5q-associated spinal muscular atrophy: clinical guidelines

List of Abbreviations

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

DNA — deoxyribonucleic acid

VC — vital capacity

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 the first second of a forced expiration maneuver

MUAP — motor unit action potential

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

PEF — peak expiratory flow

PCF — peak cough flow

PCR — polymerase chain reaction

RNA — ribonucleic acid

CPAP — from English Constant Positive Airway Pressure, CPAP

SMA — spinal muscular atrophy

ATD — assistive technology devices

FVC — forced vital capacity

RRS — rehabilitation routing scale

LeR — level of recommendation validity

LoE — level of evidence

ECG — electrocardiography

EMG — electromyography

ENMG — electroneuromyography

EchoCG — echocardiography

HFMSE — Hammersmith Functional Motor Scale Expanded

MFM-32 — Motor Function Measure 32-item

MLPA — Multiplex Ligation-dependent Probe Amplification

NIPPV — Noninvasive Positive Pressure Ventilation

RULM — Revised Upper Limb Module

SpO2 — peripheral capillary oxygen saturation measured non-invasively by pulse oximetry

Terms and Definitions

BiPAP (from English Biphasic Positive Airway Pressure, BPAP, BiPAP; according to medical device nomenclature: Portable Biphasic Positive Airway Pressure (BPAP) ventilator, Biphasic Positive Airway Pressure (BPAP) ventilator for home use) — biphasic positive airway pressure ventilation; a device that delivers different levels of positive pressure during the patient's inspiration and expiration.

Myocardial hypertrophy — pathological thickening of the heart muscle layer.

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

Cardiac chamber dilation — pathological enlargement of the heart chamber volume.

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

Capnometry and capnography — measurement and digital display of the concentration or partial pressure of carbon dioxide in the inhaled and exhaled air during the patient's respiratory cycle.

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

Contracture — limitation of passive joint movement.

Pulse oximetry — a method for determining blood oxygen saturation and pulse rate per minute.

CPAP (from English Constant Positive Airway Pressure — constant positive airway pressure; according to medical device nomenclature: Continuous Positive Airway Pressure (CPAP) ventilator for newborns, Continuous Positive Airway Pressure (CPAP) ventilator for home use) — an individual medical device for automated long-term assisted nasal continuous positive airway pressure ventilation used by the patient during night sleep. CPAP is a small compressor that delivers a continuous stream of air under a certain pressure into the respiratory tract through a flexible tube and a sealed nasal or oro-nasal mask. Thus, it prevents the airways from collapsing and blocking the flow of air (and 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 — a three-dimensional spinal deformity.

Electromyography (EMG) — methods for studying peripheral nerves, muscles, and neuromuscular transmission. Subdivided into stimulation and needle electromyography. The method of electroneuromyography used and the scope of the study depend on the suspected level of lesion upon neurological examination.

Enteral nutrition — administration of nutrients into the gastrointestinal tract (orally, via a feeding tube, or stoma) to maintain and correct nutritional status in accordance with the patient's current energy, protein, vitamin, mineral, and micronutrient requirements.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

5q-associated, or proximal, spinal muscular atrophy (SMA) is a severe neuromuscular disorder with an autosomal recessive inheritance pattern that develops due to homozygous (less commonly, compound heterozygous) pathogenic variants in the SMN1 gene and is characterized by progressive degeneration of motor neurons in the spinal cord and brainstem, leading to progressive muscle atrophy and flaccid paresis [1].

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

SMA develops due to pathogenic variants in the SMN1 gene (English survival motor neuron), which encodes the survival motor neuron (SMN) protein. The SMN1 gene is located on chromosome 5 (locus 5q12.2-q13.3) close to the telomere, which is why it has alternative names telSMN, SMNt, and SMNT, where "t" indicates its telomeric location.

The full-length SMN protein consists of 294 amino acids and is characterized by ubiquitous expression and a wide variety of functions. Particularly high levels of this protein are found in the brain, spinal cord, kidneys, and liver, but it is also present in the heart, muscles, and other tissues.

The SMN protein is present in both the nucleus and the cytoplasm as part of SMN complexes, which are self-assembling multimeric protein structures required for pre-mRNA splicing. The SMN protein acts as a subunit of the SMN complex during the biosynthesis of small nuclear ribonucleoprotein particles (snRNPs). The SMN complex enables nuclear Sm proteins and uridine-rich small nuclear RNAs to form snRNPs involved in the pre-mRNA splicing of various genes necessary for the function of motor neurons and several other cells. In addition, the SMN protein modulates apoptosis by blocking the activation of several caspases and other key regulators of cell survival [2].

In humans and other higher primates, SMN1 has a paralogous centromeric copy — the SMN2 gene (alternative designations cenSMN, SMNc, BCD541, SMNC). In the general population (without SMA), approximately 10–15% of people lack SMN2 entirely [3]. The copy number of the SMN2 gene in SMA patients typically ranges from one to four or five (very rarely up to eight) [4,5].

Both genes (SMN1 and SMN2) consist of nine exons and differ in their nucleotide sequence by only five nucleotides [1,6]. Unlike the SMN1 gene, exon 7 of the SMN2 gene has a cytosine replaced by thymine at position 840. Although this substitution does not affect the amino acid sequence, it disrupts an exonic splicing enhancer and leads to alternative splicing of the pre-mRNA produced by the SMN2 gene, resulting in the exclusion of exon 7 in 90% of SMN2 transcripts [7,8]. This causes such transcripts to produce a defective version of the SMN protein that is rapidly subjected to intracellular degradation. Nevertheless, about 10% of the protein product generated from the SMN2 gene is a full-length functional SMN protein.

SMA develops when an individual lacks functionally working copies of the SMN1 gene. The 5q12.2-q13.3 region is complex and genetically unstable. In approximately 95% of cases, the cause of SMA is homozygous deletions of exons 7 or 7–8 of the SMN1 gene. In remaining cases, patients are found to be compound heterozygous for a deletion in one copy of the SMN1 gene and a different pathogenic variant (nonsense, missense, splice-site variants, insertions, small deletions) in the other [8].

The absence of SMN protein due to pathogenic variants on both alleles of the SMN1 gene leads to impaired snRNP biosynthesis and, consequently, impaired splicing of premature mRNAs of genes essential for motor neuron viability, which entails the progressive death of the latter. Given the ubiquitous expression of the SMN protein, in addition to dominant neurological disorders, its deficiency also causes a number of systemic disorders. This is confirmed by both experimental models and epidemiological studies [9].

In the case of heterozygous carrier status for a deletion of exons 7 or 7–8 of the SMN1 gene and the absence of pathogenic variants on the second allele of this gene, SMA does not develop. Apart from SMA, no other diseases associated with pathogenic variants in the SMN1 gene have been described to date.

Due to the fact that a small fraction of full-length SMN protein is nevertheless produced from the SMN2 gene, the SMN2 copy number is the primary modifier of SMA phenotype severity [10,11]. The more SMN2 copies an SMA patient has, the milder the disease phenotype (later age of onset, less rapid progression). Depending on the phenotypic features, 5 types of SMA are distinguished (see Table 1).

It should be noted that the determination of the SMA type is not based on the SMN2 copy number, but rather takes into account the specific course of the disease and the clinical picture in a particular patient in conjunction with molecular genetic testing data.

In addition to SMN2 copy number, another SMA phenotype modifier associated with this gene has been discovered. The missense variant c.859G>C (reference transcript NM_017411.3) in exon 7 of the SMN2 gene creates a new exonic splicing enhancer site, resulting in increased inclusion of exon 7 into the SMN2 gene transcript compared to normal [3]. For this reason, carriers of the c.859G>C variant in the SMN2 gene will exhibit a milder SMA phenotype even with a small copy number of the latter, due to a higher proportion of full-length SMN protein among SMN2 protein products.

SMN2-associated modifiers are the only validated factors influencing the SMA phenotype. The potential role of other possible modifiers (genetic, epigenetic, environmental factors) is currently being intensively studied, but there is no clinical confirmation for these data yet.

1.3 Epidemiology of the Disease or Condition

Global incidence of SMA ranges from 1 case per 6,000 newborns to 1 in 10,000 newborns; meanwhile, the carrier frequency of pathogenic variants associated with SMA is approximately 1:50 [14–16].

The prevalence of all SMA types combined, according to published data to date, in most cases ranges around 1–2 cases per 100,000 population [16].

Centralized statistics on SMA epidemiology in the Russian Federation are lacking. According to the Research Centre for Medical Genetics (RCMG), the carrier frequency of exon 7/8 deletions of the SMN1 gene in the Russian population is 1 in 36 individuals, and the estimated incidence of SMA may therefore be 1 case per 5,184 newborns [17].

1.4 Features of Coding the Disease or Condition

SMA coding according to the International Classification of Diseases (ICD), 10th Revision:

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

G12.1 Other inherited spinal muscular atrophies: used to code SMA types 2, 3, and 4.

SMA coding according to the International Classification of Diseases (ICD), 11th Revision:

8B61 Spinal muscular atrophies

8B61.0 Spinal muscular atrophy, early childhood onset, type I

8B61.1 Spinal muscular atrophy, later onset, type II

8B61.2 Spinal muscular dystrophy, juvenile form, type III

8B61.3 Adult spinal muscular atrophy, type IV

1.5 Classification of the disease or condition

The most commonly used clinical classification of SMA is based on the age of onset and phenotype severity. The basic characteristics of this classification were presented in Table 1. Below are a number of additional details for each type of SMA.

Type 0, prenatal or congenital form. Characterized by decreased fetal motor activity. Newborns show severe swallowing and breathing disorders, neonatal hypotonia, facial diplegia, arthrogryposis. Life expectancy generally does not exceed a few weeks after birth [6,12].

Type 1, known as Werdnig-Hoffmann disease, as well as acute SMA (OMIM#253300). Characterized by the development of marked weakness in infancy (in the first 5 months of life), inability to sit without support, progressive joint contractures, impaired suckling and swallowing. In the absence of rehabilitation measures and disease-modifying therapy, death usually occurs within the 2nd year of life [6,12].

Type 2, known as Dubowitz disease, as well as chronic SMA (OMIM#253550). Disease onset occurs at the age of 6–18 months. Children with type 2 SMA acquire the ability to sit independently (without support), but subsequently experience a delay in motor development with the loss of previously acquired motor skills. As the disease progresses, patients develop severe skeletal deformities, widespread joint contractures, restrictive respiratory disorders of varying severity, and a postural tremor of the fingers. Sometimes type 2 SMA is additionally divided into subtypes 2a and 2b. Type 2b SMA differs from 2a by the patients' short-lived ability to stand or even take a few steps with outside support [6,12,18].

Type 3, known as Kugelberg-Welander disease, as well as juvenile SMA (OMIM#253400). Onset occurs between 18 months and 21 years of age. Patients achieve the ability to sit, stand, and walk without support at least until puberty, after which a relatively slow loss of previously acquired motor milestones may begin. Skeletal deformities are usually mild. Life expectancy is often comparable to that of the general population. Sometimes type 3 SMA is additionally divided into subtypes 3a and 3b. In type 3a SMA, onset is noted between 18 and 36 months, whereas in type 3b it is after 36 months and up to 20 years [6,12,18].

Type 4, known as adult-onset SMA (OMIM#271150). SMA with onset of motor symptoms after the age of 20 years. This type of SMA is extremely rare and is observed in less than 5% of patients. Patients retain the ability to walk independently. Life expectancy is generally not reduced [6,12].

Currently, a somewhat different classification of SMA based on the patient's baseline motor abilities is becoming increasingly widespread [19]. According to this classification, SMA patients are divided into:

- unable to sit, or non-sitters (non-sitters) — correspond to types 0 and 1 SMA;

- capable of sitting, or sitters (sitters) — correspond to type 2 SMA;

- capable of walking, or walkers (walkers) — correspond to types 3 and 4 SMA.

