate that the administration of onasemnogene abeparvovec at the therapeutic dose in patients with both pre-symptomatic and symptomatic SMA provides a rapid therapeutic effect that increases over time, improves survival, and enhances motor function as assessed by various motor scales compared to the natural history of the disease [101, 104, 106, 132, 133, 140-143].

Comments: to date, accumulated data indicate that even patients identified through newborn screening may show early signs of SMA shortly after birth; therefore, it is critical to initiate therapy as early as possible to improve prognosis [155, 156, 158-161]. At the same time, it should be kept in mind that in patients with severe symptoms (such as invasive mechanical ventilation, non-invasive ventilation for more than 16 hours per day, absence of swallowing function due to bulbar syndrome, and flaccid tetraplegia), irreversible degeneration of motor neurons and muscle tissue is likely the most significant factor contributing to a lack of expected efficacy or phenotypic recovery, regardless of the amount of SMN protein produced by any therapeutic approach.

Comments: intrathecal administration (NMU: Administration of medicinal products into the spinal canal) of nusinersen** may be accompanied by adverse events associated with lumbar puncture (NMU: spinal puncture): fever, headache, back pain, vomiting, post-puncture syndrome.

Performing an intrathecal puncture may be difficult in the presence of severe spinal deformity or implanted metal hardware. Severe scoliosis and implanted metal hardware without a window for access are contraindications to the use of nusinersen**.

Following administration of nusinersen**, transient changes may be observed: thrombocytopenia, coagulation disorders, and nephrotoxicity.

Comment: following the administration of nusinersen**, transient changes may be observed: thrombocytopenia, coagulation disorders, and nephrotoxicity.

Comments: the main contraindications to the drug are the presence of antibodies to AAV9; other contraindications may include liver disease, mechanical ventilation or non-invasive ventilation for more than 16 hours per day, inability to swallow due to bulbar syndrome, and flaccid tetraplegia. In patients with a severe functional status and a prolonged disease course, administration of the drug may not yield the proper effect. Onasemnogene abeparvovec, administered as a single dose, is a non-replicating recombinant adeno-associated viral (AAV) vector containing a modified nucleic acid sequence of the SMN1 gene. Upon entering the motor neuron nucleus, the transgene compensates for the gene function lost due to the mutation without integrating into human DNA and restores the production of SMN protein, which is responsible for the preservation and development of motor neurons [102-104]. Testing for antibodies to adeno-associated virus serotype 9 (AAV9) must be performed in patients to confirm eligibility for gene replacement therapy. The drug is administered as an intravenous infusion. Gene replacement therapy must be administered in a hospital setting equipped with either an intensive care unit or a critical care unit. The most frequent adverse effects of onasemnogene abeparvovec are elevated hepatic transaminases, hepatotoxicity, vomiting, and pyrexia. For 24 hours before and after the onasemnogene abeparvovec infusion, glucocorticoid immunomodulation is required (see the next statement). In the post-infusion period, it is necessary to monitor laboratory parameters of liver function (determination of blood ALT activity, blood AST activity, and total blood bilirubin level), blood platelet count, and blood troponin I level, as well as monitor potential adverse events for at least 3 months after the onasemnogene abeparvovec infusion and in other cases when clinically indicated [101].

Comments: combination therapy should also include the prescription of nusinersen** or risdiplam** after the administration of onasemnogene abeparvovec, taking into account that the effect of a single infusion is presumed to last throughout the patient's lifetime [101]. Currently, there is no evidence of the efficacy and safety of combination therapy in SMA patients compared to monotherapy; therefore, combination therapy should not be used in routine clinical practice [104]. At present, there are no results from clinical studies or systematic reviews investigating the correlation between SMN protein expression levels and the severity of clinical response [101, 104, 108].

Comments: according to the prescribing information for risdiplam**, there are limited safety data from post-marketing use of risdiplam** at the recommended dose in patients < 16 days old. The safety and efficacy of risdiplam** in preterm newborns before reaching a corrected age of 16 days have not been established [147].

Comments: early initiation of disease-modifying therapy in patients with 5 copies of the SMN2 gene immediately after genetic confirmation of the diagnosis during newborn screening may provide clinical benefits for SMA patients, leading to an improved prognosis and the opportunity for normal development alongside healthy peers [153].

Comments: bridging therapy (short-term therapy with other disease-modifying agents for up to 4 months inclusive) prior to gene replacement therapy may be relevant for SMA patients with a transient increase in antibodies to adeno-associated virus serotype 9 (AAV9), as studies confirm the short-term nature of transient increases in AAV9 antibody titers [147, 148]. In SMA patients identified through newborn screening, the elevated AAV9 antibody titer is due to transplacental transfer of IgG antibodies; on average, the AAV9 antibody titer normalizes to ≤ 1:50 within 6 weeks and depends on the initial elevation degree [147, 148]. Antibody levels are tested every 2–4 weeks depending on the baseline antibody level. Once AAV9 antibody levels normalize to no more than 1:50, consider proceeding with gene replacement therapy.

Comments: switching from one drug to another within disease-modifying therapy can only be performed based on medical indications, as direct comparative clinical trials of these drugs do not exist due to the complexity of forming comparison groups. The choice of drug should be determined by the attending neurologist, taking into account the number of SMN2 gene copies, the patient's baseline functional status, the route of administration, dosing frequency, and the presence of adverse events.

Comments: evidence indicates that patients with medical indications for a change in therapy may derive additional clinical benefits. However, when choosing a therapy-switch strategy, the benefit-risk ratio should always be carefully weighed. In the absence of objective advantages favoring a change in therapy, such an approach is not advisable.

Criteria for a suboptimal response to therapy (insufficient therapeutic efficacy) in patients with SMA may include the following characteristics [152]:

1) overall deterioration in score confirmed by two consecutive measurements using any 2 of the following 3 scales: a) the patient loses > 2 points on the horizontal push or 1 point on other HINE scales, excluding intentional grasp; b) the patient loses > 4 points on the CHOP INTEND scale; c) the patient loses > 3 points on the HFMSE scale.

2) and/or deterioration of respiratory function: an increase in the need for respiratory support over 24 hours and/or for the given patient, an atypical increase in the number of respiratory infections requiring hospital treatment that cannot be explained by aspiration or lung disease.

Evaluation should be performed 12 months after initiating therapy compared to baseline values. In this regard, the patient's baseline general condition and motor status are of critical importance.

3.1.2 Symptomatic pharmacotherapy

Comments: the use of mucolytic agents without therapeutic indications may lead to the liquefaction of secretions of normal viscosity and an increased secretory load.

Comments: at the same time, in patients with type I SMA and frequently ill patients with other SMA types presenting with foci of chronic infection, early initiation of antibiotic therapy for infectious diseases is of paramount importance.

Comments: the required dose of the drug is determined based on body weight in accordance with the product instructions. Patients with hypersalivation are also indicated for oral cavity sanitation [70].

3.2 Surgical Treatment

Surgical treatment of patients with 5q SMA primarily consists of corrective instrumented spinal surgery, as the use of orthopedic devices is palliative in nature and cannot halt the deformity. Patients may also require surgery due to pain syndromes associated with musculoskeletal disorders or fractures.

Comments: when deciding on surgical intervention, it is important to consider impaired respiratory function, rib cage deformity, hyperkyphosis, impact on patient mobility and functioning, pelvic tilt, and trunk imbalance. Surgical intervention should be postponed in children under 4 years of age [20].

Comments: fractures occur in patients with 5q SMA who are unable to walk independently (early and late non-ambulatory stages) following minor trauma, associated with low skeletal loading due to restricted verticalization, osteoporosis, and possible vitamin D deficiency. When choosing a conservative treatment path involving casting (application of a circular plaster cast, removal of a circular plaster cast), prolonged immobilization should be avoided.

Comments: prior to gastrostomy, temporary feeding via a nasogastric or nasojejunal tube is necessary. In older patients capable of performing spirometry (assessment of unforced respiratory volumes and flows), this assessment must be performed prior to gastrostomy and should yield at least 50% of the predicted value. Gastrostomy is possible at lower FVC values, but the complication risk will increase as spirometry parameters decline. It should be kept in mind that in patients under 7 years of age, the assessment of unforced respiratory volumes and flows (FVC and FEV1) may be erroneous due to improper breathing maneuver technique.

