The Natural History of Patients With Mutations in SEPN1 (SELENON) or LAMA2

Study Overview
=================
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.

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

Conditions
-----------------
MDC1A, SELENON-related Myopathy

Intervention / Treatment
-----------------
* Other: No intervention


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| SELENON- or LAMA2-related muscular dystrophy<br>Participants diagnosed with congenital myopathy/muscular dystrophy due to mutations in the SEPN1 (SELENON) or LAMA2 gene | Other: No intervention<br>* This concerns a natural history study; no interventions will be used<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Motor Function Measure (MFM)-32 (older than 7 years) or MFM-20 (2 to 7 years old) | 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. | Change from baseline at 6 months, 12 months and 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accelerometry (2 years and older) - change of physical activity in daily life | Physical activity in daily life will be assessed by wearing an accelerometer (GENEActiv original devices) for 7 days. The main point of interest includes the change of physical activity in daily life over a period of 1,5 year | Change from baseline at 6 months, 12 months and 18 months | 
| Change of activity limitations - ACTIVLIM (6 years and older) | ACTIVLIM assesses the ability to perform 22 activities of daily life on a 3-point scale from impossible to easy. The main point of interest includes the change of activity limitations over a period of 1,5 year. Additionally, the ACTIVLIM scores of participants will be compared to reference values. | 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) | Balance will be assessed through the Pediatric balance scale (2 - 17 years) or the Mini Balance Evaluation System Test (miniBEST) (18 years and older). The Pediatric Balance Scale is a modified version of the Berg Balance Scale that is used to assess functional balance skills in school-aged children with mild to moderate motor impairments. The miniBEST evaluates balance control by scoring of exercises that belong to one of the following categories: anticipatory postural changes, reactive postural control, sensory orientation and walking. The main point of interest includes the change of balance scores over a period of 1,5 year. Additionally, the balance score of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of bone density - DEXA scan (2 years and older) | The bone density of the spine and hip will be measured by a DEXA scan. The main point of interest includes the change of bone density over a period of 1 year. Additionally, bone density of participants will be compared to reference values. | Change from baseline at 12 months | 
| Change of Borg Rating Scale of Perceived Exertion (5 years and older) - physical activity intensity level | Borg Rating Scale of Perceived Exertion is a way of measuring physical activity intensity level. Perceived exertion is based on the physical sensations a person experiences during physical activity. Participants will be asked to score the intensity level at the beginning and at the end of the 6MWT. The main point of interest includes the change of perceived exertion over a period of 1,5 year. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of cardiac function (2 years and older) | Cardiac function will be assessed using standardized cardiac ultrasound protocols with speckle tracking, including global longitudinal strain (GLS), 3D left ventricle ejection fraction (LVEF), right ventricle s' and right ventricle fractional area change (RV FAC) combined with standard electrocardiography (ECG). The main point of interest includes the change of cardiac function over a period of 1 year. Additionally, cardiac function of participants will be compared to reference values. | Change from baseline at 12 months | 
| Change of The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score (children under the age of 2 years) | CHOP INTEND has been shown to be valid for the assessment of motor skills of children below 2 years of age. The main point of interest includes the change of CHOP INTEND score over a period of 1,5 year. Additionally, the CHOP INTEND score of participant will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of fatigue (adults, 18 years and older) - Checklist Individual Strength (CIS) | The CIS is a questionnaire rating four subscales: subjective tiredness, concentration, motivation and physical activity. It consists of 20 items on a 7-point scale. The main point of interest includes the change of fatigue over a period of 1,5 year. Additionally, fatigue scores of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of fatigue (pediatric, 2-17 years old) - PedsQL Multidimensional Fatigue Scale (MFS) | The PedsQL MFS assesses subjective fatigue in three domains, namely General Fatigue Scale, Sleep/Rest Fatigue Scale, and Cognitive Fatigue Scale. The main point of interest includes the change of fatigue over a period of 1,5 year. Additionally, fatigue scores of participants will be compared to reference values. | 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) | The EK2 is a questionnaire that was designed to measure functional ability of activities in daily living in non-ambulant Duchenne muscular dystrophy patients. This questionnaire is only available in English. Therefore, only participants of 16 years and older who have a sufficient understanding of the English language will be asked to complete this questionnaire. The main point of interest includes the change of functional ability in daily life over a period of 1,5 year. Additionally, EK2 scores of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of Functional Ambulation Category (FAC) (5 years and older) | The FAC assesses functional ambulation in participants.The main point of interest includes the change of FAC over a period of 1,5 year. