Duchenne Muscular Dystrophy. Becker Muscular Dystrophy: Clinical Guidelines

List of Abbreviations

BP — blood pressure

ALT — alanine aminotransferase

ACE — angiotensin-converting enzyme

AST — aspartate aminotransferase

GGT — gamma-glutamyl transferase

GC — glucocorticosteroids (H02: corticosteroids for systemic use)

DNA — deoxyribonucleic acid

CP — cerebral palsy

FVC — forced vital capacity

IMV — invasive mechanical ventilation

IHC — immunohistochemical study

CT — computed tomography

CK — creatine kinase

LDH — lactate dehydrogenase

PT — physical therapy

BMD — Becker muscular dystrophy

DMD — Duchenne muscular dystrophy

ICF — International Classification of Functioning, Disability and Health

INR — international normalized ratio

MEF_25-75 — maximal expiratory flows at 25, 50, and 75% of forced vital capacity

BMD — bone mineral density

mRNA — messenger ribonucleic acid

MRI — magnetic resonance imaging

OCD — obsessive-compulsive disorder

FEV₁ — forced expiratory volume in the first second

LGMD — limb-girdle muscular dystrophies

CNS PI — perinatal central nervous system injury

PEF — peak expiratory flow

PCR — polymerase chain reaction

ASD — autism spectrum disorders

FES — fat embolism syndrome

ADHD — attention deficit hyperactivity disorder

MEF_25-75 — mean expiratory flow between 25 and 75% of forced vital capacity

EF — left ventricular ejection fraction

PFT — pulmonary function testing

FVC — forced vital capacity

RR — respiratory rate

HR — heart rate

LoE — level of evidence

US — ultrasound

LeR — level of recommendation validity

ALP — alkaline phosphatase

ECG — electrocardiography

ENMG — electroneuromyography

EMG — electromyography

EchoCG — echocardiography

DMD — dystrophin gene

MLPA — multiplex ligation-dependent probe amplification

NGS — next-generation sequencing

NSAA — North Star Ambulatory Assessment

NT-proBNP — N-terminal pro-brain natriuretic peptide

OMIM — Online Mendelian Inheritance in Man

6MWT — the six-minute walking test

Terms and Definitions

Ambulatory patient — a patient capable of independent walking.

Cardiomyopathy — a heterogeneous group of myocardial diseases associated with mechanical or electrical dysfunction, which usually manifests as inappropriate hypertrophy or dilation. Cardiomyopathies may either affect only the heart in isolation or be part of a generalized systemic disease, often leading to cardiovascular death or disability caused by progressive heart failure.

Limb-girdle muscular dystrophies — a group of muscular dystrophies characterized by involvement of the proximal upper and lower extremities.

Muscle pseudohypertrophy is a visual enlargement of individual muscle groups due to their replacement by adipose or fibrous tissue.

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

Becker muscular dystrophy (BMD) is an inherited X-linked recessive neuromuscular disorder caused by mutations in the dystrophin gene (DMD) that lead to insufficient dystrophin function. It has a later onset, causes milder symptoms, and represents a milder variant of the disease in which dystrophin protein synthesis is incomplete, resulting in a slightly shortened yet fully functional protein.

Duchenne muscular dystrophy (DMD) is an inherited X-linked recessive neuromuscular disorder caused by mutations in the DMD gene that lead to the absence or insufficient function of dystrophin. It has an early onset and causes a severe clinical course.

Electromyography (EMG, ENMG, myography, electroneuromyography) is a method for studying bioelectric potentials arising in human and animal skeletal muscles during muscle fiber excitation; the recording of spontaneous, voluntary, and evoked electrical activity of muscles.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Progressive Duchenne muscular dystrophy (DMD) (OMIM # 310200) is an inherited X-linked neuromuscular disorder caused by pathogenic variants in the DMD gene, which encodes the dystrophin protein, characterized by the absence or insufficient function of dystrophin. It typically affects boys in childhood. It is characterized by proximal limb muscle weakness and calf muscle hypertrophy. On average, by the age of 11, patients lose the ability to walk independently and become non-ambulatory. Death usually occurs by the age of 20 due to cardiorespiratory complications [1–3].

Clinically, 2 forms are distinguished: progressive Duchenne muscular dystrophy (DMD) and progressive Becker muscular dystrophy (BMD). Progressive Duchenne muscular dystrophy (Duchenne muscular dystrophy) is the most severe form with manifestation at the age of 2–5 years and a progressive malignant course: the development of flaccid paresis, paralysis, joint contractures, and immobility. Progressive Becker muscular dystrophy (Becker muscular dystrophy, BMD) is a benign form of the disease with a late onset at 10–20 years and slow progression of muscle weakness symptoms, preserving the ability to walk independently for 15–20 years from the onset of the disease [29].

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

DMD and BMD are caused by pathogenic variants in the dystrophin gene (DMD), leading to a deficiency and/or impaired function of the protein of the same name. Usually, these variants are inherited from a healthy carrier mother; in one-third of cases, the genetic changes arise spontaneously (de novo). The dystrophin gene is one of the largest human genes, containing 79 exons. The disease is caused in ~65% of cases by large deletions; in ~10% by duplications, and the remaining cases are single-nucleotide substitutions, of which 10–15% are nonsense variants (variants leading to a premature stop codon and impaired protein synthesis) [4].

The dystrophin protein is involved in the function of the skeletal muscles, respiratory, and cardiovascular systems—it links the internal cytoskeleton to sarco- and dystroglycans in the membrane and extracellular matrix, ensuring the mechanical and structural stability of the muscle fiber membrane during contraction. Dystrophin also acts as a shock absorber, ensuring the return of the muscle to its initial state after contraction. As the disease progresses, muscle fibers are replaced by fibrous and adipose tissue. Lower molecular weight isoforms of the dystrophin protein are involved in the functioning of various organs and systems, and are implicated in brain cell function [5, 102].

1.3 Epidemiology of the Disease or Condition

According to various sources, the incidence of DMD is estimated at 1:3500–6000 live male births [6]. According to the most up-to-date scientific data, the global incidence of DMD is 1:5000 live male births [25–27]. The incidence of BMD is estimated at 1 in 20,000 live male births [25–27]. Incidence data in the Russian Federation are currently unavailable.

1.4 Features of Coding the Disease or Condition

According to ICD-10, the disease belongs to Class VI, Diseases of the nervous system, G71.0 — Muscular dystrophy.

1.5 Classification of the disease or condition

DMD belongs to the group of limb-girdle muscular dystrophies (LGMD) characterized by preferential involvement of the proximal upper and lower extremities. Depending on symptom progression, 5 stages of DMD are distinguished.

Stage 1 — asymptomatic (preclinical). At this stage, the diagnosis may be suspected if elevated blood creatine phosphokinase (CPK) activity is detected, along with an unexplained increase in transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (AST)) or a family history of the disease, and is established following molecular genetic testing.

Stage 2 (early ambulatory) — the ability to walk independently is preserved. This stage is characterized by the following symptoms: increasing muscle weakness, rapid fatigue, frequent falls, use of Gowers' maneuver when rising from sitting and lying positions, waddling gait, toe walking, and calf muscle pseudohypertrophy. The ability to climb stairs is preserved.

Stage 3 (late ambulatory) — the ability to walk independently is preserved, but an exacerbation of all symptoms from Stage 2 is noted (increased difficulty walking, loss of the ability to climb stairs and rise from the floor).

Stage 4 (early non-ambulatory) — the ability to walk independently is lost, assistive devices are required for mobility, scoliosis develops, and upper limb motor activity is preserved.

Stage 5 (late non-ambulatory) — upper limb functions are restricted, maintaining posture becomes difficult, and cardiac and respiratory failure progress [1, 2, 37].

1.6 Clinical presentation of the disease or condition

Most boys are diagnosed with DMD only when the first signs of the disease appear after a period of relative motor well-being. During this period (up to 2–3 years of age), intensive natural development of skeletal muscles occurs, prevailing over dystrophic processes; therefore, symptoms of the disease are usually mild or require an in-depth and careful search to detect. However, upon careful examination and history-taking, speech and motor development delay is often revealed at this stage of the disease. The child starts holding their head up, sitting, and walking independently later. In DMD, children often start walking at 18 months of age or older. Asymptomatic elevation of CPK and transaminases may also be an incidental finding. Elevation of CPK (tenfold or even hundredfold) is observed immediately after the boy's birth and during the ambulatory stages of the disease, and should be considered by the physician as a definitive reason to suspect DMD and conduct further tests to confirm or rule out this disease (see Section 2.3). Elevations in ALT and AST (also frequently tenfold) and lactate dehydrogenase (LDH) (several-fold) in DMD are of muscular, rather than hepatic, origin.

At the early ambulatory stage (usually from 3–5 years of age), the following classic signs of DMD are observed: progressive muscle weakness (more pronounced in the proximal parts of the arms and legs), reduced exercise tolerance, rapid fatigue, clumsiness, frequent falls, and difficulty climbing stairs. When rising from a sitting position on the floor or a squatting position, the patient uses Gowers' maneuver ("climbing up oneself" — resting hands on their own thighs to help push themselves into an upright position), and the gait becomes waddling (so-called "waddling gait"). Toe walking or walking on the balls of the feet is characteristic. Upon examination, calf muscle pseudohypertrophy, "winged" scapulae, lumbar hyperlordosis, and decreased tendon reflexes and muscle tone may be detected. At this stage (at 3–5 years), cardiac involvement (cardiomyopathy) can already be detected in 5% of cases in the form of systolic myocardial dysfunction (left ventricular ejection fraction reduced below 55% on Teichholz method evaluation) [12]. At the same time, left ventricular size is typically not enlarged. Electrocardiography (ECG) reveals daytime and nighttime tachycardia; shortening of the PQ interval, signs of increased electrical activity of the right ventricle (R wave > S wave in leads V1-V2), as well as increased Q wave amplitude in leads III, aVF, and V5–V6 [28, 83–93].

At the late ambulatory stage, muscle weakness steadily progresses. Walking becomes significantly impaired, spinal hyperlordosis increases, and contractures develop (ankle contractures appear among the first). At the age of 6–9 years, cardiomyopathy is detected in 18% of cases as systolic myocardial dysfunction. According to guidelines, annual cardiac evaluation and prescription of ACE inhibitors are required.

or angiotensin II receptor blockers by the time the patient reaches 10 years of age [28, 83, 93].

The early non-ambulatory stage is characterized by the loss of the ability to move independently; the child is forced to use a wheelchair, which they can operate independently as long as upper limb motor activity is preserved. Disease progression leads to the development of flexion contractures of the knee, hip, and elbow joints. A pronounced S-shaped scoliosis develops. Heart and lung failure begin to manifest. At the age of 10–13 years, due to reduced physical activity (primarily due to the loss of independent ambulation), the physiological load on the myocardium decreases. Cardiomyopathy in the form of systolic myocardial dysfunction at this stage of the disease is detected in 18% of cases [28, 83–93].

At the late non-ambulatory stage, upper limb function is gradually lost [3, 6, 7]. Heart and lung failure increase further.

Cardiac fibrosis leads to the development of dilated cardiomyopathy, as well as myocardial rhythm and conduction disorders. The detection rate of cardiomyopathy increases to 38% at 14 years of age, to 57% at 15 years, and in individuals older than 18 years, it exceeds 61% of cases [8, 9].

Cardiac pathology may remain subclinical for a long time (without overt symptoms of heart failure) because the signs of stage IIA chronic heart failure are noticeable only during physical exertion, but at the non-ambulatory stage, the patient cannot afford the physical exertion necessary to manifest heart failure. As the disease progresses, the patient develops pronounced tachycardia, which may later be joined by edema, and dyspnea (the time of onset of which depends on the condition of the respiratory muscles). With a critical decrease in ejection fraction (EF < 35%), as well as against the background of left ventricular fibrosis, anasarca, ascites, marked weakness, and tachycardia develop [28, 83–93]. In these cases, cardiac arrhythmias of various types may occur at any stage [28].

Lung involvement leads to chronic respiratory infections in all patients. With the loss of ambulation, vital capacity (VC) steadily decreases by 8–12% per year. Obstructive sleep apnea is detected in the majority of patients [14].

Studies show a significantly higher prevalence of cognitive and behavioral disorders among individuals with DMD compared to the general population. It has been repeatedly reported that patients with DMD have elevated rates of attention deficit hyperactivity disorder (ADHD, or code "F90 Hyperkinetic disorders" according to the ICD-10 adapted in the Russian Federation), autism spectrum disorders (ASD, or code "F84 Pervasive developmental disorders" according to the ICD-10 adapted in the Russian Federation), learning disorders (code "F81 Specific developmental disorders of scholastic skills" according to the ICD-10 adapted in the Russian Federation), intellectual disabilities (code "F70-F79 Mental retardation" according to the ICD-10 adapted in the Russian Federation), obsessive-compulsive disorder (OCD), anxiety disorders, and behavioral disorders (code "F91 Conduct disorders" according to the ICD-10 adapted in the Russian Federation) [168, 169]. Additionally, regular systemic corticosteroid therapy (ATC: H02) can lead to mental state alterations in patients with DMD and the development of various psychiatric disorders: ranging from mood disturbances and increased irritability to psychotic disorders [171, 172]. All of the above requires psychiatrists (paediatric psychiatrists) to pay additional attention to patients with DMD.

Due to the regular intake of systemic corticosteroids, many patients develop adverse events such as growth and puberty disorders, adrenal insufficiency, impaired glucose tolerance and type 2 diabetes mellitus, arterial hypertension, worsening osteoporosis, and cataract formation. All of these disorders require mandatory correction and follow-up by specialized medical professionals.