Comments: the decision to transition to a tracheostomy must be made taking into account the patient's and family's best interests, clinical status, prognosis, and future quality of life. A tracheostomy should not be placed solely for the purpose of airway clearance. A tracheostomy is placed when the child requires non-invasive ventilation (NIV) for more than 18 hours. The option of ventilation via temporary/permanent tracheostomy may be considered in cases of recurrent pneumonia in non-ambulatory patients, although it should be borne in mind that this approach does not always lead to an improved quality of life and a reduction in hospitalizations. In any case, temporary/permanent tracheostomy placement is performed electively (not in acute situations, placement of a temporary/permanent tracheostomy in ambulatory patients is not justified.

3.3 Other Treatment

3.3.1 Medical nutrition therapy

Comments: when formulating a diet for 5q SMA patients, the requirement for calories (by calculating resting energy expenditure adjusted for activity level), macro- and micronutrients, and fluids is evaluated [77]. General standardized formulas are used for nutritional calculations [78].

Comments: metabolic disorders can develop in SMA patients, especially during emergency conditions: metabolic acidosis, fatty acid oxidation disorders, hyperlipidemia, hyper- or hypoglycemia, and muscular mitochondrial dysfunction. Impaired glucose metabolism has been noted in some SMA patients with obesity. In acute conditions, it is essential to ensure adequate fluid intake and minimize the duration of fasting. Protein-containing feeding should be provided within 6 hours. Monitoring of electrolyte levels (blood sodium assay, blood potassium assay, blood chloride assay), blood glucose assay, and, if necessary, correction are required.

Comments: thick liquids are safer regarding aspiration than more fluid ones. It is necessary to use denser nutritional formulas, gelatinous food forms, and liquid purees. Commercially available maltodextrin-based liquid thickeners can be used.

Comments: the benefit of prescribing an amino acid formula as opposed to intact protein for 5q SMA patients in their first year of life, as well as for children over one year old receiving nutrition via a nasogastric tube or gastrostomy who do not have a cow's milk protein allergy, has not been proven. Dietary recommendations are based on individual tolerance. SMA patients require dairy formulas (based on cow's milk proteins) appropriate for their age. Feeding with extensively hydrolyzed protein or amino acid formulas is indicated for patients with cow's milk protein allergies, in the postoperative period and critical conditions with impaired digestion, as well as for those receiving nutrition via a nasointestinal tube (intestinal tube) or enterostomy.

Comments: modern enteral nutrition formulas are balanced in their composition of basic nutrients—proteins, fats, carbohydrates, and contain vitamins, macro-, and micronutrients. They vary in caloric density—hypo-, normo-, and hypercaloric—and protein content. Enteral nutrition formulas are selected individually depending on requirements.

Comments: a comprehensive approach using diet therapy is applied to correct constipation; with medication therapy and mechanical bowel evacuation applied if necessary.

3.3.2 Respiratory support

Assessment and support of respiratory function must be given the highest priority in the management of a 5q SMA patient. Recently, the treatment paradigm for pulmonary manifestations of 5q SMA has shifted from a reactive approach, which involved initiating airway clearance and ventilation measures only when clear indications were present, to a preventive approach involving the implementation of these therapies at earlier stages of the disease. The treatment plan is determined by a respiratory therapist; in domestic practice, this is a fairly wide range of various specialists—anesthesiologists-intensivists, pulmonologists, as well as neurologists and pediatricians focused on neuromuscular disorders.

The key respiratory-related problems in children with SMA are the following: impaired coughing leading to insufficient clearance of secretions from the lower respiratory tracts, nocturnal hypoventilation; chest and lung hypoplasia, and recurrent infections that exacerbate muscle weakness. The main ways to address these tasks are airway clearance and non-invasive positive pressure ventilation (NIPPV). The basic principles of airway clearance should be followed:

1. Manual and mechanical auxiliary devices for restoring cough function should be utilized for daily use in more severely affected patients. Caregivers must be trained in the use of these devices;

2. Caregivers must also be proficient in pulmonary secretion clearance techniques, including postural drainage, and be informed about chest physiotherapy methods (drainage massage);

3. Oximetry data serve as an indicator of therapy effectiveness. Suctioning can be useful for clearing secretions after assisted coughing has been provided.

Comments: electrical aspiration and the use of a mechanical insufflator-aspirator should be performed in every patient with ineffective coughing. The main methods of sputum drainage for bedridden and seated patients are a combination of several techniques: a mechanical insufflator-aspirator (cough assist device) with manual chest compressions or postural drainage combined with electrical aspiration. In young and uncooperative children, insufflator-aspirators with an inspiratory trigger function should be used to avoid lung injury if such children hold their breath and resist coughing. A relative contraindication to the use of an insufflator-aspirator is chronic lung disease (e.g., emphysema). The use of an insufflator-aspirator in such a situation should be weighed against the possible risks of pneumothorax.

Other methods of preventing hypoventilation (postural drainage and percussion massage — see Section 4.1.1. "Non-technical rehabilitation methods for non-ambulatory patients").

Comments: the decision to use NIV is made on an individual basis in each specific case. It is unquestionably necessary in the presence of daytime hypercapnia. Nocturnal NIV reduces sleep-disordered breathing symptoms and improves quality of life. NIV must be combined with airway clearance techniques. The use of NIV with a high pressure gradient, even for short daytime periods, can improve chest and lung development as well as reduce rib and sternal deformity in non-ambulatory and ambulatory patients. Individual sizing and fitting of NIV masks is mandatory. This is carried out following an examination of the child, with the option to choose from several mask types of different sizes, taking into account the anatomical features of facial structure. It is essential to have and use two different masks alternately to reduce the risk of pressure ulcers and facial skeleton deformity. The mask type depends on the child's age, preferences, and other circumstances. Optimally, all types of masks should be used. The adjustment of NIV parameters must be performed under the control of gas exchange indicators (nocturnal pulse oximetry, capnometry, capnography, or blood gas and acid-base analysis), taking into account respiratory muscle work and patient subjective comfort.

Comments: patients' parents must be provided with medical equipment — an Ambu-type manual resuscitator, an electric suction unit with a rechargeable battery if necessary, and a medical device for respiratory therapy (positive airway pressure ventilator - BiPAP device) for home monitoring of respiratory functions. Parents must be trained in the rules of their use.

Comments: if the need for NIV arises in acute situations, the availability of equipment for home-based NIV must be considered.

3.3.3 Palliative care

Palliative care is an approach that aims to improve the quality of life of patients and their families facing life-threatening illness. This goal is achieved by preventing and relieving suffering through early identification, thorough assessment, and management of pain and other distressing physical symptoms, as well as the provision of psychosocial and spiritual support [81]. The main task of palliative care is to achieve, maintain, preserve, and enhance the quality of life of the patient as much as possible. However, only the patient in need of palliative care can define what "quality of life" means [82]. It is important not to contrast active (interventional) treatment with palliative care, but rather to complement each other.

The lack of consensus and differing views on the palliative and interventional approaches to treating SMA patients is acknowledged in a number of policy documents on this disease [83]. In the absence of disease-modifying therapy for SMA, a number of families perceived the interventional approach, especially tracheostomy, as creating a conflict between quality of life and its duration, as prolonging the patient's suffering rather than alleviating the burden of their disease [84]. Expert consensus was reached that when managing patients with spinal muscular atrophy, it is necessary to fully outline the range of therapeutic options for them and correctly inform them that choosing palliative or interventional supportive care is not merely a binary choice (choosing one of two) [84]. Thus, the international working group in 2007 was unable to reach agreement regarding palliative care and could only acknowledge significant ethical issues that must be considered when making care decisions in the context of SMA, currently also taking into account recent therapeutic approaches [83]. Subsequent publications have also failed to establish a consensus regarding standards of palliative care as applied to SMA [85].

The availability of pathogenetic treatment methods provides substantial grounds for hope for changing the prognosis, but certain issues require further study before a standard of palliative care for SMA can be developed, including the need to clarify the meaning of palliative care for SMA patients [57]. International experts acknowledge that the key task is to abandon the dichotomous model that pits active treatment against palliative care, in favor of a complementary model [57].

Comments: the decision regarding the use of long-term mechanical ventilation (MV) involves weighing numerous pros and cons, is subjective, and cannot be made unilaterally by a single party (either the patient's side or the physician's side alone). An ethical approach in this case would be one in which the personal opinions and beliefs of the physician can be presented to the family along with the proposed treatment options [87]. The results of several studies indicate significant differences in the attitudes and clinical practices of physicians regarding respiratory support in type 1 SMA patients [88-89]. Parents and other caregivers believe they should have the right to choose for or against the use of home mechanical ventilation. Stress and anxiety among parents in such situations were caused by inadequate support (financial, psychological, and practical) [89]. It must be acknowledged that, unfortunately, in actual clinical practice, the decision to initiate invasive mechanical ventilation may be made without the consent of the child's legal representatives. The lack of an informed choice and a template-based approach to treatment hinder planning and limit decision-making capacity [86].

