What is this summary about? This article describes results from Study 041. Study 041 was a clinical study of ataluren, a treatment for people living with nonsense mutation Duchenne muscular dystrophy (nmDMD for short). Over time, people living with nmDMD experience muscle loss and reduced muscle strength and function (decline in muscle function). The researchers wanted to know whether 72 weeks of treatment with ataluren slowed the decline in muscle function in a large group of people living with nmDMD. To determine this, they compared the effects of ataluren with the effects of a placebo, which is a treatment that looks the same as the study treatment but has no active ingredients. The study also looked at the safety of ataluren over the 72 weeks of treatment. Ataluren has previously been compared with placebo in 48-week long clinical trials. What were the results? In this study, 359 people took at least one dose of ataluren or placebo, even if they later switched or didn’t stick to the treatment plan. Over 72 weeks, ability to walk and physical function declined less in people receiving ataluren than in people receiving placebo. This means that their physical abilities were maintained for longer if they took ataluren. The number of side effects were generally similar between people who took ataluren and those who took placebo. What do the results of Study 041 mean? These results help to confirm that 72 weeks of treatment with ataluren (compared with 72 weeks of placebo treatment) slows down the decline in muscle function experienced by people living with nmDMD. Results also confirmed that side effects reported were similar with ataluren and placebo. These results likely show that people who receive ataluren can maintain their independence for a longer time. This study is the largest phase 3 clinical study of people living with nmDMD that has been done so far.

Duchenne muscular dystrophy (DMD) is typically described in boys with a pathogenic variant in the DMD. However, in certain cases, females may also exhibit symptoms of this X-linked disorder. In the present study, the cause of Duchenne muscular dystrophy in three girls was reciprocal translocations t(X;2), t(X;12), and t(X;16), with breakpoints located within the DMD gene sequence. All patients had global development delay, predominantly proximal muscle weakness, calf muscle hypertrophy, and elevated creatine kinase levels up to 100 times the normal range (16,000-26,694 U/L). All underwent cardiac ultrasound and electromyography, and two of the girls also had muscle MRI data. After receiving negative results of MLPA aimed at the detection of DMD deletions and duplications, as well as the limb-girdle muscular dystrophy gene panel sequencing, the patients were referred to whole genome sequencing, which allowed to detect a translocation involving the short arm of the X chromosome and with breakpoints in the DMD. Karyotyping confirmed reciprocal translocations in all patients, with de novo status established in all three cases. The results of this study contribute to the understanding of clinical polymorphism and genetic heterogeneity of the disease, highlighting the importance of a comprehensive approach to genetic diagnostics in atypical cases.

Spinal muscular atrophy (SMA) is a group of genetically heterogeneous neuromuscular diseases characterized by progressive loss of motor neurons in the anterior horns of the spinal cord. The prevalence of SMA is approximately 1 case per 10,000 live births. SMA is caused by a mutation in the SMN1 gene, which encodes survival motor neuron protein. The disease phenotype depends on the number of copies of the SMN2 pseudogene, which encodes an unstable isoform of the same protein. Despite the introduction of new drugs which help increase SMN protein levels, there is still a need to collect and systematize data on the natural history of the disease and evaluate the efficacies of new therapeutic approaches. Results from 12 retrospective and prospective studies conducted over the past 16 years, addressing the natural history of the disease in 646 children with SMA type I, are analyzed. The mean age at onset of symptoms was 2.1 ± 0.7 months and the first documented symptoms were muscle hypotonia, respiratory distress syndrome, and feeding difficulties. The mean age at death was 19.2 ± 10.1 months, the median age at reaching the combined endpoint (defined as the onset of death or the date of initiation of long-term respiratory support) was 7.7 months (95

