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

Background:

Congenital myasthenic syndromes (CMSs) are a group of inherited disorders that affect how the nerves communicate with muscles. These can cause many problems that affect how people can move and use their bodies.

Objective:

This is a natural history study to learn more about how CMSs affect the body and cause changes over time.

Eligibility:

People aged 6 months or older with a CMS. The study will focus on DOK7- and COLQ-related CMSs, as well as other forms.

Design:

Participants will have up to 7 visits in 5 years. At each visit, participants will undergo many tests, including:

Physical exam with blood and urine tests.

Tests of their heart and lung function.

Exams of the eyes, lungs, muscles, and nerves. These will be done with different specialists.

Exams of the arms and hands and of body use and movements. These will also be done with specialists.

Photos and videos may be taken.

Muscle ultrasound. Participants will lie still as a wand is rubbed over their skin.

Magnetic resonance imaging (MRI) scans. Participants will lie still on a bed that slides partway into a large tube. A parent or other person may remain in the room, too. The scan will take 60 minutes.

Electromyography (EMG). Participants will lie still or may be asked to move around. A machine will measure the electrical activity in their muscles.

An activity monitor may be placed on the participant s wrist, ankle, or hip for up to 2 weeks. The monitor is about the size of a wristwatch.

A sample of skin may be removed....

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)

Eligibility Criteria:
* 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.