Comments: palliative care can be provided at all stages of managing a patient with SMA: at diagnosis, during key therapeutic decision-making, in the event of life-threatening conditions, and in the terminal phase of the disease.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

It is currently proven that regular physical therapy and rehabilitation of patients can change the natural history curve of 5q SMA: increase the life expectancy and quality of life of patients, and improve their functional and social status. The implementation of this concept is possible only in a goal-oriented rehabilitation format. Thus, the rehabilitation of patients with 5q SMA aims to achieve the following goals: increase patient mobility; slow down the progression of muscle atrophy; prevent the development of secondary orthopedic complications. Goals should be set both in everyday work with the child (lifestyle rehabilitation — which is a joint effort of a physical and rehabilitation medicine physician, parents, and sometimes the child themselves) for longer-term goals, and with each visit of the child to a rehabilitation center for a course of rehabilitation—for short-term and deferred goals.

The process of achieving the set rehabilitation goals defines the following tasks:

1. prevent the formation of habitual vicious positioning of the limbs and their segments, and, as a result, early contractures;

2. slow down the process of disuse muscle atrophy;

3. prevent degenerative shortening of muscle fibers;

4. prolong the functional activity of patients;

5. prevent the development of joint contractures in the limbs;

6. increase patient mobility (maintain/increase the range and amplitude of movements);

7. create conditions for the physiological development and physiological functioning of internal organs and systems.

Rehabilitation methods for 5q SMA are divided into non-technical (these include physical therapy: therapeutic exercise, massage; muscle stretching, etc.) and technical (orthotics and bracing of the trunk and limbs), including surgical correction of orthopedic problems that prevent their effective performance, as well as other methods (application of circular plaster casts; robotic mechanotherapy for peripheral nervous system diseases, use of rehabilitation exercise equipment; therapeutic swimming in a pool and physiotherapy).

During rehabilitation measures, it is necessary to:

1. try to integrate physical therapy and regular exercises into the child's daily activities and form a lifestyle based on them;

2. take into account that fatigue is the dominant symptom in children, and therefore distribute physical exertion evenly throughout the day — "little and often";

3. stay "a step ahead" — set rehabilitation goals for the next few months taking into account the patient's current musculoskeletal status and predicted deterioration;

4. it is important that all skeletal muscles are engaged in the child's daily life and none remain inactive.

Some rehabilitation advice is of a general nature and should be implemented for all patients with 5q SMA. However, when talking about the rehabilitation of patients with 5q SMA, a more correct approach is not to rank patients by disease type (SMA I, SMA II, SMA III), but to divide them into functional classes (see above):

1. non-ambulatory (non-sitting) patients;

2. sitting patients — capable of active verticalization in a sitting position without support;

3. ambulatory patients — capable of walking without assistive devices.

This functional classification allows for the specification of rehabilitation tasks for a specific patient taking into account their capabilities (see sections 4.1, 4.2, and 4.3 below). It is worth noting that to date, there are no clearly defined unambiguous time (sitting/walking time) or other (distance/steps - for ambulatory patients) criteria for classifying patients as sitting or walking patients, so the choice must be made based on the patient's priority independent position and the motor function they use.

Comments: measures are needed to adapt the home (and other) environment to ensure maximum independence of patients through the safety and accessibility of all necessary means.

Comments: it is important to fight to preserve the movements that the child currently has. For this, it is good to use a kinesiotherapeutic play approach when involving the child in exercises.

Comments: the massage is percussion-based and its main purpose is the drainage of the upper respiratory tract. Daily percussion chest massages (MMS: medical chest massage) (tapping/vibrations along the tracheobronchial tree from the lower parts of the lungs to the upper ones) are combined with postural drainage to remove accumulated sputum.

Comments: patients need stretching exercises accompanied by light massage (warming effect). The minimum frequency of sessions for stretching and increasing the range of motion for non-ambulatory patients is 3-5 times a week, for sitting patients — 5-7 times a week. The duration of sessions for effective stretching and increasing the range of motion depends on the specific needs of the patient, the condition of the joints, and the goals of rehabilitation.

Comments: swimming classes are useful and enjoyable for patients with SMA. Water neutralizes the effect of gravity on the child's body, allowing them to feel their body differently. Swimming is a good aerobic workout. This is a variant of active physical therapy for a child with SMA. In addition, swimming improves the emotional state of children. The method has no absolute contraindications in SMA. The water temperature in the pool should be 30^o-33^o (optimal temperature range for the best muscle metabolism). The first few sessions should take place not only with parents, but also with an instructor who will train the parents. Before each session, it is necessary to assess the child's somatic well-being.

Comments: a stationary bicycle (exercise bike) can well be used for bedridden patients.

Comments: rehabilitation exercise equipment (exercise bike) can be used for bedridden patients, a set of rehabilitation products for musculoskeletal disorders and other rehabilitation equipment for sitting patients, and all of the above plus a treadmill for ambulatory patients.

Comments: specifics of applying a circular plaster cast in patients with SMA include short-course casting (5 days on, 2 days off).

Comments: this technique can be used in children with SMA. Tape is able to take on part of the muscle load, thereby allowing the patient to feel their own muscle working. Preference is given to monotaping (taping a single limb), which allows the child to "focus" on the limb and feel the muscle trigger of the taped limb.

4.1 Rehabilitation of non-ambulatory patients

The primary position for these patients at home is the "supine" position, which carries the risk of developing habitual (fixed) vicious postures of the limbs and their segments due to the action of gravity on the limbs and the patient's inability to perform antigravity movements, as well as the occurrence of complications. Thus, the posture characteristic of such children (due to weakness of the hip adductor muscles)—"lying on the back with outwardly rotated hips"—contributes not only to the formation of paralytic hip dislocations, but also to the development of severe pressure ulcers on the greater trochanters. In this context, it is crucial that the child's position in bed and on any other surface is functionally advantageous and prevents the manifestation of vicious postures and their complications. To this end, frequent changes of body position in bed are indicated; the use of improvised aids that can easily change shape and support the weight of the limb, thereby mimicking the antigravity effect (e.g., a mattress filled with millet). Stimulation of daily activity: games and other active pursuits, both with and without special devices (e.g., lightweight toys), should be utilized to the maximum possible extent.

Goals of rehabilitation for bedridden patients:

• increasing the volume and amplitude of active/passive movements in any body segment and limbs;

• improving head control / movement in the transverse plane in the supine position;

• improving manual dexterity;

• creating conditions for the development and normal functioning of internal organs;

• slowing down the development of true muscle atrophy and disuse atrophy;

• mobilization of joints and prevention of contractures.

4.1.1 Non-technical rehabilitation methods for non-ambulatory patients

Comments: during physical therapy sessions with bedridden patients, it is convenient to use rubber or fabric bands to suspend limb segments. This method is suitable for use on both upper (shoulders) and lower limbs (thigh-knee-shin). For example, to preserve the functional activity of the upper limbs, the method of eliminating gravitational forces by suspending the proximal segments of the upper limbs on bands can be used, thereby enabling movement of the entire upper limb and, in addition, complementing the diagnostic search for "working" muscles in a deeply paretic upper limb segment (thus, a shoulder suspended on a band can move, for example, in the transverse/frontal planes, which helps to detect "living" muscle portions, often the deltoid muscle portions in the shoulder). This same method helps facilitate play or hand manipulation (e.g., for a "pointing" gesture when working with cards).

Comments: patients with SMA are characterized by bulbar function disorders, which share a common origin but develop through two main mechanisms—mechanical and oropharyngeal. Patients with SMA of all clinical types I-III are prone (to a greater or lesser extent) to: reduced mouth opening and jaw rigidity (decreased ability to wide/sufficiently open the mouth, provided by lower jaw movement), difficulties in moving the food bolus within the oral cavity, chewing difficulties and rapid fatigue of the chewing muscles, poor voice production quality, and swallowing problems.