OBJECTIVE:To characterize whole-body intramuscular fat distribution pattern in patients with sarcoglycanopathies and explore correlations with disease severity, duration and age at onset. METHODS:Retrospective, cross-sectional, multicentric study enrolling patients with variants in one of the four sarcoglycan genes who underwent whole-body muscle MRI. Intramuscular fatty replacement was evaluated on T1-weighted images and represented by heatmaps. Dimensionality reduction and linear spline models examined relationships between patterns of intramuscular fat replacement and clinical findings. RESULTS:MRI scans from 64 patients (age range 4-67 years) covering 4160 muscles were analyzed. Disease severity ranged from asymptomatic (9%) to non-ambulant (39%) patients. Sarcoglycanopathies showed consistent, selective patterns of muscle involvement across genotypes. Latissimus dorsi and subscapularis were the earliest affected muscles in the upper body, whereas head, neck and forearm muscles remained largely preserved. Distinct gradients characterized the topography of degeneration both within individual muscles and along body and limb axes. Disease severity correlated with MRI changes in both upper and lower body muscles, and with one of the dimensions identified by the multi-correspondence analysis. Patients with onset in the first decade showed a steeper cross-sectional association between disease duration and MRI abnormalities, while later-onset patients displayed a more gradual, linear relationship. INTERPRETATION:Sarcoglycanopathies display selective muscle vulnerability with characteristic gradients of fat replacement. Scapular girdle muscles are affected early in the disease course. Intramuscular fat correlates with functional impairment and disease duration, supporting its use as a surrogate endpoint in clinical trials. Age at onset emerges as a critical prognostic factor.

BACKGROUND:Risdiplam, an oral pre-messenger RNA splicing modifier, is an efficacious treatment for persons with symptomatic spinal muscular atrophy (SMA). The safety and efficacy of risdiplam in presymptomatic disease are unclear. METHODS:We conducted an open-label study of daily oral risdiplam (with the dose adjusted to 0.2 mg per kilogram of body weight) in infants 1 day (birth) to 42 days of age with genetically diagnosed SMA but without strongly suggestive clinical signs or symptoms. The primary outcome, assessed in infants with two SMN2 copies and a baseline ulnar compound muscle action potential (CMAP) amplitude of at least 1.5 mV, was the ability to sit without support at month 12. Natural history studies have shown that the majority of infants with two SMN2 copies who are untreated would have a severe SMA phenotype (type 1), would never sit independently, would receive permanent ventilation and feeding support, or would die by 13 months of age. Secondary outcomes that were assessed over a period of 24 months included survival, ventilatory support, motor milestones, the development of clinically manifested SMA, feeding, and growth. RESULTS:A total of 26 infants with two, three, or four or more copies of SMN2 were enrolled. After 12 months of treatment, 21 infants (81%) could sit unsupported for 30 seconds, 14 (54%) could stand alone, and 11 (42%) could walk alone. A total of 4 of 5 infants (80%; 95% confidence interval, 28 to 100) with two SMN2 copies and a baseline ulnar CMAP amplitude of at least 1.5 mV were able to sit without support for at least 5 seconds. Three infants were withdrawn from the study by a parent or caregiver after the month 12 visit. Of 23 infants who completed 24 months of treatment, all were alive without the use of permanent ventilation or feeding support. Over a period of 24 months, nine treatment-related adverse events were reported in 7 infants; none of these events were serious. CONCLUSIONS:Infants up to 6 weeks of age with genetically diagnosed SMA who were treated with risdiplam before the development of clinical signs or symptoms appeared to have better functional and survival outcomes at 12 and 24 months than untreated infants in natural history studies. Larger, controlled studies with longer follow-up are needed to further understand the relative efficacy and safety of presymptomatic treatment of SMA with risdiplam. (Funded by F. Hoffmann-La Roche; RAINBOWFISH ClinicalTrials.gov number, NCT03779334.).

Aim: To report the efficacy and safety of ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) from the phase III, 72-week, placebo-controlled period of Study 041. Materials & methods: Inclusion criteria: boys with nmDMD aged ≥5 years, on a stable corticosteroid regimen for ≥12 months, and baseline 6-minute walk distance (6MWD) ≥150 m. Randomization: 1:1, ataluren (40 mg/kg/day):placebo. Primary end point: slope of 6MWD change (average rate of change). Secondary end points: changes in 6MWD, time to 10% persistent worsening in 6MWD, North Star Ambulatory Assessment score, timed function tests and safety. Study populations: intention-to-treat; patients aged ≥7 to ≤16 years with baseline 6MWD ≥300 m and stand from supine ≥5 s; patients with baseline 6MWD 300–400 m. Results: In the intention-to-treat population (n = 359), over 72 weeks, ataluren reduced the rate of 6MWD decline by 21% (p = 0.0248), reduced the average 6MWD change (p = 0.0248), delayed time to 10% persistent worsening in 6MWD (p = 0.0078), and reduced North Star Ambulatory Assessment total score decline (p = 0.0235), change in 10 m walk/run time (p = 0.0422) and change in time to climb four stairs (p = 0.0293) versus placebo. In the 6MWD 300–400 m subgroup (n = 169), ataluren reduced the rate of 6MWD decline by 30% (p = 0.0310) versus placebo. Ataluren treatment benefits were seen in secondary end points in this subgroup, except for change in time to descend four stairs. In the 6MWD ≥300 m and time to stand from supine ≥5s subgroup (n = 185), there was a 9% slower rate of 6MWD decline for ataluren versus placebo over 72 weeks (p = 0.3626). Ataluren reduced change in time to climb four stairs (p = 0.0179) versus placebo in this subgroup; no treatment benefits were seen for other secondary end points. Ataluren was well tolerated (serious adverse events: ataluren, 7.1%; placebo, 6.8%); no deaths occurred. Conclusion: Long-term ataluren treatment has a favorable benefit–risk profile, slowing motor function decline in the largest phase III nmDMD study to date.