1.6 Clinical presentation of the disease or condition

Type 0 SMA represents the most severe variant of the disease. According to some authors, the proportion of patients with type 0 SMA among all patients with this disease may be about 1.8%. The most frequent initial manifestation of type 0 SMA is decreased fetal movement, which pregnant women note at 24–38 weeks of gestation (median 32 weeks). Immediately after birth, infants show profound muscular hypotonia and respiratory disorders requiring ventilatory support in the first hours of life. Most such newborns are unable to suck or swallow, and bilateral facial muscle plegia is detected. Congenital heart defects (most commonly atrial or ventricular septal defects) are found in many infants with type 0 SMA. Life expectancy in type 0 SMA does not exceed several weeks [20–22].

Type 1 SMA accounts for about 45% of all cases of this disease. This type of SMA debuts at the age under 6 months. Children develop severe muscle weakness with the inability to hold the head up, respiratory failure, and an inability to roll over and sit without support. Symmetrical proximal muscle weakness dominates. Deep reflexes are absent. Feeding difficulties and food aspiration are frequently noted. Given the relative preservation of diaphragmatic strength compared to the intercostal and chest muscles, most patients exhibit bell-shaped chest deformity and paradoxical breathing. Fasciculations and atrophy are detected in the tongue. Over time, scoliosis and joint contractures develop. Without disease-modifying treatment and rehabilitation measures, death occurs before the age of 2 years [12,23]. Nevertheless, with the active introduction of disease-modifying therapy, patients with type 1 SMA in the future will likely be able to transition into the adult age category against the background of a changing natural history of SMA.

Type 2 SMA debuts at the age of 6–18 months (according to the Polish SMA registry of 790 patients, the mean age of onset is 11.5 months), has a less severe course, and accounts for about 30% of all SMA cases [13]. About 70% of patients with this type of SMA survive to 25 years of age. At the peak of their achieved motor skills, patients with type 2 SMA can sit without support (typically by 9 months of age) and independently hold their head up, but subsequently, as the disease progresses and in the absence of disease-modifying therapy, a regression of motor abilities develops. In type 2 SMA, tongue muscle fasciculations and postural-kinetic tremor of the fingers are frequently noted. As SMA progresses, severe kyphoscoliotic spinal deformity and widespread joint contractures (including jaw joint ankylosis) progress. Spinal and chest deformities are associated with greater severity of respiratory disorders and frequently require surgical correction. Due to diffuse (more proximally pronounced) muscle weakness, cough weakness, restrictive respiratory disorders, choking, and aspiration during meals are noted; there is an increased tendency toward respiratory infections. Breathing and swallowing difficulties are reported by more than 75% of patients with type 2 SMA [24]. According to a small observational study, out of 24 patients with type 2 SMA, 12 had hip dislocation and 8 had hip subluxation [25].

According to the largest to date observational long-term (more than 8 years) study involving 348 patients with type 2 SMA, the most intensive progression of respiratory disorders (about 4%/year of the predicted forced vital capacity (FVC)) is observed in the period from 5 to 13 years of age, after which the rate of progression decreases to 1%/year of the predicted FVC [26]. According to another study involving 82 patients with type 2 SMA, the rates of decline (as a percentage of the predicted value) in forced expiratory volume in 1 second (FEV1) as the disease progressed were 1.29%/year for subtype 2a and 1.37%/year for subtype 2b. FVC decreased by 1.32%/year in subtype 2a and by 1.4% in subtype 2b. Vital capacity (VC) worsened by an average of 1.57%/year in subtype 2a and 1.65%/year in subtype 2b [18].

Almost all patients with type 2 SMA experience sleep disorders, daytime fatigue and drowsiness, increased tiredness, and the need to "conserve" movements [12,23,24]. In addition, obesity may develop in some patients with type 2 SMA [19].

In type 3 SMA, the onset of motor disorders is noted at the age from 18 months to 21 years (according to the Polish SMA registry, the mean age of onset is 4.54 years) [13]. This type of SMA accounts for about 20% of all cases of the disease. Patients with type 3 SMA retain the ability to walk independently for some (often long) time (meanwhile, falls may occur, and walking stairs, running, and rising from a sitting position are difficult). If the onset of the disease occurred at an age under 3 years (subtype 3a), the loss of the ability to walk generally develops in the second decade of life; if type 3 SMA manifested after 3 years, the ability to walk may be preserved even after reaching 20 years of age [12]. According to a small observational study, out of 17 patients with type 3 SMA, 2 had hip dislocation and 5 had hip subluxation [25].

According to published data, the estimated probability of preserved walking ability in type 3 SMA is 80% after 10 years of disease, 68% after 20 years of disease, and 61% after 30 years of disease. Carriage of 4 copies of the SMN2 gene is associated with a greater chance of maintaining walking ability (82% after 20 years of disease versus 60% after the same duration of disease in carriers of 3 copies of SMN2). The mean age of potential loss of walking ability is 14 years (± 11 years) [13].

Problems with swallowing food and breathing are reported by less than 34% of patients with type 3 SMA [24]. Respiratory disorders are most often not so severe. According to the largest to date observational long-term (more than 8 years) study involving 89 non-ambulatory patients with type 3 SMA, the most pronounced progression of respiratory disorders (about 3%/year of the predicted FVC) is observed between 8 and 13 years of age; thereafter, the rate of progression decreases to 0.9%/year of the predicted FVC [26]. According to another study involving 78 patients with type 3 SMA, the rates of decline (as a percentage of the predicted value) in FEV1 as the disease progressed were 0.73%/year for subtype 3a; for subtype 3b this value was 0.11%, but was not statistically significant due to the small number of patients with this subtype. FVC decreased by 0.67%/year in subtype 3a and by 0.23% in subtype 3b (the latter value may be overestimated due to the small number of observations of patients with this subtype). VC worsened by an average of 1.06%/year in subtype 3a [18].

The leg muscles in type 3 SMA are affected significantly more severely than the arm muscles. Postural hand tremor is also detected in type 3 SMA. Increased fatigability and tiredness can significantly impair the quality of life of patients with this type of SMA. The most rapid deterioration in the functional capabilities of patients with type 3 SMA is observed during puberty [12,13,23].

Scoliotic spinal deformity in type 3 SMA is generally minimally pronounced. Life expectancy does not differ from that of the general population [27]. Obesity may develop in patients with type 3 SMA [19].

Type 4 SMA accounts for less than 5% of all SMA patients [27]. Onset is most commonly observed around the age of 30. At the onset of the disease, muscle atrophy may have an asymmetrical character and primarily involves the deltoid muscles, triceps, and quadriceps [6]. Subsequently, increased fatigue, fasciculations (more frequently in the thighs), hand tremor, and more rarely, calf pseudohypertrophy gradually join in [28]. The course of type 4 SMA is relatively benign; if the ability to walk independently is lost, it is after 50 years of age. Due to the phenotypic features of type 4 SMA, its diagnosis can be difficult if clinicians lack clinical awareness. According to an analysis of a cohort of 20 patients with type 4 SMA, all were initially monitored with incorrect diagnoses (e.g., limb-girdle muscular dystrophy, amyotrophic lateral sclerosis, etc.), and the mean time to establish the correct diagnosis was 12.4 years [28].

Cardiac pathology (heart rhythm disturbances, cardiac enlargement, etc.) can be detected in all types of SMA, but it is relatively rare in types 2, 3, and 4 SMA [29].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing 5q SMA with onset in adulthood.

The diagnosis of 5q SMA is established based on complaints, anamnesis, and characteristic clinical symptoms of proximal muscle hypotonia and muscle weakness associated with lower motor neuron lesions. The validity of the 5q SMA diagnosis must be confirmed by objective results of molecular genetic testing (see 2.3 Laboratory diagnostic tests). The main clinical symptoms of the disease that necessitate mandatory exclusion of 5q SMA via genetic testing include:

· Symmetric hypotrophy and hypotonia of the proximal lower limb muscles with pronounced pelvic girdle muscle weakness. Hypotonia and hypotrophy of muscles may predominate in the iliopsoas muscles, gluteal muscles, and predominantly in the anterior and medial thigh muscle groups [105, 106]. Patients experience difficulties when climbing stairs and rising from a chair. Gowers' sign is often positive: to rise from a squatting position, the patient supports themselves with their hands on the floor and then stands up by resting their hands on their knees. Gait disturbances—specifically a waddling gait (dysbasia)—may develop [107];

· Symmetric hypotrophy and hypotonia of the proximal upper limb muscles, which may be more pronounced in the deltoid and triceps brachii muscles compared to the biceps brachii [106];

· Symmetric reduction or absence of deep tendon reflexes in the limbs;

· Muscle fasciculations, which can be either generalized or segmental in distribution [108];

· Postural hand tremor.

In patients with disease onset after 18 years of age, the anamnesis is typically characterized by a slow, progressive increase in neurological deficit (over 5 years). Disease onset is usually associated with increasing proximal lower limb muscle weakness. Despite the variety of phenotypic manifestations of adult-onset 5q SMA, bulbar symptoms, chest deformity, and intercostal muscle hypotrophy are not characteristic of this patient category, and spinal scoliosis is either absent or minimally expressed [108, 109]. If the diagnosis of SMA is not confirmed by molecular genetic analysis and/or an atypical SMA phenotype is present, needle electromyography and stimulation electroneuromyography are performed to determine the symptoms of lower motor neuron lesions (see 2.4.1 Instrumental examinations for SMA diagnosis).

2.1 Complaints and Anamnesis

The main features of complaints and anamnestic data are described in the "Clinical Presentation" section. Complaints that require separate clarification are presented below.

It is necessary in adult patients with SMA:

- to actively elicit complaints indicating sleep-disordered breathing: snoring and/or frequent awakenings during sleep, daytime sleepiness, and increased fatigue (for early detection of hypoventilation and sleep apnea);

- to clarify the frequency of infectious diseases and antibiotic therapy over the past 12 months (for proper assessment of the patients' somatic status);

- to clarify complaints of ineffective cough (for timely detection of inadequate clearance of secretions from the lower airways and hypoventilation, primarily in patients with type 2 SMA);

- to clarify complaints indicating dysphagia: impaired swallowing of liquids and/or solid food, the sensation of food getting stuck in the throat during swallowing, coughing or choking before, during, or after swallowing, and a hoarse or "wet" voice after swallowing (for timely correction of these disorders);

- to clarify the presence of symptoms of gastroesophageal reflux, constipation, nausea, or vomiting in SMA patients (for timely diagnosis of gastrointestinal tract dysfunction) [19, 24, 29, 121].

2.2 Physical Examination

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

Clinical examination of patients with SMA includes a physical examination focusing on the musculoskeletal system, as well as a neurological examination and assessment of existing functional impairments. Depending on the type of SMA, the range of aspects required for mandatory assessment may vary. The main possible findings during physical examination are presented in the "Clinical Presentation" section. The features of physical examination in adult patients with SMA are outlined below.

Comments: physical examination is performed regularly, every 6 months or more often if necessary. Regular monitoring of the musculoskeletal system and related functional impairments will help timely identify changes requiring correction and evaluate disease dynamics. Analysis of the course of type 2 and type 3 SMA in a cohort of 268 patients aged 2.5 to 55.5 years showed that minimal functional changes occurred over 12 months; deterioration in a small number of patients was associated with increased contractures, sudden worsening of scoliosis, or significant weight gain [31].

Comments: this functional class is more common in patients with type 2 SMA. In addition to routine neurological examination, clinical evaluation of adult patients with SMA can be performed using the MFM32 [19, 32, 33] and HFMSE [19, 34] scales. In addition, the RULM scale can be used to assess upper limb function [19, 35]. It is worth noting that these scales have so-called "floor" and "ceiling" effects—limitations in the ability to comprehensively capture every possible deterioration or improvement in the patient's condition and quality of life. Considering the significant phenotypic heterogeneity of SMA in adults, it should be borne in mind that the use of clinical scales is most valid when interpreted at the group level; when applied to an individual patient, the interpretation of score dynamics on the scales should be approached with caution, and overall scale scores at the individual level should not be regarded as the sole indicators of disease course, as they do not characterize patients' functional capabilities in daily life [36].

Assessment of contractures may be accompanied by additional measurement of the range of motion in the joint using a goniometer.

