Clinical trial NCT04478981: The Natural History of Patients With Mutations in SEPN1 (SELENON) or LAMA2
Official title: 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: MDC1A
SELENON-related Myopathy
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
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2020-07-21
Enrollment: 38
Sex: ALL
Minimum age (years): 1
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
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.

Brief 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.

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

Primary outcomes:
measure: Change of Motor Function Measure (MFM)-32 (older than 7 years) or MFM-20 (2 to 7 years old)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
Secondary outcomes:
measure: Accelerometry (2 years and older) - change of physical activity in daily life
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of activity limitations - ACTIVLIM (6 years and older)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of balance by Pediatric balance scale (2 - 17 years) or Mini Balance Evaluation System Test (miniBEST) (18 years and older)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of bone density - DEXA scan (2 years and older)
timeFrame: Change from baseline at 12 months
measure: Change of Borg Rating Scale of Perceived Exertion (5 years and older) - physical activity intensity level
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of cardiac function (2 years and older)
timeFrame: Change from baseline at 12 months
measure: Change of The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score (children under the age of 2 years)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of fatigue (adults, 18 years and older) - Checklist Individual Strength (CIS)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of fatigue (pediatric, 2-17 years old) - PedsQL Multidimensional Fatigue Scale (MFS)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of functional ability in daily life - Egen klassifikation scale version 2 (EK2) (16 years and older)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of Functional Ambulation Category (FAC) (5 years and older)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of Graded and Timed function tests
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of Hammersmith Infant Neurological Examination (HINE) (under the age of 2 years)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of Hammersmith Functional Motor Scale (HFMS) (2 years and older, non-ambulant)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of Impact on Participation and Autonomy (IPA) (18 years and older)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of maximal voluntary isometric contraction (5 years and older) (Newton)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: McGill pain questionnaire (12 years and older) - Change of location, level and characteristics of pain
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of muscle atrophy (cm) and fattening (echo-intensity) by muscle ultrasound
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of muscle fattening, atrophy, inflammation and fibrosis by qualitative and quantitative full body muscle MRI
timeFrame: Change from baseline at 12 months
measure: Change of muscle power by muscle power measurements (Medical Research Council (MRC) scale) (2 years and older)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function (5 years and older) - change of forced vital capacity (percentage predicted)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function (5 years and older) - change of forced expiratory volume in the first second (liter) (percentage predicted)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function (5 years and older) - change of peak expiratory flow (liter per second)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function (5 years and older) - change of vital capacity (percentage predicted)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function (5 years and older) - change of peak cough flow (liter per second)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function (5 years and older) - change of maximal expiratory pressure (cmH2O)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function (5 years and older) - change of maximal inspiratory pressure (cmH2O)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function (5 years and older) - change of sniff nasal inspiratory pressure (cmH2O)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function - change of diaphragm thickness (mm)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function - change of diaphragm thickening (ratio)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Pulmonary function - change of diaphragm excursion (cm)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of Quality of life (adult, 18 years and older) by SF36/RAND36
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of Quality of life (adult, 18 years and older) by Individualized Neuromuscular Quality of Life (INQoL).
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of Quality of Life (pediatric, 2-17 years old) by PedsQL generic quality of life
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of Quality of Life (pediatric, 2-17 years old) by PedsQL neuromuscular module (NMM)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of range of motion of ankles and elbows
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of spine deformity (degree) (2 years and older)
timeFrame: Change from baseline at 12 months
measure: Change of Brooke and Vignos scale (2 years and older)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
measure: Change of Wong-Baker Faces Pain Scale (2 years and older)
timeFrame: Change from baseline at 6 months, 12 months and 18 months
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboudumc
state: Gelderland
Study officials:
affiliation: Radboud University Medical Center
name: Nicol Voermans
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Nguyen Q, Lim KRQ, Yokota T. Current understanding and treatment of cardiac and skeletal muscle pathology in laminin-alpha2 chain-deficient congenital muscular dystrophy. Appl Clin Genet. 2019 Jul 3;12:113-130. doi: 10.2147/TACG.S187481. eCollection 2019.
citation: Moulin M, Ferreiro A. Muscle redox disturbances and oxidative stress as pathomechanisms and therapeutic targets in early-onset myopathies. Semin Cell Dev Biol. 2017 Apr;64:213-223. doi: 10.1016/j.semcdb.2016.08.003. Epub 2016 Aug 12.
citation: de Vries PR, Janssen M, Spaans E, de Groot I, Janssen A, Smeitink J, Koene S. Natural variability of daily physical activity measured by accelerometry in children with a mitochondrial disease. Mitochondrion. 2019 Jul;47:30-37. doi: 10.1016/j.mito.2019.04.005. Epub 2019 Apr 20.
citation: Bouman K, Groothuis JT, Doorduin J, van Alfen N, Udink Ten Cate FEA, van den Heuvel FMA, Nijveldt R, van Tilburg WCM, Buckens SCFM, Dittrich ATM, Draaisma JMT, Janssen MCH, Kamsteeg EJ, van Kleef ESB, Koene S, Smeitink JAM, Kusters B, van Tienen FHJ, Smeets HJM, van Engelen BGM, Erasmus CE, Voermans NC. Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study. BMC Neurol. 2021 Aug 12;21(1):313. doi: 10.1186/s12883-021-02336-z.