Spinal muscular atrophy (SMA) is a devastating disease that is the leading genetic cause of death in infants and young children. It includes a broad spectrum of phenotypes that are classified into clinical groups based on the age of onset and maximum motor function achieved. The most common form of SMA is due to a defect in the survival motor neuron 1 gene (SMN1) localized to 5q11.2-q13.3. The development of clinical symptoms and disease progression is thought to be due to decreased levels of survival motor neuron (SMN) protein. SMA type 1 results in almost inevitable mortality within the first 2 years of life. The first two drugs approved globally for the treatment of SMA were the antisense oligonucleotide nusinersen (Spinraza), and the gene therapy onasemnogene abeparvovec-xioi (Zolgensma). Both interventions have approval and restrictions on use in different countries around the world. Despite these approved therapies, the medical unmet need in SMA (the majority of patients with SMA are not on a disease-modifying therapy) remains high with therapies in the pipeline to address some of the remaining limitations. The third and more recently approved drug for SMA is risdiplam (Evrysdi), an orally administered, centrally and peripherally distributed small molecule that modulates SMN2 pre-mRNA splicing toward the production of full-length SMN2 mRNA to increase functional SMN protein levels. In Russia the drug risdiplam was approved for use on November 26, 2020 with indications for the treatment of SMA in patients aged 2 months and older, and in 2023 the indications were expanded - use is allowed starting from the birth. Risdiplam is widely distributed into the CNS and peripheral tissues including muscles. Following risdiplam administration, SMN protein levels compared with baseline levels increase between 2- and 6-fold depending on the SMA phenotype treated. The risdiplam clinical development program currently has four ongoing clinical trials assessing its safety and efficacy. Clinical trials included more than 450 patients receiving risdiplam to date, has been well tolerated and no treatment-related safety findings leading to study withdrawal have been observed. Data from real clinical practice - more than 11.000 patients worldwide receive therapy with risdiplam, also confirm the safety and good tolerability of the drug.

Прогрессирующая мышечная дистрофия Дюшенна (ПМД Дюшенна) является наиболее распространенным нервно-мышечным заболеванием в мире. ПМД Дюшенна относится к группе так называемых дистрофинопатий, связанных с мутациями в гене DMD, наследуется по Х-сцепленному рецессивному типу и обусловлена либо полным отсутствием белка дистрофина, либо его дефектным синтезом. В настоящее время появилось несколько патогенетических лекарственных препаратов, направленных на восстановление синтеза белка дистрофина. Одним из них является антисмысловой олигонуклеотид касимерсен, работающий по технологии экзон-скиппинга 45 экзона. В статье представлен первый опыт применения препарата касимерсен у 6 пациентов из России, причем пациенты значимо отличались друг от друга по функциональному статусу и имеющимся осложнениям основного заболевания. У всех пациентов применение касимерсена было безопасным, не было выявлено никаких нежелательных явлений, связанных с применением препарата. А у одного из пациентов, находящегося на ранней амбулаторной стадии болезни, которому патогенетическая терапия была инициирована в возрасте 7 лет, констатирована выраженная положительная динамика в виде прироста дистанции на 140 метров по результатам 6-минутного теста ходьбы и увеличения на 10 баллов по шкале «Северная Звезда». Duchenne muscular dystrophy (DMD) is the most common neuromuscular disease in the world. DMD belongs to the group of so-called dystrophinopathies associated with mutations in the DMD gene, is inherited in an X-linked recessive manner and is caused by either the complete absence of the dystrophin protein or its defective synthesis. Currently, several pathogenetic drugs have appeared aimed at restoring the synthesis of the dystrophin protein. One of them is the antisense oligonucleotide casimersen, which works using exon skipping technology of exon 45 in DMD gene. The article presents the first experience of using the drug casimersen in 6 patients from Russia, and the patients differed significantly from each other in functional status and existing complications of the underlying disease. In all patients, the use of casimersen was safe, and no adverse events associated with the use of the drug were identified. And in one of the patients, who was at an early outpatient stage of the disease, for whom pathogenetic therapy was initiated at the age of 7 years, pronounced positive dynamics were noted in the form of an increase in distance by 140 meters according to the results of a 6-minute walking test and an increase of 10 points on the «North Star».