Clinical evaluation of breathing includes determining skin color, cough effectiveness, measuring respiratory rate, measuring chest circumference, determining chest excursion, and detecting signs of respiratory muscle dysfunction (presence of paradoxical breathing, use of accessory respiratory muscles).

Clinical assessment of pain intensity and fatigue may be supplemented by the use of visual analogue scales and questionnaires [19].

Clinical assessment of condition dynamics may be supplemented by recording changes reported by the patient themselves that are important for their daily activities.

Comments: in the natural course of the disease this functional class is most frequently encountered in patients with type 3 and 4 SMA (without treatment). In addition to a routine neurological examination, the clinical assessment of adult SMA patients can be performed using the MFM32 [19,32,33] and HFMSE [19,34] scales. Furthermore, the RULM scale [19,35] can be used to assess upper limb function. According to natural history studies of type 3 SMA, the HFMSE scale detects the progression of this disease subtype (significant and valid deterioration in the total score) when monitored over a period of at least 12 months [37,38], whereas the MFM32 scale can register the progression of type 2 and 3 SMA when monitored for at least 2 years [39]. Thus, the aforementioned scales exhibit so-called "floor" and "ceiling" effects—limitations in their ability to comprehensively capture any potential deterioration or improvement in the patient's condition and quality of life. Considering the significant phenotypic heterogeneity of SMA in adults, it must be taken into account that clinical scales are most valid when interpreted at the group level; when applied to an individual patient, the interpretation of score dynamics should be approached with caution, and individual total scores on these scales should not be viewed as the sole indicators of disease course, as they do not characterize patients' functional capabilities in daily life [36].

Assessment of contractures may be accompanied by additional measurement of the range of motion in the joint using a goniometer.

Clinical evaluation of breathing includes determining skin color, cough effectiveness, measuring respiratory rate, measuring chest circumference, determining chest excursion, and detecting signs of respiratory muscle dysfunction (presence of paradoxical breathing, use of accessory respiratory muscles).

Clinical assessment of pain intensity and fatigue may be supplemented by the use of visual analogue scales and questionnaires [19]. For ambulant patients with type 3 SMA and patients with type 4 SMA, the 6-minute walk test allows for the evaluation of lower limb function and overall exercise tolerance [19, 40].

Comments: the scales are provided in the Appendix. It is preferable that scale assessments are performed by specially trained professionals. In the absence of a certified specialist, it is advisable to refer the patient to a center where such specialists are available.

Comments: skinfold thickness measurement (skinfoldometry) can be used for a preliminary assessment of nutritional status. Alterations in nutritional status are frequently observed in SMA patients. Non-ambulant patients and those with dysphagia are at an increased risk of malnutrition. Sitting and ambulant patients are at risk of obesity due to reduced energy expenditure resulting from decreased activity following the loss of the ability to walk [41].

Comments: special attention during examination should be paid to the absence of gag and palatal reflexes, difficulties with chewing and swallowing food, prolonged meal times, and the presence of temporomandibular joint contracture.

2.3 Laboratory Diagnostics

Comments: the "gold standard" of molecular genetic testing for 5q SMA is the analysis of the copy number of the SMN1 and SMN2 genes. This test is performed using real-time PCR or quantitative MLPA analysis. The diagnosis is confirmed upon detection of homozygous deletions of exon 7 or exons 7-8 (i.e., in both copies of the gene).

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

Comments: the absence of deletions of exon 7 or exons 7-8 of the SMN1 gene is defined as the presence of 2 or more copies of the SMN1 gene by real-time PCR or quantitative MLPA analysis. In cases of consanguineous marriages, it is recommended to search for single-nucleotide pathogenic variants in the SMN1 gene using direct automated Sanger sequencing even if deletions of exon 7 or exons 7-8 of the SMN1 gene are absent.

Comments: it must be borne in mind that the SMA type in a specific patient cannot be established based on the copy number of the SMN2 gene, as it is determined solely on a clinical basis. When counseling patients and their families, it should be explained that despite the close correlation between the SMN2 copy number and prognosis, exceptions exist due to other SMA phenotype modifiers.

Comments: molecular genetic testing for pathogenic variants in the SMN1 gene is also indicated for new spouses of parents of affected children in subsequent marriages (if family planning is intended), spouses of adult SMA patients when planning children, close relatives (siblings of patients and siblings of patients' parents) for offspring risk assessment, as well as sperm and oocyte donors in extracorporeal fertilization. Furthermore, molecular genetic testing for pathogenic variants in the SMN1 gene is recommended when planning pregnancy in consanguineous marriages. Couples in which each partner is a confirmed heterozygous carrier of a deletion of exon 7 or exons 7–8 of the SMN1 gene must be informed about the availability of prenatal (during pregnancy) or preimplantation (using extracorporeal fertilization) DNA diagnostics (see the Prevention section).

Comments: the level of creatine kinase (creatine phosphokinase, CPK) is usually normal or only slightly elevated; however, isolated cases with a pronounced (10-fold) increase in CPK activity have been described.

Comments: this test is performed dynamically as clinically indicated.

Comments: if signs of ketoacidosis are present, the detection of ketone bodies in the urine is additionally indicated.

Comments: it is also necessary to test blood levels of ionized calcium, inorganic phosphorus, and parathyroid hormone, as well as to determine blood alkaline phosphatase activity in all patients with a confirmed diagnosis of SMA to rule out potential mineral metabolism disorders and provide subsequent correction. There is a consensus regarding the need to perform this test once a year.

2.4 Instrumental Diagnostics

2.4.1 Instrumental examinations for the diagnosis of SMA

Comments: when performing this study, it is extremely important to rule out the involvement of sensory fibers of peripheral nerves (1 nerve in the arm and 1 nerve in the leg) and signs of demyelination in the motor fibers of peripheral nerves (1 nerve in the arm and 1 nerve in the leg); it is necessary to examine skeletal muscles with a needle electrode at three levels when SMA is suspected.

EMG should not delay genetic testing, which is the method of choice for diagnosing the disease.

During instrumental examination of patients with suspected SMA for initial diagnosis, needle electromyography (EMG) and stimulation electroneuromyography (ENMG) should be used simultaneously to establish the neuronal level of damage to the peripheral neuromotor apparatus. Needle EMG is of decisive importance: it allows for the examination of a specific muscle and the determination of the severity of denervation activity in it, as well as changes in the morphology of motor unit action potentials (MUAPs) and the interference pattern. Needle EMG is characterized by an increase in the amplitude of the interference pattern, a rarefied interference pattern, the appearance of various spontaneous activity potentials (fasciculation potentials, fibrillation potentials, positive sharp waves, high-frequency complex discharges); MUAP parameters change in a neurogenic manner: MUAP duration is increased, and amplitude is elevated. For needle EMG, it is necessary to select clinically moderately affected muscles. Stimulation ENMG provides additional information: assessing the response of spinal motor neurons when studying F-waves and conduction parameters along motor and sensory nerves. Stimulation ENMG in SMA reveals changes in F-waves: the appearance of giant F-waves, paired and repetitive F-waves, or scattered F-waves, or their absence (F-wave blocks). Conduction velocities and M-response amplitudes along peripheral motor fibers can be either normal or reduced due to secondary axonal changes. An important component of the ENMG study is the exclusion of other levels of involvement (primarily primary muscular).

Comments: when SMA is suspected, MRI should not delay genetic testing, which is the method of choice for diagnosing the disease.

In patients with SMA, muscle MRI reveals atrophy and fatty replacement of muscle tissue. In the thighs, the greatest involvement is typical for the anterior muscle compartment, while the gracilis and other medial muscles are relatively spared or less affected; in the posterior compartment, the semitendinosus muscle is maximally affected first. At the lower leg level, the soleus muscle and flexors are most severely affected, while the extensors are involved to a lesser degree. Nevertheless, such an atrophy pattern is not specific to SMA alone and is also found in other variants of genetic spinal muscular atrophies, for example, those associated with pathogenic variants in the DYNCH1H1, BICD2, or TRPV4 genes [62].

2.4.2 Instrumental diagnostics for cardiac complications of 5q SMA

Comments: in adult patients with SMA, cardiac involvement is uncommon and manifests primarily as cardiac arrhythmias. If complaints or clinical symptoms of cardiovascular system involvement appear, the frequency of monitoring and the need for echocardiography are decided individually for each patient. Some adult patients—predominantly those with type 2 SMA—may develop dilated cardiomyopathy [29, 65].

2.4.3 Instrumental diagnostic tests for musculoskeletal complications of 5q SMA

Comments: this study is also required in preparation for orthopedic surgery. If osteoporosis is detected in the lumbar spine, whole-body X-ray densitometry is indicated. Patients with SMA are characterized by a high frequency of fractures and osteopenia. These risks are caused not only by muscle weakness and low patient mobility, but also by the fact that the SMN gene plays a role in bone metabolism.

Comments: spine radiography (cervical, thoracic, and lumbar spine including the pelvis and hip joints) is performed in anteroposterior and lateral projections. The study is conducted in the most upright position possible for the patient, assumed independently of assistive devices. Hip joint radiography is necessary if there is a clinical suspicion of hip dislocation or subluxation. In adult patients with type 2 SMA and scoliosis >20°, spine radiography is performed annually to monitor kyphoscoliosis progression and determine further orthopedic management tactics. The frequency of examinations should be specified by a specialist or a multidisciplinary team.

Magnetic resonance imaging of the spine, computed tomography of the spine, and ultrasound of the spine may also be performed if indicated [66, 67].

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

Comments: normally, saturation levels range from 95–100%. If SpO2 is below 90%, emergency measures must be taken. Saturation between 94–90% is considered borderline. Patients with hypoventilation are advised to have a pulse oximeter at home.

Comments: unprovoked respiratory volume and flow studies must be performed in patients with type 2 SMA and non-ambulatory patients with type 3 SMA once a year [18,26]; in ambulatory patients with type 3 SMA and patients with type 4 SMA, pulmonary function testing may be performed once every 4 years (more frequently if there are clinical indications, specifically the onset of snoring, nocturnal awakenings, or daytime sleepiness), because natural history data for SMA show that negative dynamics can be detected in ambulatory patients with types 3 and 4 SMA precisely over such a time interval [29]. The parameter used to monitor respiratory muscle strength in SMA patients capable of performing the test is forced vital capacity (FVC). Patients with an FVC of 20% to 50% of predicted are at increased risk for pulmonary complications, and patients with an FVC <20% are at an even higher risk due to daytime ventilatory failure. Patients with an FVC >60% typically have a low risk of nocturnal hypoventilation [68]. A peak cough flow (PCF) of less than 270 L/min indicates reduced cough efficacy, while less than 160 L/min indicates an ineffective cough and a high risk of respiratory tract infections [29,69].

Comments: polysomnography / cardiorespiratory monitoring is performed to diagnose obstructive sleep apnea, which helps determine the nature of respiratory disorders. Adult patients with type 2 SMA are at risk for sleep-related breathing disorders (most commonly hypoventilation) due to decreased tidal volume, impaired diaphragmatic function, and reduced function of the intercostal and accessory respiratory muscles. Such patients may also develop an obstructive syndrome caused by weakness of the laryngeal and pharyngeal muscles, predisposing them to airway collapse. In accordance with Order No. 804n of the Russian Ministry of Health dated October 13, 2017, "On Approval of the Nomenclature of Medical Services," the service "Polysomnography" is not listed; therefore, a set of services may be used: video-electroencephalography monitoring, 24-hour ambulatory blood pressure monitoring, electrocardiogram recording, electrocardiographic data monitoring, Holter heart rhythm monitoring, electrocardiographic data decoding, description and interpretation, cutaneous electromyography (one anatomical zone), electrooculography, and determination of tissue partial oxygen pressure (oximetry)

2.5 Other Procedures

The management of patients with SMA implies a multidisciplinary approach. Specialist consultations may be provided to patients at various stages of medical care, including during the disease diagnostic period.

