A Prospective Natural History and Outcome Measure Validation Study of Congenital Myasthenic Syndromes

Study Description: This natural history and outcome measure validation study aims to longitudinally characterize the clinical manifestations of all congenital myasthenic syndromes (CMS), with a focus on DOK7 and COLQ-related CMS. Both are ultra-rare inherited disorders of the neuromuscular junction. This study will also assess the validity and interrater reliability of outcome measures to support clinical trial readiness in these populations. Primary Objective: Characterize baseline clinical manifestations and CMS disease course over one year. Co-Primary Objective: Assess the validity and interrater reliability of outcome measures in CMS. Secondary Objectives: Characterize the extended disease course of CMS (Years 2 through 5) Exploratory Objectives: Biomarker identification, accelerometer validation, and MCID estimation. Primary Endpoints: Change from baseline to Year 1 in the following (as age-appropriate and tolerated-performed in all participants unless age ranges specified): * Physical strength * MRC scale (all; as tolerated/developmentally appropriate) * Quantitative muscle assessment of shoulder abductors, elbow flexors/extensors, hip flexors and knee extensors/flexors (QMA \>=7y) * Myotools grip and pinch strength (\>=6y) * Physical performance * Six-minute walk test distance (\>=6y) * Repeated 1 minute sit to stand (\>=2y) * Performance of Upper Limb (PUL) (\>=2y) * Time of outstretched arm (\>=2y) * Disease severity --Quantitative Myasthenia Gravis (QMG) Score (\>= 12y) * Motor function \<2y * Hammersmith infant neurological scale score (\<2y) * Sitting balance score (\<2y) * Motor function \>2y * Motor function measure score (MFM20, 2-6y) (MFM32, \>=7y) * Time to ascend four stairs, descend four stairs, supine to stand (\>=5y) * Development --Developmental motor scale quotients (\<5y) * Pulmonary function \>=5y * Forced vital capacity (FVC) * Slow vital capacity (SVC) * Forced vital capacity at 1 second (FEV1) * Maximum inspiratory and expiratory pressures (MIP/MEP) * End-tidal CO2 (ETCO2) * Quality of life * Myasthenia Quality of Life (PM-QOL15 \<18y, MG-QOL15 \>=18) * PROMIS-57 Profile (\>=18y) * PROMIS Ped-25 Profile (8-17y) * PROMIS Parent Proxy CAT (5-7y) * NeuroQoL (fatigue and upper and lower limb function domains, (\>=8y) * MG-ADL (\>=18y) * Serious adverse and disease-related events * Narrative clinician description * Causality assessment (related or unrelated to the research or disease) * Event severity (CTCAE v5) * Event MedDRA system organ class, and preferred term Co-Primary Endpoints: Interrater reliability in physical strength, physical performance, motor function, and quality of life primary endpoints. Secondary Endpoints: Change over time in primary endpoints (Years 2 through 5). Exploratory Endpoints: * Physical performance * Timed up and go (TUG) test x3 (\>=2y) * Wearable sensor metrics during physical performance tests * Biomechanics * Stride length, cadence, velocity captured in clinic by wearable device * Stride velocity 95th centile * Free-living physical activity * Endpoints collected over 2-week data capture period will include: * Number of sit-to-stand transitions * Step count * Average cadence per walking episode * Number of falls * Activity counts (light, moderate, vigorous, moderate to vigorous) * Upper limb movements * Proposal to use in infants/toddlers, use of one device/chest strap. * Ophthalmology * Marginal reflex distance (Ptosis) * Pupillometry * Ocular Motility utilizing Modified Goldmann Perimeter per NEI * Quality of life * CMS-ST- Infant/Young Child 6 months - \<=3 years of age * CMS-ST Child/Adult (4 years - \<=18 years) * Biomarkers * Peripheral biomarkers * Optional skin punch biopsy (fibroblast culture) * Imaging * Muscle MRI lower extremities (T1 and Dixon) * Muscle ultrasound (echogenicity) * Nerve function --EMG/NCS (sfEMG and RNS) * Measurement of AE burden * Adverse Event Unit (AEU)