ArthrogryposisFSS-EDICT INCT01306994
Study of Resting and Exercising Body Functioning in Freeman-Sheldon Syndrome and Related Conditions
An observational study of Arthrogryposis and Craniofacial Abnormalities, run by Freeman-Sheldon Research Group, Inc. at 1 site in United States.
Trial summary
The hypotheses of the present study of Freeman-Sheldon syndrome (FSS) and related conditions are: (1) that exercise capacity is lower in FSS patients versus normal controls, and the lower exercise capacity is due to changes in the muscles' normal structure and an inability of sufficient quantity of the energy molecule… Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Arthrogryposis, Craniofacial Abnormalities
- What is being tested?
- Lactate, Glucose, and Adenosine Triphosphate Blood Levels, Physiological Stress Test and Functional Enquiry Form
- Type of treatment
- Surgery or procedure
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2014to Jun 2022
- 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 Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: Patients world-wide are welcome, so-long as they have a qualifying diagnosis. Healthy controls are welcome world-wide, as well.
Syndrome Group Inclusion Criteria:
- Freeman-Sheldon syndrome,
- Sheldon-Hall syndrome,
- Distal arthrogryposis type 1, or
- Distal arthrogryposis type 3
- Deceased patients with enough clinical information available to satisfy study requirements
Syndrome Group Exclusion Criteria:
- Individuals not confirmed to have a condition under study
- Deceased patients without enough clinical information available to satisfy study requirements
- Patients with other anomalies, not having one of the above syndromes
- Patients or parents of minor children not willing to give consent
- Mature female patients who are pregnant or breast-feeding will be reassessed for consideration for enrolment.
- Mature female patients who are currently experiencing menses will be reassessed for consideration for enrolment.
- Patients with active, acute comorbid illness will be reassessed for consideration for enrolment.
Control Group Inclusion Criteria:
- Subjects must be healthy and free of active disease.
- Subject or parent of minor child must be willing to give consent.
- Subjects must fall within the age-bracket to be matched with a Syndrome Group patient already screened and enroled in the study
- Subjects must be non-tobacco users and non-drinkers.
Control Group Exclusion Criteria:
- Subjects exceptional for their age in body weight, stature, or habitus according to commonly accepted guidelines
- Subjects with active psychiatric illness, as manifested by abnormal mental status examination
- Subjects with active physical illness, especially respiratory or cardiac problem, as manifested by abnormal findings on physical examination
- Subjects with significant diagnosis of a constitutional disease or genetic disorder
- Subjects with a history of severe trauma resulting in either an anatomical of physiological deformity that impairs function
- Non-living subjects
- Candidates who fail the stress test
- Mature female subjects who are pregnant or breast-feeding will be reassessed for consideration for enrolment.
- Mature female subjects who are currently experiencing menses will be reassessed for consideration for enrolment.
- Subjects with active, acute illness will be reassessed for consideration for enrolment.
- Any other condition or anomaly expected to affect current physiology listed in AFI-48-123.
Trial locations and contacts
1 site in 1 country.
United States1 site
Freeman-Sheldon Research Group, Inc. Headquarters
Buckhannon, West Virginia, 26201
About this study
Official title: Freeman-Sheldon Syndrome Evaluation and Diagnosis in Clinical Settings (FSS-EDICT) I: a Case-Control, Cross-Sectional Study of Baseline and Stress Physiology Parameters
The hypotheses of the present study of Freeman-Sheldon syndrome (FSS) and related conditions are: (1) that exercise capacity is lower in FSS patients versus normal controls, and the lower exercise capacity is due to changes in the muscles' normal structure and an inability of sufficient quantity of the energy molecule to bind to muscle; (2) this muscle problem reduces amount of air that can get in the lung and amount of oxygen carried in the blood, which then has the effect of increasing heart and respiration rates, blood pressure, and deep body temperature, and produces muscle rigidity; (3) the events noted above, when they occur during cardiac stress testing, are related to a problem similar to malignant hyperthermia (MH) reported in some muscle disorders without use of drugs known to cause MH. MH (a life-threatening metabolic reaction that classically is triggered when susceptible persons receive certain drugs used in anaesthesia.
