The Natural History of Patients With Congenital Muscular Dystrophies Due to Mutations in the SELENON or LAMA2 Genes: Working Towards Trial-readiness in Two Mitochondrial Myopathy Mimics
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 38
- 试验地点
- 1
- 主要终点
- Change of Motor Function Measure (MFM)-32 (older than 7 years) or MFM-20 (2 to 7 years old)
研究概览
简要总结
SEPN1 (SELENON) is a rare congenital myopathy due to mutations in the SELENON gene. MDC1A is a rare congenital muscle dystrophy due to mutations in the LAMA2 gene. Currently, not much is known about the natural history of these two muscle diseases and no (curative) treatment options exist. The investigators aim to study the natural history of SELENON- and LAMA2-related myopathy/congenital muscular dystrophy patients and prepare for future trials by selection of the most appropriate outcome measures. To this end, a standard medical history, neurological examination, functional measures, questionnaires, cardiac examination, respiratory function tests, radiological examination and accelerometry will be performed over an one and-a-half year period.
详细描述
Rationale: Patients with mutations in the SELENON gene suffer from slowly progressive congenital muscular dystrophy with early onset rigidity of the spine and potentially life-threatening respiratory insufficiency. The protein encoded by SELENON, selenoprotein-1, functions as an endogeneous antioxidant and executes a role in cellular redox metabolism. The first results of an intervention study using KH176, currently under development for mitochondrial disease, in an animal model (Sepn1 knock out zebrafish) showed improved muscular function. Patients with mutations in LAMA2 gene causing merosin-deficient congenital muscular dystrophy (MDC1A) have a similar phenotype as those with mutations in SELENON gene. Key characteristics include congenital hypotonia, delayed motor development and contractures. For them no treatment is available either. Since not much is known about the clinical progression of these two congenital muscle diseases, there is an urgent need for natural history-outcome measure studies to reach trial-readiness enabling smooth transition towards clinical trials.
Objective
The primary objective is to identify and follow (i.e. describe the natural history of) patients with congenital myopathy/muscular dystrophy due to mutations in SELENON- or LAMA2 genes. The secondary objectives are: 1. to select appropriate outcome measures based on the natural history data. 2. to determine the necessity for routine cardiological and respiratory screening.
Study design: This is an observational study. A standard medical history, neurological examination, functional measures, questionnaires, cardiac examination, respiratory function tests, radiological examination (qualitative and quantitative full body MRI, muscle ultrasound, DEXA scan, X-ray of the spine) and accelerometry will be performed. For each participant, the investigators will perform four six-monthly measurements over an one-and-a-half year period. If more than 20 patients are willing to participate in this study, the investigators will select per muscle disease 10 participants that are representative of the entire patient population (based on age, gender, disease severity etc.). Patients that are not included in this study and patients that are not able to or do not wish to visit the Radboudumc will be retrospectively analyzed through medical records. Additionally, they will receive questionnaires, which can be completed at home.
Study population: all patients with congenital myopathy/muscular dystrophy due to mutations in the SELENON or LAMA2 genes.
Risk and benefit assessment: This study does not concern any product (medicinal product, food product, or medical device). There is a small risk for minor injury, e.g. when a participant falls. However, since the investigators use all functional test using movements to which most participants are familiar (i.e. walking, transfers, etc), the participant will be able to estimate his/her own risk. The investigators don't include tests in which they push participants to their physical limits. The investigators conclude that this study has a negligible risk. A benefit includes the possibility for participants to get a detailed analysis on their own health. Additionally, participants will contribute to the design of future clinical trials on possible treatment options.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 1 Day 至 100 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing and able to complete (part of the) measurement protocol
- •Willing and able to travel to Nijmegen (The Netherlands)
- •Dutch-speaking
- •Genetically-confirmed muscle disease caused by mutations in SELENON (SEPN1): congenital muscular dystrophy with early spine rigidity or congenital myopathy (multicore/minicore disease, congenital fiber type size disproportion)
- •Genetically confirmed muscular dystrophy caused by mutations in LAMA2: merosin-deficient muscular dystrophy 1A (early-onset LAMA2-related muscular dystrophy) or childhood-onset limb-girdle type muscular dystrophy (late-onset LAMA2-related muscular dystrophy)
排除标准
- 未提供
结局指标
主要结局
Change of Motor Function Measure (MFM)-32 (older than 7 years) or MFM-20 (2 to 7 years old)
时间窗: Change from baseline at 6 months, 12 months and 18 months
Global motor functioning. The items of the MFM are classified in 3 domains: D1: Standing and transfers (13 items, sub score range 0-39) D2: Axial and proximal motor function (12 items, sub score range 0-36) D3: Distal motor function (7 items, sub score range 0-21) Each item is scored on a 0-3 scale. Each sub score will be calculated as the percentage of total possible score achieved. Higher scores indicate a better outcome. The range of the total score is 0-96, again recalculated as the percentage of total possible score achieved. The main point of interest includes the change of MFM score over a period of 1,5 year. Additionally, MFM scores of participants will be compared to reference values.
