Myasthenic Syndromes, CongenitalNCT06630650
A Prospective Natural History and Outcome Measure Validation Study of Congenital Myasthenic Syndromes
An observational study of Myasthenic Syndromes, Congenital, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 6 months to 99 years
- Conditions the study is for
- Myasthenic Syndromes, Congenital
- How many people
- 75 participants
- Where
- 1 siteUnited States
- Study dates
- 12 May 2025to 2 Dec 2044
- Phase
- Observational
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months to 99 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Patients with congenital myasthenic syndromes with a focus on DOK7 and COLQ subtypes.
Who may be able to join
- 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).
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
NIH Clinical Center Office of Patient Recruitment (OPR), 800-411-1222 ext. TTY dial 711, ccopr@nih.gov
About this study
Official title: A Single Center 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.
Read more
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....
Read the detailed description
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)
- Conditions
- Myasthenic Syndromes, Congenital
- Keywords
- Congenital Myasthenic Syndrome, Collagen Q, Downstream of tyrosine kinase 7, DOK7, COLQ
- Medical subject headings
- Myasthenic Syndromes, Congenital
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| COLQ-related CMS | Genetically confirmed COLQ-related CMS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Characterize baseline clinical manifestations and CMS disease
Measured: One year
Assess the validity and interrater reliability of outcome measures in CMS
Measured: 5 Years
Secondary outcomes (1)
Characterize the extended disease course of CMS
Measured: Years 2-5
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Oct 2024
- Study start12 May 2025
- Primary completion2 Dec 2042 (estimated)
- Study completion2 Dec 2044 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (37)Papers the sponsor has linked to this study.
- Other trials for Myasthenic Syndromes, CongenitalStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 75 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Christopher Grunseich, M.D., Principal investigator, National Institute of Neurological Disorders and Stroke (NINDS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06630650
- Sponsor's protocol ID
- 10002093
- Other IDs
- 002093-N
- Status last verified
- 11 Aug 2026
- First submitted
- 6 Oct 2024
- Last updated
- 13 Aug 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Brooks PJ, Ottinger EA, Portero D, Lomash RM, Alimardanov A, Terse P, Xu X, Chandler RJ, Geist Hauserman J, Esposito E, Bonnemann CG, Venditti CP, Austin CP, Pariser A, Lo DC. The Platform Vector Gene Therapies Project: Increasing the Efficiency of Adeno-Associated Virus Gene Therapy Clinical Trial Startup. Hum Gene Ther. 2020 Oct;31(19-20):1034-1042. doi: 10.1089/hum.2020.259. No abstract available.
PubMed 32993373Nicole S, Azuma Y, Bauche S, Eymard B, Lochmuller H, Slater C. Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions. J Neuromuscul Dis. 2017;4(4):269-284. doi: 10.3233/JND-170257.
PubMed 29125502Maggi L, Bernasconi P, D'Amico A, Brugnoni R, Fiorillo C, Garibaldi M, Astrea G, Bruno C, Santorelli FM, Liguori R, Antonini G, Evoli A, Bertini E, Rodolico C, Mantegazza R. Italian recommendations for diagnosis and management of congenital myasthenic syndromes. Neurol Sci. 2019 Mar;40(3):457-468. doi: 10.1007/s10072-018-3682-x. Epub 2018 Dec 15.
PubMed 30554356Bergamin E, Hallock PT, Burden SJ, Hubbard SR. The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Mol Cell. 2010 Jul 9;39(1):100-9. doi: 10.1016/j.molcel.2010.06.007.
PubMed 20603078Sigoillot SM, Bourgeois F, Lambergeon M, Strochlic L, Legay C. ColQ controls postsynaptic differentiation at the neuromuscular junction. J Neurosci. 2010 Jan 6;30(1):13-23. doi: 10.1523/JNEUROSCI.4374-09.2010.
PubMed 20053883Hallock PT, Xu CF, Park TJ, Neubert TA, Curran T, Burden SJ. Dok-7 regulates neuromuscular synapse formation by recruiting Crk and Crk-L. Genes Dev. 2010 Nov 1;24(21):2451-61. doi: 10.1101/gad.1977710.
PubMed 21041412Palace J, Lashley D, Newsom-Davis J, Cossins J, Maxwell S, Kennett R, Jayawant S, Yamanashi Y, Beeson D. Clinical features of the DOK7 neuromuscular junction synaptopathy. Brain. 2007 Jun;130(Pt 6):1507-15. doi: 10.1093/brain/awm072. Epub 2007 Apr 23.
PubMed 17452375Lee M, Beeson D, Palace J. Therapeutic strategies for congenital myasthenic syndromes. Ann N Y Acad Sci. 2018 Jan;1412(1):129-136. doi: 10.1111/nyas.13538.
PubMed 29381222McMacken GM, Spendiff S, Whittaker RG, O'Connor E, Howarth RM, Boczonadi V, Horvath R, Slater CR, Lochmuller H. Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome. Hum Mol Genet. 2019 Jul 15;28(14):2339-2351. doi: 10.1093/hmg/ddz059.
PubMed 31220253James MA. Use of the Medical Research Council muscle strength grading system in the upper extremity. J Hand Surg Am. 2007 Feb;32(2):154-6. doi: 10.1016/j.jhsa.2006.11.008. No abstract available.
PubMed 17275587Fernandez-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO, Shrader JA, Lehky TJ, Li L, Ryder JE, Levy EW, Solomon BI, Harris-Love MO, La Pean A, Schindler AB, Chen C, Di Prospero NA, Fischbeck KH. Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial. Lancet Neurol. 2011 Feb;10(2):140-7. doi: 10.1016/S1474-4422(10)70321-5. Epub 2011 Jan 6.
PubMed 21216197Bortolani S, Brusa C, Rolle E, Monforte M, De Arcangelis V, Ricci E, Mongini TE, Tasca G. Technology outcome measures in neuromuscular disorders: A systematic review. Eur J Neurol. 2022 Apr;29(4):1266-1278. doi: 10.1111/ene.15235. Epub 2022 Jan 10.
PubMed 34962693Bruggeman BS, Vincent HK, Chi X, Filipp SL, Mercado R, Modave F, Guo Y, Gurka MJ, Bernier A. Simple tests of cardiorespiratory fitness in a pediatric population. PLoS One. 2020 Sep 4;15(9):e0238863. doi: 10.1371/journal.pone.0238863. eCollection 2020.
PubMed 32886730Servais L, Mercuri E, Straub V, Guglieri M, Seferian AM, Scoto M, Leone D, Koenig E, Khan N, Dugar A, Wang X, Han B, Wang D, Muntoni F; SKIP-NMD Study Group. Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial. Nucleic Acid Ther. 2022 Feb;32(1):29-39. doi: 10.1089/nat.2021.0043. Epub 2021 Nov 17.
PubMed 34788571de Lattre C, Payan C, Vuillerot C, Rippert P, de Castro D, Berard C, Poirot I; MFM-20 Study Group. Motor function measure: validation of a short form for young children with neuromuscular diseases. Arch Phys Med Rehabil. 2013 Nov;94(11):2218-26. doi: 10.1016/j.apmr.2013.04.001. Epub 2013 Apr 18.
PubMed 23602884