Osteoporosis occurs in all children with DMD and is detected while the boys are still capable of independent ambulation. Bone density continues to decrease with age. Long bone fractures associated with osteoporosis and frequent falls are common, occurring in approximately 21–44% of patients [19, 20].

Patients with DMD frequently experience gastrointestinal complications and feeding difficulties that lead to nutrient and fluid imbalance, weight loss, or conversely, weight gain. In the late stage of the disease, dysphagia and mandibular contracture appear.

In most cases, death in patients with DMD results from heart and respiratory failure in the late second to mid-third decade of life. Nevertheless, timely initiation of standard therapy—systemic corticosteroids, correction and monitoring of vitamin D levels, physical therapy, regular physical activity and rehabilitation measures, timely monitoring of cardiovascular and respiratory systems, coupled with the advent of disease-modifying therapies, significantly increase the life expectancy and quality of life of patients with DMD today [178–180].

BMD is a milder form of the disease. Onset occurs significantly later, at 10–20 years of age. The disease progresses slowly and rarely leads to disability before 40 years of age. Intellect is usually preserved in BMD. BMD is characterized by myocardial involvement and the development of hypertrophic or dilated cardiomyopathy (up to 50% of cases) [29].

In approximately 8% of cases, manifestations of DMD can be observed in heterozygous female carriers of the defective gene. This may result from abnormalities such as X-chromosome lyonization (inactivation), or complete or mosaic forms of Turner syndrome. Clinical manifestations typically debut during periods of hormonal shifts, such as pregnancy, menarche, and menopause. The disease in women usually (but not always) runs a significantly milder course than in men. In addition to muscle weakness, cardiovascular abnormalities such as cardiac arrhythmias and the development of dilated cardiomyopathy are quite common [30].

Differential diagnosis of DMD/BMD is performed with all diseases whose primary clinical manifestation is muscle weakness [137, 139]. The list of main diseases included in the differential diagnosis of DMD/BMD is presented in Appendix A3.2.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Please note that in accordance with the requirements for the development of clinical guidelines, each recommendation statement must indicate the strength of recommendations and the evidence base in accordance with the grading scales for the levels of evidentiary certainty (LEC) and the levels of recommendation persuasiveness (LRP). For many statements, the LRP and LEC will be low due to the lack of high-design clinical trials dedicated to them. Despite this, they are necessary elements of patient examination to establish a diagnosis and choose treatment tactics.

The diagnosis of DMD/BMD is established based on a combination of findings:

• anamnestic data,

• clinical findings,

• laboratory test results (biochemical and molecular genetic analysis).

Differential diagnosis should be approached with particular care (see Appendix A3.2).

Criteria for establishing diagnosis and conditions.

The diagnosis is established based on the results of molecular genetic testing if pathogenic (likely pathogenic) variants in the DMD gene are detected.

2.1 Complaints and Anamnesis

When taking the medical history and complaints, attention should be paid to:

• asymptomatic elevation of serum transaminases (ALT, AST), CK, and LDH activity;

• motor and speech developmental delay;

• calf muscle pseudohypertrophy;

• increased fatigue (decreased endurance);

• frequent falls or clumsiness;

• altered gait pattern;

• difficulty climbing stairs;

• difficulty performing routine motor tasks (squatting, running, or overcoming obstacles), inability to jump;

• use of Gowers' maneuver when rising from the floor;

• toe-walking;

• decreased muscle tone;

• decreased or absent tendon reflexes;

• muscle pain;

• back pain;

• equinus foot deformity;

• loss of independent ambulation;

• behavioral disorders;

• speech delay or articulation disorders;

• learning and attention difficulties;

• generalized muscle weakness and rapid physical fatigue;

• cardiomyopathy [1–3, 6, 39, 42].

Anamnestic events to look out for in patients with suspected DMD/BMD:

• male sex of the patient;

• diagnosed progressive muscular dystrophy in maternal male relatives or an unspecified neuromuscular disorder;

• confirmed presence in the family of female carriers of a pathogenic variant in the DMD gene;

• delayed attainment of independent walking;

• delayed speech development;

• history of significantly elevated CK;

Complaints and medical history are also described in the section "Clinical presentation of the disease or condition (group of diseases or conditions)".

2.2 Physical Examination

Physical examination of patients with suspected DMD / BMD includes:

• height measurement;

• body weight measurement;

• visual assessment of gait: myopathic, waddling (duck-like) gait;

• visual inspection of muscles: calf muscle pseudohypertrophy; proximal distribution of muscle hypo/atrophies and paresis;

• muscle tone examination: decreased muscle tone, more pronounced in the proximal segments; examination of limb muscle strength (determination of the dynamic strength of an individual muscle) with assessment of the child's active head lifting from the supine position, independent (unassisted) raising of the child to a vertical position from the supine position, and from a sitting position on a chair: detection of weakness in proximal muscles, pelvic and shoulder girdle muscles, and axial muscles;

• examination of tendon reflexes: decreased or absent tendon reflexes;

• examination of the osteoarticular system assessing posture, range of active and passive movements (determination of the range of passive movement of a single joint in one plane; determination of the range of active movement of a single joint in one plane), manual muscle testing (muscle palpation): lumbar hyperlordosis, stiffness or contractures of the ankle joints, scoliosis, "winged" scapulae, chest deformity, flattening and deformity of the feet;

• assessment of the child's neuropsychological development and its age-appropriateness through examination and interview: attention deficit hyperactivity disorder (ADHD), autistic features, obsessive-compulsive disorders, non-progressive cognitive impairments (impaired short-term verbal memory, dyslexia, specific learning disorders; presence of emotional disorders: depression, anxiety, affectivity);

• cardiovascular system examination (blood pressure measurement in peripheral arteries, heart rate measurement): increased heart rate, elevated blood pressure;

• respiratory system examination (respiratory rate measurement): increased respiratory rate, decreased breath sounds on auscultation [1, 2, 38].

Detailed physical examination data are described in the section "Clinical presentation of the disease or condition (group of diseases or conditions)".

2.3 Laboratory Diagnostics

Early diagnosis of DMD and BMD is the key to proper patient management and the timely use of available therapy and rehabilitation regimens to prevent complications and preserve patients' quality and life expectancy.

Comment: an elevated CK level is an obligatory, early preclinical sign. A characteristic feature of DMD is a 10-100-fold increase in CK. In outpatients, it is mandatory to test blood creatine kinase activity in all children presenting to a pediatrician, neurologist, pediatric psychiatrist, infectious disease specialist, trauma and orthopedic surgeon, gastroenterologist, or pediatric cardiologist when presenting with symptoms such as motor, speech/psychospeech developmental delay or general developmental disorders (intellectual disabilities, ASD), fatigue, clumsiness, flat feet, frequent falls, sporadic toe-walking, diagnoses of cerebral palsy (CP), perinatal central nervous system (CNS) injury, ASD, elevated ALT, AST, LDH levels, asymptomatic hepatitis of unclear etiology, unspecified muscle function disorders (frequent tripping, falling, low motor activity, etc.), Gowers' sign when rising from a lying position, a family history burdened with DMD, or a close relative with an unspecified neuromuscular disease. Upon admission to a neurological department, it is mandatory to test CK, ALT, AST, LDH, and ALP (determination of blood creatine kinase activity, blood alanine aminotransferase activity, blood aspartate aminotransferase activity, blood lactate dehydrogenase activity, blood alkaline phosphatase activity).

Comment: the study is performed during initial diagnosis and does not need to be repeated once the diagnosis is established. First step: determination of large deletions and duplications in the DMD gene using multiplex ligation-dependent probe amplification (MLPA). Second step: if no large deletions or duplications are found in the DMD gene, gene sequencing should be performed to detect single nucleotide variants. High-throughput sequencing (targeted or whole-exome) is the method of choice. The proposed algorithm detects 98% of variants in the DMD gene. If single nucleotide variants are detected by high-throughput sequencing, validation of the results by Sanger sequencing may be prescribed if indicated, as determined by a geneticist.

Comment: in most cases, genetic research methods are sufficient to confirm the diagnosis. It must be remembered that genetic testing makes it possible to confirm, but does not allow to exclude the presence of the disease. In cases where genetic testing fails to confirm DMD/BMD (e.g., when variants of uncertain clinical significance are detected that cannot be classified at the time of examination), given the appropriate clinical presentation and taking into account that other neuromuscular diseases have been excluded, a muscle biopsy and pathoanatomical examination of the muscle tissue biopsy (surgical) material using immunohistochemical methods with subsequent analysis for the presence of dystrophin protein may be performed.

2.4 Instrumental Diagnostics

The listed clinical and instrumental diagnostic methods are necessary for the primary and differential diagnosis of the disease.

Comments: assessment of external respiration function is carried out by spirometry (testing of forced respiratory volumes, unforced respiratory volumes and flows), annually (or twice a year if necessary) starting from the age of 5, if feasible.

Comment: performed according to indications (for the purpose of differential diagnosis, as an additional method to confirm the diagnosis in questionable cases, and to analyze disease progression over time. This diagnostic method is supplementary. Muscle MRI (magnetic resonance imaging of the muscular system) allows visualization of the degree of dystrophy and fibrosis of muscle tissue. A characteristic pattern of thigh muscle involvement is visualized (maximal involvement of the thigh adductors with preservation of the gracilis and sartorius muscles) along with lower leg involvement (fatty infiltration in the soleus and peroneus muscles and relative preservation of the tibialis anterior muscle) [94].

Comments: radiography of the thoracic and lumbar spine in lateral projection is performed every 1-2 years in patients receiving systemic corticosteroids, and every 3 years in patients not receiving systemic corticosteroids [1], and is performed twice a year in patients who have lost the ability to walk who present with back pain, scoliosis, and hyperlordosis.

Comments: performed regularly in children starting from the second stage (early ambulatory) of disease progression. Patients with DMD/BMD are characterized by a high incidence of osteopenia and fractures of the vertebrae and long tubular bones. These risks are due to muscle weakness, use of systemic corticosteroids, and low mobility of patients [1].

Comments: these diagnostic methods allow the detection of heart rate, rhythm, and conduction disorders, signs of systolic dysfunction, dilatory disorders, myocardial hypertrophy, and mitral regurgitation.

Comments: at the ambulatory stage, it may be necessary to perform sleep studies with capnography, especially in the presence of weight gain due to systemic corticosteroid therapy and symptoms of sleep-disordered breathing (sleep apnea). Sleep studies can also be used as an alternative method for monitoring pulmonary function abnormalities in patients who cannot undergo pulmonary function testing (testing of forced respiratory volumes, unforced respiratory volumes, and flows). Patients who are non-ambulatory and have symptoms of sleep-disordered breathing should undergo sleep studies at least once a year.

Comments: cardiorespiratory monitoring (continuous recording of breathing parameters, heart rate, and oxygen levels) is performed to evaluate heart rhythm, oxygen saturation levels, and the number of nighttime breathing pauses. This test is important to confirm chronic respiratory failure and to determine the need for additional respiratory support.

2.5 Other Procedures

Comment: during the initial consultation, the geneticist performs an examination and preliminary differential diagnosis, and determines the scope of molecular genetic testing. During the follow-up consultation, the geneticist interprets the results of molecular genetic testing, determines the need for additional studies (validation, segregation, functional studies), and explains the obtained results to the patient's legal representatives. Interpretation of results and determination of molecular genetic diagnostic tactics by other specialists is unacceptable.

Comment: the frequency of follow-up for ambulatory patients – once every 12 months, for non-ambulatory patients – once every 6 months. Assessment of motor functions and range of motion may also be performed by a physical and rehabilitation medicine physician or a specialist fulfilling that role, possessing the appropriate knowledge (Appendices A3.3, A3.5, A3.6, G1-G7).

Comments: consultation regarding palliative care may be provided at all stages of managing a patient with DMD/BMD: upon diagnosis, during key therapeutic decision-making, when life-threatening conditions arise, and in the terminal phase of the disease.

Comments: the choice of pain intensity assessment methods (including pain rating scales) is determined by the attending physician, depending on the child's age and clinical status.

Comments: frequency: 1–2 times a year.

Comments: the management of patients with DMD is based on systematic, reproducible studies of the musculoskeletal system [2].

The progression of DMD cannot be assessed using blood biochemical markers. For this nosology, functional tests serve this role.

Specialized functional tests include the assessment of movement patterns and a series of standard tests specific to DMD and other neuromuscular diseases. The primary methods for clinical assessment of the functional status of ambulatory patients are the North Star Ambulatory Assessment (NSAA) and timed functional tests. Assessments using the NSAA scale and timed tests make it possible to detect minimal clinically important differences and predict changes in motor function, which are important for monitoring clinical disease progression and evaluating therapeutic efficacy.

In clinical practice, functional changes should be predicted taking into account the patient's capabilities (ambulatory status), limitations inherent to effort-based tests, the impact of musculoskeletal pathology (e.g., contractures) on these test results, and genetic factors [184-187].

Comments: it is necessary to assess the range of active and passive motion in the ankle, knee, hip, shoulder, elbow, wrist, and small joints of the hand in each possible plane, combined with functional tests (Ely's test, hamstring test, Silfverskiöld test), recording the data in the patient's medical history and comparing them with previous examination data; the required frequency of the examination — once every 6 months.

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

Treatment of DMD/BMD includes both disease-modifying (pathogenetic) treatment and symptomatic therapy [178-180]. Management of patients with DMD requires a multidisciplinary approach involving a medical geneticist, neurologist, pulmonologist, pediatric cardiologist, cardiologist, gastroenterologist, pediatric endocrinologist, endocrinologist, orthopedic trauma surgeon, dietitian, child psychiatrist, pediatrician / general practitioner (family physician) / internist, ophthalmologist, anesthesiologist-intensivist, medical psychologist, physical therapy physician (or physiotherapist, physical and rehabilitation medicine physician), palliative care physician, physical rehabilitation specialist (kinesiotherapist), and other specialists with experience in treating this rare disease. If symptoms of target organ damage are present, consultation with a subspecialist is required.

