ABSTRACT
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.
Subject(s)
Muscular Atrophy, Spinal , Child , Infant , Humans , Child, Preschool , Muscular Atrophy, Spinal/drug therapy , Muscular Atrophy, Spinal/genetics , Pyrimidines/therapeutic use , Azo Compounds/therapeutic use , RNA Splicing , Transcription FactorsABSTRACT
OBJECTIVE: To characterize sleep disorders in children and adults with different forms of myotonic dystrophy type 1 (DM1), to assess their impact on cognitive functions, excessive daytime sleepiness (EDS) and fatigue, to determine the relationship of EDS, fatigue, and sleep disorders with the quality of life of patients. MATERIAL AND METHODS: The study included 48 adults and 9 children with confirmed DM1. Patients underwent an assessment of clinical and anamnestic data, neurological, cognitive status, severity of EDS, fatigue, quality of life according to 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), the severity of muscle weakness (p=0.033), especially the neck muscles (p=0.018). In patients with OSAS and nocturnal hypoxemia, an increase in the duration of the 1st stage of sleep (p=0.008) and in the microactivation index (p=0.005) was revealed. EDS and fatigue were present in 31 (64.6%) and 34 (70.8%) adults, respectively, in 9 (18.8%) they emerged at the onset of the disease. The greater severity of muscle symptoms, anxiety, depression contributed to increased fatigue in adults and the presence of obesity and type 2 diabetes mellitus contributed to EDS. Increased fatigue affects the quality of life to a greater extent than EDS and sleep disturbances. CONCLUSION: OSAS, the development of which is facilitated by the presence of muscle weakness and obesity, is the leading syndrome among the spectrum of sleep disorders in all age groups. Cognitive and emotional impairments are not the result of sleep apnea, but rather develop because of a primary CNS lesion. The presence of increased fatigue reduced the quality of life of patients.