Spinal muscular atrophy (SMA) is a hereditary, autosomal recessive disease that debuts at different ages. Neurological symptoms are progressive and lead to significant limitation of life activity and reduced life expectancy. Currently, there are several drugs for the pathogenetical treatment of SMA. This article reflects the evolution of clinicians’ views on the treatment of patients with SMA as scientific evidence from clinical trials and experience in managing patients in real‑world clinical practice accumulates. The biggest debate is about the treatment of patients with 4 copies of the SMN2 gene. An analysis of the “SMA Families” patient registry database was carried out; data on two patients with 4 copies of the SMN2 gene with early onset of the disease were presented.

Introduction. Spinal muscular atrophy (SMA) 5q is a severe hereditary neuromuscular disorder, one of the serious manifestations of which is the development of progressive respiratory insufficiency. The administration of pathogenetic therapy leads to decreased symptoms of respiratory failure, which reduces the risk of lethal outcome and is fundamental for stabilizing the progression of physical development and new motor skills in SMA patients. The aim — to present experience of onasmenogen abeparvovec (OA) gene replacement therapy (GRT) in patients with SMA type 1 and severe respiratory failure combined with chronic bronchopulmonary infection caused by nosocomial multidrug-resistant microflora in real clinical practice. Materials and methods. Five patients with SMA type 1 and respiratory failure of second degree complicated by chronic bronchopulmonary infection were enrolled in this study. All patients were performed a comprehensive clinical, laboratory, and radiologic examination before and for two years after GRT OA administration toof evaluate the severity of respiratory disturbances. The efficiency of OA therapy was estimated with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), and motor development was assessed by the Hammersmith Infant Neurologic Examination Part 2 (HINE-2). Results. The medical records of 5 (four boys and one girl ) patients with SMA type 1 at the mean age of 19 months (13 to 27 months) at the time of GRT OA administration were analyzed, of them. All patients had been treated with a different type of pathogenetic therapy before GRT OA. After the preventive, personalized antibacterial therapy, all patients experienced GRT OA administration without exacerbation of chronic bronchopulmonary infection, despite hormonal therapy in an immunosuppressive dose (1 mg/kg). There were no lethal outcomes during two years after GRT OA. Over the first year, patients demonstrated a progressive increase in motor skills with further stabilization, but during the second year of follow-up, two patients showed moderate regression of motor skills after pneumonia. One of five patients had a positive lung function dynamics and eradication of highly pathogenic bacterial microflora from the respiratory tract. Conclusions. It is comparatively safe to administer GRT OA in children with SMA type 1 and chronic respiratory infection. However, changing pathogenetic therapy to GRT OA in the cases we presented did not have clinically significant advantages and required more careful patient preparation. Additional risks associated with the occurrence of immune-mediated adverse events due to concomitant hormonal therapy, which can be avoided on other types of pathogenetic therapy, should be considered.

