The Natural History of Patients With Mutations in SEPN1 (SELENON) or LAMA2
Condition: MDC1A; SELENON-related Myopathy
MeSH terms: Muscular Dystrophies; Muscular Diseases
Study type: Observational

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.
    

Detailed description: 
      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.
    

Intervention name(s): No intervention
Intervention type(s): Other
Intervention description(s): This concerns a natural history study; no interventions will be used
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients with a congenital myopathy/muscular dystrophy due to mutations in SELENON- or
        LAMA2 genes will be identified through contact with genetic diagnostic services,
        rehabilitation centers, and muscle disease experts in The Netherlands and Dutch-speaking
        Belgium. Patients with a congenital myopathy/muscular dystrophy due to SELENON (prevalence
        0.5:1000,000) or LAMA2 (4 in 500,000) mutations are rare and no Dutch registry exists.
        Therefore the investigators can only estimate the number of patients.
      
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