Comments: initial and follow-up consultations are indicated with a neurologist, geneticist, orthopedic traumatologist, pulmonologist, gastroenterologist, nutritionist, cardiologist, endocrinologist, physicians and other specialists from a medical organization or its structural subdivision providing specialized palliative medical care, general practitioner (therapist), neurosurgeon, anesthesiologist-intensivist, surgeon, endoscopist, otorhinolaryngologist, thoracic surgeon, dentist, maxillofacial surgeon, psychotherapist, physical and rehabilitation medicine physician, palliative care physician, medical psychologist, as well as physicians of other specialties and specialists.

Comments: if the neurologist confirms the probability of SMA, they must refer the patient for genetic testing.

Comment: based on the results of DNA diagnostics, a follow-up appointment (examination, consultation) with a geneticist is required to discuss the results of molecular genetic testing and genetic risks within the family.

Comments: the specialist's examination includes assessing the range of motion in joints and the presence of spinal curvatures, as well as evaluating muscle strength and functional capabilities for each limb and joint. Issues regarding necessary orthotics are addressed. During the follow-up consultation, the progression of skeletal deformities is assessed, orthotic and postural control technologies are selected, and indications for surgical orthopedic treatment are discussed.

Comments: the pulmonologist determines whether the patient requires additional examinations and which ones (blood gas analysis, chest X-ray, cardiorespiratory monitoring, spirometry).

Comments: for these purposes, an initial appointment (examination, consultation) with a thoracic surgeon may also be required. Tracheostomy may be indicated for patients at an advanced stage of the disease, but it is increasingly rarely used in patients with SMA. It is believed that in the vast majority of cases, tracheostomy placement can be avoided. However, decannulation of patients who are already on invasive mechanical ventilation can be difficult. The otorhinolaryngologist and thoracic surgeon determine the tactics for tracheostomy cannula placement if indicated.

Comments: this is primarily necessary for patients with nutritional status disorders or those at risk of undernutrition or overnutrition.

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

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

3.1 Pharmacotherapy

Currently, pharmacotherapy for SMA includes drugs for pathogenetic (replenishing SMN protein deficiency) and symptomatic treatment.

3.1.1 Disease-modifying pharmacotherapy

Pathogenetic therapy for SMA includes two fundamental approaches:

– modification of SMN2 gene pre-mRNA splicing to include exon 7 in the mature mRNA and increase the production of functional SMN protein using an antisense oligonucleotide (nusinersen**) or a low-molecular-weight compound ("small molecule" — risdiplam**) [70];

– replacement gene therapy: use of the recombinant vector drug onasemnogene abeparvovec based on adeno-associated virus serotype 9, designed to ensure the synthesis of functional SMN protein [71].

Nusinersen** was registered in the Russian Federation in August 2019. [52] It is a drug for intrathecal administration (via lumbar puncture). Lumbar puncture can be performed with or without local or general anesthesia, which is determined by the presence of possible contraindications to local and (or) general anesthetics in a specific patient, combined with the discretion of the physician performing the procedure and the internal regulations of the healthcare facility where nusinersen** administration is carried out.

Risdiplam** was registered in the Russian Federation in November 2020. [53] The route of administration of risdiplam** is oral, which allows treatment to be conducted on an outpatient basis.

Onasemnogene abeparvovec was registered in the Russian Federation in December 2021 [72]. The drug is administered as a single intravenous infusion. Indications for the use of the drug — biallelic mutation in the SMN1 gene and a clinical diagnosis of type 1 SMA, or a biallelic mutation in the SMN1 gene and no more than 3 copies of the SMN2 gene. One of the main limitations for the use of the drug is a patient body weight of more than 21 kg, which makes its use impossible in adult patients.

Indications for the use of nusinersen** and risdiplam** are SMA of all types, without restriction on the type of disease, age of onset, or current age of the patient.

Comments: simultaneous use of two pathogenetic therapy drugs for SMA that affect SMN2 gene splicing (e.g., nusinersen** and risdiplam**) is not indicated. Considering the unified pathophysiological mechanisms of the course and relentless progression of SMA across its various types, the patient's current condition should not be considered a reason to refuse pathogenetic therapy. For the same reason, the use of the "rehabilitation potential" concept to determine the need for pathogenetic treatment in SMA is incorrect.

Comments: currently active clinical trials of nusinersen** (SHINE, ASCEND, and DEVOTE) include patients over 18 years of age, but their results have not yet been published. Nevertheless, results from observational [75–80] and retrospective [81–83] studies evaluating tolerability, changes in SMA clinical scales in adult patients, respiratory function parameters, muscle strength, and patient-reported outcomes have been published. Combined data from over 1,200 SMA patients analyzed in these studies indicate sufficient safety of nusinersen** in adult SMA patients, as well as improvement or stabilization of patients' scores on clinical scales across various age groups. A systematic review and meta-analysis of nusinersen** treatment results, including 15 publications on adults, confirmed with a high degree of certainty the efficacy of nusinersen** in patients with type 2 and 3 SMA according to the HFMSE, RULM, and 6MWT motor function scales when administered for 10–14 months [84].

Intrathecal administration of nusinersen** may be accompanied by adverse events associated with the lumbar puncture procedure: fever, headache, back pain, nausea, vomiting [52, 75-83].

Thrombocytopenia, blood coagulation disorders, and nephrotoxicity have been described with subcutaneous or intravenous administration of certain antisense oligonucleotides, which is reflected in the product information for nusinersen**. If clinically indicated, laboratory tests for platelet count and blood coagulation parameters must be performed prior to drug administration [52].

Comments: an algorithm for performing intrathecal administration under imaging guidance is proposed. In the absence of metal implants or spinal fusion of the posterior bony elements of the spine, lumbar puncture is performed under fluoroscopic control. In the presence of spinal fusion, selecting the optimal technique for the manipulation (interspinous or neuroforaminal approach) should be based on pre-procedure CT results. If lumbar puncture at the C1-C2 level is considered, magnetic resonance imaging of the spine (one region) is indicated prior to the procedure.

Comments: the neurosurgeon determines the feasibility of performing a lumbar puncture, the puncture level, and the technique for its execution in order to administer pathogenetic therapy, based on physical examination and the results of pre-procedure studies (CT, MRI, X-ray).

Comments: in patients with severe spinal deformity, lumbar punctures and intrathecal drug administrations may be performed under anesthesia.

Comments: Study BP39055 (SUNFISH) evaluated the use of risdiplam** in patients matching the clinical manifestations of type 2 and 3 SMA, aged 2 to 25 years at screening. This study included patients with severe spinal deformities, pronounced widespread joint contractures, and those who underwent prior surgical treatment for spinal deformities. The results of this study demonstrated statistically significant efficacy for the primary endpoint and an acceptable safety profile in this age group. The study showed statistically significant clinical improvements over 12 months of therapy according to the MFM-32 and RULM scales [88]. According to pharmacokinetic studies, body weight and age may influence the pharmacokinetics of risdiplam**; however, no changes in the safety and efficacy profile of the drug were identified [89].

The most frequent adverse reactions associated with risdiplam** use may include diarrhea and skin rash, which resolve spontaneously [53].

Comments: Clinical data on the use of risdiplam** in pregnant women are lacking. Studies of risdiplam** in animals have shown embryo-fetal toxicity as well as reversible effects on male fertility. For this reason, male patients should not donate sperm during treatment and for 4 months following the administration of the last dose of risdiplam** [53]. A viable option is sperm cryopreservation for male patients with SMA prior to initiating risdiplam** treatment.

Data on the excretion of risdiplam** into human breast milk are lacking. Studies in rats have shown that risdiplam** passes into milk; therefore, breastfeeding should be discontinued during maternal treatment with risdiplam** [88].

3.1.2. Symptomatic pharmacotherapy

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

Comments: Patients with hypersalivation are also indicated for oral cavity sanitization [91]. Botulinum toxin type A** injections into the salivary glands must be performed under ultrasound guidance of the salivary glands.

3.2 Surgical Treatment

Surgical treatment for patients with SMA is represented predominantly by corrective instrumented spinal interventions, which nevertheless have a palliative character and do not halt progressive deformity. Additionally, surgical interventions in SMA may be performed due to pain syndrome resulting from musculoskeletal pathology and potential fractures. Most commonly, adult patients with SMA (predominantly those with type 2 SMA) undergo surgical correction of spinal deformities before reaching 18 years of age.

Comments: When deciding on surgical intervention, it is recommended to take into account respiratory function decline, rib deformity, hyperkyphosis, impact on patient mobility and functioning, pelvic tilt, and trunk imbalance.

Comments: When choosing conservative treatment with casting (application of a circular plaster cast, removal of a circular plaster cast), prolonged immobilization (more than 4 weeks) should be avoided, as this may exacerbate muscle atrophy and osteoporosis.

Comments: A gastrostomy is placed most frequently for supplemental nutrition rather than for a complete transition to tube feeding. An analysis of 122 type 2 SMA patients aged 1 to 47 years revealed that 25% (30 individuals) had swallowing disorders, with choking episodes being noted more frequently specifically in adult patients (older than 20 years). Only 1 out of 48 adult patients had a gastrostomy, yet he continued to consume part of his food orally [93]. In older patients, prior to gastrostomy placement, it is recommended to determine FVC, which should be at least 50% of the predicted value; in the case of lower FVC, the risk of complications increases as spirometric parameters decline.

If necessary, specialist consultations are possible (anesthesiologist-resuscitator, primary surgeon, clinical nutritionist, general practitioner, endoscopist); laboratory tests are performed (determination of main blood groups by ABO system, determination of Rh factor [D antigen], determination of subgroup and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy, determination of hepatitis B virus surface antigen [HBsAg] in blood, determination of antibodies to hepatitis C virus in blood, determination of human immunodeficiency virus HIV-1 IgM and IgG antibodies in blood, determination of antibodies to Treponema pallidum in blood, coagulogram [provisional assessment of hemostasis], complete blood count, general clinical blood chemistry, urinalysis, blood gas and acid-base balance analysis); and instrumental diagnostic methods (esophagogastroduodenoscopy, echocardiography, ultrasound duplex scanning of upper extremity arteries and veins, ultrasound duplex scanning of lower extremity arteries and veins, complex ultrasound of abdominal organs, electrocardiogram recording, targeted chest X-ray, X-ray control of contrast agent passage through the stomach, small intestine and colon, forced spirometry [unprovoked respiratory volumes and flows], ultrasound detection of fluid in the abdominal cavity, targeted chest X-ray).

After the wound has healed, it is necessary to train the patient and caregivers in self-care for the gastrostomy [94]. Thorough care of the gastrostomy tube correlates with a reduction in the risk of delayed complications and determines its longevity [94]. The gastrostomy tube must be replaced every 6–18 months or as needed according to the manufacturer's instructions. Specialist monitoring is required to timely determine the indications for replacing or removing the gastrostomy tube (consultations with a surgeon, anesthesiologist-resuscitator, neurologist, general practitioner, palliative care physician). If necessary, the following tests may be performed: coagulogram [provisional assessment of hemostasis], complete blood count, general clinical blood chemistry, urinalysis, electrocardiogram recording.

Following gastrostomy, an individualized nutrition plan using specialized nutritional formulas is selected by a gastroenterologist and a clinical nutritionist [94].

Comments: if necessary, specialist consultations are available: clinical nutritionist, neurologist, otorhinolaryngologist, general practitioner, palliative care physician, medical psychologist. If necessary, laboratory tests may be performed (complete blood count, general clinical blood chemistry, urinalysis, blood gas and acid-base balance analysis), along with instrumental investigations (videolaryngoscopy, pharyngoscopy, targeted chest X-ray, contrast esophagoscopy, pulse oximetry, cardiorespiratory monitoring).

After nasogastric tube placement, it is necessary to instruct the patient and caregivers on home care and feeding rules. Upon expiration of the service life or in case of tube obstruction, replacement is required. If tube feeding is needed for more than 4 weeks, consider gastrostomy placement (see above) [94].

Comments: in adult SMA patients, non-invasive ventilation (NIV) is the preferred management strategy for respiratory disorders. The need for tracheostomy in adult SMA patients arises extremely rarely. Most commonly, this option is considered in severely debilitated type 2 SMA patients. The decision to transition to a tracheostomy should be made taking into account the patient's and family's preferences, clinical status, prognosis, and future quality of life.