Background. Existing registries of patients with spinal muscular atrophy (SMA) 5q serve as a valuable source of information on identified patients. Information on the characteristics of Russian patients with SMA 5q and the therapy administered in real clinical practice is currently limited.Aim. To describe a cohort of Russian patients with a confirmed diagnosis of SMA 5q and to evaluate patient routing data in real clinical practice settings in Russia.Materials and methods. The present study was a descriptive non-interventional retrospective cohort study in patients diagnosed with SMA 5q who were enrolled in the Russian patient registry between January 1, 2020 and March 31, 2023. Study participants who met the inclusion criteria were automatically identified in the integrated database of the SMA 5q patient registry. Data were uploaded into validated electronic charts, verified and analyzed using descriptive statistics methods. Results. As of March 31, 2023, the Russian SMA registry contained information on 1408 patients from all federal districts and obtained epidemiological, sociodemographic and clinical characteristics of patients, as well as routes to diagnosis and treatment regimens for patients. The median time from disease onset to confirmed diagnosis was 3 months in patients with SMA type 1, 9 months in patients with SMA type 2, 20 months in patients with SMA type 3 and 68 months in patients with SMA type 4. The median time from confirmed diagnosis to the start of disease-modifying therapy was 0.5 months in SMA patients identified by neonatal screening, 21 months in patients with SMA type 1, 59 months in patients with SMA type 2, 47 months in patients with SMA type 3 and 87 months in patients with SMA type 4.Conclusion. This retrospective analysis was carried out in order to identify recent approaches to the diagnosis and treatment of SMA used in real-world clinical practice in Russia. The identified parameters (duration from the disease onset to confirmed diagnosis, duration from the confirmed diagnosis to disease-modifying therapy initiation) indicate that more widespread use of newborn screening and more rapid treatment initiation are unmet needs for SMA patients in Russia.

Duchenne muscular dystrophy is a genetic, X-linked, relentlessly progressive disease. Due to a genetic defect, the reading frame is disrupted during the synthesis of the dystrophin protein, resulting in its loss of functionality. As a result of the absence of dystrophin, there is a gradual destruction of muscle cells. In recent years, pathogenetic therapy for Duchenne muscular dystrophy has become available in Russia. However, the therapy available in Russia is specific, depending on the mutation variant, and may be recommended for approximately one third of patients. This article discusses the features of exon-skipping therapy, the clinical effectiveness, and safety of this group of drugs. The effectiveness and safety of the therapy are demonstrated through a clinical case of a patient receiving one of the drugs in this group.

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre‑mRNA splicing modifier that has been widely approved for the treatment of spinal muscular atrophy (SMA). RAINBOWFISH (NCT03779334) is a global, open-label, single-arm, multicentre, Phase 2 study assessing the efficacy, safety and pharmacokinetics/pharmacodynamics of risdiplam in infants with genetically diagnosed and presymptomatic SMA from birth to 6 weeks of age (at first dose), regardless of SMN2 copy number. The study enrolled 26 infants: eight infants had two SMN2 copies, 13 infants had three SMN2 copies and five infants had ≥4 SMN2 copies. The primary efficacy (PE) population (n=5) had two SMN2 copies and baseline compound muscle action potential (CMAP) amplitudes ≥1.5mV. Drug dosage was adjusted to achieve a target exposure of approximately 2,000 ng∙ hr/mL. The primary endpoint was met after 12 months of risdiplam treatment with 4/5 (80%) infants in the PE population able to sit without support for ≥5 seconds (Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, third edition [BSID-III]). Irrespective of CMAP amplitude, 7/8 infants with two SMN2 copies were able to sit without support for ≥30 seconds (BSID‑III Item 26), including all infants with CMAP amplitude <1.5 mV (n=3). Out of 26 infants, 24 (92%) were able to sit without support, 13 (50%) were able to stand unaided and 12 (46%) were able to walk independently at Month 12, as assessed by the Hammersmith Infant Neurological Examination, Module 2. At Month 12, all infants were alive without permanent ventilation, maintained their swallowing and feeding abilities and no adverse events (AEs) led to withdrawal or treatment discontinuation. Most AEs were not considered treatment-related and resolved over time. One infant met the criteria for development of clinically manifested SMA. Here we report, for the first-time, the 2-year efficacy and safety data from RAINBOWFISH.