Thus, earlier introduction into the individual rehabilitation program can help counteract the listed changes or improve baseline indicators and the quality of life of patients (for example, achieving the ability to eat more comfortably by mouth)—in the presence of existing abnormalities (both when choosing specific techniques and, more importantly, when combining them in the patient's individual rehabilitation program). It is also possible to supplement these methods with physical therapy methods (myostimulation) and taping.

Comments: from the perspective of the rehabilitation approach for patients with SMA, massage should not have a catabolic effect on muscles: excessive force is excluded, but reasonable exposure avoids fatigue and achieves muscle "activation" under the physician's supervision. Massage can be either stimulating or relaxing depending on the objectives (e.g., scheduling procedures throughout the day or pain relief/relaxation after intensive physical therapy). It improves blood supply, muscle nutrition, warming, fiber stretching, and proprioceptor stimulation. Along with physical therapy, massage helps achieve rehabilitation goals, including the key objective: teaching the patient to feel and use the necessary muscles in motor acts. This is especially relevant against the background of therapy with positive dynamics, when the acquisition of new motor skills is possible (within neuro-orthopedic limitations) [126, 127].

4.1.2 Technical aids for rehabilitation of non-ambulatory patients

To achieve the set rehabilitation goals, a strict adherence to the principles of postural management is employed, which includes proper positioning (in the standing position — verticalization, as well as spending time in the correct sitting position during the day) and orthotization of the trunk and limbs.

Comments: verticalization of the patient using a standing frame is required for a total of at least 1 hour a day, depending on the child's capabilities. For patients who have never been able to sit, verticalization may be indicated starting from the age of 14 months.

Comments: standing frames must feature a functional headrest that provides lateral and anteroposterior head stabilization without restricting head movement; trunk supports at the chest and pelvic levels; lower limb fixators at the lower thirds of the thighs and knee joints; a footplate with adjustable tilt angle; and a tray. For non-ambulatory patients, it is essential to have the ability to verticalize in a standing frame in an "abducted hips" position (an additional function in standing frames), which increases the congruence of joint surfaces, promotes the development of hip joints, and prevents hip dislocations.

Comments: orthoses are technical rehabilitation aids used to alter the structural and functional characteristics of the neuromuscular and skeletal systems, providing, depending on medical indications, orthopedic correction, offloading, fixation, and activation of motor functions. The total time spent in orthoses is up to 8-12 hours a day. The minimum frequency of orthosis use for non-ambulatory patients is 5 times a week. Chest fixation is necessary for positional stabilization, prevention of scoliosis, and stimulation of functional activity. Neck fixation is often used to support the head to minimize the risk of suffocation in the upright position, as head control function is often absent or impaired.

Comments: for mobility and transportation, it is necessary to use manually propelled wheelchairs with additional head and body fixation (support), indoor and stroller-type, and power wheelchairs with additional head and body fixation (support) featuring custom insert molds ("turtle shells"). These are custom-made based on a volumetric three-dimensional model of the posterior body surface, being molded inserts installed on a wheelchair wheel base of the appropriate size and purpose. When selecting a wheelchair and a functional chair, the specialist must take into account the need for additional elements to maintain the recommended posture and include this in the product recommendations. It should be ensured that the patient achieves maximum functional independence and comfort while in the wheelchair.

Comments: for spending time in the "sitting" position, seating supports or indoor wheelchairs with additional head and body fixation (support) are used. The "sitting" position during the day is also achieved by staying in a stroller-type wheelchair. Sitting in the technical device should be performed while wearing ankle-foot orthoses. Staying in the correct "sitting" position is indicated for a total of up to 6 hours a day. Additional functions in the seating device should include: a functional headrest (Russian Medical Nomenclature: adjustable headrest) (or head positioning using a Glisson loop) that provides lateral and anteroposterior head stabilization without restricting head movement; a seat with adjustable depth, width, and tilt angle. Structurally, the seat is divided into pelvic and thigh sections, which allows for the most complete resolution of the child's balance and symmetry problems caused by secondary orthopedic complications. A height- and tilt-adjustable backrest; a trunk support (vest), a pelvic restraint belt, adjustable armrests; separate, adjustable footrests with foot fixators; a tray; an anti-decubitus cushion.

Comments: the corset for patients with SMA is a functionally corrective one "with pelvic support," which preserves spinal column balance, prevents bell-shaped chest deformity, and does not impair external respiration function. A "breathing window" and a gastrostomy opening (if present) may be required. The total time spent in the corset can be up to 6-8 hours a day.

4.2 Rehabilitation of sitting patients

For ambulatory patients, it is important to observe both the principle of dosing physical exertion and the principle of integrating physical therapy into the child's lifestyle.

One of the primary and favorite positions for such children is the "sitting" position, which, due to the main symptom of the disease (skeletal muscle weakness), the inability to independently change body position/posture (reposition themselves while sitting), and deficits in postural control, can lead to an asymmetric sitting pattern with an uneven distribution of support on the pelvic bones (right/left) with pelvic tilt (suprapelvic due to genetic scoliosis) and rapidly provoke the development of scoliotic spinal deformity. Therefore, special attention must be paid to the symmetrical development of the patients' physique and correct positioning.

Goals of rehabilitation for ambulatory patients:

1. increasing patient mobility;

2. slowing down the progression of muscle weakness, loss of function, and disuse atrophy;

3. improving manual dexterity;

4. creating conditions for the development and normal functioning of internal organs;

5. joint mobilization and prevention of contracture formation;

6. formation and maintenance of posture symmetry;

7. prevention of scoliotic spinal deformity and pelvic tilt;

8. teaching everyday living and self-care skills in the environment;

9. special importance in physical therapy is given to forming posture symmetry and minimizing differences in development and function between the right and left limbs.

Comments: the device is designed specifically for patients with flaccid paralysis and lower extremity muscle strength of less than 2 points. A distinctive feature of this orthosis is the ability to mechanically assist the child's efforts by reciprocally moving the lower extremities in a symmetrical posture. Such a device allows the patient to maintain an upright position and move with the support of a walker without parental assistance, provided there is sufficient arm strength. This capability has a profound impact on the child's development as an independent individual with the ability to stand upright and move in that position. The vertical posture prevents pulmonary congestion, thereby reducing the risk of complications from ARVI, and improves gastrointestinal and urinary tract passage. Axial skeletal load prevents the development of osteoporosis and secondary bone and joint deformities.

Standing should be encouraged. Supported standing time should be up to 60 minutes, with a minimum frequency of 3–5 times per week and an optimal frequency of 5–7 times per week.

Comments: static, dynamic, and functional orthoses are used for positioning and verticalization of patients. The corset is custom-made for the child based on a cast or a three-dimensional digital model of the trunk obtained via volumetric scanning using Glisson loop traction for head suspension or in a horizontal position with deformity correction. A power wheelchair with a standing function can be used for verticalization. Vertical positioning devices are important for facilitating lower extremity stretching, improving body functions and bone health, ensuring an upright posture, and improving the alignment of the spine and entire body. Proactive use of functional and corrective corsets is necessary in non-ambulatory SMA patients receiving disease-modifying drug therapy to prevent the progression of scoliotic deformity, prevent secondary chest deformities, and increase activity [97].

Comments: the minimum frequency of wearing orthoses is 5 times per week.

Comments: when selecting wheelchairs, one should be guided by the patient's maximum functional independence and comfort in the chair; preference should be given to active-type wheelchairs and power wheelchairs.

Comments: it is necessary to involve an occupational therapist both in the selection of the physical exercise and stretching program and for recommendations regarding social interactions, such as attending educational institutions, career choices, and participation in social activities.

Comments: patients with SMA are characterized by bulbar function disorders, which share a common origin but develop through two main mechanisms—mechanical and oropharyngeal. Patients with SMA of all clinical types I-III are prone (to a greater or lesser extent) to: reduced mouth opening and jaw rigidity (decreased ability to wide/sufficiently open the mouth, provided by lower jaw movement), difficulties in moving the food bolus within the oral cavity, chewing difficulties and rapid fatigue of the chewing muscles, poor voice production quality, and swallowing problems.

Thus, earlier introduction into the individual rehabilitation program can help counteract the listed changes, or improve baseline parameters and patients' quality of life (for example, when achieving the ability to eat more comfortably orally) — in the presence of existing deviations (both when choosing specific methods and, more preferentially, when combining them in the patient's individual rehabilitation program). It is also possible to supplement these methods with physical therapy methods (myostimulation) and taping.