Read the detailed description
This study is a research project initiated by the graduate research student (Mikaela I. Poling) and assisted by the clinical genetics fellow and graduate student (Andrés Morales) in partial fulfilment the requirements for their Masters degrees in Clinical and Applied Physiology, under approval, direction, and supervision of the study PI (Rodger J. McCormick).
Importance of Present Study:
FSS is a rare human neuromusculoskeletal disorder present before birth, involving primarily limb and craniofacial deformities. There are no prospective studies addressing physiological parameters, which are necessary to enable understanding of the underlying pathology and pathophysiology of Freeman-Sheldon syndrome. Elucidating any deviations in baseline and stress physiological parameters in FSS patients versus standard normal values and normal control subjects is of critical importance in tailoring therapeutic interventions to this challenging patient population.
Background:
Vanek et al. (1986) purposed FSS spectrum is a non-progressive congenital myopathy, giving pathological and electromyographical (EMG) evidence. They found white fibrose tissue within histologically normal muscle fibres, resulting in abnormal EMGs.
Toydemir et al. (2006) showed that mutations in embryonic myosin heavy chain 3 (MYH3), caused classic FSS phenotype, in which they screened 28 probands. In 20 patients, new missense mutations caused substitution of arginine at position 672 (arg672) by histidine or cytosine; arg672 is found in all myosin proteins post-embryonically. Of the remaining six patients in whom mutations were found, three had new missense or familial mutations; three other patients with sporadic expression had new, which were also found in Sheldon-Hall syndrome (SHS); two patients had no recognized mutations. They postulated these allelic variations at arg672 could affect adenosine triphosphate (ATP) binding. It is unknown how these mutations might correlate to the phenotypes observed. Their laboratory, including Stevenson et al. (2006) also presented strong evidence that FSS and SHS and similar distal arthrogryposes (DA) were distinct entities based on phenotype, natural history, and genotype.
Portillo et al. (unpublished data), in study of biopsies from their patient, found no evidence of muscle in the superior orbicularis oculi and found highly variable fibre size as a single pathological feature in a single vastus lateralis biopsy. Clinically, their patient, who had to-date the most severe expression of FSS, exhibited no function of the superior eyelid and reasonable muscle tone, bulk, and strength in the thigh. These findings suggested variable syndromic affectation by body region. They reported exertional dyspnea and resting tachycardia, without pathological features, in their patient and anecdotal information concerning exertional dyspnea in two other adult FSS patients. They also documented the occurrence of unexplained, seemingly stress-induced, episodic fever in their patient that resembled the malignant hyperthermia (MH) clinical triad of hyperthermia, tachycardia, and muscle rigidity.
In addition to age, gender, physical activity status, and concomitant disease and disability, maximal oxygen uptake, a function of exercise capacity, is genetically-controlled, and as already documented in other muscle disorders, the idiopathic febrile episodes reported by Portillo et al. may share physiological and biochemical similarities to the well-defined congenital muscle anomaly MH, which classically occurs when susceptible individuals receive inhaled anaesthetics, such as ether and halothane, or depolarizing muscle relaxants during surgery. Together, these clinical observations suggested there may be some syndromic relationship to exercise capacity and development of MH-like febrile syndrome, and it will be important to demonstrate these findings in a controlled experimental setting.
Significant differences among the similar distal arthrogryposes (DAs) may exist, with respect to the above, and this will be important to define experimentally, as well. Data concerning baseline and stress physiology in FSS and similar DAs could help to further define the distinct DA phenotypes clinically similar to FSS, contributing to nosological classification of FSS and related entities. This study will include FSS, Sheldon-Hall syndrome, DA type 1, and DA type 3.
- Conditions
- Arthrogryposis, Craniofacial Abnormalities
- Being tested
- Lactate, Glucose, and Adenosine Triphosphate Blood Levels, Physiological Stress Test, Functional Enquiry Form, Strength, Joint ROM, Girth and Length Measurements, Study Physical Examination
- Keywords
- Exercise Test, Bicycle Ergometry Test, Stress Test
- Medical subject headings
- Arthrogryposis, Craniofacial Abnormalities
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lactate, Glucose, and Adenosine Triphosphate Blood LevelsOther
Also called ATP levels, ATP blood levels, adenosine triphosphate test, blood test for ATP
Completed during the clinical examination and exercise test by the researchers, lactate, glucose, and free and total adenosine triphosphate blood levels are determined at rest and during exercise.