Objectives . To characterize sleep disorders in children and adults with different forms of myotonic dystrophy type 1 (DM1) and to evaluate their impact on cognitive functions, excessive daytime sleepiness (EDS), and fatigue. To determine the relationship between EDS, fatigue, and sleep disorders and patients’ quality of life. Materials and methods . The study included 48 adults and nine children with confirmed DM1. Patients underwent assessment of clinical and history data, neurological and cognitive status, extent of EDS and fatigue, and quality of life using international scales and questionnaires. Polysomnography was performed to identify sleep disorders. Results . Obstructive sleep apnea syndrome (OSAS) was found in 78% of children and 79.2% of adults. The severity of OSAS in adults, in contrast to children, was influenced by obesity ( p < 0.001) and the extent of muscle weakness ( p = 0.033), especially of the neck muscles ( p = 0.018). Increases in the duration of stage I sleep ( p = 0.008) and the microactivation index ( p = 0.005) were detected in patients with OSAS and nocturnal hypoxemia. EDS and fatigue were present in 31 (64.6%) and 34 (70.8%) adults, respectively, and in nine (18.8%) at disease onset. Greater severity of muscle symptoms, anxiety, and depression contributed to increased fatigue in adults and the presence of obesity and type 2 diabetes mellitus contributed to EDS. Increased fatigue had a greater impact on quality of life than EDS and sleep disturbances. Conclusions . OSAS occupies the leading position among the spectrum of sleep disorders in all age groups and its development is facilitated by the presence of muscle weakness and obesity. Cognitive and emotional disturbances do not result from sleep apnea, but rather develop as a result of primary damage to the central nervous system. The presence of increased fatigue reduces patients’ quality of life.

Proximal spinal muscular atrophy 5q is an autosomal recessive neuromuscular disease. This disorder is characterized by progressive symptoms of flaccid paralysis and muscular atrophy due to degeneration of α-motor neurons in the anterior horns of the spinal cord. The disease is caused by the lack of a fully functional SMN protein due to homozygous deletion of exon 7 in the SMN1 gene. For a long time, spinal muscular atrophy was the leading genetic cause of infant mortality. With the introduction of modern pathogenetic treatment methods that modify the disease, the duration and quality of life of patients increases, and a “blurring of boundaries” between types of spinal muscular atrophy and the formation of new phenotypes happens. In this regard, approaches to patient management, including approaches to the assessment and correction of respiratory disorders, are changing. The review of the available medical literature was conducted. The clinical studies on spinal muscular atrophy in the natural course of the disease and with the use of pathogenetic drugs were analyzed, as well as the data on the state of the respiratory system of the patients.

Spinal muscular atrophy 5q (SMA) is one of the most common inherited neuromuscular diseases in children with an autosomal recessive type of inheritance. Homozygous deletion of exons 7 or 7–8 of the SMN1 gene encoding the motor neuron survival protein is responsible for 95 % of cases. SMA is characterized by a steadily progressive course with the development of paresis, muscle atrophy, loss of previously acquired motor skills, respiratory failure and skeletal deformities. The introduction of pathogenetic therapy in recent years has significantly changed the trajectory of SMA – patients survive, restore previously lost motor skills and acquire new ones. The clinical classification, which includes 5 types of SMA, is currently not a reliable reflection of the functional state of the child in dynamics. In 2005, a functional classification was recommended based on the patient’s current status: non-sitters (lying), sitters, and walkers. The article provides a summary of historical concepts regarding functional classification in SMA patients, as well as the criteria used in clinical trials and observations. We proposed criteria for categorizing SMA patients into a specific functional class by analyzing the available literature and making recommendations on using the classification in real clinical practice.

Background. Myotonic dystrophy type 1 (DM1) is a hereditary slowly progressive multisystem disease with an autosomal dominant mode of inheritance, caused by the expansion of trinucleotide (CTG)n repeats in the 3’ untranslated region of the DMPK gene. Among the clinical manifestations of DM1, an important place is occupied by symptoms of damage to the central nervous system, in particular cognitive and emotional disorders.Aim. To evaluate the type of cognitive and emotional impairments in patients with different forms of DM1 and their impact on quality of life.Materials and methods. 60 patients with genetically confirmed DM1 were examined (average age 37.0 ± 12.4 years; 36 (60.0 %) of them were men). All patients underwent neuropsychological testing using the Montreal Cognitive RatingScale, Mini‑Mental State Examination, Addenbrooke’s III, Wechsler tests, pathfinding, symbolic and numeric modalities, Luria’s 10 Words, Frontal Dysfunction Battery; assessment of emotional disturbances using the Hospital Anxiety and Depression Rating Scale and the Apathy Scale; quality of life assessment – 36‑Item Short‑Form Medical Outcomes Study. Brain magnetic resonance imaging was performed in 53 patients to assess the severity of white matter lesions and gray matter atrophy.Results. The study included 8 (13.3 %) patients with congenital, 19 (31.7 %) – childhood, 33 (55 %) – adult forms of MD1. The group of patients with the congenital form had the most severe cognitive deficits, especially in tests of executive functions and visuospatial perception. Cognitive impairment was also characteristic of the adult form, but to a lesser extent. Compared to controls, patients with DM1 were significantly more likely to exhibit apathy (p = 0.002) rather than anxiety and depression. In DM1, damage to both the white and gray matter of the brain was established, and a connection between damage to the gray matter and depression (r = 0.296) and apathy (r = –0.291) was revealed. The quality of life is largely influenced by emotional disorders (anxiety, r = –0.577; depression, r = –0.650; apathy, r = –0.545).Conclusion. In patients with DM1, a typical pattern of cognitive impairment has not been identified; different domains of cognitive functions are affected. The greatest cognitive deficit is typical for the group of patients with the congenital form. A connection between damage to the gray matter of the brain and emotional disorders has been revealed.The presence of the latter reduces the quality of life of patients with DM1.

