Clinical Trial Finder

• -

  INCLUSION CRITERIA:

  In order to be eligible to participate in this study, an individual must meet all of the following criteria: - Stated willingness to comply with all study procedures and availability for the duration of the study.

• - Male or female, aged >= 6 months of age.

• - Clinically stable as evidenced by medical record review and remote screening questionnaire.

• - Genetically confirmed congenital myasthenic syndrome (pathogenic or likely pathogenic variants identified by CLIA testing in an established CMS-related gene including but not limited to DOK7, COLQ, CHRNE, RAPSN, CHAT, GFPT1, DPAGT1 OR pathogenic/likely pathogenic variant in combination with a variant of uncertain significance (VUS) AND additional clinical supporting evidence of CMS).

• - Agreement to adhere to Lifestyle Considerations throughout study duration.

• - Ability of subject to understand and the willingness to provide informed consent (>=18 years of age) and assent (>=7 years of age).

EXCLUSION CRITERIA:

• - Received gene transfer therapy.

• - Pregnant women (prior to enrollment) - Ongoing medical condition or medication use that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study or safety of the subject.

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)

Arms

: COLQ-related CMS

Genetically confirmed COLQ-related CMS

Interventions