the natural history of patients with mutations in sepn1 (selenon) or lama2

Conditions: MDC1A; SELENON-related Myopathy

Summary: 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.

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.

Eligibility criteria:
inclusion criteria: * 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) exclusion criteria: * none

Keywords: mdc1a lama2-related muscular dystrophy lama2 laminin2 / genetics laminin2 / deficiency selenon sepn1 multi-minicore disease rigid spine muscular dystrophy selenoproteins / genetics natural history study outcome measures congenital muscular dystrophy congenital myopathy muscle disease