Background: Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre mRNA splicing modifier that has been approved in more than 90 countries worldwide. Methods: RAINBOWFISH (NCT03779334) is an open-label, single-arm, multicenter study assessing the efficacy, safety and pharmacokinetics/pharmacodynamics (PK/PD) of risdiplam in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (SMA) from birth-6 weeks of age (at first dose), regardless of SMN2 copy number. The primary endpoint is the proportion of infants, with two SMN2 copies and baseline compound muscle action potential (CMAP) amplitude ≥1.5mV, who are able to sit without support for ≥5 seconds (assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, third edition). Secondary endpoints include: the development of clinically manifested SMA; survival and permanent ventilation; motor milestone achievement; motor function; growth measures; nutritional status; CMAP; PK/PD; and safety monitoring. Results: The median age at first dose was 26.5 days (range: 16-40 days) for the first 18 enrolled infants (data cut-off: 1 July 2021). No treatment-related serious adverse events were reported in infants treated for ≤22.8 months. A preliminary analysis of seven infants treated for ≥12 months demonstrated that most reached near maximum scores on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale by 4-5 months of age and achieved motor milestones within World Health Organization windows for healthy children. All seven infants treated for ≥12 months were alive without permanent ventilation, maintained swallowing and feeding abilities, and had not required hospitalization. Conclusion: Here we report for the first-time results from the RAINBOWFISH primary analysis conducted at Month 12.