Comments: from the perspective of the rehabilitation approach for patients with SMA, massage should not have a catabolic effect on muscles: excessive force is excluded, but reasonable exposure avoids fatigue and achieves muscle "activation" under the physician's supervision. Massage can be either stimulating or relaxing depending on the objectives (e.g., scheduling procedures throughout the day or pain relief/relaxation after intensive physical therapy). It improves blood supply, muscle nutrition, warming, fiber stretching, and proprioceptor stimulation. Along with physical therapy, massage helps achieve rehabilitation goals, including the key objective: teaching the patient to feel and use the necessary muscles in motor acts. This is especially relevant against the background of therapy with positive dynamics, when the acquisition of new motor skills is possible (within neuro-orthopedic limitations) [126, 127].

4.3 Rehabilitation of ambulatory patients

For ambulatory patients (ambulatory stage), the priority of the principles of physical load dosing and the integration of physical therapy into the child's daily life is maintained.

Children in this group strive for active movement and walking, however, due to skeletal muscle weakness and low endurance, they frequently need rest, often adopting a defective "sitting" posture. In general, compared to sitting children, walking children are characterized by a milder course of secondary orthopedic complications (such as the development of joint contractures in the extremities and the formation of scoliotic spinal deformity) and their progression. The goals of rehabilitation for walking patients are approximately the same as for sitting patients, with the addition of the goal of increasing endurance/tolerance to physical exertion.

Comments: over time, maintaining the ability to walk for patients with SMA is achieved with the help of additional support devices. When selecting additional support devices to prolong walking in patients with SMA, it is necessary to rely on the patient's current status (preserving activity and the individual's social status) rather than the predicted course, thereby offering more disabling devices for the child.

Comments: from the perspective of the rehabilitation approach for patients with SMA, massage should not have a catabolic effect on muscles: excessive force is excluded, but reasonable exposure avoids fatigue and achieves muscle "activation" under the physician's supervision. Massage can be either stimulating or relaxing depending on the objectives (e.g., scheduling procedures throughout the day or pain relief/relaxation after intensive physical therapy). It improves blood supply, muscle nutrition, warming, fiber stretching, and proprioceptor stimulation. Along with physical therapy, massage helps achieve rehabilitation goals, including the key objective: teaching the patient to feel and use the necessary muscles in motor acts. This is especially relevant against the background of therapy with positive dynamics, when the acquisition of new motor skills is possible (within neuro-orthopedic limitations) [126, 127].

5. Prevention and Dispensary Observation

Comments: the drug J06BB16 #palivizumab** is administered intramuscularly, preferably into the anterolateral thigh. Vaccination should be carried out during the seasonal surge in the incidence of respiratory syncytial virus. According to the vaccination schedule, the patient must receive the first 3 doses of the pneumococcal vaccination** before the age of one year, and the 4th dose after 12 months. All other vaccines are administered to children with 5q SMA in accordance with the National Immunization Schedule.

6. Organization of Medical Care

6.1 Indications for hospitalization:

6.1.1 Indications for elective hospitalization in a pediatric neurology department:

• all patients with 5q SMA once a year for functional motor assessment, screening for complications of the disease—respiratory, skeletal-articular, and gastroenterological, as well as for rehabilitation.

• all patients with 5q SMA for the administration of nusinersen**.

  In international practice, nusinersen** can be administered in a day hospital setting.

• all patients with 5q SMA requiring evaluation prior to surgical orthopedic intervention.

  Indications for patient discharge following scheduled hospitalization in a pediatric neurology department:

• fulfillment of the patient examination plan, including the assessment of respiratory disorders;

• implementation of rehabilitation measures;

• clear recommendations for further monitoring and treatment.

  Indications for scheduled hospitalization in a pediatric surgery department:

• patients with 5q SMA requiring gastrostomy;

• patients with 5q SMA requiring temporary/permanent tracheostomy,

  Sometimes a tracheostomy is placed due to emergency indications, and the child requires emergency hospitalization.

6.1.2 Indications for emergency hospitalization:

• The development of "usual" diseases in a patient with 5q SMA (acute viral infection, bronchitis, gastroenteritis with dehydration, appendicitis, and other acute inflammatory processes), unforeseen fractures, planned surgical procedures (e.g., gastric tube placement, femoral osteotomy), but running a severe course given the specifics of the disease.

  The goal of patient care in an acute situation is to normalize gas exchange by preventing atelectasis and clearing the airways. In most cases, whenever possible, these objectives should be achieved using non-invasive mechanical ventilation.

• The development of severe life-threatening respiratory disorders with hypoventilation and apnea, without concomitant diseases, while the respiratory disorders require resuscitation measures; hospitalization is indicated in medical organizations that have an anesthesiology and resuscitation department or an intensive care unit (ward) in their structure and provide round-the-clock medical monitoring and treatment for children.

  When executing emergency care protocols, it is necessary to contact the multidisciplinary team (neurological and pulmonological), typically including a neurologist who is aware of the disease course and potential problems of the specific patient. Oxygen in patients with SMA should be used with caution. Secondary hypoxemia due to hypoventilation can be confused with hypoxemia due to other causes, such as mucus plugging or atelectasis. Capnometry or the study of acid-base balance and blood gases will help select the correct oxygen administration mode.

6.2 Principles of organizing medical care for patients with 5q SMA

The diagnosis of SMA raises many questions for the patient's relatives and for the specialists working with such patients. Numerous problems arise upon the detection and progression of SMA, the resolution of which requires competent organization of the care process with the participation of a multidisciplinary team of specialists and compliance with the basic principles and approaches to its delivery.

These principles must be observed at any stage of medical care, both at the time of diagnosis and at any stage of patient follow-up.

• The patient and their representatives must receive complete information about the disease, its course, pathogenesis, prognoses, complications, and methods of potential therapy.

• The diagnosis of SMA implies the possibility of providing primary health care, specialized medical care, and palliative medical care at all stages of the disease.

• Upon diagnosing SMA, the family should be referred to a specialist experienced in working with SMA patients who possesses up-to-date information on the disease course and the possibility of participating in clinical trials (of new drugs and/or medical devices). It is also important to inform families about existing public organizations working with this patient group.

• A multidisciplinary team of specialists should be involved in monitoring an SMA patient, consisting of: a neurologist, a pediatrician/general practitioner, a geneticist, a respiratory support specialist (pulmonologist and/or anesthesiologist-resuscitator), a cardiologist, a traumatologist-orthopedist, a surgeon, a medical rehabilitation physician and physical therapist, a nutritionist, a gastroenterologist, as well as staff of medical organizations (and their subdivisions) providing specialized palliative medical care to children. Other specialists should be involved as specific problems arise.

  The neurologist, as a specialist in neuromuscular diseases, provides primary follow-up for patients with 5q SMA. The neurologist's duties include examining and diagnosing, informing the family about the disease, drawing up a multidisciplinary follow-up plan, monitoring the patient, assessing the dynamics and degree of disease progression during regular examinations, and prescribing supportive therapy. At the stage of specialized medical care, the neurologist participates in assessing the patient's functional status (assessment using neuromuscular impairment scales in SMA). When drawing up the multidisciplinary follow-up plan, the neurologist determines the frequency of follow-up visits with other specialists of the multidisciplinary team in accordance with the patient's current condition. At each examination, the neurologist reassesses the patient's current condition and accordingly makes adjustments to the multidisciplinary follow-up plan. In their recommendations, the neurologist indicates the technical rehabilitation aids, medical equipment, orthopedic correction devices, medications, medical devices, etc. required by the patient in accordance with the identified needs of the patient.

• Compliance with the principle of "early intervention," which implies the prevention of inevitably arising complications against the background of disease progression and the early use of technical rehabilitation aids, medical equipment, and other therapy methods.

• Provision of patients with proximal 5q spinal muscular atrophy with medical devices intended to support the functions of human organs and systems for home use in the provision of palliative medical care in accordance with the List of such medical devices is carried out in accordance with existing legislation (clause 4, article 36 of Federal Law No. 323 "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation"; Order of the Russian Ministry of Health No. 398n dated July 9, 2025, "On Approval of the List of Medical Devices Intended to Support the Functions of Human Organs and Systems Provided to a Patient in the Provision of Palliative Medical Care for Home Use").

7. Additional Information

No additional information available.