Before tracheostomy placement, specialist consultations are required: anesthesiologist-resuscitator, surgeon, neurologist, otorhinolaryngologist, general practitioner, pulmonologist, thoracic surgeon, palliative care physician, and involvement of other specialists as needed. Required range of laboratory tests before surgical intervention: determination of hepatitis B virus surface antigen (HBsAg) in blood, determination of antibodies to hepatitis C virus in blood, determination of human immunodeficiency virus HIV-1 IgM and IgG antibodies in blood, determination of antibodies to Treponema pallidum in blood, coagulogram (provisional assessment of hemostasis), complete blood count, general clinical blood chemistry, blood gas and acid-base balance analysis. Potential required instrumental investigations: transcutaneous partial pressure of oxygen monitoring, targeted chest X-ray, capnography, capnometry, forced spirometry (unprovoked respiratory volumes and flows), pulse oximetry, cardiorespiratory monitoring.

After tracheostomy placement, it is necessary to train the patient and caregivers in care procedures. Regular specialist monitoring is required for the timely replacement of the tracheostomy tube. The tracheostomy tube must be replaced every 2–4 weeks depending on the manufacturer's material.

Long-term non-invasive ventilation (NIV) or mechanical ventilation (MV) requires monitoring by the following specialists: initial consultation (examination, evaluation) by an anesthesiologist-resuscitologist, initial consultation (examination, evaluation) by a gastroenterologist, initial consultation (examination, evaluation) by a dietitian, initial consultation (examination, evaluation) by a cardiologist, consultation (examination, evaluation) by a physical therapy physician, initial consultation (examination, evaluation) by a neurologist, initial consultation (examination, evaluation) by an otorhinolaryngologist, initial consultation (examination, evaluation) by a general practitioner/internist, initial consultation (examination, evaluation) by a pulmonologist, initial consultation (examination, evaluation) by a trauma surgeon/orthopedist, consultation (examination, evaluation) by a physiotherapist, initial consultation (examination, evaluation) by a palliative care physician, initial consultation (testing, evaluation) by a medical psychologist. If necessary, the following laboratory tests may be performed: determination of blood 25-OH vitamin D levels, detection of ketone bodies in urine, microbiological (culture) sputum test for aerobic and facultative anaerobic microorganisms, microbiological (culture) test of tonsil and posterior pharyngeal wall mucus for aerobic and facultative anaerobic microorganisms, complete blood count (CBC), general clinical biochemical blood test, routine urinalysis, evaluation of acid-base balance and blood gases. If necessary, the following instrumental examinations may be performed: tracheoscopy, echocardiography, comprehensive abdominal ultrasound, kidney ultrasound, electrocardiography, transcutaneous monitoring of partial oxygen pressure, cervical spine radiography, thoracolumbar spine radiography, pelvic radiography, X-ray densitometry, lumbar spine X-ray densitometry, hip joint radiography, targeted chest radiography, capnometry, pulse oximetry, continuous bedside monitoring of vital functions and parameters, cardiorespiratory monitoring. If necessary, the following treatment methods may be applied: gastrostomy, nasointestinal tube placement, nasogastric tube placement, medical speech therapy procedure using interactive information technologies, macroenvironment adaptation procedures, suction of mucus from the upper respiratory tract, tracheostomy tube replacement, artificial lung ventilation, therapeutic physical training for joint diseases and injuries, therapeutic physical training for peripheral nervous system diseases, therapeutic exercise using suspension systems, general medical massage, medical facial massage, medical neck massage, medical upper extremity massage, medical lower extremity massage, medical back massage, therapeutic physical training for upper respiratory tract diseases, medical chest massage, medical rehabilitation services for patients with neuro-orthopedic pathology using medical taping methods, development of an individual speech therapy rehabilitation program.

3.3 Other Treatment

3.3.1. Diet therapy

Comment: consultations should be carried out annually.

Comments: when compiling a diet for patients with SMA, the need for calories (using the calculation of resting energy expenditure corrected for the activity level), macro- and micronutrients, and fluids is evaluated. General standardized formulas are used to calculate nutrition [95].

Comments: patients with SMA may develop metabolic disorders (during fasting, prolonged intervals between meals, or in emergency conditions), such as metabolic acidosis, fatty acid oxidation disorders, hyperlipidemia, hyper- or hypoglycemia, and muscle mitochondrial dysfunction.

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

Comments: modern enteral nutrition formulas have a balanced composition of core nutrients. Enteral nutrition formulas are selected individually based on patient needs.

Comments: a comprehensive approach is used to manage constipation, including dietary therapy, and when necessary, medical therapy and mechanical bowel evacuation. In the presence of hard stools, oral osmotic laxatives are prescribed: lactulose** or macrogol** preparations. Dosage titration is performed individually until a clinical effect is achieved. Treatment duration ranges from short courses to continuous administration.

3.3.2. Respiratory support

Assessment and support of respiratory function must be given the highest priority in the management of patients with SMA. Recently, the treatment paradigm for pulmonary manifestations in SMA has shifted from a reactive approach—where airway clearance and ventilation measures are initiated only when clear indications arise—to a proactive (preventive) approach introducing these therapies at earlier stages of the disease. The treatment plan is determined by a respiratory therapist, which may include specialists in various fields: anesthesiologists-intensivists, pulmonologists, neurologists, and palliative care physicians specialized in neuromuscular disorders.

The key respiratory-related issues in SMA patients include impaired coughing leading to inadequate lower airway clearance, sleep-related hypoventilation, chest and lung hypoplasia (primarily seen in adults with type 2 SMA), and recurrent infections that exacerbate muscle weakness. The main approaches to addressing these challenges are airway clearance and non-invasive positive pressure ventilation (NIV). The fundamental principles of airway clearance must be followed.

1. Manual and mechanical cough assist devices are essential 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 physical therapy methods (drainage massage).

3. Oximetry data serve as an indicator of therapeutic efficacy. Suction devices can be useful for removing secretions after cough assistance has been provided.

Comments: patients must be provided with appropriate equipment. Electric suctioning and the use of an insufflator-exsufflator should be performed in any patient with an ineffective cough. The main sputum drainage methods for bedridden and seated patients involve a combination of several techniques: a mechanical insufflator-exsufflator (cough assist) and manual chest compressions or postural drainage combined with an electric suction device. A relative contraindication to the use of an insufflator-exsufflator is chronic lung disease (e.g., emphysema). The use of an insufflator-exsufflator in such situations must be weighed against the potential risks of pneumothorax.

Other methods for preventing hypoventilation (postural drainage and percussive massage — see Section 4.1.1. Rehabilitation).

Comments: the decision to initiate NIV is made on an individual basis for each specific case. It is required in the presence of daytime hypercapnia. Nocturnal NIV reduces sleep-related breathing disorders and improves quality of life. NIV must be combined with airway clearance techniques. Individual mask fitting for NIV should be performed. The fitting is based on patient examination, allowing for the selection from several mask types and sizes taking into account facial anatomical features. It is necessary to have and alternate between two different masks simultaneously to reduce the risk of pressure ulcers and facial skeletal deformation. The titration of NIV parameters should be guided by gas exchange monitoring (nocturnal pulse oximetry, capnometry, capnography, or acid-base and blood gas analysis), taking into account respiratory muscle workload and patient subjective comfort.

Comments: patients and their caregivers must be provided with medical equipment, including an Ambu-type manual resuscitator, an electric suction pump with a rechargeable battery if needed, and a medical device for respiratory therapy (BiPAP device) for home respiratory monitoring. Patients and caregivers must be trained in the use of the listed equipment.

Comments: if NIV becomes necessary in acute situations, the availability of home NIV equipment should be evaluated. The administration of pure oxygen inhalation without additional ventilatory support (e.g., NIV) is not indicated in SMA, as it may lead to worsening acidosis.

If necessary, consultations with specialists are available: anesthesiologist-intensivist, neurologist, otolaryngologist, general practitioner, pulmonologist, dentist, maxillofacial surgeon, palliative care physician, and medical psychologist. If necessary, continuous bedside monitoring of vital functions and parameters can be performed [66].

3.3.3. Palliative medical care

Palliative care is a comprehensive approach that includes medical interventions, psychological support, and nursing care aimed at improving the quality of life of incurable patients and directed at relieving pain and other severe disease manifestations. The goal of palliative care is to improve the quality of life for patients and their families facing a 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 [96]. The primary objective of palliative care is to support, preserve, and enhance the patient's quality of life as much as possible. However, defining what "quality of life" means can only be done by the patient themselves [97]. It is important not to contrast active (interventional) treatment with palliative care, but rather to have them complement each other.

When managing patients with spinal muscular atrophy, it is essential to fully inform them about the range of therapeutic options and properly discuss that choosing palliative or interventional supportive care is not merely a binary choice (choosing one over the other). However, to date, a general consensus regarding standards of palliative care for SMA has not been reached, which is reflected in a number of guideline documents for the management of patients with this disease [29].

Comments: Palliative medical 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. When providing palliative care, the patient is provided with medical devices for home use intended to support the functions of the human body's organs and systems.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

It is now proven that regular physical therapy and rehabilitation of patients can alter the natural course of SMA, increasing the life expectancy and quality of life of patients, as well as improving their functional status. The implementation of this concept is only possible in a goal-oriented rehabilitation format.

Rehabilitation of patients with SMA has the following goals: increasing patient mobility, slowing the progression of muscle atrophy, and preventing the development of secondary orthopedic complications.

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

- preventing the formation of habitual faulty limb and segment positioning and, consequently, the more rapid progression of contractures;

- slowing down the process of disuse muscle atrophy;

- preventing degenerative shortening of muscle fibers;

- prolonging the functional activity of patients;

- preventing the development of limb joint contractures;

- increasing patient mobility (maintaining/increasing the range and amplitude of motion);

- ensuring more physiological functioning of internal organs and systems.

Medical rehabilitation services for a patient with peripheral nervous system disorders in SMA include the use of physical rehabilitation tools and methods (therapeutic gymnastics, massage, physiotherapy, mechanotherapy including robotic therapy, exercise equipment training, hydrokinetotherapy), orthotics, surgical correction if necessary, early use of assistive rehabilitation devices, speech therapy, and occupational therapy.

When conducting rehabilitation measures, it is necessary to:

- try to integrate physical therapy and regular exercise into the patient's daily routine and form a lifestyle based on them;

- take into account that the dominant symptom in SMA patients is fatigue and increased exhaustion, distributing physical exertion throughout the day in frequent but short periods;

- set rehabilitation goals for the next few months ahead, taking into account the patient's current musculoskeletal status and projected deteriorations;

- engage all skeletal muscles in the patient's daily life whenever possible.

Some rehabilitation recommendations are general in nature and should be applied to all patients with SMA. Medical rehabilitation measures are carried out depending on the patient's functional status (rather than the clinical type of SMA):

- unable to sit (late non-ambulatory stage) (Rehabilitation Status Scale 5-6);

- able to sit (early non-ambulatory stage) (Rehabilitation Status Scale 3-4);

- able to walk (ambulatory stage) (Rehabilitation Status Scale 2).

Such functional classification makes it possible to specify rehabilitation tasks for each patient, taking into account their capabilities (see sections 4.1, 4.2, and 4.3 below), as well as to organize the necessary specialized care for the patient, and prepare specialists, equipment, and facilities for medical rehabilitation measures.

Comments: for bedridden patients, rehabilitation exercise equipment can be used (e.g., stationary bikes); for sitting patients, a set of rehabilitation products for musculoskeletal disorders and other rehabilitation equipment can be used; for ambulatory patients, all of the above, as well as a standard mechanical or motorized treadmill.

Stretching exercises accompanied by light massage (warming effect) may be performed [19]. The minimum frequency of sessions for stretching and increasing range of motion for bedridden patients is 3–5 times a week, and for sitting patients, 5–7 times a week. The duration of sessions for effective stretching and range of motion increase depends on the patient's specific needs, joint condition, and rehabilitation goals.