Physiological Stress TestProcedure or surgery
Also called stress test, graded exercise test, maximal exercise test, VO2 max test
During exercise, heart and lung function are monitored for changes caused by exercise, which increases the body's need for oxygen and puts extra demands on the heart. In this study, testing is done using a cycle ergometer and conducted according to the standardised exponential exercise protocol (STEEP).
Functional Enquiry FormOther
Also called FSRG Form 08, health history, review of systems, systems review
Evaluated before clinical examination, it is a checklist of medical problems.
Strength, Joint ROM, Girth and Length MeasurementsOther
Also called SF 527, Standard Form 527, musculoskeletal examination, musculoskeletal exam
Completed during the clinical examination by the researchers, it is a structured approach to evaluation of muscles, joints, arms, thighs, and legs.
Study Physical ExaminationOther
Also called FSRG Form 14, physical examination, physical evaluation, physical assessment
Completed during the clinical examination by the researchers, it is a structured approach to a full physical examination (minus breasts, genitalia, or rectum).
Observational Gait AnalysisOther
Also called FSRG 10, gait analysis, functional gait analysis
Completed during the clinical examination by researchers, it is a structured approach to evaluation of a person's walking.
Mental Health InterviewOther
Also called psychiatric examination, psychiatric evaluation, psychiatric assessment, psychiatric interview
Completed during the clinical examination by the researchers, it is a general evaluation of mental health status.
| Study group | Role | What they receive |
|---|---|---|
| Syndrome Group | Individuals with Freeman-Sheldon, Sheldon-Hall, distal arthrogryposis type 1, or distal arthrogryposis type 3 Receives: Other: Lactate, Glucose, and Adenosine Triphosphate Blood Levels; Procedure: Physiological Stress Test; Other: Functional Enquiry Form; Other: Strength, Joint ROM, Girth and Length Measurements; Other: Study Physical Examination; Other: Observational Gait Analysis; Other: Mental Health Interview | |
| Control Group | Healthy individuals Receives: Other: Lactate, Glucose, and Adenosine Triphosphate Blood Levels; Procedure: Physiological Stress Test; Other: Functional Enquiry Form; Other: Strength, Joint ROM, Girth and Length Measurements; Other: Study Physical Examination; Other: Observational Gait Analysis; Other: Mental Health Interview |
What is being measured
The primary outcome is the main question the study is designed to answer.
Heart rate
Increased heart rate, measured electrocardiographically, is used as an index of cardiovascular strain imposed by needs during exercise and exaggerated by Freeman-Sheldon and related conditions.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Oxygen Consumption
Oxygen consumption, measured by ventilation of expired oxygen, is used as a measure of physiological strain imposed by metabolic needs during exercise and exaggerated by Freeman-Sheldon and related conditions.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Secondary outcomes (12)
Non-Invasive Arterial Blood Pressure
Increased non-invasive arterial blood pressure rate is used as an index of cardiovascular strain imposed by needs during exercise and exaggerated by Freeman-Sheldon and related conditions.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Spirometry (Forced Expiratory Volume/Forced Vital Capacity)
Decreased ability of the lungs to move air, measured by forced expiration, is used as an index of strain imposed by Freeman-Sheldon syndrome and related conditions.