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

Anisimova Inga Vadimovna — Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists, Candidate of Medical Sciences;

Artemyeva Svetlana Bronislavovna — Neurologist, Head of the Department of Psychoneurology and Epileptology, Research and Clinical Institute of Pediatrics and Pediatric Surgery named after Yu.E. Veltishchev, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Candidate of Medical Sciences;

Belousova Elena Dmitrievna — Neurologist, Head of the Department of Psychoneurology and Epileptology, Research and Clinical Institute of Pediatrics named after Yu.E. Veltishchev, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Doctor of Medical Sciences, Professor;

Vlodavets Dmitry Vladimirovich — Neurologist, Leading Researcher at the Department of Psychoneurology and Epileptology, Research and Clinical Institute of Pediatrics and Pediatric Surgery named after Yu.E. Veltishchev, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Associate Professor at the Department of Neurology, Neurosurgery and Medical Genetics named after Academician L.O. Badalyan of the Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, President of the Association of Pediatric Neurologists in Myology "NEOMIO", Candidate of Medical Sciences;

Volsky Grigory Bolislavovich — Trauma and orthopedic surgeon, Tyumen Children's Medical Rehabilitation Center "Nadezhda", Tyumen;

Voronin Sergey Vladimirovich — Chief Physician, Research Centre for Medical Genetics, Chief freelance specialist in medical genetics of the Ministry of Health of Russia in the Far Eastern Federal District, Candidate of Medical Sciences;

Germanenko Olga Yurievna — Founder and Chairman of the Board of the SMA Families Charitable Foundation;

Groznova Olga Sergeevna — Leading Researcher at the Department of Pediatric Cardiology and Heart Rhythm Disorders, Research and Clinical Institute of Pediatrics and Pediatric Surgery named after Yu.E. Veltishchev, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Doctor of Medical Sciences;

Guzeva Valentina Ivanovna — Neurologist, Head of the Department of Neurology, Neurosurgery and Medical Genetics, Saint Petersburg State Pediatric Medical University, Corresponding Member of the Russian Academy of Natural Sciences, Chief freelance specialist of the Ministry of Health of the Russian Federation, Doctor of Medical Sciences, Professor;

Zabnenkova Viktoria Vladimirovna — Medical laboratory geneticist at the Laboratory of Molecular Genetic Diagnostics No. 3, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Head of the "Genome" Shared Research Center, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Candidate of Medical Sciences;

Izhevskaya Vera Leonidovna — Geneticist, Deputy Director for Science, Research Centre for Medical Genetics named after Academician N.P. Bochkov, President of the Russian Society of Medical Geneticists, Doctor of Medical Sciences;

Ilyina Elena Stepanovna — Neurologist, Head of the Pediatric Psychoneurology Department, Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Candidate of Medical Sciences;

Kenis Vladimir Markovich — Deputy Director, Turner Scientific Research Institute for Children's Orthopedics of the Ministry of Health of Russia, St. Petersburg, Head of the Department of Foot Pathology, Neuroorthopedics and Systemic Diseases, Member of the European Paediatric Orthopaedic Society and the American Academy for Cerebral Palsy and Developmental Medicine, Doctor of Medical Sciences;

Kiselev Anton Vyacheslavovich — Head of the Laboratory of Molecular Genetics and Gene Therapy, Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Associate Member of the TREAT-NMD European Consortium, Candidate of Biological Sciences;

Kokorina Anna Aleksandrovna — Neurologist at the Children's Clinical and Diagnostic Center of the Mother and Child Clinical Hospital, Tyumen, Mother and Child Tyumen LLC;

Kolesov Sergey Vasilievich — Head of the Spine Pathology Department, National Medical Research Center of Traumatology and Orthopedics named after N.N. Priorov of the Ministry of Health of Russia, Moscow, Doctor of Medical Sciences, Professor;

Komarova Oksana Nikolaevna — Pediatrician, gastroenterologist, nutritionist, Senior Researcher at the Department of Gastroenterology, Research and Clinical Institute of Pediatrics and Pediatric Surgery named after Yu.E. Veltishchev, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Candidate of Medical Sciences;

Kuzenkova Lyudmila Mikhailovna — Neurologist, Head of the Center for Pediatric Psychoneurology, 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, Doctor of Medical Sciences, Professor;

Kurbatov Sergey Aleksandrovich — Neurologist, geneticist, functional diagnostics physician, Voronezh Regional Clinical Consultative and Diagnostic Center, Candidate of Medical Sciences, Voronezh;

Sergey I. Kutsev — Academician of the RAS, Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Chief External Expert in Medical Genetics of the Russian Ministry of Health, Chairman of the Ethics Committee of the Russian Ministry of Health, President of the Association of Medical Geneticists of Russia, Doctor of Medical Sciences;

Sergey S. Leonchuk — Orthopedic Surgeon, Head of Traumatology and Orthopedics Department No. 6 of the Clinic of Neuroorthopedics and Systemic Diseases at the National Ilizarov Medical Research Center for Traumatology and Orthopedics of the Russian Ministry of Health, Candidate of Medical Sciences, Kurgan;

Polina V. Ochirova — Scientific Secretary of the Ilizarov Center, Orthopedic Surgeon at the Clinic of Spine Pathology and Rare Diseases, Department No. 9 at the National Ilizarov Medical Research Center for Traumatology and Orthopedics of the Russian Ministry of Health, Candidate of Medical Sciences, Kurgan;

Elena V. Polevichenko — Professor at the Department of Oncology, Hematology and Radiology, Pediatric Faculty, Pirogov Russian National Research Medical University, Board Member of the Association of Professional Hospice Care Providers, Doctor of Medical Sciences;

Alexander V. Polyakov — Geneticist, Head of the DNA Diagnostics Laboratory at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Corresponding Member of the RAS, Doctor of Biological Sciences, Professor;

Dmitry A. Popkov — Higher Category Orthopedic Surgeon, Head of the Clinic of Neuroorthopedics and Systemic Diseases at the National Ilizarov Medical Research Center for Traumatology and Orthopedics of the Russian Ministry of Health, Kurgan, Doctor of Medical Sciences, Professor of the RAS, Corresponding Member of the French Academy of Sciences;

Sofia G. Popovich — Junior Researcher at the Laboratory of Nervous Diseases, Center for Pediatric Psychoneurology at the National Medical Research Center for Children's Health of the Russian Ministry of Health;

Gennady G. Prokopiev — Anesthesiologist-Intensivist, Associate Professor at the Department of Pediatric Anesthesiology and Intensive Care, Faculty of Advanced Medical Training, Pirogov Russian National Research Medical University, Leading Researcher and Head of the Department at the V.F. Voyno-Yasenetsky Scientific and Practical Center for Specialized Medical Care for Children of the Moscow Healthcare Department, Candidate of Medical Sciences;

Svetlana A. Repina — Geneticist, Department of Medical Care Organization at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Candidate of Medical Sciences;

Dmitry I. Rudenko — Deputy Chief Physician, City Multidisciplinary Hospital No. 2, Pavlov First Saint Petersburg State Medical University, Doctor of Medical Sciences, Professor;

Tatiana V. Ryabykh — Pediatrician, Head of Department – Pediatrician at "Medsi", Higher Category Physician;

Sergey O. Ryabykh — Deputy Director for Research, Head of the Department of Pediatric Traumatology and Orthopedics, Veltischev Research and Clinical Institute of Pediatrics and Pediatric Surgery, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Moscow, Professor at the Department of Traumatology and Orthopedics, Medical Faculty of SPbU, Higher Category Orthopedic Surgeon, Member of the Interregional Association of Spine Surgeons, Member of the All-Russian Society of Traumatologists and Orthopedists, Doctor of Medical Sciences;

Dmitry M. Savin — Neurosurgeon, Orthopedic Surgeon, Head of Traumatology and Orthopedics Department No. 9 at the Clinic of Spine Pathology and Rare Diseases, National Ilizarov Medical Research Center for Traumatology and Orthopedics of the Russian Ministry of Health, Candidate of Medical Sciences, Kurgan;

Elena Yu. Sapego — Neurologist, Head of the Regional Center for Pediatric Palliative Medical Care at the Oblast Children's Clinical Hospital of Sverdlovsk Oblast (Sverdlovsk Oblast), Chief External Pediatric Specialist of the Ministry of Health of the Russian Federation for Palliative Care in the Ural Federal District;

Dmitry M. Subbotin — Researcher at the Laboratory of Neurogenetics, Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists;

Vasily M. Suslov — Neurologist, Assistant Professor at the Department of Rehabilitology, Faculty of Postgraduate Education and Continuing Professional Education, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health;

Elena V. Tozliyan — Pediatric Endocrinologist, Veltischev Research and Clinical Institute of Pediatrics and Pediatric Surgery, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Candidate of Medical Sciences;