3.1 Pharmacotherapy. Disease-modifying treatment.

Comments: an ambulatory patient is a patient capable of independent walking. In clinical practice, it is proposed to interpret "ambulatory status" in DMD patients as the ability to walk without assistive devices and without specifying distance and time, and "loss of ambulatory status" as a condition in which the patient is forced to permanently use a wheelchair for mobility both outdoors and indoors [178]. A DNA nonsense variant manifests as the formation of a premature stop codon in messenger RNA (mRNA). As a result, the synthesis of full-length dystrophin protein is impaired. Nonsense variants are detected in 18-20% of Russian patients with DMD [183]. Ataluren acts at the stage of protein translation in the ribosome, allowing information to be read from the mRNA despite the presence of a premature stop codon, and synthesizing the full-length protein. Upon loss of ambulatory status, treatment with ataluren must be continued to preserve respiratory function; weight-based dose adjustment may be required. To achieve maximum efficacy of ataluren, children older than 2 years must be prescribed and treated concomitantly with systemic corticosteroids (ATX: H02), which are currently the "gold standard" of treatment for DMD patients. Systemic corticosteroids (ATX: H02) serve as the pharmacological foundation for all gene therapy drugs currently under development and in use (ATX: M09 Other drugs for disorders of the musculoskeletal system). It is also necessary to use in combination all other elements of standard comprehensive therapy — physical therapy and rehabilitation, vitamin D and its analogs (A11CC), prevention and treatment of cardiomyopathy and pulmonary pathology, and antiresorptive therapy [178-180].

Comments:deletions amenable to treatment by exon 53 skipping: 3-52, 4-52, 5-52, 6-52, 9-52, 10-52, 11-52, 13-52, 14-52, 15-52, 16-52, 17-52, 19-52, 21-52, 23-52, 24-52, 25-52, 26-52, 27-52, 28-52, 29-52, 30-52, 31-52, 32-52, 33-52, 34-52, 35-52, 36-52, 37-52, 38-52, 39-52, 40-52, 41-52, 42-52, 43-52, 45-52*, 47-52*, 48-52*, 49-52*, 50-52*, 52*, 54-58, 54-61, 54-63, 54-64, 54-66, 54-76, 54-77. The asterisk (*) marks the most common deletions amenable to treatment by exon 53 skipping. A DMD gene deletion manifests as the "dropout" of one or more exons, resulting in a reading frame shift in messenger RNA (mRNA). As a result, dystrophin protein synthesis is disrupted. Deletions amenable to viltolarsen therapy occur in approximately 5% of Russian DMD patients [165]. Single-nucleotide variants that can be corrected by exon 53 skipping may also serve as an indication for viltolarsen administration. Viltolarsen is designed to bind to exon 53 of dystrophin pre-mRNA, resulting in the exclusion of this exon during mRNA processing in patients with genetic mutations that can be corrected by exon 53 skipping. Exon 53 skipping enables the production of an internally "truncated" partially functional dystrophin protein in the target patient group. The efficacy and safety of treatment in patients undergoing permanent mechanical ventilation and in patients in the late non-ambulatory stage of the disease have not been established. When prescribing to these patients, the appropriateness of administration should be determined taking into account residual motor function, etc. In the absence of an effect, the use of the drug must be discontinued. To achieve maximum efficacy of exon-skipping mutation-correcting drugs (ATC code: M09 Other drugs for disorders of the musculoskeletal system), in children older than 2 years, they are prescribed and used concomitantly with systemic corticosteroids (ATC: H02), which are currently the "gold standard" of treatment for patients with DMD. Systemic corticosteroids (ATC: H02) serve as the pharmacological foundation for all gene therapy drugs currently under development and in use (ATC code: M09 Other drugs for disorders of the musculoskeletal system). It is also necessary to comprehensively use all other elements of standard combination therapy – physical therapy and rehabilitation, weight control, vitamin D and its analogues (A11CC), prevention and treatment of cardiomyopathy and pulmonary pathology, and antiresorptive therapy [178–180].

Systemic corticosteroid therapy.

Comments: systemic corticosteroids are the current "gold" standard of treatment for patients with DMD, as they have altered the natural course of the disease by slowing the progression of motor and pulmonary function decline, reducing the number of orthopedic complications and spinal surgeries, and increasing life expectancy [104]. Large-scale studies have demonstrated that the use of systemic corticosteroids prolongs the ambulatory phase of patients with DMD by an average of 3–5 years [36]. The initiation of hormone therapy depends on the phase of the child's motor function development, initial physical status, presence of early complications, and the form and course of the disease. Starting systemic corticosteroid therapy is not indicated for a child whose motor skills are still developing, especially if they are under 2 years of age. Typically, in a boy with DMD, motor skills continue to develop up to 4–6 years of age, albeit at a slower pace than in his peers. Systemic corticosteroids should be prescribed without waiting for the onset of motor function decline, at the point when the natural development of motor functions in the child is no longer observed (plateau phase) [34]. Initiating systemic corticosteroids before the age of seven has the most pronounced effect on the ability and duration of independent ambulation [103]. The efficacy of hormone therapy depends on the physiological characteristics of the child's body, individual tolerability, appropriate selection of the daily dose and regimen, and the monitoring and management of side effects. In case of intolerance to #prednisolone**, alternative forms of systemic corticosteroids may be used [34, 35, 37].

Comments: the following dosing regimen is indicated: the glucocorticoid dose is increased until the patient reaches a body weight of 40 kg, meaning the maximum dose is 30 mg per day [204]. If intolerable side effects are observed, the dosage should be gradually reduced by 20–25% [1]. Systemic corticosteroid therapy should be carried out on a regular basis. The most extensively studied and recommended approach is regular daily administration of #prednisolone**. Nevertheless, in some cases, depending on therapy tolerability, intermittent treatment regimens may be considered, such as hormone therapy every other day, on weekends, or 10 days on and 10 days off [2].

Comments: initiating glucocorticoid therapy during the non-ambulatory stage is also justified [2]. It may be necessary to modify the dosing schedule and reduce the dosage to minimize the likelihood of adverse effects from hormones (ATC: H02 Systemic corticosteroids).

Comment: the reduction of glucocorticoid dosage must be carried out in accordance with the standard protocol for discontinuing systemic corticosteroids [56]. An explanatory discussion must be held with the parents regarding the impossibility of abruptly stopping systemic corticosteroids.

3.2 Pharmacotherapy. Symptomatic treatment.

Treatment of cardiovascular disorders.

For #captopril**, Level of Recommendations – C (Level of Evidence – 5)

For #perindopril**, Level of Recommendations – B (Level of Evidence – 2)

Comments: for patients with BMD, these drugs are prescribed if pathological changes are detected on ECG or echocardiography (Echo-CG). To date, opinions on initiating ACE inhibitors and angiotensin II receptor blockers in patients with DMD without cardiovascular pathology differ. However, it has been demonstrated that early initiation of ACE inhibitor therapy, even in the absence of visible cardiac pathology, slows the progression of cardiovascular disorders in this group of patients. Selecting therapy requires an initial and, if necessary, follow-up consultation (examination, assessment) by a cardiologist / pediatric cardiologist [8, 9, 39, 57, 137].

Comments: this therapy should be carried out in accordance with established clinical practice guidelines. To date, there are no specific clinical guidelines for the treatment of cardiovascular pathology in patients with DMD, which is why the management of these disorders is carried out in accordance with general guidelines for treating cardiovascular diseases. For instance, in the presence of ventricular dysfunction, beta-blockers are indicated; if clear signs of heart failure are present, the use of diuretics or aldosterone antagonists may be considered [30, 31, 39, 57, 137]. To select therapy, an initial and, if necessary, follow-up consultation (examination, assessment) by a cardiologist / pediatric cardiologist is required.

Comments: selecting therapy requires an initial and, if necessary, follow-up consultation (examination, assessment) by a cardiologist / pediatric cardiologist.

Comments: selecting therapy requires an initial and, if necessary, follow-up consultation (examination, assessment) by a cardiologist / pediatric cardiologist.

Comments: selecting therapy requires an initial and, if necessary, follow-up consultation (examination, assessment) by a cardiologist / pediatric cardiologist.

Comment: maintaining an optimal vitamin D level (30–50 ng/mL / 75–125 nmol/L) throughout the lifespan of a patient with DMD has a positive effect on the disease course and quality of life. The main clinical outcomes of correcting vitamin D deficiency include the prevention of osteoporosis (especially after initiating glucocorticoid therapy), long-bone and vertebral fractures, prolonged ambulation, greater efficacy of bisphosphonate therapy (including a reduction in complications during initial use and lower jaw osteonecrosis), and a positive effect on the severity of autism spectrum symptoms. For patients on long-term glucocorticoid therapy with metabolic disorders and liver involvement, the treatment regimen may be reviewed for more effective repletion of the deficiency [105].

Comments: non-traumatic vertebral fractures and long-bone fractures are clinical manifestations of increased bone fragility [31, 32]. To determine the need for therapy and the appropriate route of administration, an initial and, if necessary, follow-up consultation (examination, assessment) by an endocrinologist / pediatric endocrinologist is required.

Comments: treatment must be coordinated with an endocrinologist / pediatric endocrinologist. A recent systematic review demonstrated that testosterone therapy** is generally well tolerated by patients with DMD, and the benefits of this treatment outweigh the potential risks of adverse effects.

Fat embolism syndrome.

Comments: approximately 25% of patients with DMD experience long-bone fractures, and 1% to 22% of fractures in DMD carry a risk of developing fat embolism syndrome (FES) [188]. FES is a life-threatening condition in DMD. Risk groups for FES include non-ambulatory adolescents aged 10 to 15 years on long-term glucocorticosteroid therapy (ATC code: H02) who are overweight, have low vitamin D levels, and exhibit severe osteopenia. The primary cause of falls is transfers or failing to use seatbelts in wheelchairs. If a child with DMD presents with altered mental status and respiratory failure, the physician should consider the likelihood of FES in the differential diagnosis. FES should always be suspected in patients with DMD who have fractures or unexplained and sudden worsening of respiratory and cardiac symptoms.

Clinical manifestations of FES can range from asymptomatic to cardiac arrest secondary to right ventricular heart failure. Symptoms typically appear within the first 12–24 hours after injury, although in some cases they may occur after 36–72 hours. According to Gurd and Wilson's criteria, the major features form a triad: petechial rash, respiratory changes, and neurological alterations. Minor features include tachycardia, retinal changes, fever, and decreased urine output. It can also provoke thrombocytopenia (over 50%), a drop in hemoglobin greater than 20%, and fat macroglobulinemia.

The lungs are usually the most severely affected organ, with rapidly progressive dyspnea and hypoxemia being the main clinical symptoms. Chest radiography (chest X-ray / digital chest X-ray) reveals diffuse bilateral infiltrates that are difficult to distinguish from pediatric acute respiratory distress syndrome. Chest CT (computed tomography of the thoracic organs / computed tomography of the thoracic organs with intravenous bolus contrast enhancement) offers no distinct diagnostic advantages over standard chest radiography (chest X-ray / digital chest X-ray); however, it is frequently performed to rule out pulmonary embolism. Alveolar hemorrhage may also be observed in FES.

The brain is the second most commonly affected organ. Neurological symptoms can vary widely from irritability, anxiety, agitation, confusion, delirium, seizures, and coma to intracranial hypertension. Brain CT is typically unremarkable. Diffusion-weighted MRI is a more specific diagnostic method.

The third most important clinical diagnostic sign is cutaneous petechiae. These 1-2 mm lesions are small hemorrhages resulting from trauma to cutaneous capillaries. The time interval between trauma and the onset of petechiae varies, as does their location, but they are most frequently detected in the axillary and upper presternal regions, on the lateral surfaces of the neck, and in the conjunctiva.

It is essential to maintain a high index of suspicion for fat embolism syndrome in patients with DMD and to provide aggressive supportive care upon admission of a child presenting with acute mental status and respiratory disturbances. Active supportive therapy is required, including mechanical ventilation, reduction of right ventricular afterload, blood transfusion, and broad-spectrum antibiotics (ATC: J01 Antibacterials for systemic use). Prevention of potential complications such as anemia, thrombocytopenia, right ventricular failure, or acute kidney injury is another key factor in the management of such patients. In the event of acute pulmonary hypertension followed by acute right-sided heart failure and cardiovascular collapse, therapy to reduce right ventricular afterload and/or inhaled nitric oxide is necessary to manage the pulmonary hypertension. Oxygenation of patients without mechanical ventilation is strictly contraindicated to prevent respiratory arrest [2].

Management of mental and behavioral disorders.

Comments: this therapy must be administered in accordance with established clinical practice guidelines and/or drug product information. To date, there are no specific clinical guidelines for the treatment of mental and/or behavioral disorders in patients with DMD; therefore, the correction of these disorders is carried out in accordance with general guidelines for the treatment of mental and behavioral disorders. An initial and follow-up (as needed) consultation (examination, assessment) by a pediatric psychiatrist is required.

Comments: this therapy must be administered in accordance with established clinical practice guidelines and/or drug product information. To date, there are no specific clinical guidelines for the treatment of mental and/or behavioral disorders in patients with DMD; therefore, the correction of these disorders is carried out in accordance with general guidelines for the treatment of mental and behavioral disorders. An initial and follow-up (as needed) consultation (examination, assessment) by a pediatric psychiatrist is required.