Comments: Swimming classes are beneficial and enjoyable for patients with SMA. Water neutralizes the effect of gravity on the body, which alters the perception of one's own body. In addition, swimming is a good option for aerobic exercise. This rehabilitation method has no absolute contraindications in SMA. The water temperature in the pool should be 30°–33°C (optimal temperature range for the best muscle metabolism). The first few sessions must be held with an instructor who will teach the patient and, if necessary, their caregiver. Before each session, the patient's somatic status must be assessed.

Comments: the specific feature of applying a circular plaster cast in SMA patients is casting in short courses (for 5 days with 2 days off).

Patients with SMA need to undergo a medical speech therapy procedure for dysphagia in adults, a medical speech therapy procedure using interactive information technologies (used in classes to improve articulation and correct speech disorders, can be used during articulation gymnastics) – including as alternative methods when integrated with the medical speech therapy procedure for dysphagia (as an effect on a single anatomical and physiological substrate) for the purpose of training chewing and swallowing muscles, preserving/improving chewing and swallowing functions, preventing/prophylaxis of jaw contractures, and training bite strength. This procedure will be useful for patients of all clinical types of SMA (speech therapy massage techniques; exercises that help engage and train chewing and swallowing muscles, including techniques using speech therapy probes; including training caregivers in postural techniques that facilitate swallowing).

Comments: for SMA patients, bulbar dysfunctions are characteristic; they share a common origin but develop through two main mechanisms—mechanical and oropharyngeal. Thus, according to numerous observations, SMA patients of all clinical types I–III (to a greater or lesser extent, respectively) exhibit: a reduced ability to open the mouth and the development of jaw rigidity (decreased capacity for wide/sufficient opening of the oral cavity provided by lower jaw movement), difficulties in moving the food bolus within the oral cavity, chewing difficulties and rapid fatigue of the masticatory muscles, poor voice production quality during speech, and swallowing problems [101, 102]. Thus, the three aforementioned recommendations, combined by this comment, when introduced early into the individual rehabilitation program, can help counteract the listed changes or improve baseline indicators and the patients' quality of life (e.g., achieving the ability to eat more comfortably by mouth) in the presence of already existing deviations (both when choosing specific methods and, more importantly, when combining them in the patient's individual rehabilitation program). It is also possible to supplement these methods with physical therapy modalities (myostimulation—muscle electrical stimulation, multifunctional muscle electrical stimulation) and taping (see above).

Comments: from the perspective of the rehabilitation approach for patients with SMA, massage probably should not induce a catabolic effect on the muscles (therefore, excessive force is not implied, but rather a reasonable one that combines an impact on the muscle where fatigue does not occur, yet the necessary muscle "engagement" and "work" are achieved, which is monitored by the physical and rehabilitation medicine physician). Massage is capable of providing both stimulating and relaxing effects on muscles (and therefore can be used for opposite tasks, for example, depending on the structuring of rehabilitation procedures throughout the day, or if necessary, to provide an analgesic/relaxing effect after intensive physical therapy/therapeutic exercise, etc.). Massage helps improve blood supply and nutrition of the muscular system, warms up muscles, stretches muscle fibers, and stimulates proprioceptors of the muscle field (segmental innervation). In the general alliance of modalities, massage, along with physical therapy/therapeutic exercise, helps achieve the goals and objectives of patient rehabilitation. One of the important tasks of using massage in patients with SMA (a shared task with physical therapy/therapeutic exercise methods) is to help the patient learn to use their muscles, learn to feel the work of specific muscles/muscle groups in a certain motor act, and learn to "engage" in work precisely those muscles that are necessary to perform a specific motor act (this becomes particularly relevant and significant in patients undergoing therapy, when positive changes in the muscles are visible, and it becomes possible and necessary for the patient to master new motor skills, which, of course, correlates with (is limited by) the severity of the neuroorthopedic syndrome).

4.1. Rehabilitation of non-sitting patients.

The main position for these patients at home is the "lying" position, which is dangerous due to the formation of habitual incorrect postures of the limbs and their segments caused by the action of gravity on the limbs and the patient's lack of ability to perform antigravity movements, as well as the development of corresponding complications. For this reason, for preventive purposes, frequent changes of body position in bed are recommended, along with the use of improvised means that can easily change their shape and take the weight of the limb upon themselves, thereby simulating an antigravity effect.

Goals of rehabilitation for non-sitting patients:

-       increasing the volume and range of active and passive movements in any segment of the body and limbs;

-       improving the degree of head movement control in the supine position;

-       improving arm movements;

-       creating conditions for the normal functioning of internal organs;

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

-       mobilization of joints and prevention of contracture formation.

4.1.1. Massage for non-sitting SMA patients.

Comments: percussion and vibration chest massage are performed.

4.1.2 Assistive technologies and rehabilitation devices (ATRD) for non-sitting patients.

To achieve the set rehabilitation goals, strict adherence to the principles of postural management is used, which includes proper positioning and orthotization of the trunk and limbs.

Comments: verticalization of the patient in a standing frame is recommended for a total of at least 1 hour a day, depending on the patient's capabilities.

Comments: standing frames must have a functional headrest that provides lateral and anteroposterior head stabilization without restricting head movement; trunk fixators 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 an attached tray. An important feature for bedridden patients is the possibility of verticalization in a standing frame in the "abducted hips" position (an additional function in standing frames).

Comments: orthoses are assistive devices used to modify the structural and functional characteristics of the neuromuscular and skeletal systems and provide, according to medical indications, orthopedic correction, unloading, 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 bedridden patients is 5 times a week. Chest fixation is recommended for position stabilization, scoliosis prevention, and stimulation of functional activity. Neck fixation is often used to support the head to minimize the risk of asphyxia in the upright position, as the 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 outdoor models, as well as power wheelchairs with additional head and body fixation (support). These are custom-made using a volumetric 3D model of the posterior body surface, forming molded seating inserts mounted on a wheelchair chassis of the appropriate size and purpose. When selecting a wheelchair and functional chair, the specialist must consider the need for additional elements to maintain the recommended posture and include this in the product recommendations. It is essential to ensure maximum functional independence and comfort while sitting in the wheelchair.

Comments: seating supports or indoor wheelchairs with additional head and body fixation (support) are used for maintaining the sitting position. Additionally, the sitting position during the day is achieved by spending time in an outdoor wheelchair. Sitting in the assistive device must be performed while wearing ankle-foot orthoses. Spending time in the correct sitting position is indicated for a total of up to 6 hours per day.

Additional components of the seating device should include: a functional headrest (or head positioning using a Glisson's loop) that provides lateral and anteroposterior head stabilization without restricting head movement; a seat with adjustable depth, width, and tilt angle. The seat design is divided into pelvic and thigh sections, which allows for the most comprehensive resolution of the patient's balance and symmetry problems caused by secondary orthopedic complications. A backrest with adjustable height and tilt angle; a trunk support (vest), a safety pelvic belt, adjustable armrests; separate, adjustable footrests with foot fixations; a tray table; an anti-decubitus cushion.

4.2. Rehabilitation of sitting patients.

For sitting patients, it is important to adhere to both the principle of dosing physical exertion and the principle of integrating physical therapy into lifestyle.

One of the primary postures for such patients is the sitting position, which, due to the main symptom of the disease (skeletal muscle weakness), the inability to independently change body position, and postural control impairments, can form an asymmetrical sitting pattern with an uneven load distribution on the pelvic bones (right/left) with pelvic tilt and exacerbate the development of scoliotic spinal deformity. Therefore, special attention must be paid to the symmetrical development of the patient's physique and correct positioning.

Goals of rehabilitation for sitting patients:

- increasing patient mobility;

- slowing down the progression of muscle weakness, loss of function, and the formation of disuse atrophy;

-       improving arm movements;

-       creating conditions for the normal functioning of internal organs;

- mobilizing joints and preventing contracture formation;

- establishing and maintaining symmetrical posture;

- preventing scoliotic spinal deformity and pelvic tilt;

- training in daily living and self-care skills within the environment.

Particular importance in physical therapy is given to establishing symmetrical posture and minimizing differences in development and function between the right and left limbs.

Comments: such an orthopedic brace is designed specifically for patients with flaccid paralysis and lower limb muscle strength of less than 2 points. A feature of this orthosis is the ability to mechanically assist the patient's efforts by reciprocally moving the lower limbs in a symmetrical posture. Such a device allows the patient to stand upright and move with the support of a walker without outside assistance, provided there is sufficient arm strength. Axial loading on the skeleton prevents the development of osteoporosis and secondary bone and joint deformities. Standing should be encouraged. The supported standing position should last 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 to change position and bring patients into an upright stance. For verticalization, it is possible to use a power wheelchair with a standing function. Upright support devices are important for facilitating lower limb stretching, as well as for improving body functions and bone health, ensuring an upright posture, and improving the alignment of the spine and entire body.

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

Comments: when selecting wheelchairs, one should aim for maximum functional independence and comfort for the patient; preference should be given to active-type wheelchairs and power wheelchairs.

Comments: an occupational therapist must be involved both when selecting the exercise and stretching program and for recommendations regarding social interactions, such as attending educational institutions, choosing a profession, and participating in social activities.

4.3. Rehabilitation of ambulatory patients.

For ambulatory patients, the priority remains the principles of dosing physical exertion and integrating physical therapy into daily life.

Patients in this group strive for active movement and walking, but due to skeletal muscle weakness and reduced endurance, they frequently need to rest, during which they often adopt an incorrect "sitting" posture. In general, ambulatory SMA patients, compared to non-ambulatory patients, exhibit a milder course of secondary orthopedic complications (both the development of limb joint contractures and the formation of scoliotic spinal deformities). The rehabilitation goals for ambulatory patients are largely the same as those for non-ambulatory patients, with the addition of increasing endurance/exercise tolerance.

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

5. Prevention and Dispensary Observation

5.1 Prevention

Comments: contraindications to vaccination in adult SMA patients do not differ from those in other categories of citizens and are carried out in accordance with the National Schedule of Preventive Vaccinations. Vaccination is also necessary against COVID-19 caused by the SARS-CoV-2 coronavirus.

Comments: prenatal DNA diagnostics (molecular genetic testing for SMN1 gene mutations in the fetus, a comprehensive set of tests for diagnosing spinal muscular atrophy), and a comprehensive test for prenatal diagnosis of fetal developmental disorders (intrauterine) are possible at various stages of pregnancy: 8–12 weeks (chorionic villi), 15–18 weeks (amniotic fluid), 20–24 weeks (cord blood). Chorionic villus sampling (CVS) is optimal: in case of an unfavorable prognosis, the pregnancy can be terminated (artificial abortion) within the standard timeframe for a medical abortion.

5.2 Dispensary monitoring

Adult SMA patients need to undergo monitoring of the following laboratory parameters: complete blood count (every 12 months and before surgery), general clinical blood chemistry (every 12 months and before surgery), urinalysis (every 12 months and before surgery), as well as instrumental studies: electrocardiogram (every 12 months and before surgery), echocardiography (as needed), comprehensive ultrasound of the abdominal organs (as needed), and renal ultrasound (as needed) to assess basic hematopoietic parameters, the presence of inflammatory processes, and the functional state of internal organs [19].

Adult SMA patients also need to undergo monitoring of the following laboratory and instrumental studies: acid-base balance and blood gas analysis (as needed), targeted chest X-ray (every 24 months), computed tomography of the chest cavity (as needed), capnography (as needed), capnometry (as needed), pulmonary function testing of unforced respiratory volumes and flows (every 6–12 months and as needed), pulse oximetry (as needed), and cardiorespiratory monitoring (as needed) to assess the main parameters of respiratory function [29].

Adult SMA patients need to undergo spine X-ray (every 12 months), hand X-ray (as needed), pelvic X-ray (as needed), X-ray densitometry (every 12 months), and hip joint X-ray (as needed) to assess the state of the musculoskeletal system [19].

6. Organization of Medical Care

6.1 Indications for hospitalization

6.1.1 Indications for elective hospitalization in an adult neurology department

- adult SMA patients lacking access to comprehensive outpatient evaluation — for functional motor assessment, screening for disease complications (respiratory, osteoarticular, and gastrointestinal, as well as for rehabilitation);

- adult SMA patients for intrathecal administration of nusinersen**;

Comments: nusinersen** may be administered in a day hospital setting.