Anastasia N. Tretyakova — Higher Category Anesthesiologist-Intensivist, National Medical Research Center of Traumatology and Orthopedics named after N.N. Priorov of the Russian Ministry of Health, Moscow;

Evgenia V. Uvakina — Candidate of Medical Sciences, Senior Researcher at the Laboratory of Nervous Diseases, Center for Pediatric Psychoneurology at the National Medical Research Center for Children's Health of the Russian Ministry of Health;

Dmitry A. Feklistov — Orthopedic Surgeon; Veltischev Research and Clinical Institute of Pediatrics and Pediatric Surgery, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation;

Egor Yu. Filatov — Orthopedic Surgeon at the Clinic of Spine Pathology and Rare Diseases, National Ilizarov Medical Research Center for Traumatology and Orthopedics of the Russian Ministry of Health, Kurgan, Candidate of Medical Sciences;

Conflict of interest:

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• Medical geneticist

• Neurologist

• Trauma and orthopedic surgeon

• Neurosurgeon

• Pediatrician

• Anesthesiologist-resuscitologist

• Gastroenterologist

• Nutritionist

• Pulmonologist

• Pediatric Cardiologist

• Physiotherapist

• Medical students, residents, postgraduate students

Methods used for evidence collection/selection: electronic database searches.

Description of methods used to assess the quality and strength of evidence: the evidence base for the recommendations includes publications from the Cochrane Library, MEDLINE, and PubMed databases.

Search depth — 10 years.

Methods used to assess the quality and strength of evidence:

• expert consensus;

• significance assessment in accordance with the rating scale (scale attached).

Methods used for evidence analysis:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Description of methods used for evidence analysis

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations. To minimize potential errors, each study was evaluated independently. Any discrepancies in evaluations were discussed by the full panel of authors. If consensus could not be reached, an independent expert was involved.

In these clinical guidelines, all information is ranked by the level of certainty (evidence) or LoC, depending on the quantity and quality of studies on the issue (Table 3 and Table 4).

Table 3. Scale for grading levels of evidence certainty (LEC) for diagnostic methods (diagnostic interventions)*

Table 4. Scale for grading levels of evidence certainty (LEC) for methods of prevention, treatment, and medical rehabilitation, including those based on natural factors (preventive, therapeutic, and rehabilitative interventions)*

The level of recommendation consensus (LRC) was then determined — Table 5

Table 5. Scale for grading levels of recommendation consensus (LRC) for methods of prevention, diagnosis, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions) *

* Materials for the development of clinical guidelines https://rosmedex.ru/kr/reco

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

1. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "ON APPROVAL OF THE NOMENCLATURE OF MEDICAL SERVICES".

2. Order of the Ministry of Health of the Russian Federation No. 700n dated October 7, 2015, "On the nomenclature of specialties of specialists with higher medical and pharmaceutical education".

3. Order of the Ministry of Health of the Russian Federation No. 1047n dated December 14, 2012, "On approval of the Procedure for providing medical care to children in the profile 'neurology'".

4. Instructions for use of the medicinal product nusinersen** dated August 19, 2019, LP-005730, available on the web portal of the State Register of Medicinal Products at: http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=53afdec7-1b35-4583-bb11-d5f7c5d2546a&t=

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What is spinal muscular atrophy?

Spinal muscular atrophy (hereinafter referred to as SMA) is a genetic, progressive, and sometimes fatal neuromuscular disease. Although new cases are relatively rare, many people live with SMA. SMA affects approximately 1 in 6,000 to 10,000 children and is the leading genetic cause of death in children under 2 years of age worldwide^2,3. Regardless of severity, all individuals with SMA lose motor function¹.

SMA is generally classified into 4 main types⁸:

SMA involves dysfunction or death of $\alpha$-motor neurons¹. Spinal $\alpha$-motor neurons innervate skeletal muscles and are responsible for muscle contraction.

Due to the lack of a specific protein—the SMN protein—SMA leads to the death of $\alpha$-motor neurons

The SMN protein is essential for the functioning of motor neurons in the spinal cord¹

In SMA, the amount of synthesized SMN protein is insufficient for neuronal survival

• SMA is caused by a deletion or mutation in the SMN1 gene, which leads to reduced levels of the SMN protein⁴

• If the SMN1 gene is non-functional, the SMN2 gene becomes the sole source of SMN protein, but it produces insufficient functional SMN protein⁶

How does spinal muscular atrophy manifest in a child?

Every patient with spinal muscular atrophy has individual impairments, and symptoms may vary depending on the age of onset and disease severity. Children may experience progressive weakness in proximal muscles, such as those of the shoulders, hips, and pelvis. Muscles involved in breathing and swallowing may also be affected.⁸

Spinal muscular atrophy does not affect neurons responsible for intelligence.^9,10,11

What do you need to know about the SMN2 gene?

All patients with spinal muscular atrophy have at least one "backup gene" called SMN2. The structure of the SMN2 gene is similar to that of the SMN1 gene, but only a small fraction of the SMN protein it produces (10%) is fully functional. This amount of SMN protein is insufficient to maintain motor neuron survival.^12-14

The number of SMN2 copies can vary; a higher number of SMN2 copies is associated with milder symptoms of spinal muscular atrophy.^14-16

Because the disease presents with a wide variety of symptoms, it is difficult to predict severity based on the number of SMN2 copies alone. Therefore, specialists recommend considering not only the number of SMN2 copies but also the child's functional abilities when making care decisions.¹⁷

How is spinal muscular atrophy inherited?

Spinal muscular atrophy — is an autosomal recessive disorder, meaning a child is at risk of developing the disease if they inherit one mutated SMN1 gene from each parent. If a child inherits only one defective SMN1 gene, they are considered a "carrier". Carriers do not have symptoms of the disease.¹⁸

If there is a family history of spinal muscular atrophy, your chances of being a carrier are higher than average. When making family planning decisions, it is helpful to consult your physician.

How is SMA diagnosed?

A medical geneticist or neurologist may order genetic testing to confirm or rule out the disease.

To confirm the diagnosis, molecular genetic blood testing is performed. It shows whether the patient has a mutation in the SMN1 gene. In addition, the number of SMN2 gene copies needs to be determined.¹⁷

Other diagnostic tests may also be prescribed, including additional genetic testing.

A comprehensive approach to medical care, involving multidisciplinary specialists, can help improve overall health and survival^17.

There are many aspects of medical care, and parents will need to make various decisions together with the doctor, as each child's symptoms manifest differently. Given that every patient with SMA has different symptoms and manifestations, team members and their degree of involvement may vary depending on needs and circumstances. Parents, as the primary members of this team, are encouraged to work closely with their child's doctor to build a care team that works best for them and their family.¹⁷

Respiratory function. Respiratory support is central to the management of patients with SMA. Due to chest muscle weakness, the ability to breathe and cough effectively may be impaired, increasing the risk of infection.²⁰

Non-invasive ventilation (NIV) encompasses methods that prevent or delay invasive intervention. Specialized equipment, such as a bilevel positive airway pressure (BiPAP) device, provides a continuous flow of air into the lungs via a mask covering the mouth and/or nose. A mechanical cough assist device can also be used at home.

Invasive mechanical ventilation ensures safe delivery of air into the lungs via an endotracheal tube inserted through the patient's mouth (tracheal intubation) or directly into the trachea through a small incision in the neck (tracheotomy).

Orthopedics. Scoliosis (curvature of the spine) is a common problem in children with spinal muscular atrophy due to muscle weakness. An orthopedic surgeon may recommend the use of posture support devices (orthoses) or surgical correction of scoliosis.¹⁹

Nutrition. Due to muscle weakness, children with SMA may lose the ability to chew and swallow. This creates a risk of inhaling food and liquids into the lungs during meals and developing respiratory infections. Parents and physicians may decide to place a temporary or permanent feeding tube to provide the child with necessary food and fluids.¹⁹ There are two types of feeding tubes: nasal and abdominal. Nasogastric tubes are inserted through the nose; food goes directly into the stomach. They are typically used when a tube is needed for a short period. Gastrostomy tubes are surgically placed through the abdominal wall into the stomach. They are easy to maintain and are a good option for children who require long-term feeding support.

Physical therapy. Children with SMA may be too weak to perform full ranges of motion. This creates a risk of developing contractures, which can later become permanent and limit movement. Therapeutic exercise may consist of flexibility and general functional ability exercises. In certain cases, a standing frame can help improve bone strength and may be used at home.¹⁹

In addition to the aforementioned specialists, the care team may also include other professionals, including physicians and staff from a medical organization or its structural subdivision providing specialized palliative medical care.