3.3 Non-pharmacological treatment

Comment: prior to gastrostomy placement, temporary feeding via a nasogastric tube is required (nasogastric tube insertion, feeding a severely ill patient orally and/or via a nasogastric tube).

Comment: advancements in care for DMD have extended the period during which patients maintain independent ambulation, reduced the prevalence of severe contractures and deformities (including disabling scoliosis), and allowed patients to preserve functional activity and participate in all aspects of life for a longer time. Rehabilitation management involves physicians, physical therapy specialists (physical rehabilitation specialists / kinesiotherapists), occupational therapists, medical speech-language pathologists, orthotists, and durable medical equipment providers.

At the onset of the disease, the main focus is on prolonging walking ability and physical development; once the teenager transitions to a wheelchair, the focus shifts to upper extremity management to preserve hand function, wheelchair positioning, and standing frames (verticalization). In later stages of the disease, respiratory rehabilitation comes to the forefront. Contracture prevention is necessary throughout the patient's entire life.

Comments: this treatment is typically initiated in the early non-ambulatory stage.

Comments: the use of cough-assist devices (mechanical insufflator-exsufflators, airway clearance systems) is extremely important, as respiratory muscle weakness leads to the inability to cough effectively and an increased risk of atelectasis, pneumonia, ventilation-perfusion mismatch, and progression of respiratory failure. Cough-assist devices (mechanical insufflator-exsufflators, airway clearance systems) are typically introduced at the end of the early non-ambulatory stage or the beginning of the late non-ambulatory stage of the disease.

Comments: these measures are usually required in the late non-ambulatory stage of the disease or in the outpatient stage if sleep apnea is present.

Comments: the use of assisted non-invasive ventilation (assisted mechanical ventilation) for more than 16 hours a day is possible using nasal masks or mouthpieces. If it is impossible to maintain adequate ventilation using non-invasive techniques, tracheostomy is indicated (permanent open tracheostomy, percutaneous dilatational tracheostomy)[39]. These measures are usually necessary in the late non-ambulatory stage of the disease.

Comments: such training sessions are conducted by medical psychologists and represent a structured program aimed at teaching parents effective approaches to parenting and interacting with children. The main objective of the training is to strengthen parent-child relationships and reduce manifestations of negative, aggressive, or defiant behavior in the child. During the sessions, parents master positive reinforcement techniques, behavior management methods through clear establishment of rules and boundaries, as well as approaches to constructive resolution of difficult situations.

3.4 Surgical treatment

Comments: foot and Achilles tendon surgeries to correct equinovarus foot deformity are aimed at increasing the range of motion in the ankle joint and improving patients' walking. These operations are indicated when quadriceps femoris muscle strength is preserved. Surgical interventions on the hip and knee joints are generally not indicated.

Comment: this intervention may be performed exclusively when there are individual potential opportunities for the patient's standing/verticalization after surgery.

Comments: a high rate of progression is considered to be ≥ 10° per year.

Comments: when deciding on surgical intervention, it is necessary to consider the decline in respiratory function, rib deformation, hyperkyphosis, the impact on the patient's mobility and functioning, pelvic tilt, and truncal imbalance. In the presence of a deformity ranging from 20° to 50°, it is advisable to use functionally corrective orthoses (braces) in children under 4 years of age and to postpone surgical intervention [39].

Comments: in this group of patients, spinal arthrodesis (spinal fusion) surgery using rigid dynamic fixation systems is advisable due to the high risk of scoliosis progression. Spinal arthrodesis (spinal fusion) with multi-anchor definitive fixation systems is usually performed in the second decade of life, when minimal additional longitudinal spinal growth is expected (Instrument set for spinal fixation implants; Spinal osteosynthesis implants and their analogs).

Comments: the use of combined endotracheal anesthesia increases the risk of rhabdomyolysis and hyperkalemia. The use of suxamethonium chloride** in these patients is strictly contraindicated (risk of rhabdomyolysis and hyperkalemia) [82]. Regional anesthesia techniques (epidural anesthesia, spinal anesthesia, combined spinal-epidural anesthesia) may be difficult to perform due to spinal curvature. Prior to any surgical intervention, a consultation with a pulmonologist (initial pulmonologist consultation/examination) and a cardiologist/pediatric cardiologist (initial cardiologist/pediatric cardiologist consultation/examination) is required. Furthermore, it should be noted that DMD/BMD patients have an increased risk of developing heart and respiratory failure during and after surgery.

3.5 Palliative medical care

Palliative care is an approach that aims to improve the quality of life of patients and their families facing life-threatening illness. This is achieved by preventing and relieving suffering through early identification, thorough assessment, and management of pain and other distressing physical symptoms, as well as providing psychosocial and spiritual support [144]. The main goal of palliative care is to achieve, support, maintain, and enhance the quality of life of the patient as much as possible. However, only the patient in need of palliative care can define what “quality of life” means to them [145]. It is important not to contrast palliative care with active (interventional) treatment, but rather to have them mutually complement each other.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

It is currently proven that regular moderate physical activity, physical therapy, and patient rehabilitation can alter the natural history trajectory of DMD/BMD: prolong the ability to walk independently, prevent the development of severe disabling contractures and complications, increase the life expectancy and quality of life of patients, and improve their functional and social status [178-180, 189-190]. Implementation of this concept is only possible in the format of personalized physical therapy and rehabilitation.

The paradigm of DMD patient care, which was based on maximum preservation of the child's energy and minimal movement, is becoming a thing of the past. It has been proven that muscle disuse in DMD leads to their atrophy [190, 191]. Moderate regular physical activity from an early age and safe sports such as walking, swimming, and unloaded stationary cycling are necessary; they stabilize the children's condition and preserve their muscles.

Rehabilitation goals must be determined both for daily work with the child (lifestyle-based rehabilitation — in this case, it is a collaborative effort between a physical and rehabilitation medicine physician (or other specialists with relevant knowledge, such as an exercise therapy physician, physical therapist, reflexotherapist, trauma-orthopedist, neurologist, etc.), parents, and sometimes the child themselves) — involving longer-term goals, and with each visit of the child to a rehabilitation course at a rehabilitation center — short-term and deferred goals.

General goals of rehabilitation for patients with DMD [189, 191]:

• enable the patient to gain control over themselves and possible movements;

• achieve balance and general motor coordination;

• delay the development of weakness in the pelvic girdle and scapular muscles;

• ensure correct posture (standing, sitting, lying down, or during movement);

• balance muscle function while avoiding fatigue;

• develop the contractile strength of the respiratory muscles;

• manage breathing through the proper use of the diaphragm;

• prevent early muscle shortening.

Rehabilitation of patients with DMD/BMD is a daily, multi-year commitment by the family. Physicians can assess the condition, set the direction, create a list of procedures, and provide training, but daily work by the family is mandatory. Families must be supported in every possible way so that they understand the necessity of daily work with the child and perform the prescribed procedures without errors.

To provide this type of care, the involvement of a physical and rehabilitation medicine physician or another physician performing this function (and others with relevant knowledge, for example: an exercise therapy physician, physical therapist, reflexotherapist, trauma-orthopedist, neurologist, etc.) is required. The physical and rehabilitation medicine physician, or the physician performing their function, monitors and implements rehabilitation programs, adapting/customizing them to the individual needs of the patient in accordance with the International Classification of Functioning, depending on the stage of the disease, mobility level, and the presence/absence of comorbid conditions [https://www.parentprojectmd.org/care/care-guidelines/by-area/physical-therapy-and-stretching/].

If necessary, a neurosurgeon, otorhinolaryngologist-audiologist, as well as a speech therapist (medical speech pathologist), defectologist, and other specialists are involved in consultation and rehabilitation care.

Patients with DMD/BMD need support to maintain the maximum level of musculoskeletal function to prevent and minimize secondary complications (development of contractures, muscle atrophy, compensatory skeletal deformity, osteopenia, osteoporosis). Regular moderate physical exercise is indicated. During rehabilitation measures, excessive loads and high-resistance eccentric exercises should be avoided [106].

Rehabilitation methods for DMD/BMD are divided into non-technical (these include physical therapy: active and passive stretching to maintain joint range of motion, exercise therapy, walking, swimming, cycling, etc.) and technical (limb orthoses), as well as mechanical and robotic methods (mechanotherapy, standing frames, use of rehabilitation simulators). During rehabilitation measures, it is necessary to:

• try to integrate physical therapy and regular physical activity into the child's daily routine, forming a lifestyle based on them;

• take into account that fatigue is the dominant symptom in children, and therefore distribute physical activity throughout the day — "little and often";

• act proactively — set rehabilitation goals for the next few months ahead, taking into account current functional test results, the patient's current musculoskeletal status, and projected deterioration.

Depending on the leading clinical symptoms, patients with DMD/BMD may be prescribed various rehabilitation programs.

1) Physical rehabilitation methods:

• active and passive stretching (independent and assisted) 5–6 times a week for at least 60 seconds per muscle group;

• prolonged stretching using positioning and splinting;

• orthotic management and taping;

• devices for standing and walking (standing frame, standing bed, for example: standing platform with accessories, electric multi-functional medical bed, rehabilitation standing frame, etc.), parapodium standing frame, for example: parapodium walkers with a standing system, lower limb and trunk supports for standing and mobility in people with disabilities, orthopedic apparatus "Dynamic Parapodium", lower limb and trunk apparatus (orthosis) - dynamic parapodium, dynamic parapodium walkers with standing system and accessories for people with disabilities, etc.);

• soft, lightweight, flexible orthopedic shoes for walking. Rigid and high – for ankle joint fixation when the patient is sitting, including in a wheelchair;

• kinesitherapy, including hydrokinesitherapy (swimming at a water temperature of 30–33°C (optimal temperature range for best muscle metabolism)) (Therapeutic exercises in the pool, Hydrokinesitherapy for heart and pericardial diseases, Hydrokinesitherapy using underwater exercise machines for heart and pericardial diseases);

• mechanotherapy, unloaded motor methods (mechanotherapy, robotic mechanotherapy, hardware statokinetic loads, therapeutic mechanotherapy in water), biofeedback training for movement coordination (stabilometric platform) to maintain functional muscle capabilities and improve movement coordination (Support reaction biofeedback training, exercise therapy exercises using suspension systems, walking simulation with stabilization, balance therapy).

2) Physical activity: to prevent atrophy and secondary complications, patients with preserved independent ambulation and patients in the early stages of losing independent ambulation should regularly engage in muscle strengthening exercises in a submaximal (light) regime under the supervision of instructors, medical staff, or trained parents.

3) Speech therapy sessions in the presence of speech, swallowing, chewing, or salivation disorders.

4) Defectology sessions in the presence of cognitive impairments.

5) Surgical intervention in the presence of skeletal deformities (according to relevant clinical guidelines), see section 3.4.

6) Assistive technology for rehabilitation and medical equipment for function compensation and adaptation:

• patient-operated wheelchairs, wheelchairs operated by the patient/attendant (manual wheelchairs, for example: mechanical wheelchair, manually propelled wheelchair, etc.);

• motorized wheelchairs operated by the patient/attendant (motorized wheelchairs, for example: electric wheelchair, power wheelchair, etc.);

• adaptive electric beds, manually operated adaptive beds, mechanical hospital beds, hydraulically operated hospital beds, standard electric hospital beds (automatically adjustable beds) [108].

• night splints (ankle-foot orthoses or braces (ankle-foot orthosis, ankle brace) prevent the development of ankle contractures;

• day splints, but not for patients who can still walk;

• long leg splints (knee-ankle-foot orthoses (lower limb orthoses)) are used during the period when walking is very difficult or impossible. The use of such orthoses can prevent joint deformation.

• Devices for verticalization (standing frames, power wheelchairs, devices to assist with standing up (for example: manual stand-assist device, electric stand-assist device, etc.); parapodium standing frame (for example: parapodium walkers with a standing system, lower limb and trunk supports to ensure verticalization and mobility of disabled individuals, orthopedic apparatus "Dynamic Parapodium", lower limb and trunk apparatus (orthosis) - dynamic parapodium, dynamic parapodium walkers with a standing system and accessories for disabled individuals, etc.) is prescribed when the patient can no longer walk;

• when flexion contractures and stiffness appear in the fingers, supportive hand splints (upper limb orthoses) are used;

• devices for non-invasive respiratory support (non-invasive mechanical ventilation, positive expiratory pressure) in case of hypoxemia. Parents should be trained in using a mechanical insufflator-exsufflator (cough assist device / airway clearance system) or an Ambu bag (manual disposable (reusable) mechanical ventilator).

7) Regular posture monitoring: prevention of symmetrical contractures in patients who are able to walk, proper seating posture in a wheelchair that maintains spinal and pelvic symmetry, as well as spinal elongation. The use of spinal fixation (braces/corsets) is not an alternative to surgical intervention and does not delay it, but may be used in cases where surgery is impossible or the optimal surgical method has not yet been chosen.

When formulating a rehabilitation diagnosis according to the International Classification of Functioning, Disability and Health (ICF) and developing an individual rehabilitation program, it is important to categorize patients by their mobility level:

• those who move by walking independently (ambulatory stage);

• those who move in a sitting position using appropriate assistive devices for rehabilitation (early non-ambulatory stage);

• those whose mobility is limited to the bed (late non-ambulatory stage).

This functional classification makes it possible to specify rehabilitation goals for an individual patient, taking into account their capabilities and needs.

Non-invasive respiratory support (non-invasive mechanical ventilation) (positive expiratory pressure) in case of hypoxemia. Parents should be trained in using a mechanical insufflator-exsufflator (cough assist device) or an Ambu bag (manual disposable (reusable) mechanical ventilator).

Night splints (ankle-foot orthoses (ankle-foot splint, ankle-foot orthosis)) prevent the development of ankle contractures.

After the loss of the ability to walk, day splints can be used, but strictly not for patients who are still able to walk.

