Современные методы терапии мышечной дистрофии Дюшенна: обзор литературы с клиническим примером

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.Прогрессирующая мышечная дистрофия Дюшенна – генетическое Х-сцепленное, неуклонно прогрессирующее заболевание. Вследствие генетической «поломки» нарушается рамка считывания при синтезе белка дистрофина, в результате чего он теряет функциональность. При отсутствии дистрофина происходит постепенное разрушение мышечных клеток. В последние несколько лет в России доступна патогенетическая терапия миодистрофии Дюшенна. Однако доступная в России терапия специфична, зависит от варианта мутации и может быть рекомендована примерно 1/3 пациентов. В настоящей статье приводятся особенности экзон-скиппинг-терапии, данные о клинической эффективности и безопасности этой группы препаратов. На клиническом примере пациента, получающего один из препаратов данной группы, демонстрируется эффективность и безопасность терапии

DMD gene molecular genetic characterization in Eastern Europe and non European countries

Duchenne muscular dystrophy (DMD) is a rare genetic neuromuscular disease affecting 1 in 3,500 male births world wide, due to a variety of dystrophin gene mutations. Diagnostic settings include MLPA (MRC-Holland) and NGS dystrophin gene sequencing (DMD MASTR assay Multiplicom). Thanks to the international DMD project we have tested 182 patients from eastern european and non-european countries: Poland (75), Hungary (19), Lithuania (6), Romania (55), Serbia (2), Croatia (8), Bosnia (2) Bulgaria (13) Cyprus (2) and 172 DNAs from Extra-European countries: Russia(1), Ukraina (92) and Algeria (79) were collected. In the European samples were identified 33 large del/dup (33.6%), 33 nonsense (33.6%), 17 smalldel/dup (18%), 16 splice site (16%) and 3 missense mutations (3%). In non-European patients we identified 73 large del/dup (62%), 20 nonsense (17%), 9 smalldel/dup (7.7%), 9 splice site (7.6%) and 4 missense mutations (3%). Sixty-two European patients and fifty-four Extra-European patients remained undiagnosed using routine methods, suggesting the presence of atypical mutations in the DMD gene or other genes involvement. The early identification of the underlying genetic mutation is critical to potentially affecting the course of Duchenne muscular dystrophy as well as the choice of treatment, the set up of appropriate and effective care and eligibility for clinical trials. Genetic counselling can also be offered to patients and families with important repercussions on reproductive choices and life style planning

Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study

Background: ANCHOVY was a global, multicenter, chart-review study that aimed to describe the natural history of Type 1 spinal muscular atrophy (SMA) from a broad geographical area and provide further contextualization of results from the FIREFISH (NCT02913482) interventional study of risdiplam treatment in Type 1 SMA. Methods: Data were extracted from medical records of patients with first symptoms attributable to Type 1 SMA between 28 days and 3 months of age, genetic confirmation of SMA, and confirmed survival of motor neuron 2 copy number of two or unknown. The study period started on 1 January 2008 for all sites; study end dates were site-specific due to local treatment availabilities. Primary endpoints were time to death and/or permanent ventilation and proportion of patients achieving motor milestones. Secondary endpoints included time to initiation of respiratory and feeding support. Results: Data for 60 patients from nine countries across Asia, Europe and North and South America were analyzed. The median age (interquartile range [IQR]) for reaching death or permanent ventilation was ~ 7.3 (5.9–10.5) months. The median age (IQR) at permanent ventilation was ~ 12.7 (6.9–16.4) months and at death was ~ 41.2 (7.3–not applicable) months. No patients were able to sit without support or achieved any level of crawling, standing or walking. Interpretation: Findings from ANCHOVY were consistent with published natural history data on Type 1 SMA demonstrating the disease’s devastating course, which markedly differed from risdiplam-treated infants (FIREFISH Part 2). The results provide meaningful additions to the literature, including a broader geographical representation

Мышечная дистрофия Дюшенна: современные подходы к ведению и лечению пациентов

Duchenne muscular dystrophy is one of the most common forms of childhood muscular dystrophies. Its incidence is 1 in 3.5–6 thousand newborn boys according to various sources. The disease is caused by the mutation in the DMD gene coding the dystrophin protein, it leads to the dystrophin absence or malfunction. The disease is characterized by proximal muscle weakness and gastrocnemius muscles pseudohypertrophy. In average, patients lose the ability to walk by themselves by the age of 11 and become nonambulatory. The authors have present modern epidemiological data and etiopathogenesis features of Duchenne muscular dystrophy, and have described clinical signs of different disease stages. The algorithm and key points of differential diagnosis are indicated. Special attention was given to the patients’ management: pathogenetic treatment and rehabilitation of pediatric patients.Мышечная дистрофия Дюшенна — одна из наиболее частых форм мышечных дистрофий детского возраста. По разным источникам, заболеваемость миодистрофией Дюшенна оценивается как 1 на 3,5–6 тыс. новорожденных мальчиков. В основе заболевания лежит мутация гена DMD, кодирующего белок дистрофин, приводящая к отсутствию или недостаточной функции дистрофина. Заболевание характеризуется слабостью проксимальных и псевдогипертрофией икроножных мышц, и в среднем к 11 годам пациенты теряют возможность самостоятельно передвигаться и становятся неамбулаторными больными. Авторами представлены современные эпидемиологические данные и особенности этиопатогенеза мышечной дистрофии Дюшенна, описаны клинические характеристики разных стадий болезни. Подробно представлен алгоритм и указаны ключевые этапы дифференциально-диагностического поиска. Особое внимание уделено вопросам лечения пациентов, в том числе патогенетическому лечению, реабилитации пациентов детского возраста