Important resources. There are international and Russian organizations, projects, and communities dedicated to making life easier for SMA patients and their families.

Patient organizations

SMA Europe — a European patient organization established in 2006 that unites patient and research organizations across Europe dedicated to spinal muscular atrophy (SMA).

Visit sma-europe.eu

SMA Families — a Russian patient organization, part of SMA Europe, established in 2015. It offers numerous projects for patients and their families, such as a hotline, and useful information, such as a detailed disease description and publication library. Visit f-sma.ru

Internet resources

TogetherInSMA — an international website designed to educate SMA patients and their families.

Visit togetherinsma.com

References:

1. CureSMA.org. Voice of the Patient Report. [Internet]: http://www.curesma.org/documents/advocacy-documents/sma-voice-of-the-patient.pdf. Accessed: January 2020.

2. VerhaartI EC, Robertson A, Wilson IJ, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy- a literature review. Orphanet J Rare Dis. 2017;12(1):124.

3. FarrarMA, KiernanMC. The genetics of spinal muscular atrophy: progress and challenges. Neurotherapeutics. 2015;12(2):290-302.

4. Lefebvre S, BürglenL, Reboullet Set al. Identification and characterization of a spinal muscular atrophy- determining gene. Cell. 1995 Jan13;80(1):155-65.

5. Farrar MA, Park SB, Vucic S, et al. Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol. 2017;81(3):355-368.

6. Hamilton G,  Gillingwater TH. Spinal muscular atrophy: going beyond the motorneuron. Trends Mol Med. 2013;19(1):40-50.

7. Rubin LR. Predicting Systemic Defects in SMA. [Internet]: http://www.smafoundation.org/wp-content/uploads/2012/03/SMA-Overview.pdf Accessed: January 2020.

8. Finke lR, et al. 209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy7-9 November2014, Heemskerk, The Netherlands. Neuromuscul Disord. 2015;25(7):593-602.

9. Cure SMA. At School. 2016. [Internet]: http://www.curesma.org/support-care/living-with-SMA/daily-life/at-school/. Accessed: January 9, 2017.

10. National Organization for Rare Disorders. Werdnig-Hoffmann Disease. 2012. [Internet]: https://rarediseases.org/rare-diseases/werdnig-hoffmann-disease/. Accessed: January 2017.

11. Iannaccone ST. Modern management of spinal muscular atrophy. J ChildNeurol. 2007;22(8):974-978.

12. Cure SMA. Cure SMA Medical Provider Information Kit. [Internet]: http://www.curesma.org/documents/support--care-documents/2016-sma-awareness-mpak.pdf. Accessed: January 2017.

13. Cherry JJ, et al. Identification of novel compounds that increase SMN protein levels using an improved SMN2 reporter cell assay. J Biomol Screen. 2012;17(4):481-495.

14. Darras BT, RoydenJones H Jr, Ryan MM, DeVivo DC, eds. Neuromuscular DisordersofInfancy, Childhood, and Adolescence: A Clinician’sApproach. 2nd Ed. London, UK: Elsevier; 2015.

15. Genetics Home Reference. SMN1 gene. 2012. [Internet]: https://ghr.nlm.nih.gov/gene/SMN1. Accessed: January 2017.

16. Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med. 2010;12(3):145-152.

17. Wang CH, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22(8):1027-1049.

18. National Organization for Rare Disorders. Spinal Muscular Atrophy. 2012. [Internet]: https://rarediseases.org/rare-diseases/#causes. Accessed: January 2017.

19. Mercuri E, Finkel RS, Muntoni F et al. Diagnosis and management of spinal muscular atrophy: Part1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115.

20. Finkel RS, Mercuri E, Meyer OH et al. Diagnosis and management of spinal muscular atrophy: Part2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207.

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

Appendix G1. Russian title: Key Milestones of Motor Activity (Section 2)*

* The scale is not validated in the Russian Federation; special training is required for its use.

Original title (if available): Hammersmith Infant Neurological Exam -

Source (official developer website, validation publication): Bishop KM, Montes J, Finkel RS. Motor milestone assessment of infants with spinal muscular atrophy using the Hammersmith Infant Neurological Exam - Part 2: Experience from a nusinersen clinical study. Muscle Nerve. 2018 Jan;57(1):142-146. doi: 10.1002/mus.25705. Epub 2017 Jun 14.

Type (underline): rating scale.

Purpose: general assessment of motor activity in an infant with type I SMA; can be used to assess treatment efficacy.

Content (template):

Appendix G2. Russian title: Motor Function Scale for SMA*

* The scale is not validated in the Russian Federation; special training is required for its use.

Original title (if available): The Hammersmith Functional Motor Scale Expanded (HFMSE).

Source (official developer website, validation publication):  Pera MC, Coratti G, Forcina N, Mazzone ES, Scoto M, Montes J, Pasternak A, Mayhew A, Messina S, Sframeli M, Main M, Lofra RM, Duong T, Ramsey D, Dunaway S, Salazar R, Fanelli L, Civitello M, de Sanctis R, Antonaci L, Lapenta L, Lucibello S, Pane M, Day J, Darras BT, De Vivo DC, Muntoni F, Finkel R, Mercuri E. Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC Neurol. 2017 Feb 23;17(1):39. doi: 10.1186/s12883-017-0790-9.

Type (underline): rating scale.

Purpose: functional assessment of motor activity in an SMA patient; can be used to assess treatment efficacy.

Content (template):

Scoring key: Circle the highest level of current independent movements and during follow-up evaluations. Scores more clearly demonstrate positive or negative trends in motor development.

OC = limited by contracture

Appendix G3. Russian title: Revised Upper Limb Module*

* The scale is not validated in the Russian Federation; special training is required for its use.

Original title (if available): Revised Upper Limb Module (RULM).

Source (official developer website, validation publication): Mazzone ES, Mayhew A, Montes J, Ramsey D, Fanelli L, Young SD, Salazar R, De Sanctis R, Pasternak A, Glanzman A, Coratti G, Civitello M, Forcina N, Gee R, Duong T, Pane M, Scoto M, Pera MC, Messina S, Tennekoon G, Day JW, Darras BT, De Vivo DC, Finkel R, Muntoni F, Mercuri E. Revised upper limb module for spinal muscular atrophy: Development of a new module. Muscle Nerve. 2017 Jun;55(6):869-874. doi: 10.1002/mus.25430. Epub 2017 Feb 6.

Type (underline): rating scale.

Purpose: functional assessment of upper limb movements in children and adults with type II and type III SMA; can be used to assess treatment efficacy.

Content (template):

Expanded scale:

Key (interpretation): scored in points at the time of examination and subsequently over time.

Appendix G4. Russian title: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders

Original title (if available): The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Development (CHOP-INTEND).

Source (official developer website, validation publication): Glanzman AM, McDermott MP, Montes J, Martens WB, Flickinger J, Riley S, et al. Validation of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatric Physical Therapy: The official publication of the Section on Pediatrics of the American Physical Therapy Association. 2011;23(4):322-6.

Type (underline): rating scale.

Purpose: used to assess motor function in SMA patients who are unable to walk independently.

Content (template):

Key (interpretation): scored in points at the time of examination and subsequently over time.

Appendix G5. Russian title: 32-Item Motor Function Measure*

* The scale is not validated in the Russian Federation; special training is required for its use.

Russian title: 32-item Motor Function Measure.

Original title (if available): The 32-item Motor Function Measure (MFM-32).

Source (official developer website, validation publication): https://mfm-nmd.org

Bérard C, Payan C, Hodgkinson I, Fermanian J; MFM Collaborative Study Group. A motor function measure for neuromuscular diseases. Construction and validation study. Neuromuscul Disord. 2005 Jul;15(7):463-70. doi: 10.1016/j.nmd.2005.03.004

Trundell D, Le Scouiller S, Le Goff L, Gorni K, Vuillerot C (2020) Assessment of the validity and reliability of the 32-item Motor Function Measure in individuals with Type 2 or non-ambulant Type 3 spinal muscular atrophy. PLOS ONE 15(9): e0238786.

Type (underline): rating scale.

Purpose: functional assessment of motor activity in an SMA patient; can be used to assess treatment efficacy.

Content (template):

Key (interpretation): scored in points at the time of examination and subsequently over time.