Long leg splints (knee-ankle-foot orthoses (lower limb orthoses)) are used at rest during the period when it is already difficult or impossible for the child to walk. The use of such orthoses can prevent contractures and deformation of the knee and ankle joints.

Standing devices (standing frames, power wheelchairs, standing-up assistance devices (e.g., manual standing aid, electric standing aid, etc.)) are necessary for non-ambulatory patients.

When flexion contractures and finger stiffness develop, supportive hand splints (upper limb orthoses) are used.

Regular posture monitoring: prevention of symmetrical contractures in patients who are able to walk, proper positioning in a wheelchair to maintain spinal and pelvic symmetry. The use of spinal fixation (corsets/braces) is not indicated due to respiratory muscle weakness, but may be used in cases where surgery is impossible or the optimal surgical method has not yet been chosen.

Comments: the course of DMD in each individual patient depends on a combination of many factors: the type and location of the mutation, genetic modifiers, age at diagnosis, adherence to comprehensive care standards, and the quality of family care (knowledge, compliance, patience, consistency, resourcefulness) [189, 198]. Medical care for children with DMD in the early stages of the disease aims to prevent, deter, and slow down the progression of complications and to preserve the ability to walk independently for as long as possible. A crucial component is daily physical therapy. This involves joint care — maintaining the range of motion and preventing contractures. One-third of children prematurely lose the ability to walk due to ankle contractures and foot deformity. This is also essential for preserving hand function. Contractures are not an inevitable feature of DMD, but rather the result of improper patient management or lack thereof. Lifelong daily physical therapy helps avoid these complications. Depending on indications, the methods listed at the beginning of the section may be used [189].

Comments: measures to adapt the home (and other) environment are necessary to ensure maximum patient independence through the safety and accessibility of all required means. Possible home adaptive equipment includes: an electric wheelchair (electric wheelchair), standing frame, patient lift (hoist) for safe transfer, ramps, stair lifts, mobile electric rehabilitation patient lifts with accessories, bathroom and toilet aids, special beds and mattresses, etc.

Comments: effective maintenance of joint range of motion, muscle extensibility, and the prevention of contractures and joint deformities require many coordinated interventions, including active muscle lengthening; daily passive stretching of joints, muscles, and soft tissues at risk of tightness identified during preliminary assessment; prolonged lengthening (splints); maintenance of optimal positioning throughout the day using orthoses (in non-ambulatory patients), standing devices (standing frames, parapodium standing frames (e.g., parapodium walkers with a standing system, lower limb and trunk supports for standing and mobility in individuals with disabilities, "Dynamic Parapodium" orthopedic appliance, lower limb and trunk appliance (orthosis) - dynamic parapodium, dynamic parapodium walkers for individuals with disabilities with a standing system and accessories, etc.), personalized mobility devices (patient-operated wheelchairs, patient/attendant-operated wheelchairs (manual wheelchairs, e.g., mechanical wheelchair, manually propelled wheelchair, etc.), patient/attendant-operated motorized wheelchairs (motorized wheelchairs, e.g., electric wheelchair, powered wheelchair, etc.) and adaptive equipment (adaptive motorized beds, manually operated adaptive beds, mechanical hospital beds, hydraulically operated hospital beds, standard motorized hospital beds (automatically adjustable beds, day/night splints (ankle-foot splints or orthoses (ankle-foot splint, ankle-foot orthosis), long leg splints (knee-ankle-foot orthoses, lower limb orthoses), upper limb orthoses), manual standing aid, electric standing aid, etc.

Daily preventive active and passive stretching of the ankles, knees, hips, wrists, hands, and neck must be performed. Parents and patients must be trained in the correct execution of active and passive stretching by a physical and rehabilitation medicine physician or a physician performing this function (medical rehabilitation specialist, exercise therapy physician), after which these exercises are performed on a daily basis. Stretching must be pain-free and initiated before joint range of motion decreases. Regular and proper performance of active and passive stretching is essential for preventing contractures. The total daily time of joint immobilization in the proper position, especially concerning the ankles (active and passive stretching, splints/orthoses, footrests), should be 7-8 hours.

Fibrotic changes in the muscles in DMD begin as early as in newborns, which emphasizes the importance and necessity of early prevention of muscle contractures. This helps preserve the patient's mobility, functionality, and range of joint motion throughout life in DMD [108].

Comments: orthoses are rehabilitation medical devices used to modify the structural and functional characteristics of the neuromuscular and skeletal systems, providing orthopedic correction, offloading, fixation, and motor function activation depending on medical indications. The total time spent wearing orthoses for ambulatory patients — up to 8–12 hours a day, 5 days a week.

Orthoses should be custom-made for each patient under the supervision of a physical and rehabilitation medicine physician or another specialist with appropriate knowledge (e.g., a physical rehabilitation specialist, kinesiotherapist, or exercise therapy physician). For ambulatory patients, they are used for nighttime stretching.

Daytime use of ankle-foot orthoses (AFOs) may be employed for stretching or positioning in patients who have lost the ability to walk independently. Knee-ankle-foot orthoses (KAFOs) may be used in non-ambulatory patients. The use of wrist or hand splints (wrist orthoses, hand orthoses) for stretching the long flexors/extensors and wrist flexors/extensors of the fingers is possible at any stage of the disease.

Comments: weight-bearing standing devices for individuals with absent or mild lower limb contractures are necessary in the late ambulatory and early non-ambulatory stages, including standing frames, motorized wheelchairs with a standing function (orthopedic device for prevention and rehabilitation: wheelchair with accessories). They provide more positive effects than conventional knee-ankle-foot orthoses (KAFOs). The following can also be used for standing: standing frames/standing beds (e.g., electric multi-functional medical bed), parapodium standing frames (e.g., parapodium walkers with a standing system, lower limb and trunk supports for standing and mobility, "Dynamic Parapodium" orthopedic apparatus, lower limb and trunk apparatus (orthosis) – dynamic parapodium, dynamic parapodium walkers with a standing system and accessories for individuals with disabilities, etc.), etc. [108].

Comments: high-resistance exercises must be avoided, and exercise performance must be closely monitored to prevent overexertion. It is extremely critical to ensure adequate rest between exercises and to exercise caution regarding potentially reduced cardiorespiratory capacity and the risk of muscle injury, even with good clinical functioning. Activities such as swimming and cycling are appropriate [109, 111, 113].

The use of hydrokinesitherapy to support motor function in boys with DMD is widely supported in the medical literature [199, 200]. Data supporting the use of hydrokinesitherapy programs to improve lung function in DMD have been published [201, 202].

The goals of hydrokinesitherapy in DMD are to maximize lung volume, prevent contractures and preserve joint ranges of motion, prolong ambulation, slow down the progression of cardiomyopathy and respiratory failure, and prevent the development of osteoporosis.

The method has no absolute contraindications in DMD/BMD. Principles of hydrokinesitherapy in DMD: safety, comfort, moderate load, variety, and emotional engagement. It is appropriate at any stage of the disease and at any age, ideally started early. Session duration is 30–45 minutes, preferably in a game format; water temperature is preferably 32^°C, and depth should preferably be chosen according to height.

In DMD, rehabilitation cannot restore destroyed muscle tissue, but it can prevent the development of non-mandatory disabling complications and slow down disease progression.

The first few sessions should be conducted not only with the parents but also with an instructor who will train the parents. The child's somatic well-being must be assessed before each session.

Comments: transient speech development delays are common in preschoolers with DMD, while specific learning disorders/deficits (dyslexia, dysgraphia, dyscalculia) are common in school-aged children. Unlike the core symptoms of DMD, speech and learning difficulties are not progressive; in many cases, boys eventually "catch up" with their peers, especially when a preschool speech therapist and an experienced educator skilled in teaching and adapting children with dyslexia/dyscalculia at school are involved in a timely manner [193, 194].

The most common disorders in patients with DMD are emotional/behavioral regulation impairments (38.7%), ADHD (31.4%), OCD (25.0%), and speech development delay (24.4%). The majority of patients (72.7%) exhibited at least one of the above. Furthermore, emotional and behavioral disorders, including depression, aggressive behavior, and anxiety, are more common in patients with DMD compared to the healthy population. The risk of developing these symptoms appears to be elevated in patients with pathogenic variants in the terminal third of the dystrophin gene, which lead to impaired formation of a larger number of protein isoforms [185, 194-197].

Children with DMD find it more difficult to control their impulsivity and emotions than other children of their age. They frequently demonstrate reduced cognitive flexibility, which can lead to disobedience and oppositional behavior. They may experience difficulties adapting to changes. They may also take systemic corticosteroids (ATC: H02), the side effects of which can affect their behavior—for example, making them more excitable and active than normal [193].

Behavioral and emotional regulation problems are more characteristic of ambulatory children with DMD (17.8%) compared to non-ambulatory patients (10%) [203].

Because oppositional defiant behavior (ODV/ODD) frequently stems from ADHD, it is rarely studied independently when considering a cohort of children with DMD. However, oppositional defiant behavior, along with other manifestations, constitutes the "core" of the so-called "Duchenne personality".

Medical services per the nomenclature of medical services: Medical speech-language pathology assessment for dysphagia, Medical speech-language pathology assessment for dysarthria, Medical speech-language pathology procedure for dysarthria, Medical speech-language pathology tonal-rhythmic procedure, Medical speech-language pathology procedure using interactive information technologies.

Comments: psychological care and support is an essential element for the successful socialization of patients with DMD/BMD. In addition, it may be needed by the patient's relatives. It is necessary to regularly assess the psychological status of the patient and their loved ones, and provide timely psychological support. If medical correction of mental disorders is required, a child psychiatrist should be involved.

4.1 Rehabilitation of ambulatory patients

For ambulatory patients, the priority remains the principles of regular moderate physical activity and the integration of physical therapy into the child's daily life in order to increase the duration of independent walking (ambulatory period) and prevent secondary, non-mandatory disabling complications of the disease. Rehabilitation goals for ambulatory patients depend on the patient's condition and are individualized:

• increasing endurance/tolerance to physical loads;

• preserving patient mobility;

• developing the respiratory system, increasing lung volume;

• developing movement coordination and balance, slowing down the progression of muscle weakness, loss of function, and the development of disuse atrophy;

• preserving/improving upper and lower limb function;

• counteracting the progression of osteoporosis;

• creating conditions for the development and normal functioning of internal organs and preventing scoliotic spinal deformity;

• developing joint range of motion, preserving range of motion in joints (especially regarding the ankle joint), foot valgus deformity, and preventing the formation of contractures;

• establishing and maintaining postural symmetry;

• preventing and correcting cognitive and speech disorders;

• teaching domestic and self-care skills in the environment.

Comment: the use of ankle-foot orthoses should be initiated when the range of ankle dorsiflexion decreases to 10 degrees or less according to goniometry data.

Comment: the use of ankle-foot orthoses should be initiated when patients begin toe-striking or walking on the forefoot. The use of the orthosis will allow patients to maintain a physiologically advantageous foot position during walking without loss of mobility and will reduce the risk of ankle contractures with the loss of ambulation.

4.2 Rehabilitation of non-ambulatory seated patients

For non-ambulatory (seated) patients, both compliance with the principle of physical load dosing and the integration of physical therapy into the child's lifestyle are important. One of the leading and preferred positions 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/posture (move in the «sitting» position), and postural control flaws, can form an asymmetrical posture pattern with uneven load distribution on the pelvic bones (right/left) with pelvic tilt (due to scoliosis) and rapidly provoke the development of scoliotic spinal deformity. Therefore, special attention should be paid to the symmetrical development of the patients' physique and proper positioning.

Rehabilitation tasks for non-ambulatory patients:

• preserving the active use of hands and any possible movements;

• slowing down the progression of muscle weakness, loss of function, and the development of disuse atrophy;

• preventing and treating osteoporosis to preserve the musculoskeletal system, reducing the risks of vertebral compression fractures and long bone fractures, and creating conditions for the development and normal functioning of internal organs;

• stretching joints and muscles in problem areas to prevent the formation of contractures;

• establishing and maintaining postural symmetry;

• preventing scoliotic spinal deformity and pelvic tilt by properly positioning the patient in the wheelchair and continuing glucocorticosteroid therapy in reduced doses;

• preventing and correcting speech disorders, salivation disorders, chewing, and swallowing;

• preserving respiratory system capabilities, initiating respiratory support;

• preventing the formation of pressure ulcers;

• teaching domestic and self-care skills in the environment.

Comments: the minimum frequency of being in orthoses is 5 times a week. Use during daytime in a sitting or standing position is possible. If there is a risk of developing deformities that hinder positioning (verticalization) or the use of shoes, constant wearing of ankle-foot orthoses may be used.

Comments: when selecting wheelchairs, one should be guided by maximum functional independence and comfort for the patient in the chair; preference should be given to active wheelchairs and powered wheelchairs.

Comments: an occupational therapist (ergotherapist and/or physical and rehabilitation medicine physician, medical rehabilitation physician, or another physician performing this function) should be involved both in selecting the exercise and stretching program and in providing recommendations regarding social interactions, such as attending educational institutions, career choice, and participation in social activities.

4.3 Rehabilitation of bedridden patients

The primary position for these patients at home is the "lying" position, which is dangerous due to the development of habitual (memorable) fixed postural deformities of the limbs and their segments caused by the action of gravity on the limbs and the patient's inability to perform antigravity movements, as well as the occurrence of complications. Thus, the "supine position with external hip rotation" posture characteristic of such children (due to the weakness of the hip adductor muscles) contributes not only to the development of paralytic hip dislocations but also to the occurrence of severe pressure ulcers in the greater trochanter area. In this context, it is crucial that the patient's position in bed and on any other surface is functionally advantageous and prevents the manifestation of fixed postural deformities and their complications. For this purpose, frequent changes of body position in bed are advisable, along with the use of makeshift aids that can easily change their shape and support the weight of the limb, thereby simulating an antigravity effect.