Objective: To determine the efficacy and safety of risdiplam in infants with Type 1 SMA after 36 months of treatment. Background: Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier that has been approved in more than 90 countries worldwide. Design/Methods: FIREFISH (NCT02913482) is a multicenter, open-label, two-part study of risdiplam in infants with Type 1 SMA and two SMN2 gene copies (inclusion criteria: 1–7 months old at enrollment). FIREFISH Part 1 assessed the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam doses. Pivotal Part 2 assessed the safety and efficacy of risdiplam over 24 months at the dose selected from Part 1. Thereafter, infants entered a 3-year open-label extension phase and continue to receive risdiplam at the pivotal dose. Results: Pooled safety and efficacy data were available from 58 enrolled infants who received risdiplam treatment (Part 1 high-dose cohort, n=17; and Part 2, N=41). As of the cut-off date (23 November 2021), there were no treatment-related adverse events leading to withdrawal, no additional deaths since the clinical cut-off date of the primary analysis (14 November 2019), and no additional infants meeting the definition of permanent ventilation since Month 24. At Month 36, 84% of infants were alive and did not require permanent ventilation. In FIREFISH, infants have achieved motor milestones not observed in the natural history of Type 1 SMA. Overall, infants have maintained or improved their motor skills in terms of developmental milestones and motor function between Month 24 and Month 36. Conclusions: FIREFISH Parts 1 and 2 are ongoing globally and will provide further safety and efficacy data of risdiplam in Type 1 SMA. Disclosure: The institution of Dr. Darras has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus. Dr. Darras has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicus. The institution of Dr. Darras has received research support from National Institutes of Health/National Institute of Neurological Disorders and Stroke,. The institution of Dr. Darras has received research support from Slaney Family Fund for SMA. The institution of Dr. Darras has received research support from Spinal Muscular Atrophy Foundation. The institution of Dr. Darras has received research support from CureSMA. The institution of Dr. Darras has received research support from Working on Walking Fund . The institution of Dr. Darras has received research support from CHERISH, CS2/CS12 . The institution of Dr. Darras has received research support from Biogen for CS11. The institution of Dr. Darras has received research support from AveXis. The institution of Dr. Darras has received research support from Sarepta Pharmaceuticals. The institution of Dr. Darras has received research support from PTC Therapeutics. The institution of Dr. Darras has received research support from Roche. The institution of Dr. Darras has received research support from Santhera. The institution of Dr. Darras has received research support from Scholar Rock. The institution of Dr. Darras has received research support from Fibrogen. The institution of Dr. Darras has received research support from Summit. Dr. Darras has received publishing royalties from a publication relating to health care. Dr. Darras has received publishing royalties from a publication relating to health care. Giovanni Baranello has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Giovanni Baranello has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Giovanni Baranello has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AveXis. Giovanni Baranello has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Giovanni Baranello has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AveXis. Giovanni Baranello has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Giovanni Baranello has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for AveXis. The institution of Giovanni Baranello has received research support from Great Ormond Street Hospital Charity. Odile Boespflug-Tanguy has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Minoryx. Odile Boespflug-Tanguy has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Inventiva. Odile Boespflug-Tanguy has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for BLUEBIRD. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Affinia Therapeutics. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis Gene Therapy. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avidity. Dr. Day has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Muscular Dystrophy Association. The institution of Dr. Day has received research support from Audentes. The institution of Dr. Day has received research support from Novartis Gene Therapy. The institution of Dr. Day has received research support from Biogen. The institution of Dr. Day has received research support from Cytokinetics. The institution of Dr. Day has received research support from Roche/Genentech. The institution of Dr. Day has received research support from Sanofi/Genzyme. The institution of Dr. Day has received research support from Sarepta. The institution of Dr. Day has received research support from Scholar Rock. Dr. Day has received intellectual property interests from a discovery or technology relating to health care. Nicholas Deconinck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for biogen. Nicholas Deconinck has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for roche. Nicholas Deconinck has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for avexis. Nicholas Deconinck has received publishing royalties from a publication relating to health care. Andrea Klein has nothing to disclose. Ricardo Masson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche, Biogen, Avexis. Ricardo Masson has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche, Biogen, Avexis. Dr. Mazurkiewicz Beldzin has received personal compensation in the range of $0-$499 for serving as a Consultant for Biogen, . Dr. Mazurkiewicz Beldzin has received personal compensation in the range of $0-$499 for serving as a Consultant for Novartis. Dr. Mazurkiewicz Beldzin has received personal compensation in the range of $0-$499 for serving as a Consultant for Roche. Dr. Mazurkiewicz Beldzin has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Mazurkiewicz Beldzin has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Eugenio Mercuri has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta, Santhera, PTC, Pfizer, Roche, Biogen, Avexis Novartis, Scholar Rock, Cytokinetics. Eugenio Mercuri has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sarepta, Santhera, PTC, Pfizer, Roche, Biogen, Avexis Novartis. The institution of Eugenio Mercuri has received research support from biogen. Kristy Rose has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Roche. Kristy Rose has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Kristy Rose has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Roche. Kristy Rose has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dmitry Vlodavets has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AveXis. Dmitry Vlodavets has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche . Dmitry Vlodavets has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dmitry Vlodavets has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen. Dmitry Vlodavets has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Novartis. Dmitry Vlodavets has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Roche. Dmitry Vlodavets has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for PTC Therapeutics. Dmitry Vlodavets has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dmitry Vlodavets has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for PTC Therapeutics. Dmitry Vlodavets has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Hui Xiong has nothing to disclose. Edmar Zanoteli has nothing to disclose. Muna El-Khairi has received personal compensation for serving as an employee of Roche Products Limited. Marianne Gerber has received personal compensation for serving as an employee of Roche. Marianne Gerber has received stock or an ownership interest from F Hoffmann La Roche . Dr. Gorni has received personal compensation for serving as an employee of Hoffman La Roche. Heidemarie Kletzl has received personal compensation for serving as an employee of Hoffmann-La Roche. Laura Palfreeman has received personal compensation for serving as an employee of Roche. Angela Dodman has received personal compensation for serving as an employee of F. Hoffman-La Roche Ltd. The institution of Laurent Servais has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Laurent Servais has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. The institution of Laurent Servais has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Avexis. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dynacure. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Audentes. The institution of Laurent Servais has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Pfizer. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Santhera. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for RegenexBio. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Affinia. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Anagenesis. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Catabasis. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Evox. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lupin. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fibrogen.