Measured: Evaluated before and after exercise, during two study visits (lasting an average of 1-3 hours)
Saturation of Peripheral Oxygen
Decreased saturation of peripheral oxygen, measured by pulse oxymetry, is used as a measure of physiological strain imposed by metabolic needs during exercise and exaggerated by Freeman-Sheldon and related conditions.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Respiratory Rate
Increased respiratory rate, measured by plethysmograph, is used as a measure of physiological strain imposed by metabolic needs during exercise and exaggerated by Freeman-Sheldon and related conditions.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Heart Rhythm
Heart rhythms, monitored by electrocardiograph, are used as an index of cardiovascular strain imposed by needs during exercise and exaggerated by Freeman-Sheldon and related conditions.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Core Temperature
Increased core temperature, measured as oesophageal temperature, is used as a measure of physiological strain imposed by metabolic needs during exercise and exaggerated by Freeman-Sheldon, related conditions, and malignant hyperthermia.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Adenosine Triphosphate
Decreased adenosine triphosphate, measured as capillary blood level, is used as a measure of physiological strain imposed by metabolic needs during exercise and exaggerated by Freeman-Sheldon and related conditions.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Perceived Exertion
Increased perceived exertion, measured using the Borg scale, are used as an index of fatigue.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Muscle Rigidity
Increased muscle rigidity, evaluated by clinical examination and patient self-report, is used as an indicator of malignant hyperthermia, when increased core temperature, heart rate, and respiratory rate are present.
Measured: Evaluated while exercising, during second of two study visits (lasting an average of 1-3 hours)
Functional and Health-Related Quality of Life
Functional and health-related quality of life, measured with the Medical Outcomes Trust Short Form (36) Health Survey (SF-36), is used as a general prediction of expected physical exercise capacity.
Measured: Evaluated in first of two study visits, lasting an average of 1-3 hours
Lactic Acid
Lactic acid, measured by capillary blood level, is used as a measure of physiological strain imposed by metabolic needs during exercise and exaggerated by Freeman-Sheldon and related conditions.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Glucose
Glucose, measured by capillary blood level, is used as an index of physiological strain, together with lactic acid and adenosine triphosphate capillary blood levels, imposed by metabolic needs during exercise and exaggerated by Freeman-Sheldon and related conditions.
Measured: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2011 (estimated)
- Study startMar 2014
- Primary completionJun 2022
- Study completionJun 2022
Why it stopped: Lack of patient interest
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for ArthrogryposisStudies 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
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Freeman-Sheldon Research Group, Inc.
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01306994
- Sponsor's protocol ID
- 000079
- Other IDs
- U1111-1120-5931
- Acronym
- FSS-EDICT I
- Status last verified
- Jun 2022
- First submitted
- 26 Feb 2011
- Last updated
- 6 Jun 2022
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No: We do not intend to share any individual participant data.
Publications
Vanek J, Janda J, Amblerova V, Losan F. Freeman-Sheldon syndrome: a disorder of congenital myopathic origin? J Med Genet. 1986 Jun;23(3):231-6. doi: 10.1136/jmg.23.3.231.
PubMed 3723551Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006 May;38(5):561-5. doi: 10.1038/ng1775. Epub 2006 Apr 16.
PubMed 16642020Stevenson DA, Carey JC, Palumbos J, Rutherford A, Dolcourt J, Bamshad MJ. Clinical characteristics and natural history of Freeman-Sheldon syndrome. Pediatrics. 2006 Mar;117(3):754-62. doi: 10.1542/peds.2005-1219.
PubMed 16510655Portillo AL, Chamberlain RL, McCormick RJ, Poling MI. Histopathological and Operative Findings in a Severe Case of Freeman-Sheldon Syndrome: Implications for Nosology and Therapy. (Unpubl.) 2010.
Litman RS, Rosenberg H. Malignant hyperthermia: update on susceptibility testing. JAMA. 2005 Jun 15;293(23):2918-24. doi: 10.1001/jama.293.23.2918.
PubMed 15956637McCormick RJ. A Proposal for a Thesis: Heat Tolerance in Exercising Lean and Obese Middle-Aged Men. DEd diss., the Pennsylvania State University, 1973.
Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16. Epub 2009 Jan 15.
PubMed 19436827Northridge DB, Grant S, Ford I, Christie J, McLenachan J, Connelly D, McMurray J, Ray S, Henderson E, Dargie HJ. Novel exercise protocol suitable for use on a treadmill or a bicycle ergometer. Br Heart J. 1990 Nov;64(5):313-6. doi: 10.1136/hrt.64.5.313.
PubMed 2245110Franklin B, Fern A, Fowler A, Spring T, Dejong A. Exercise physiologist's role in clinical practice. Br J Sports Med. 2009 Feb;43(2):93-8. doi: 10.1136/bjsm.2008.055202. Epub 2008 Dec 2.
PubMed 19050005