Rehabilitation objectives for bedridden patients:

• positioning/changing positions in bed for the purpose of adequate ventilation of all lung segments, and using techniques that promote effective sputum drainage from the bronchial tree when necessary;

• maintaining the range and amplitude of active/passive movements in any body segment and limbs;

• preserving movements in the supine position;

• preserving hand movement capabilities and any other movements;

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

• slowing down the development of disuse atrophy;

• developing joint range of motion and stretching muscles in problem areas to prevent contracture formation;

• prevention and correction of speech disorders, sialorrhea, chewing, and swallowing disorders.

4.3.1 Non-technical methods of rehabilitation for bedridden patients

Comment: during physical therapy sessions with bedridden patients, it is convenient to suspend limb segments. This method is suitable for use on both the upper (shoulders) and lower extremities (hip-knee-shin). For example, to maintain the functional activity of the upper extremities, one can use the method of eliminating gravitational forces by suspending the proximal segments of the upper extremities on straps, thereby enabling movements of the entire upper limb.

4.3.2 Technical methods/devices for rehabilitation of bedridden patients

Postural management, which includes proper positioning (in the "standing" position — verticalization (totaling at least 1 hour per day), spending time during the day in the appropriate "sitting" position), limb orthotizing, and the use of specialized and adapted positioning devices (orthostatic support systems including rolls, molded pillows of various stiffness and configuration), in order to impart the necessary functional position with appropriate trunk fixation, head support, and upper extremity support. 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 [117].

Comments: for spending time in the "sitting" position, seating supports or indoor wheelchairs with additional fixation (support) for the head, legs, arms, and body are used. Sitting in the technical aid is possible while wearing ankle-foot orthoses (AFOs) or high orthopedic shoes. Staying in the correct "sitting" position totals up to 6 hours a day. Additional functions in the seating device should include: a functional headrest (adjustable headrest) providing lateral and anteroposterior head stabilization without restricting head movement; a seat with adjustable depth, width, and tilt angle, structurally divided into pelvic and thigh parts, which allows for the most comprehensive resolution of the patient's balance and symmetry problems caused by secondary orthopedic complications; a height- and tilt-adjustable backrest; a trunk support (vest), a safety pelvic belt, adjustable armrests; separate, adjustable footrests with foot fixators; an attached tray; an anti-decubitus cushion.

Comments: if the patient already has formed contractures, but with the possibility of at least partial correction, it is necessary to continue using orthoses in the position of maximum possible correction to prevent the worsening of deformity, the development of pain syndrome, and the inability to wear shoes.

5. Prevention and Dispensary Observation

5.1 Prevention

Comment: families with children suffering from DMD/BMD are indicated for medical genetic counseling to determine the genetic risk of having subsequent children with DMD. In DMD/BMD, the genetic risk for siblings (brothers/sisters of the proband) is that all girls will be healthy, while for boys the risk is high at 50%. In families with a child suffering from DMD/BMD, prenatal and preimplantation diagnosis is possible. Prenatal diagnosis is also indicated if the patient's mother is not a carrier of the disease, due to the possibility of gonadal mosaicism (a 15% risk if the family has a child with DMD). For this, parents need to contact specialized diagnostic laboratories and medical centers.

Prenatal diagnosis is carried out using molecular genetic methods at 9–11 weeks of pregnancy and/or using amniotic fluid cells and umbilical cord blood at 20–22 weeks of pregnancy. Chorionic villus sampling is optimal: in case of an unfavorable prognosis, the pregnancy can be terminated within the timeframe of a standard medical abortion. Preimplantation genetic diagnosis of the embryo (using in vitro fertilization) is performed for the mother of a DMD/BMD patient, as well as for women with confirmed heterozygous carriage of a mutation in the DMD gene, in order to prevent the recurrence of a child with DMD/BMD in the family.

Molecular genetic testing must be performed on the patients' mothers and siblings, including female siblings.

Comment: vaccination is administered to children with DMD/BMD in accordance with the National Immunization Schedule. DMD is not an indication for medical exemption from vaccinations; on the contrary, children with chronic diseases need protection against infectious diseases more than healthy ones. It is advisable to complete live-virus vaccinations before starting systemic corticosteroids [1–3].

Comment: Decreased bone mineral density is a common manifestation in patients with DMD. In ambulatory children, gait instability and difficulty maintaining balance due to muscle weakness, combined with osteoporosis, increase the risk of bone and spinal fractures. Balance exercises on a stabilometric platform and hydrokinesiotherapy are indicated. The most frequent cause of falls in non-ambulatory DMD patients is not being secured in the wheelchair or patient transfers. Education can be provided by the attending neurologist, a physical and rehabilitation medicine physician, or a specialist performing this function (medical rehabilitation specialist: exercise therapy physician, etc.).

5.2 Dispensary monitoring

Regular monitoring and examination by a multidisciplinary team is an important aspect of the management of patients with DMD/BMD. The schedule of examinations and visits to subspecialists is presented in Appendix A3.4.

Comment: Frequency: at least once every 6 months.

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

Comment: See Section 4 "Medical rehabilitation, medical indications and contraindications for the use of rehabilitation methods, including those based on natural therapeutic factors".

Comment: Height assessment can be performed by the neurologist, pediatrician, or pediatric endocrinologist who regularly follows the patient. Any of the following signs should be regarded as growth retardation: growth velocity less than 4 cm/year, height < 3rd percentile, or a downward shift across height percentiles [79]. If growth retardation is detected, the patient should be referred for an initial or follow-up consultation with a pediatric endocrinologist/endocrinologist.

Comment: Pubertal assessment can be performed by the neurologist, pediatrician, or pediatric endocrinologist who regularly follows the patient. A testicular volume < 4 cm³ at age 14 years or older should be regarded as a clear sign of delayed puberty [79]. If delayed puberty is detected, an initial or follow-up consultation with a pediatric endocrinologist is required.

Comments: Frequency: at least once every 6 months.

Comment: At least twice a year. If vitamin D insufficiency or deficiency is detected the patient must be referred for an initial or follow-up consultation with a pediatric endocrinologist/endocrinologist and receive appropriate medical correction. Patients with DMD/BMD, especially those receiving systemic glucocorticoid therapy (ATC: H02 Systemic corticosteroids), should be regularly screened for hypocalcemia and vitamin D deficiency. Vitamin D and its analogs can also be prescribed for prophylactic purposes, particularly during the autumn-winter period. Normalizing vitamin D levels is also necessary prior to initiating antiresorptive bisphosphonate therapy and when preparing for surgical treatment.

Comments: The scope of investigations and further diagnostic tactics are determined by the nephrologist.

Instrumental examinations.

Comments:

Comments: as a rule, vertebral compression fractures and scoliotic spinal deformity in patients with DMD/BMD manifest in the late ambulatory stage and early non-ambulatory stage. The study is performed in patients presenting with pain symptoms or posture disorders at least once a year, as well as after the patient becomes non-ambulatory, and subsequently once every 6 months if scoliosis or spinal pain progresses.

Comments: performed in children older than 6 years with a frequency of once a year.

Comments: all main parameters are measured (VC, FVC, FEV₁, FEF_25-75 (if possible), MEF_25-75, PEF_exp) once a year; when FVC values decrease below 60%, testing is performed once every 6 months.

Comments: once every 6 months. When possible, capnography is indicated as the most sensitive method for diagnosing early respiratory failure [10–13, 39, 80, 81].

Other methods.

Comment: during the initial consultation, the geneticist performs an examination and preliminary differential diagnosis, and determines the scope of molecular genetic testing. During the follow-up consultation, the geneticist interprets the results of molecular genetic testing, determines the need for additional studies (validation, segregation, functional studies), and explains the obtained results to the patient's legal representatives. Interpretation of results and determination of molecular genetic diagnostic tactics by other specialists is unacceptable.

Comment: frequency of monitoring for ambulatory patients – once every 12 months, for non-ambulatory patients – once every 6 months. Assessment of motor functions and range of motion may also be performed by a physical and rehabilitation medicine physician or a specialist performing this function (medical rehabilitation specialist: physical therapy physician, etc.) (Appendices A3.3, A3.5, A3.6, G1-G7).

Comment: Frequency: at least once every 6 months.

Comments: frequency is once every 12 months, more frequently in cases of delayed puberty, growth retardation, impaired glucose tolerance, diabetes mellitus, obesity, Cushing's syndrome, and other potential side effects of systemic corticosteroid therapy, for additional diagnostics and necessary medical correction.

Comments: frequency: as clinically indicated, but at least once every 12 months.

Comments: frequency: as clinically indicated. The weight of children with DMD exhibits changes characteristic of the disease and typically increases first after initiating glucocorticoid therapy as standard treatment, and a second time after the loss of ambulation. Weight and body mass index are prognostic factors for the course of DMD. Overweight in a child with DMD is a prognostic factor for a more rapid decline in 6-minute walk test performance and a future need for permanent respiratory support [189]. Excess weight increases the risk of long bone fractures, subsequently leading to a higher incidence of fat embolism syndrome. Other complications of increased weight include hypertension, diabetes, and more pronounced cardiomyopathy. Normal weight is a proven factor for a more favorable course of DMD [2]. In advanced stages of the disease, with progressive swallowing problems and gastrointestinal muscle weakness, asthenia frequently develops, requiring nutritional support via a feeding tube or gastrostomy [2].

Comments: performing spirometry (testing of unforced respiratory volumes and flows) to assess external respiration function with measurement of all main parameters (VC, FVC, FEV₁, FEF_25-75, MEF_25-75, PEF_exp), frequency – at least once every 6 months. During the outpatient stage of the disease, patients should be trained in performing spirometry (testing of unforced respiratory volumes and flows). Patients should have a pulse oximeter at home for regular oxygen saturation measurements.

Comments: this method must be performed in overweight patients receiving systemic corticosteroids.

Comments: at the time of diagnosis and thereafter starting from the late outpatient stage — once a year, starting from the early non-ambulatory stage — once every 6 months, more frequently as clinically indicated.

Comments: frequency — at the time of diagnosis and thereafter at least once a year. Monitoring may be more frequent as the disease progresses and cardiovascular pathology develops. In addition, all patients with DMD/BMD require an initial (and follow-up, if necessary) consultation (examination) with a cardiologist/pediatric cardiologist, as well as an electrocardiogram and echocardiography prior to elective surgery [31, 39].

Comments: at least once a year; if possible and necessary, echocardiography may be replaced by cardiac and great vessel magnetic resonance imaging. As prescribed by the cardiologist, Holter ECG monitoring should also be used.

Comments: frequency — as clinically indicated.

Comments: frequency — as clinically indicated.

Comments: decreased bone mineral density is a common symptom in patients with DMD/BMD. Unsteady gait and difficulty maintaining balance due to muscle weakness, combined with osteoporosis, pose a risk of bone and vertebral fractures. All patients with DMD/BMD, regardless of the degree of immobility (e.g., wheelchair users), must be instructed in all precautions to prevent falls and fractures in everyday life. Patients and family members should be informed of all the consequences of inadequate management of osteoporosis and the potential development of fat embolism syndrome, a life-threatening condition frequently seen in DMD.

Comments: frequency — at least once every 12 months for non-ambulatory patients, more frequently if necessary.

6. Organization of Medical Care

Indications for planned hospitalization in a medical organization [76]:

• differential diagnosis and establishment of a definitive diagnosis, treatment requiring round-the-clock medical supervision;

• selection of the optimal regimen and dose of systemic corticosteroids;

• selection of specific pathogenetic therapy depending on the type and location of genetic variants;

• surgical interventions for the correction of scoliosis, foot deformity, and Achilles tendon surgery;

• treatment of osteoporosis;

• gastrostomy placement (gastrostomy);

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

• a condition requiring high-tech treatment and rehabilitation methods;

• the need for various expert evaluations or examinations in a medical institution when outpatient performance is not feasible and dynamic observation is required.

Indications for emergency hospitalization to a medical organization [75]:

• bone fractures;

• fat embolism syndrome resulting from low-energy fractures of long bones;

• adrenal insufficiency in patients receiving systemic corticosteroids, against the background of fever, vomiting, psychological stress, or surgery [2];

• serious respiratory complications — severe pneumonia, aspiration, grade 2–3 respiratory failure, acute diseases, exacerbations of chronic conditions, poisoning and injuries, conditions requiring intensive care and transfer to intensive care units or intensive care wards, as well as round-the-clock medical supervision and special diagnostic and therapeutic procedures;

• serious cardiovascular complications – carditis, heart failure, arrhythmia.

Indications for discharging the patient from the medical organization [76]:

• absence of a threat to the patient's life;

• absence of the risk of developing complications requiring emergency treatment;

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

• no need for continuous physician and round-the-clock medical supervision for the underlying disease;

• need for transfer of the patient to another medical organization or social welfare institution [2].

7. Additional Information

Early diagnosis of DMD and initiation of therapy help improve prognosis and slow disease progression. Regional pilot projects have been launched for early screening of children with DMD based on blood creatine kinase (CK) levels during routine health checks at 1 year of age, as well as selective screening in hospitals in the presence of certain symptoms. The inclusion of DMD in mass newborn screening programs in the Russian Federation starting in 2026 is currently under consideration.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

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

2. Svetlana B. Artemyeva — Cand. of Sci. (Med.), Neurologist, Head of the Psychoneurology and Epileptology Department at the Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

3. Alexander A. Baranov — Academician of the Russian Academy of Sciences, Professor, Dr. of Sci. (Med.); Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Professor at the Department of Pediatrics and Pediatric Rheumatology of the V.F. Vorhois Child Health Institute of the I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Chief freelance pediatric specialist of the Russian Ministry of Health.