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of Graded and Timed function tests | The time it takes to complete functions of the lower extremity will be assessed with the 30 seconds sit to stand test, Timed up and Go, and the time it takes to climb 4 stairs and to rise from the floor (2 years and older); 6 minute walking test and 10 meter walking test (5 years and older); The main point of interest includes the change of Graded and Timed function tests over a period of 1,5 year. Additionally, values of the Graded and Timed function tests of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of Hammersmith Infant Neurological Examination (HINE) (under the age of 2 years) | HINE is designed to be a simple and scorable method for evaluating infants from 2 months to 2 years of age. It includes 3 sections that assess different aspects of neurologic function, including neurological examination, developmental milestones and behavioral assessment. The main point of interest includes the change of HINE score over a period of 1,5 year. Additionally, HINE scores of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of Hammersmith Functional Motor Scale (HFMS) (2 years and older, non-ambulant) | The HFMS was originally developed to assess the physical abilities of children with non-ambulant Spinal Muscular Atrophy (SMA). It consists of 20 items that were considered as important to measure the physical functioning of those patients. The main point of interest includes the change of HFMS scores. Additionally, HFMS scores of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of Impact on Participation and Autonomy (IPA) (18 years and older) | Questionnaire about participation and autonomy in daily life. The main point of interest includes the change of IPA scores over a period of 1,5 year. Additionally, IPA scores of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of maximal voluntary isometric contraction (5 years and older) (Newton) | Maximal voluntary isometric contraction will be measured by hand-held dynamometry (both hands, m. biceps brachii, m. quadriceps). The main point of interest includes the change of maximal voluntary isometric contraction over a period of 1,5 year. Additionally, maximal voluntary isometric contraction of participants will be compared to reference values. | 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 | Questionnaire in which the location, level and characteristics of pain are assessed. The main point of interest is the change of location, level and characteristics of pain over a period of 1,5 year. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of muscle atrophy (cm) and fattening (echo-intensity) by muscle ultrasound | Muscle atrophy and fattening of the leg, arm, back and abdominal muscles will be assessed by muscle ultrasound.The main point of interest includes the change of muscle atrophy and fattening over a period of 1,5 year. Additionally, muscle atrophy and fattening of participants will be compared to reference values. | 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 | A full body muscle MRI will be performed in participants who are able to lie supine and still for 60 minutes (participants of 10 years and older) and who are not dependent on respiratory equipment. Muscle fattening will be assessed by Regions of Interest (ROIs) (quantitative) and modified Mercuri score (semi-quantitative). Atrophy will be assessed by muscle volume score (semi-quantitative). Inflammation will be assessed by Malattia score (semi-quantitative). The presence and pattern of muscle fibrosis will be noted.The main point of interest includes the change of muscle fattening, atrophy, inflammation and fibrosis over a period of 1 year. Additionally, these values will be compared to reference values. | Change from baseline at 12 months | 
| Change of muscle power by muscle power measurements (Medical Research Council (MRC) scale) (2 years and older) | Muscle power of individual muscle groups can be assessed by muscle power measurements and graded in correspondence with the MRC scale. The main point of interest includes the change of MRC score in participants over a period of 1,5 year. | Change from baseline at 6 months, 12 months and 18 months | 
| Pulmonary function (5 years and older) - change of forced vital capacity (percentage predicted) | Obtained with handheld spirometry in sit and supine. The main point of interest includes the change of forced vital capacity over a period of 1,5 year. Additionally, forced vital capacity of participants will be compared to reference values. | 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) | Obtained with handheld spirometry in sit and supine. The main point of interest includes the change of forced expiratory volume in the first second over a period of 1,5 year. Additionally, change of forced expiratory volume in the first second of participants will be compared to reference values. | 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) | Obtained with handheld spirometry in sit and supine. The main point of interest includes the change of peak expiratory flow over a period of 1,5 year. Additionally, peak expiratory flow in participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Pulmonary function (5 years and older) - change of vital capacity (percentage predicted) | Obtained with handheld spirometry in sit and supine. The main point of interest includes the change of vital capacity over a period of 1,5 