- adult SMA patients requiring evaluation prior to orthopedic surgery.

Indications for patient discharge after planned hospitalization in an adult neurology department:

- completion of the patient's evaluation plan, including assessment of respiratory disorders;

- delivery of rehabilitation measures;

- clarification of recommendations for further follow-up and treatment.

Indications for elective hospitalization in an adult surgery department:

- SMA patients requiring gastrostomy placement;

- SMA patients requiring tracheostomy placement.

Indications for elective hospitalization in an adult palliative care unit:

- severe pain syndrome refractory to outpatient treatment, including at home;

- severe manifestations requiring symptomatic treatment under medical supervision in an inpatient setting;

- selection of therapy regimens for continued home treatment;

- performance of medical interventions that cannot be carried out in an outpatient setting, including at home.

If an adult patient is diagnosed with a comorbid condition requiring surgical intervention, this must be performed on an elective basis with prior preparation and evaluation. The risks of elective surgery are much lower than the risks of emergency interventions.

6.1.2. Indications for emergency hospitalization:

- Development of "common" diseases in a patient with SMA (acute viral infection, bronchitis, gastroenteritis with dehydration, appendicitis, and other acute inflammatory processes), unforeseen fractures, planned surgical procedures (e.g., gastrostomy tube placement, hip osteotomy), but proceeding severely given the specifics of the disease.

Comments: 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 tasks should be addressed using non-invasive mechanical ventilation.

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

Comments: when following emergency care protocols, it is necessary to contact a multidisciplinary team (neurological and pulmonological), including a physician, usually 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 acid-base and blood gas analysis will help choose the correct ventilation mode.

Indications for scheduled hospitalization

6.2 Principles of organizing medical care for patients with SMA

The diagnosis of SMA raises many questions for the patient's relatives and specialists working with such patients. Numerous problems arise during the detection and progression of SMA, which require 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 provision.

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, specialized, and palliative medical care at all stages of the disease.

Upon diagnosis of SMA, the patient should be referred to a specialist experienced in working with SMA, possessing 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 patients and their families about existing public organizations working with this group of people, and about the palliative care service.

The observation of a patient with SMA must involve a multidisciplinary team of specialists consisting of: a neurologist, general practitioner/internist, geneticist, respiratory support specialist (pulmonologist and/or anesthesiologist-intensivist), cardiologist, trauma surgeon/orthopedist, surgeon, medical rehabilitation physician and physical therapist, nutritionist/dietitian, gastroenterologist, palliative care physician, as well as staff of medical organizations (and their subdivisions) providing specialized palliative medical care. Other specialists should be involved as specific problems arise.

Comments: the neurologist, as a specialist in neuromuscular diseases, performs the primary monitoring of patients with SMA. The neurologist's duties include examination and diagnosis, informing the family about the disease, drawing up a multidisciplinary monitoring plan, observing the patient, assessing the dynamics and degree of disease progression during regular examinations, and prescribing therapy. At the stage of specialized medical care, the neurologist participates in assessing the patient's functional state (assessment using neuromuscular impairment scales for SMA). When drawing up the multidisciplinary monitoring plan, the neurologist determines the frequency of follow-up by other specialists of the multidisciplinary team according to the patient's current state. At each examination, the neurologist re-evaluates the patient's current state and accordingly makes adjustments to the multidisciplinary monitoring plan. In their recommendations, the neurologist indicates the technical rehabilitation means, medical equipment, orthopedic correction devices, medicinal products, medical devices, etc. needed by the patient in accordance with the identified patient needs and recommendations of core specialists.

It is necessary to follow 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 means, medical equipment, and other therapy methods.

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Inga V. Anisimova, Geneticist, Head of the Department of Medical Care Organization at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, PhD in Medical Sciences

Svetlana B. Artemyeva, Neurologist, Head of the Pediatric Psychoneurology Department-2 of the Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University (RNIMU) of the Russian Ministry of Health, PhD in Medical Sciences

Elena D. Belousova, Neurologist, Head of the Department of Psychoneurology and Epileptology of the Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University (RNIMU) of the Russian Ministry of Health, Professor, MD

Grigory B. Volsky, Trauma Surgeon and Orthopedic Surgeon, Tyumen Regional Children's Rehabilitation Center "Nadezhda", Tyumen

Dmitry V. Vlodavets, Neurologist, Leading Researcher at the Department of Psychoneurology and Epileptology of the Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University (RNIMU) of the Russian Ministry of Health, Associate Professor at the Department of Neurology, Neurosurgery and Medical Genetics named after Academician L.O. Badalyan of the Pediatric Faculty at the Pirogov Russian National Research Medical University of the Russian Ministry of Health, President of the Association of Pediatric Neurologists in the Field of Myology "NEOMIO", PhD in Medical Sciences

Olga Yu. Germanenko, Founder and Director of the "Families of SMA" Charitable Foundation for Patients with Spinal Muscular Atrophy and Other Neuromuscular Diseases

Valentina I. Guzeva, Neurologist, Head of the Department of Neurology, Neurosurgery and Medical Genetics at the Saint Petersburg State Pediatric Medical University, Corresponding Member of the Russian Academy of Natural Sciences, Chief freelance pediatric specialist neurologist of the Russian Ministry of Health, Professor, MD

Victoria V. Zabnenkova, Laboratory Geneticist, PhD in Medical Sciences, Senior Researcher at the DNA Diagnostics Laboratory of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, PhD in Biological Sciences

Galina E. Ivanova, Chairperson of the All-Russian Public Organization for Assistance to the Development of Medical Rehabilitology "Union of Rehabilitologists of Russia", Chief Specialist in Medical Rehabilitation of the Ministry of Health of the Russian Federation, FMBA of Russia, Head of the Department of Medical Rehabilitation of the Faculty of Additional Professional Education at the Pirogov Russian National Research Medical University, Head of the Scientific Research Center for Medical Rehabilitation at the Federal Center for Brain Research and Neurotechnologies of the FMBA of Russia, MD, Professor

Sergey N. Illarioshkin, Neurologist, MD, Prof., Academician of the Russian Academy of Sciences, Director of the Institute of Brain at the Research Center of Neurology, Deputy Director for Science at the Research Center of Neurology

Vladimir M. Kenis, Deputy Director of the Turner Scientific and Research Institute for Children's Orthopedics of the Russian Ministry of Health, St. Petersburg, Head of the Department of Foot Pathology, Neuroorthopedics and Systemic Diseases, MD, Member of the European Paediatric Orthopaedic Society (EPOS) and the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM)

Sergey A. Klyushnikov, Neurologist, PhD in Medical Sciences, Leading Researcher at the 5th Neurological Department with a Molecular Genetic Laboratory of the Institute of Clinical and Preventive Neurology at the Research Center of Neurology

Sergey V. Kolesov, Head of the Spinal Pathology Department at the Priorov National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health, Moscow, MD, Professor

Oksana N. Komarova, Pediatrician, Gastroenterologist, Nutritionist, Senior Researcher at the Gastroenterology Department of the Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University (RNIMU) of the Russian Ministry of Health, PhD in Medical Sciences

Sergey A. Kurbatov, PhD in Medical Sciences, Highest-category Geneticist, Neurologist, Geneticist, Functional Diagnostics Physician at "Zdravy Rebenok" LLC (Voronezh), Senior Researcher at the Research Institute of Experimental Biology and Medicine, Voronezh State Medical University named after N.N. Burdenko; Chief Medical Advisor for Rare Diseases at Semantic Hub LLC, Moscow

Sergey I. Kutsev, Academician of the Russian Academy of Sciences, Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Chief Freelance Specialist in Medical Genetics of the Russian Ministry of Health, President of the Association of Medical Geneticists of Russia, MD

Diana V. Nevzorova, Chairperson of the Board of the Non-Profit Organization "Association of Professional Participants in Hospice Care", Director of the Federal Scientific and Practical Center for Palliative Medical Care at the Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), PhD in Medical Sciences

Sergey S. Nikitin, Chairperson of the Regional Public Organization "Society of Specialists in Neuromuscular Diseases", Head of the Department of Genetics of Nervous Diseases at the Research Centre for Medical Genetics, MD, Professor

Aleksandr V. Polyakov, Head of the DNA Diagnostics Laboratory at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Corresponding Member of the Russian Academy of Sciences, Doctor of Biological Sciences, Professor

Dmitry I. Rudenko, Deputy Chief Physician of the City Multidisciplinary Hospital No. 2 of St. Petersburg, Pavlov First Saint Petersburg State Medical University, MD, Professor

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

Natalia A. Suponeva, Neurologist, Functional Diagnostics Physician, MD, Prof., Corresponding Member of the Russian Academy of Sciences, Director of the Institute of Neurorehabilitation and Restorative Technologies at the Research Center of Neurology

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

Yulia A. Shpilyukova, Neurologist, PhD in Medical Sciences, Researcher at the 5th Neurological Department with a Molecular Genetic Laboratory of the Institute of Clinical and Preventive Neurology at the Research Center of Neurology

Vasily A. Shtabnitsky, Pulmonologist, Associate Professor at the Department of Pulmonology of the Faculty of Additional Professional Education at the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Expert at the "Live Now" Charitable Foundation, PhD in Medical Sciences

Irina P. Yastrebtseva, Neurologist, Physical and Rehabilitation Medicine Physician, Assoc. Prof., Professor at the Department of Neurology and Neurosurgery of the Ivanovo State Medical Academy of the Russian Ministry of Health, MD

Conflict of interest:

Svetlana B. Artemyeva

Educational grants and lecture fees from Janssen, Roche, PTC regarding neuromuscular diseases. Conflict of interest disclosure: has no financial interests in the mentioned companies, did not participate in writing the section "Pathogenetic Therapy".

Elena D. Belousova

Lecture fee from Janssen. Conflict of interest disclosure: the lecture discussed only issues related to SMA diagnostics.

Dmitry V. Vlodavets

Principal investigator in international clinical trials sponsored by PTC Therapeutics, F. Hoffmann-La Roche, Novartis, Biogen, NS Pharma, Sarepta Therapeutics, Pfizer, AveXis; lecture fees from PTC Therapeutics, F. Hoffmann-La Roche, Janssen, Novartis, Pik-Farma. Conflict of interest disclosure: has no financial interests in the mentioned companies, did not participate in writing the section "Pathogenetic Therapy".

Olga Yu. Germanenko

Lecture fees and travel expense compensation for participation in advisory boards from Biogen, Novartis Gene Therapies, Novartis, Roche. Conflict of interest disclosure: has no financial interests in the mentioned companies; lectures and advisory boards discussed patient journey pathways for spinal muscular atrophy. Did not participate in writing the section "Pathogenetic Therapy".

Sergey N. Illarioshkin

Lecture fees from Roche-Moscow and Janssen. Conflict of interest disclosure: the lecture discussed only pathophysiology and diagnostics of SMA; has no financial interests in the mentioned companies.

Sergey A. Kurbatov

Honoraria from Janssen for lectures. Conflict of interest management: the lecture discussed only the pathophysiology and diagnosis of SMA.

Klyushnikov Sergey Anatolyevich

Honoraria from Janssen for lectures. Conflict of interest management: the lecture discussed only the pathophysiology of SMA and the procedure of lumbar puncture; no financial interests in the mentioned company.

Suponeva Natalia Aleksandrovna

Honoraria from Roche-Moscow and Janssen for lectures. Conflict of interest management: the lecture discussed only physical rehabilitation in SMA; no financial interests in the mentioned companies.

Shpilyukova Yulia Aleksandrovna

Honoraria from Roche-Moscow and Janssen for lectures. Conflict of interest management: no financial interests in the mentioned companies.

Shtabnitskiy Vasily Andreevich

Honorarium from Janssen for a lecture. Conflict of interest management: the lecture discussed only respiratory support in SMA.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Neurologists, orthopedic traumatologists, neurosurgeons, anesthesiologists-resuscitators, gastroenterologists, dietitians, pulmonologists, cardiologists, exercise therapy doctors, physical and rehabilitation medicine doctors, endocrinologists, general practitioners.