4. Tatyana T. Batysheva — Professor, Dr. of Sci. (Med.), President of the Association of Pediatric Rehabilitologists of Russia, Director of the Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Healthcare Department, Head of the Department of Pediatric Neurology, Physical and Radiological Medicine of the Faculty of Continuous Medical Education of RUDN University, Chief freelance pediatric rehabilitologist of the Russian Ministry of Health, Honored Doctor of Russia.

5. Sergey B. Bondarenko — Cand. of Sci. (Med.), Pediatric Surgeon, Shcherbinka Polyclinic of the Moscow Healthcare Department, Chief freelance pediatric surgeon of the Western Administrative Okrug of Moscow.

6. Elena D. Belousova — Dr. of Sci. (Med.), Professor, Neurologist, Head of the Psychoneurology and Epileptology Department at the Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

7. Olga V. Bykova — Dr. of Sci. (Med.), Head of the Research Department at the Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Healthcare Department, Professor at the Department of Pediatric Neurology, Physical and Radiological Medicine of the Faculty of Continuous Medical Education of RUDN University, Moscow.

8. Nato D. Vashakmadze — Dr. of Sci. (Med.), Head of the Department of Orphan Diseases and Prevention of Disabling Conditions at the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics of the Institute of Maternity and Childhood of the Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University), Member of the Union of Pediatrists of Russia.

9. Elena A. Vishneva — D.Sc. in Medicine, Professor of the Russian Academy of Sciences, Deputy Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Center of Surgery; Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Member of the Union of Pediatricians of Russia.

10. Dmitry V. Vlodavets — Ph.D. in Medicine, Neurologist, Senior Researcher at the Department of Psychoneurology and Epileptology, Veltischev Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

11. Sergey V. Voronin — Ph.D. in Medicine, Chief Physician, Research Centre for Medical Genetics; Chief Freelance Specialist in Medical Genetics of the Russian Ministry of Health in the Far Eastern Federal District.

12. Tatiana A. Gremyakova — D.Sc. in Medicine, Head of the Pediatric High-Tech Neuromuscular Center, Central Clinical Hospital with Policlinic of the Administration of the President of the Russian Federation; Member of the International Advisory Board of the DMD Patient Community; President of the Gordeeva Charitable Foundation (Member of the Association of Professional Hospice Care Workers, Union of Pediatricians of Russia, World Duchenne Organization).

13. Olga S. Groznova — D.Sc. in Medicine, Leading Researcher at the Department of Pediatric Cardiology and Arrhythmology, Veltischev Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

14. Valentina I. Guzeva — Honored Scientist of the Russian Federation, D.Sc. in Medicine, Professor, Chief Freelance Pediatric Neurologist of the Russian Ministry of Health, Head of the Department of Neurology, Neurosurgery, and Medical Genetics, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation.

15. Victoria V. Guzeva — D.Sc. in Medicine, Professor, Professor at the Department of Neurology, Neurosurgery, and Medical Genetics, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation.

16. Oksana V. Guzeva — D.Sc. in Medicine, Professor, Professor at the Department of Neurology, Neurosurgery, and Medical Genetics, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation.

17. Y.A. Klimov — Ph.D. in Medicine, Deputy Director for Medical Work, Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Healthcare Department; Head of the Department of Neurology and Neurosurgery, Russian State Social University.

18. Lyudmila M. Kuzenkova — D.Sc. in Medicine, Professor, Head of the Center of Pediatric Psychoneurology, Head of the Department of Psychoneurology and Psychosomatic Pathology, National Medical Research Center for Children's Health of the Russian Ministry of Health; Member of the Association of Medical Geneticists (AMG).

19. Aleksey L. Kurenkov — D.Sc. in Medicine, Head of the Laboratory of Nervous Diseases, National Medical Research Center for Children's Health of the Russian Ministry of Health.

20. Sergey I. Kutsev — Academician of the Russian Academy of Sciences, D.Sc. in Medicine, Director of the Bochkov Research Centre for Medical Genetics, Chief Freelance Specialist in Medical Genetics of the Russian Ministry of Health, President of the Association of Medical Geneticists of Russia.

21. Olga A. Laisheva — D.Sc. in Medicine, Professor at the Department of Rehabilitation, Sports Medicine, and Physical Culture, Solovyov Institute of Preventive Medicine, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Head of the Medical Rehabilitation Center, Russian Children's Clinical Hospital, a branch of Pirogov Russian National Research Medical University of the Russian Ministry of Health.

22. Svetlana V. Mikhailova — D.Sc. in Medicine, Head of the Department of Medical Genetics, Russian Children's Clinical Hospital of the Russian Ministry of Health.

23. Lyudmila P. Nazarenko — D.Sc. in Medicine, Professor, Honored Doctor of the Russian Federation, Deputy Director for Research and Clinical Work, Head of the Laboratory of Hereditary Pathology, Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences.

24. Leyla S. Namazova-Baranova — Academician of the Russian Academy of Sciences, Professor, D.Sc. in Medicine, President of the Union of Pediatricians of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Center of Surgery; Head of the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Chief Freelance Pediatric Specialist in Preventive Medicine of the Russian Ministry of Health.

25. Sergey S. Nikitin — D.Sc. in Medicine, Professor, Head of the Department of Genetics of Nervous Diseases, Bochkov Research Centre for Medical Genetics.

26. Artem Yu. Novikov — Child Psychiatrist, Rassvet Clinic.

27. Tatiana V. Podkletnova — Ph.D. in Medicine, Neurologist, Senior Researcher at the Laboratory of Nervous Diseases, National Medical Research Center for Children's Health of the Russian Ministry of Health.

28. Elena V. Polevichenko — D.Sc. in Medicine, Professor at the Department of Oncology, Hematology, and Radiology of the Pediatric Faculty, Pirogov Russian National Research Medical University; Chief Freelance Pediatric Specialist in Palliative Medical Care of the Russian Ministry of Health; Member of the Board of the Association of Professional Hospice Care Workers.

29. Alexander V. Polyakov — Corresponding Member of the Russian Academy of Sciences, D.Sc. in Biology, Professor, Head of the DNA Diagnostics Laboratory, Bochkov Research Centre for Medical Genetics.

30. Sofia G. Popovich — Researcher at the Laboratory of Nervous Diseases, Neurologist at the Department of Psychoneurology and Neurorehabilitation, National Medical Research Center for Children's Health of the Russian Ministry of Health.

31. Gennady G. Prokopyev — Ph.D. in Medicine, Anesthesiologist-Resuscitator, Associate Professor at the Department of Pediatric Anesthesiology and Intensive Care, Faculty of Advanced Training for Physicians, Pirogov Russian National Research Medical University; Leading Researcher and Head of the Department, Scientific and Practical Center for Specialized Medical Care for Children named after V.F. Voyno-Yasenetsky of the Moscow Healthcare Department.

32. Dmitry I. Rudenko — D.Sc. in Medicine, Professor, Deputy Chief Physician, City Multidisciplinary Hospital No. 2, Pavlov First Saint Petersburg State Medical University.

33. Svetlana A. Repina — Ph.D. in Medicine, Geneticist at the Bochkov Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists, Member of the Association of Medical Geneticists.

34. Sergey O. Ryabykh — D.Sc. in Medicine, Deputy Director for Research, Head of the Department of Pediatric Traumatology and Orthopedics, Veltischev Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Moscow; Professor at the Department of Traumatology and Orthopedics, Faculty of Medicine, Saint Petersburg State University; Highest Category Traumatologist-Orthopedist; Member of the Interregional Association of Spine Surgeons of Russia, Member of the All-Russian Society of Traumatologists-Orthopedists.

35. Gulzhan E. Sakbaeva — Head of the Department of Pediatric Neurology, Central Clinical Hospital with Policlinic of the Administration of the President of the Russian Federation.

36. Elena Yu. Sapego — Neurologist, Head of the Department of Palliative Medical Care for Children, Regional Children's Clinical Hospital, Yekaterinburg.

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

38. Liliya R. Selimzyanova — Ph.D. in Medicine, Head of the Department of Standardization and Study of Evidence-Based Medicine Principles, Research Institute of Pediatrics and Child Health, Petrovsky National Research Center of Surgery; Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health; Associate Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Member of the Union of Pediatricians of Russia.

39. Olga Ya. Smirnova — Geneticist at the Medical Genetics Department, Krasnopolsky Moscow Regional Research Institute of Obstetrics and Gynecology (MONIKI); Member of the Union of Pediatricians of Russia, Member of the Association of Medical Geneticists.

40. Andrey A. Stepanov — D.Sc. in Medicine, Professor, Chief Freelance Pediatric Specialist of the Administration of the President of the Russian Federation, Deputy Chief Physician for Medical Work, Central Clinical Hospital with Policlinic of the Administration of the President of the Russian Federation.

41. Dmitry M. Subbotin — Researcher at the Laboratory of Neurogenetics, Geneticist at the Bochkov Research Centre for Medical Genetics, Member of the Association of Medical Geneticists.

42. Vasily M. Suslov — Ph.D. in Medicine, Associate Professor at the Department of Rehabilitology, Faculty of Professional Development and Postgraduate Education, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health.

43. S.V. Tikhonov — Ph.D. in Biology, Scientific Secretary, Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Healthcare Department; Associate Professor at the Department of Neurology, Physical and Rehabilitation Medicine, Faculty of Continuous Medical Education, RUDN University, Moscow.

44. Elena V. Tozliyan — Cand. of Sci. (Med.), Pediatric Endocrinologist, Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University, Russian Ministry of Health.

45. Dmitry A. Feklistov — Orthopedic Trauma Surgeon, Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University, Russian Ministry of Health.

46. Evgenia M. Tsvetkova — MBA, Head of the Rehabilitation Center, Central Clinical Hospital with Policlinic of the Administration of the President of the Russian Federation.

47. Nadezhda I. Shakhovskaya — Cand. of Sci. (Med.), Deputy Chief Physician for Medical Affairs, Moscow Region Psychoneurological Hospital for Children with Central Nervous System Lesions and Mental Disorders, Honored Healthcare Worker of the Moscow Region.

48. Ekaterina V. Schrader — Pediatric Endocrinologist, Central Clinical Hospital with Policlinic of the Administration of the President of the Russian Federation.

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

Appendix A2. Methodology for Developing Clinical Guidelines

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

Target audience for these clinical guidelines:

1. Pediatricians;

2. Neurologists;

3. Medical geneticists;

4. General practitioners (family physicians);

5. General practitioners;

6. Laboratory geneticists;

7. Cardiologists;

8. Pediatric cardiologists;

9. Palliative care physicians;

10. Endocrinologists;

11. Radiologists;

12. Functional diagnostics physicians;

13. Pulmonologists;

14. Gastroenterologists;

15. Trauma and orthopedic surgeons;

16. Ophthalmologists;

17. Otorhinolaryngologists;

18. Medical psychologists;

19. Medical students;

20. Residents in training.

Table 1. Scale for assessing the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

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

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

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

4. Order of the Russian Ministry of Health No. 203n of April 14, 2025, "On Approval of Criteria for Assessing the Quality of Medical Care".

5. Order of the Russian Ministry of Health No. 208n and Ministry of Labor of the Russian Federation No. 243n of April 14, 2025, "On Approval of the Regulations on the Organization of Palliative Medical Care, Including the Procedure for Interaction Between Medical Organizations, Social Welfare Organizations, and Public Associations and Other Non-Profit Organizations Operating in Healthcare".

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

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

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

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

2. Order of the Russian Ministry of Health No. 205n of May 2, 2023 (as amended on June 3, 2025), "On Approval of the Nomenclature of Positions for Medical and Pharmaceutical Workers".

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

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

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

Appendix A3.1 Main symptoms of DMD

Appendix A3.2 Main diseases for differential diagnosis of DMD

Appendix A3.3 Performing motor tests in DMD

Appendix A3.4 Monitoring the condition of a patient with DMD

¹ - in patients receiving systemic corticosteroid therapy

² - in the absence of systemic corticosteroid therapy

To monitor the condition of patients receiving disease-modifying therapy, follow-up is required at least once a year in specialized centers capable of providing medical care in accordance with these clinical guidelines.

Appendix A3.5 Timed test: ascending 4 stairs

The test does not require complex equipment and can be performed in both inpatient and outpatient settings.

Required equipment: stopwatch, stairs.

During the test, the patient is instructed to climb 4 steps on a staircase, after which the time spent climbing the steps is recorded.

Appendix A3.6 Timed test: descending 4 stairs

The test does not require complex equipment and can be performed in both inpatient and outpatient settings.

Required equipment: stopwatch, stairs.

During the test, the patient is instructed to descend 4 steps on a staircase, after which the time spent descending the steps is recorded.

Appendix A3.7 Measurement of joint range of motion (Goniometry)

Initial objective: to identify decreased range of motion in joints and/or the presence of joint contractures that may contribute to/lead to functional deterioration, musculoskeletal impairments, or skin problems. Identifying the need for additional/alternative medical/surgical intervention (use of orthoses, splinting, standing devices, muscle lengthening surgery).

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Progressive Duchenne muscular dystrophy

Duchenne muscular dystrophy belongs to a class of muscle diseases collectively known as «dystrophinopathies». Dystrophinopathies develop due to a lack of synthesis of the muscle protein dystrophin. The disease has severe symptoms and a malignant course. The incidence of DMD is approximately 1 case per 3,500–5,000 live male births. The disease occurs in virtually all ethnic groups. Becker muscular dystrophy has less pronounced, more benign manifestations because the synthesis of a shortened version of dystrophin is preserved.