次要结局
- Change of activity limitations - ACTIVLIM (6 years and older)(Change from baseline at 6 months, 12 months and 18 months)
- Change of balance by Pediatric balance scale (2 - 17 years) or Mini Balance Evaluation System Test (miniBEST) (18 years and older)(Change from baseline at 6 months, 12 months and 18 months)
- Change of bone density - DEXA scan (2 years and older)(Change from baseline at 12 months)
- Change of fatigue (adults, 18 years and older) - Checklist Individual Strength (CIS)(Change from baseline at 6 months, 12 months and 18 months)
- Accelerometry (2 years and older) - change of physical activity in daily life(Change from baseline at 6 months, 12 months and 18 months)
- Change of Borg Rating Scale of Perceived Exertion (5 years and older) - physical activity intensity level(Change from baseline at 6 months, 12 months and 18 months)
- Change of cardiac function (2 years and older)(Change from baseline at 12 months)
- Change of maximal voluntary isometric contraction (5 years and older) (Newton)(Change from baseline at 6 months, 12 months and 18 months)
- Change of The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score (children under the age of 2 years)(Change from baseline at 6 months, 12 months and 18 months)
- Change of fatigue (pediatric, 2-17 years old) - PedsQL Multidimensional Fatigue Scale (MFS)(Change from baseline at 6 months, 12 months and 18 months)
- Change of functional ability in daily life - Egen klassifikation scale version 2 (EK2) (16 years and older)(Change from baseline at 6 months, 12 months and 18 months)
- Change of Graded and Timed function tests(Change from baseline at 6 months, 12 months and 18 months)
- Change of Hammersmith Infant Neurological Examination (HINE) (under the age of 2 years)(Change from baseline at 6 months, 12 months and 18 months)
- Change of Impact on Participation and Autonomy (IPA) (18 years and older)(Change from baseline at 6 months, 12 months and 18 months)
- Pulmonary function (5 years and older) - change of forced vital capacity (percentage predicted)(Change from baseline at 6 months, 12 months and 18 months)
- Pulmonary function (5 years and older) - change of forced expiratory volume in the first second (liter) (percentage predicted)(Change from baseline at 6 months, 12 months and 18 months)
- Pulmonary function (5 years and older) - change of peak expiratory flow (liter per second)(Change from baseline at 6 months, 12 months and 18 months)
- Change of Functional Ambulation Category (FAC) (5 years and older)(Change from baseline at 6 months, 12 months and 18 months)
- Change of Hammersmith Functional Motor Scale (HFMS) (2 years and older, non-ambulant)(Change from baseline at 6 months, 12 months and 18 months)
- Change of muscle atrophy (cm) and fattening (echo-intensity) by muscle ultrasound(Change from baseline at 6 months, 12 months and 18 months)
- Pulmonary function (5 years and older) - change of vital capacity (percentage predicted)(Change from baseline at 6 months, 12 months and 18 months)
- Pulmonary function (5 years and older) - change of maximal inspiratory pressure (cmH2O)(Change from baseline at 6 months, 12 months and 18 months)
- Pulmonary function - change of diaphragm excursion (cm)(Change from baseline at 6 months, 12 months and 18 months)
- Change of Brooke and Vignos scale (2 years and older)(Change from baseline at 6 months, 12 months and 18 months)
- Change of Wong-Baker Faces Pain Scale (2 years and older)(Change from baseline at 6 months, 12 months and 18 months)
- McGill pain questionnaire (12 years and older) - Change of location, level and characteristics of pain(Change from baseline at 6 months, 12 months and 18 months)
- Change of Quality of life (adult, 18 years and older) by Individualized Neuromuscular Quality of Life (INQoL).(Change from baseline at 6 months, 12 months and 18 months)
- Change of Quality of Life (pediatric, 2-17 years old) by PedsQL neuromuscular module (NMM)(Change from baseline at 6 months, 12 months and 18 months)
- Change of muscle fattening, atrophy, inflammation and fibrosis by qualitative and quantitative full body muscle MRI(Change from baseline at 12 months)
- Change of muscle power by muscle power measurements (Medical Research Council (MRC) scale) (2 years and older)(Change from baseline at 6 months, 12 months and 18 months)
- Pulmonary function (5 years and older) - change of maximal expiratory pressure (cmH2O)(Change from baseline at 6 months, 12 months and 18 months)
- Pulmonary function (5 years and older) - change of sniff nasal inspiratory pressure (cmH2O)(Change from baseline at 6 months, 12 months and 18 months)
- Change of Quality of life (adult, 18 years and older) by SF36/RAND36(Change from baseline at 6 months, 12 months and 18 months)
- Pulmonary function (5 years and older) - change of peak cough flow (liter per second)(Change from baseline at 6 months, 12 months and 18 months)
- Pulmonary function - change of diaphragm thickening (ratio)(Change from baseline at 6 months, 12 months and 18 months)
- Change of range of motion of ankles and elbows(Change from baseline at 6 months, 12 months and 18 months)
- Change of spine deformity (degree) (2 years and older)(Change from baseline at 12 months)
- Pulmonary function - change of diaphragm thickness (mm)(Change from baseline at 6 months, 12 months and 18 months)
- Change of Quality of Life (pediatric, 2-17 years old) by PedsQL generic quality of life(Change from baseline at 6 months, 12 months and 18 months)