2. Medical students, residents, post-graduate students.

Methods used for evidence collection/selection: searching electronic databases.

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 according to the rating scheme (scheme 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 grade of recommendations. To minimize potential errors, each study was evaluated independently. Any discrepancies in evaluations were discussed by the full author group. If consensus could not be reached, an independent expert was involved.

In these clinical guidelines, all information is ranked by the level of evidence (LE) depending on the quantity and quality of studies on the given topic (Table 2 and Table 3).

Table 2

Scale for assessing the level of evidence for diagnostic interventions*.

Table 3

Scale for determining the level of evidence for therapeutic, rehabilitative, and preventive interventions*.

Next, the grade of recommendation (GR) was determined — Table 4

Table 4

Scale for determining the grade of recommendations for diagnostic, therapeutic, and preventive measures.*

* Materials for developing clinical guidelines https://rosmedex.ru/kr/reco

Procedure for updating clinical guidelines.

The mechanism for updating the 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 regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to the 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 (as amended on September 24, 2020, with rev. dated October 26, 2022) "On Approval of the Nomenclature of Medical Services";

2. Order of the Russian Ministry of Health No. 700n dated October 7, 2015 (as amended on December 9, 2019) "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education";

3. Order of the Russian Ministry of Health No. 926n dated November 15, 2012 "On Approval of the Procedure for Providing Medical Care to the Adult Population for Nervous System Diseases";

4. Instructions for use of the medicinal product nusinersen**, available on the State Register of Medicines web portal at the link:

https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=1122c0fa-2d51-462b-b3b9-f3482f3aa446&t=

5. Instructions for use of the medicinal product risdiplam**, available on the State Register of Medicines web portal at the link:

https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=997acb67-4bc6-48f0-b173-886c29314b5a&t=

Appendix B. Physician Action Algorithms

SMA Diagnosis Algorithm

Algorithm for orthopedic diagnosis and treatment tactics for scoliosis in an adult patient with SMA

Algorithm for respiratory support in a patient with SMA

Appendix C. Patient Information

What is spinal muscular atrophy?

Spinal muscular atrophy (hereinafter referred to as SMA) is a genetic neuromuscular disease that affects motor neurons and leads to progressive muscle weakness1. The disease is progressive in nature: weakness begins in the muscles of the limbs and trunk and, as the disease progresses, reaches the muscles responsible for swallowing and breathing.

The prevalence of all SMA types combined, according to currently published data, mostly ranges from 1 to 2 cases per 100,000 population2. Regardless of severity, all people with SMA gradually lose motor functions1.

SMA is usually subdivided into 4 main types8:

Genetic features of SMA

The cause of the disease is a defect in the SMN1 gene. Normally, the SMN1 gene produces a specific type of protein — SMN (survival motor neuron protein), which is responsible for the transmission of neuromuscular impulses necessary for muscle function.

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

In SMA, the SMN1 gene is absent or damaged, and therefore cannot produce the SMN protein. As a result, α-motor neurons undergo death1. The α-motor neurons of the spinal cord conduct impulses to the muscles and are responsible for their contraction. In SMA, this transmission is impaired, leading to muscle weakness and atrophy.

All SMA patients have at least one copy of a "backup gene" called SMN2. The structure of the SMN2 gene is similar to that of the SMN1 gene, but only a small portion of the SMN protein it produces (10–20%) is fully functional. This amount of SMN protein is insufficient to maintain motor neuron survival.

The role of the SMN2 gene

The number of SMN2 gene copies can vary. This parameter is used to determine the potential prognosis of disease progression — a higher number of SMN2 copies is associated with lower severity of SMA symptoms. However, this correlation is not absolute. 14-16

Since the disease can manifest across different age ranges and with a wide spectrum of symptoms, it is difficult to predict the severity based solely on the number of SMN2 copies. Specialists recommend taking into account not only the number of SMN2 copies, but also the patient's functional abilities.

Inducing the production of a larger amount of SMN protein from the SMN2 gene is the basis of disease-modifying therapies registered in Russia for the treatment of SMA.

How is spinal muscular atrophy inherited?

Spinal muscular atrophy is an autosomal recessive disease, meaning a person is at risk of developing the disease if they inherit one mutated SMN1 gene from each parent. If a person inherits only one defective SMN1 gene, they are considered a "carrier". Carriers have no symptoms of the disease.

If there is a family history of spinal muscular atrophy, your chances of being a carrier, as well as the risks for future offspring, will be higher than average. When making family planning decisions, it is recommended to seek genetic counseling.

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 (DNA) blood testing is performed. It shows whether the patient has a pathogenic variant in the SMN1 gene. In addition, the number of SMN2 gene copies must be determined.

Other diagnostic tests may also be prescribed, including additional genetic testing, electromyography, or a blood test to measure the activity of the enzyme creatine kinase. These tests cannot confirm an SMA diagnosis with high accuracy, but they allow for the exclusion of other similar diseases.

How does spinal muscular atrophy manifest?

Every SMA patient has individual impairments, and symptoms may vary depending on the age of onset and the severity of the disease. A universal manifestation is progressive muscle weakness and wasting. Muscles located closer to the center of the body (shoulders, hips, and pelvis) are affected first. Muscles involved in breathing and swallowing may also be affected; furthermore, in SMA, the function of other organs and body systems is impaired, which determines the systemic nature of the developing disorders.

SMA does not affect intelligence and cognitive abilities.

As a rule, the earlier the first signs of the disease appear, the more pronounced the symptoms are, the faster the disease progresses, and the greater the scope of medical and social assistance that may be needed.

Depending on the type of SMA, the age of disease onset, and functional status, the appearance and development of pathological symptoms proceed at different rates, but the main impairments characteristic of the disease can be identified.

Movement

● Mobility restriction: independent movements are minimal or completely absent (SMA1); leg movements are weakened or completely absent, arm movements are weakened, tremor may be observed (SMA2); difficulty with independent locomotion, inability to travel long distances, difficulty climbing stairs, need for assistive support devices to stand and walk (SMA3).

●         Pressure ulcers: risk increases with the patient's body weight and age.

●         High risk of contractures and other deformities, as well as scoliosis, joint arthrosis, osteoporosis, and fractures.

●         Chest deformity

●         Other movement disorders

Respiration

●         Weakness of the respiratory muscles and chest deformities lead to inadequate independent breathing and insufficient pulmonary ventilation.

●         Impairment of the cough reflex and airway clearance.

●         Swallowing disorders, risk of food and saliva aspiration, and, consequently, a high risk of airway obstruction, hypoxia, or asphyxia.

●         Respiratory illnesses cause a severe regression of respiratory function, with frequent infections increasing muscle weakness.

●         Breathing difficulties at night.

Nutrition

●         Underweight/overweight due to inadequate nutrition.

●         Feeding difficulties, impaired chewing and swallowing, risk of aspiration.

●         Impaired bowel motility.

●         Gastroenterological disorders

●         Bulbar syndrome.

The above are only the most common areas of manifestation in SMA. However, this list is not exhaustive, and other disorders may also occur.

What care may be needed for SMA?

A comprehensive approach to medical care involving specialists from a wide variety of fields can help improve overall health and survival.

Given that each SMA patient has different symptoms and manifestations, the members of the therapeutic team and their degree of involvement may vary depending on needs and circumstances.

It is crucial to have access to a multidisciplinary team of specialists in various fields. Palliative care physicians must be included in the multidisciplinary team.

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

In SMA, it is important to receive regular respiratory support consultations. Furthermore, to address emerging problems, it is important to use a preventive approach, i.e., starting at mild, early symptoms.

An electric suction device can be used to clear the upper airways in bedridden and seated patients (in ambulatory patients, the use of an electric suction device may be required during periods of infection and other weakening episodes). A cough assist device is used to clear the lower airways and assist with coughing in the same situations. These devices can be used at home.

It is recommended to have a pulse oximeter at home to monitor blood oxygen saturation. In case of breathing disorders, early initiation of ventilation and respiratory muscle training are important.

Once breathing failure manifestations are established (including early ones), it is important to timely initiate non-invasive positive pressure ventilation (NIV). NIV should be delivered via a bilevel positive airway pressure (BiPAP) device, which provides a continuous flow of air into the lungs through a mask covering the mouth and/or nose. The mask must be selected individually.

In SMA, oxygen should be used with caution (prolonged use without additional ventilatory support or outside of end-of-life palliative care is unacceptable).

To diagnose respiratory disorders, it is important to regularly assess respiratory function (spirometry) and perform other nighttime (prolonged) respiratory studies (e.g., nocturnal pulse oximetry, polysomnography, etc.).

Nutrition. Due to muscle weakness, patients with SMA may experience difficulties with eating, requiring modification of food consistency and feeding practices.

Due to mobility limitations, weight excess or deficit may develop, requiring dietary changes.

In SMA, bowel motility disorders and other gastroenterological issues (such as reflux, elevated ketones, etc.) frequently occur.

In severe progression, the ability to chew and swallow may be impaired. There is a risk of inhaling food and liquid into the lungs during meals and developing respiratory infections. This may require the use of a nasogastric tube or gastrostomy temporarily or permanently, and a partial or full transition to tube feeding.

It is important to undergo regular examinations and consult a dietitian/gastroenterologist to correct emerging nutritional and gastrointestinal disorders.

Orthopedics. Scoliosis (spinal curvature) is a common problem in patients with SMA caused by muscle weakness. Among adult patients, scoliosis is most pronounced in type 2 SMA. An orthopedist may recommend postural support devices (orthotics) or surgical correction of scoliosis.19

In addition, there is a risk of developing contractures (reduced joint mobility), which may subsequently become permanent and limit movement; dislocations and subluxations are also possible. An orthopedic surgeon may recommend various types of orthoses and technical rehabilitation aids to address these issues.

To prevent the development of contractures and scoliosis, it is important to apply a preventive approach and use orthopedic devices that can correct disorders at an early stage, along with regular follow-up with an orthopedist.

One of the frequent problems in SMA is bone fragility (osteopenia) and the potential risk of developing osteoporosis. Dietary changes for prevention, examination, and an endocrinologist consultation may be needed.

Physical therapy and rehabilitation. Patients with SMA may experience difficulties performing full-range movements. Depending on the functional state of the individual patient, there is a need to apply physical therapy and rehabilitation techniques.

Regular physical therapy and rehabilitation should be ongoing for all patients with SMA. The best way is to integrate physical activity, special exercises, and methods into your daily life.

The main areas will include:

-        Prevention of secondary complications

-        Maintenance and improvement of motor skills

-        Maintenance of daily quality of life and independence

-        Postural management (proper body positioning), e.g., posture control, control of emerging asymmetry due to scoliosis and other deformities

-        Increasing range of motion

-        Pain management

-        Use of orthopedic devices and technical rehabilitation aids

Social activity

It is extremely important to maintain your maximum comfortable level of activity and social contacts. Remember that the disease is only part of your life, and it is important not to limit yourself to "treatment and rehabilitation." Your life is much more multifaceted than the disease, no matter what severe manifestations of it you face.

Having the opportunity to study, work, and realize yourself in creativity, profession, and family life is an integral part of living with a diagnosis.

Timely and comprehensive medical care is necessary, however, it should not take over your entire life. Maintain a positive mindset and leave room for life according to your personal interests.

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

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

Appendix G1. Hammersmith Functional Motor Scale Expanded for SMA

Russian title: Hammersmith Functional Motor Scale Expanded in SMA

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 a patient with SMA, can be used to evaluate therapy efficacy

Content (template):

Scale key: Circle the highest level of independent movement currently and during follow-up assessments. Scoring clearly demonstrates positive or negative changes in motor development.

OC = limited by contracture

Appendix G2. Motor Function Measure 32-Item Scale*

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

Russian name: 32-item Motor Function Measure

Original name (if any): 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 a patient with SMA, can be used to evaluate therapy efficacy

Content (template):

Key (interpretation): scored in points at the time of examination and subsequently during follow-up.

Appendix G3. Revised Upper Limb Module*

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

Russian name: Revised Upper Limb Module

Original name (if any): 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 SMA type II and SMA III, can be used to evaluate therapy effectiveness

Content (template):

Extended scale

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