DMD is a rare hereditary disease. As a result of a mutation in the DMD gene, a deficiency and/or dysfunction of the dystrophin protein develops. The mutation is usually inherited; in one-third of cases, a spontaneous mutation (de novo) occurs. The dystrophin gene is one of the largest human genes, containing 79 exons. In ~65% of cases, large deletions occur; ~10% of mutations are duplications, and the remaining cases are point and small mutations, of which 10-15% are nonsense mutations.

The dystrophin protein is involved in the function of skeletal muscles, respiratory muscles, and the cardiovascular system. It links the internal cytoskeleton to sarco- and dystroglycans in the membrane and extracellular matrix, ensuring mechanical and structural stability of the muscle fiber membrane during contraction. Dystrophin also acts as a shock absorber, ensuring the return of the muscle to its initial state after tension. As the disease progresses, muscle fibers are destroyed and replaced by fibrous and adipose tissue.

The disease manifests at the age of 1–5 years, progresses rapidly, and usually leads to death by the age of 25. Most commonly, patient death results from respiratory failure, heart failure, or intercurrent infections.

Most patients are characterized by delayed early motor development milestones. At the onset of independent walking, frequent falls, stumbling, motor clumsiness, and rapid fatigue are noted. Gradually, the gait becomes waddling, and difficulties arise when climbing stairs and rising from a squatting position, when patients are forced to use Gowers' auxiliary maneuvers («climbing up oneself»). In the early stages of the disease, muscle pseudohypertrophy is detected, resulting from the proliferation of connective and adipose tissue replacing dying muscle fibers. The most common localization is in the gastrocnemius, deltoid, quadriceps, and triceps muscles, creating a false impression of an athletic physique in the patient. As the disease progresses, muscle pseudohypertrophy transforms into hypo- and atrophy. The spread of the pathological process is ascending. The muscles of the pelvic girdle and proximal lower extremities are affected first, followed by the muscles of the shoulder girdle, back, and proximal upper extremities. Patients retain the ability to walk independently up to 10–12 years of age, after which they use a wheelchair exclusively. Already in the early stages of the disease, knee reflexes are reduced or extinguished. The Achilles reflex, as well as tendon reflexes from the arms, may remain preserved for a long time. As the pathological process develops in the muscles, secondary spinal deformities (increased lordosis and kyphosis, scoliosis), chest deformities (saddle- and pigeon-chest type), and foot deformities occur, as well as tendon retractions with the development of joint contractures. A characteristic sign of the disease is cardiomyopathy, which manifests as symptoms of left ventricular hypertrophy and arrhythmia. In 25–30% of patients, intellectual disability, neurodevelopmental disorders, and behavioral peculiarities are diagnosed.

Early and late symptoms of DMD are distinguished

Inheritance.

X-linked recessive, meaning it affects almost exclusively males, while females with a damaged gene on one of the X chromosomes are DMD carriers. However, in rare cases, females can also suffer from Duchenne muscular dystrophy. The reasons for this may include preferential inactivation of the X chromosome with the normal allele in heterozygous carriers of the mutant dystrophin gene, an X-autosome translocation involving this gene, hemizygosity for the mutant allele, and the presence of phenocopies (diseases associated with impairments of other proteins belonging to the dystrophin-glycoprotein complex). In approximately 2/3 of cases, the son receives the damaged chromosome from a carrier mother; in other cases, the disease arises as a result of a de novo mutation in the mother's or father's germ cells (this is how girls who are carriers of the defective gene appear), or in the precursors of these cells. Approximately 30% of all disease cases are associated with the emergence of new mutations in the dystrophin gene, while the remaining 70% are due to maternal carrier status of a pathological mutation in one of the X chromosomes. It is believed that 6-7% of all sporadic cases of the disease are the result of gonadal mosaicism—the presence in a woman's ovaries of several generations of oocytes with normal and mutant alleles of the dystrophin gene.

Diagnosis.

Doctors may suspect the disease based on clinical symptoms. Next, laboratory tests and instrumental examinations are performed. When Duchenne muscular dystrophy is suspected, the most common first test is a blood test to determine the level of creatine kinase (CK). In patients with DMD, CK levels are 10–100 times higher than normal. If elevated CK levels are detected, genetic testing should be performed to search for changes in DNA (genetic mutations) characteristic of DMD. You can also discuss the genetic testing results with medical geneticists, how they may affect your child, and potentially other family members.

Treatment.

DMD management is based on a multidisciplinary approach involving specialists from various fields, with the mandatory participation of family members and a coordinating physician.

Comprehensive standard therapy initiated upon early diagnosis, in the early stages of DMD, aimed at preventing complications, preserving functions, and slowing the course of the disease makes it milder, preserves the ability to walk independently for additional years, reduces the number of disabling complications non-essential to the nosology, improves quality of life, delays the age at which corrective treatments are needed, and increases the overall and functionally active life expectancy of patients by many years.

Proper management of a child with DMD:

o Range of motion in joints is preserved, especially regarding the ankle joint

o Absence of foot valgus deformity

o Logbook of the child's condition and functional test results – 6MWT, 4-step stair climb, rise from supine position, 10-meter run, weight, height (monthly)

o Vitamin D level above 30 ng/mL, monitored twice a year

o Glucocorticosteroids (ATC: H02 Systemic corticosteroids), no later than 6 years of age, starting with minimal doses and increasing to recommended or tolerated ones

o Adjustment of the regimen and dosage of steroids (ATC: H02 Systemic corticosteroids) upon growth cessation; height must increase by at least 4 cm annually

o Normal weight of the child regardless of steroid intake (ATC: H02 Systemic corticosteroids) achieved through proactive diet optimization

o Active and passive stretches, night splints, footrests, growing chair daily, ankle joint fixation for a total of at least 8 hours a day

o Warm pool with lung development exercises, bicycle, stationary bike

o Consideration of the specific neurodevelopmental characteristics of the individual child

o Health status monitoring 1–2 times a year

A more favorable course of the disease, quality of life for the patient and their family can be achieved by prolonging the early ambulatory stage of DMD, preventing the onset of disabling complications, slowing disease progression, and preserving the functional capabilities that children have at this stage.

It is possible and necessary to change the trajectory of the disease, slow its progression, and translate it into a milder form by following the formula: "prevent, slow down, preserve." For a progressive disease like DMD, the "restore" function is not yet available.

We are already witnessing a change in the course of the disease—comprehensive standard therapy (GCS, physical therapy, cardioprophylaxis and therapy, osteoporosis prevention in children with DMD) prolongs their ability to walk until 12–15 years of age. They have no contractures, fractures of the long tubular bones of the legs and disabling scoliosis occur less frequently, lung volume is larger, and the need for respiratory support and the development of cardiomyopathy are delayed. This represents an entirely different quality of life, and new opportunities for socialization, education, and work.

Pathogenetic therapy aimed at restoring the missing dystrophin protein or eliminating secondary pathology has emerged, and some medications are available to Russian patients. Timely administration and combination of pathogenetic and comprehensive standard therapies increase their efficacy. The clinical efficacy of pathogenetic therapies depends on the patient's functional status, the stage of disease progression, the preservation of muscles and other organs and systems, and includes stabilization and improvement of functional status, slowing of disease progression, prolonging the children's ability to walk for several years, improvement in timed and motor function tests, preservation of hand function, and stabilization of cardiac and respiratory function. Demonstrating clinical efficacy requires months and years of drug administration.

Patients receiving targeted investigational pathogenetic therapies demonstrate sustained improvement, stabilization, and, with some drugs, significant health improvements. In international practice, patients with DMD walk until twenty years of age and beyond, get an education, work, and start families.

Medical genetic counseling.

It is very important for families to visit a geneticist. A medical geneticist can correctly determine the tactics and subsequently interpret the results of DNA diagnostics. After diagnosis confirmation, they will explain the risk of having another child with DMD in the family and what needs to be done to prevent it, identify relatives who need screening, and discuss prenatal diagnostics.

Prenatal diagnostics is performed at 9–11 weeks of gestation. In the sample known as chorionic villi (from which the placenta subsequently forms), enzyme activity is determined, and testing is performed to detect mutations in the DMD gene. Based on the analysis, a conclusion is made as to whether the fetus is healthy or affected. Modern technologies also make preimplantation genetic diagnosis possible. Fertilization is carried out in vitro, then at the stage of several blastomeres, only embryos free of the familial mutation are selected and implanted into the mother's body. This procedure carries its own risks, which can be explained by a medical geneticist.

DMD is included in the list of orphan diseases.

Family support.

The success of treatment depends on the family just as much as on the physician. DMD is a chronic disease in which the daily efforts of the family are of paramount importance. It is necessary to provide care for the child, be responsible and compliant parents, follow recommendations, and under no circumstances lose hope. Currently, there are proven treatments and support methods for patients with DMD that yield tangible results and alter the natural course of the disease. Pathogenetic therapy has emerged. And even if you cannot completely defeat the disease, changing the life of your loved one for the better and making them happy is within your power.

Important resources. There are international and Russian organizations, projects, and communities designed to help ease the lives of DMD patients and their families.

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

Appendix G1. Scale for assessing the preservation of lower limb muscle function

Russian title: Vignos scale for lower extremity function.

Original title: Vignos Scale.

Source: [96].

Type: rating scale.

Purpose: clinical assessment of lower extremity muscle function.

Content:

Key (interpretation): normal is 1; 10 = no function.

Appendix G2. Scale for assessing the preservation of upper limb muscle function

Russian title: Brooke scale for upper extremity function.

Original title: Brooke Scale.

Source: [97].

Type: rating scale.

Purpose: clinical assessment of upper extremity muscle function.

Content:

Key (interpretation): normal is 1; 5 = no function.

Appendix G3. Adapted Hammersmith Motor Function Scale

Russian title: Hammersmith functional motor scale, adapted.

Original title: Hammersmith Motor Ability Scale (HMAS).

Source: [98].

Type: rating scale.

Purpose: assessment of the degree of activity limitation in patients with DMD/BMD, the rate of disease progression, and treatment response dynamics.

Content:

Key (interpretation): consists of 20 items, each scored 2, 1, or 0 points according to the degree of execution.

Appendix G4. 6MWT — 6-minute walk test

Russian title: 6-minute walk test.

Original title: The six minute walking test (6MWT).

Source: [99].

Type: other.

Purpose: to determine the endurance of ambulatory patients in order to assess treatment efficacy and disease progression.

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

Key (interpretation): comparison is made with the results of a test performed previously (before treatment, during treatment, etc.).

It should be remembered that this test has the following absolute contraindications: unstable angina pectoris and myocardial infarction within the last 1 month. Relative contraindications are: resting heart rate (HR) above 120 beats/min, systolic blood pressure (BP) > 180 mm Hg, and diastolic BP > 100 mm Hg. Stable angina is not an absolute contraindication for the test, but it should be performed with caution while taking antianginal medications (ATC: C01D Vasodilators used in cardiac diseases) as indicated.

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

The test must be stopped immediately if the following occur:

1) Chest pain;

2) Intolerable dyspnea;

3) Leg cramps;

4) Severe instability and swaying while walking;

5) Excessive sweating;

6) Sudden change in skin color (pallor).

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

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

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

Appendix G5. Methods for assessing the neuromuscular system in Duchenne muscular dystrophy

Russian title: Methods for assessing the neuromuscular system in Duchenne muscular dystrophy.

Original title: Neuromuscular assessments for patients with Duchenne muscular dystrophy.

Source: [1].

Type: rating scale.

Purpose: regular assessment of disease progression (testing strength, range of motion, posture, gait, timed tests), monitoring the ability to cope with daily activities, and making decisions regarding therapeutic interventions.

Content:

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

Appendix G6. North Star Ambulatory Assessment

Russian name: North Star Ambulatory Assessment.

Original name: North Star Ambulatory Assessment, NSAA.

Source: [100].

Type: rating scale.

Purpose: assessment of the patient's functional capabilities.

Content:

Key (interpretation): NSAA is a 17-item scale used to assess the patient's functional abilities: 0 (unable), 1 (performs independently, but with modifications), 2 (performs without compensation).

Notes:

• it is forbidden to perform standing tests in the presence of lower extremity injuries. However, the patient may be asked to perform head lifts and transitions to a sitting position if able to do so. 'Comments' should be noted in the worksheet;

• NSAA tests must be performed in the suggested order (note: the current order of tasks has been modified for a more efficient assessment and differs from the sequence of studies used in previous versions);

• DO NOT use mats;

• please note that time in seconds is rounded to the nearest tenth of a second in all timed tasks (e.g., rising from the floor or 10-m run);

• performance of the exercises is scored as follows:

  2 = 'Normal' – no deviations;

  1 = With minor modifications, but the patient completes the task without additional assistance;

  0 = Unable to complete the task independently;

• if, in your opinion, the patient could achieve a higher score that was lowered due to failure to meet certain conditions or insufficient understanding of the task, ask them to repeat the exercise and rescore their performance.

• If you are unsure whether a performance can be scored higher, assign the lower score.

Preparation:

• measure 10 meters in a long, quiet corridor or room. Mark the finish line at the 11-meter mark to ensure the patient actually runs through the 10-meter mark rather than slowing down before the finish;

• ensure a clean floor space of 3 × 3.5 m, sufficient for performing other tasks (e.g., rising from the floor).

Appendix G7. Upper limb performance module for DMD

Russian title: Performance of the Upper Limb Module for DMD.

Original title (if applicable): Performance of the Upper Limb Module for DMD 2.0 (PUL or DMD) Worksheet.

Source (official developer website, validation publication): [138].

Type (underline): rating scale, index, questionnaire, other (specify).

Purpose: functional assessment of upper extremity movements in patients with DMD/BMD; can be used to evaluate therapeutic efficacy.

Content (template):