year. Additionally, vital capacity in participants will be compared to reference values. | 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) | Obtained with handheld spirometry in sit. The main point of interest includes the change of peak cough flow over a period of 1,5 year. Additionally, peak cough flow in participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Pulmonary function (5 years and older) - change of maximal expiratory pressure (cmH2O) | Obtained with handheld device. The main point of interest includes the change of maximal expiratory pressure over a period of 1,5 year. Additionally, maximal expiratory pressure of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Pulmonary function (5 years and older) - change of maximal inspiratory pressure (cmH2O) | Obtained with handheld device. The main point of interest includes the change of maximal inspiratory pressure over a period of 1,5 year. Additionally, maximal inspiratory pressure of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Pulmonary function (5 years and older) - change of sniff nasal inspiratory pressure (cmH2O) | Obtained with handheld device. The main point of interest includes the change of sniff nasal inspiratory pressure over a period of 1,5 year. Additionally, sniff nasal inspiratory pressure of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Pulmonary function - change of diaphragm thickness (mm) | Obtained with ultrasound. The main point of interest includes the change of diaphragm thickness over a period of 1,5 year. Additionally, the diaphragm thickness of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Pulmonary function - change of diaphragm thickening (ratio) | Obtained with ultrasound. The main point of interest includes the change of diaphragm thickening over a period of 1,5 year. Additionally, diaphragm thickening of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Pulmonary function - change of diaphragm excursion (cm) | Obtained with ultrasound. The main point of interest includes the change of diaphragm excursion over a period of 1,5 year. Additionally, diaphragm excursion will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of Quality of life (adult, 18 years and older) by SF36/RAND36 | The adult Quality of Life is measured by the SF36/RAND36 questionnaire. The SF36/RAND36 addresses eight concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. The main point of interest includes the change of Quality of Life over a period of 1,5 year. Additionally, Quality of Life of participants will be compared to reference values. | 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). | The adult Quality of Life is measured by the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. The INQoL is a validated muscle disease specific measure of quality of life, which can be used for individuals or large samples. The main point of interest includes the change of Quality of Life over a period of 1,5 year. Additionally, Quality of Life of participants will be compared to reference values. | 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 | The pediatric Quality of Life is measured by PedsQL generic quality of life. The PedsQL generic quality of life questionnaire consists of 8 items on physical functioning, 5 items on emotional functioning, 5 items on social functioning, and 5 items on school functioning. Each item is scored on a 0-4 scale. The items are reversed scored and linearly transformed to a 0-100 scale, so that higher scores indicate a better outcome. The main point of interest includes the change of Quality of Life over a period of 1,5 year. Additionally, Quality of Life of participants will be compared to reference values. | 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) | The PedsQL NMM questionnaire consists of 25 questions in three domains: Neuromuscular disease, communication and family resources. The main point of interest includes the change of Quality of Life over a period of 1,5 year. Additionally, Quality of Life of participants will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of range of motion of ankles and elbows | The range of motion of the ankles and elbows is noted bilaterally by goniometry. The main point of interest includes the change of range of motion of ankles and elbows over a period of 1,5 year. Additionally, the range of motion of ankles and elbows will be compared to reference values. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of spine deformity (degree) (2 years and older) | Spine deformity (scoliosis, lordosis, kyphosis) will be assessed by a full spine X-ray in lateral and anteroposterior direction in a sitting position and in flexion-extension in a lying position. The main point of interest includes the change of spine deformity over a period of 1 year. Additionally, spine deformity of participants will be compared to reference values. | Change from baseline at 12 months | 
| Change of Brooke and Vignos scale (2 years and older) | The Brooke and Vignos scales provide ordinal data to assess the upper and lower extremity functions. The main point of interest includes the change of Brooke and Vignos scale over a period of 1,5 year. | Change from baseline at 6 months, 12 months and 18 months | 
| Change of Wong-Baker Faces Pain Scale (2 years and older) | The Wong-Baker Faces Pain Scale was originally created for children to help them communicate about their pain. The main point of interest includes the change of the Wong-Baker Faces Pain Scale over a period of 1,5 year. | Change from baseline at 6 months, 12 months and 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Congenital myopathy, 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, Muscle disease