An observational study in Arthrogryposis and Craniofacial Abnormalities, sponsored by Freeman-Sheldon Research Group, Inc.. Withdrawn at 1 site in United States. Per ClinicalTrials.gov, last updated 2022-06-06.
Sponsored by Freeman-Sheldon Research Group, Inc. · Observational
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.
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.
16 studies on the registry are indexed under Arthrogryposis; 5 are open to participants now.
Browse Arthrogryposis studies →Freeman-Sheldon Research Group, Inc. is the lead sponsor of 4 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
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:
Syndrome Group Exclusion Criteria:
Control Group Inclusion Criteria:
Control Group Exclusion Criteria:
Individuals with Freeman-Sheldon, Sheldon-Hall, distal arthrogryposis type 1, or distal arthrogryposis type 3
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
Healthy individuals
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
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.
Also known as: ATP levels, ATP blood levels, adenosine triphosphate test, blood test for ATP, blood test for adenosine triphosphate, ATP blood test, adenosine triphosphate blood test, ATP test, glucose test, glucose blood test, sugar test, lactic acid levels, lactic acid blood test, lactate blood test, lactate levels
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).
Also known as: stress test, graded exercise test, maximal exercise test, VO2 max test, maximal oxygen uptake test, exercise tolerance test, exercise stress test
Evaluated before clinical examination, it is a checklist of medical problems.
Also known as: FSRG Form 08, health history, review of systems, systems review, medical history, personal health history
Completed during the clinical examination by the researchers, it is a structured approach to evaluation of muscles, joints, arms, thighs, and legs.
Also known as: SF 527, Standard Form 527, musculoskeletal examination, musculoskeletal exam, musculoskeletal evaluation, musculoskeletal assessment, extremity examination, extremity evaluation, extremity assessment, extremity exam
Completed during the clinical examination by the researchers, it is a structured approach to a full physical examination (minus breasts, genitalia, or rectum).
Also known as: FSRG Form 14, physical examination, physical evaluation, physical assessment, medical examination, medical evaluation, medical assessment, full medical examination, full medical evaluation, full medical assessment, periodic medical examination, periodic medical evaluation, periodic medical assessment, annual medical examination, annual medical evaluation, annual medical assessment, yearly medical examination, yearly medical evaluation, yearly medical assessment, full physical examination, full physical evaluation, full physical assessment, complete physical examination, complete physical evaluation, complete physical assessment, yearly physical examination, yearly physical evaluation, yearly physical assessment, annual physical examination, annual physical evaluation, annual physical assessment, periodic physical examination, periodic physical evaluation, periodic physical assessment, screening physical examination, screening physical evaluation, screening physical assessment, screening physical, physical, periodic physical, annual physical, annual check-up, annual check up, yearly physical, yearly check up, yearly check-up, check up, check-up, medical check-up, medical check up, annual medical check-up, annual medical check up, yearly medical check-up, yearly medical check up, periodic medical check-up, periodic medical check up, periodic health evaluation, periodic health assessment, annual health evaluation, annual health assessment, yearly health evaluation, yearly health assessment, screening health evaluation, screening health assessment, screening medical examination, screening medical evaluation, screening medical assessment, med check
Completed during the clinical examination by researchers, it is a structured approach to evaluation of a person's walking.
Also known as: FSRG 10, gait analysis, functional gait analysis
Completed during the clinical examination by the researchers, it is a general evaluation of mental health status.
Also known as: psychiatric examination, psychiatric evaluation, psychiatric assessment, psychiatric interview, diagnostic mental health examination, diagnostic mental health evaluation, diagnostic mental health assessment, diagnostic psychiatric examination, diagnostic psychiatric evaluation, diagnostic psychiatric assessment, diagnostic psychiatric interview, intake examination, intake evaluation, intake assessment, intake interview, mental health evaluation, mental health examination, mental health assessment, psychological examination, psychological evaluation, psychological assessment, psychological interview, psychological intake examination, psychological intake evaluation, psychological intake assessment, psychological intake interview
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.
Time frame: 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.
Time frame: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)
Body Composition
Body composition, measured by calliper, together with direct indices of physiological strain, is used to determined metabolic disease burden of Freeman-Sheldon syndrome and related conditions.
Time frame: Evaluated before exercise, during two study visits (lasting an average of 1-3 hours)
Hand Grip Strength
Decreased hand grip strength, measured by a hand dynamometer, is used as an index of physiological strain imposed by Freeman-Sheldon and related conditions
Time frame: Evaluated during the first of two study visits
Plan to share: No — We do not intend to share any individual participant data.
Ran from Mar 2014 to primary completion in Jun 2022, 99 months.
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Freeman-Sheldon Research Group, Inc.