Study of Resting and Exercising Body Functioning in Freeman-Sheldon Syndrome and Related Conditions (FSS-EDICT I)

This study is currently recruiting participants.
Verified October 2013 by Freeman-Sheldon Research Group, Inc.
Sponsor:
Information provided by (Responsible Party):
Freeman-Sheldon Research Group, Inc.
ClinicalTrials.gov Identifier:
NCT01306994
First received: February 26, 2011
Last updated: October 22, 2013
Last verified: October 2013

February 26, 2011
October 22, 2013
February 2011
Not Provided
Heart rate [ Time Frame: Evaluated during two study visits, lasting an average of 1-3 hours ] [ Designated as safety issue: Yes ]
Increased heart rate is used as an index of cardiovascular strain.
Same as current
Complete list of historical versions of study NCT01306994 on ClinicalTrials.gov Archive Site
  • Non-Invasive Arterial Blood Pressure [ Time Frame: Evaluated during two study visits, lasting an average of 1-3 hours ] [ Designated as safety issue: Yes ]
    Increased non-invasive arterial blood pressure rate is used as an index of cardiovascular strain.
  • Lung Volumes [ Time Frame: Evaluated during two study visits, lasting an average of 1-3 hours ] [ Designated as safety issue: Yes ]
    Decreased lung volumes are used as an index of strain caused by Freeman-Sheldon syndrome and related conditions.
  • Saturation of Peripheral Oxygen [ Time Frame: Evaluated during two study visits, lasting an average of 1-3 hours ] [ Designated as safety issue: Yes ]
    Decreased saturation of peripheral oxygen is used as an index of strain caused by Freeman-Sheldon syndrome and related conditions.
  • Respiratory Rate [ Time Frame: Evaluated during two study visits, lasting an average of 1-3 hours ] [ Designated as safety issue: Yes ]
    Increased respiratory rate is used as an index of cardiovascular strain.
  • Electrocardiogram Tracings [ Time Frame: Evaluated during two study visits, lasting an average of 1-3 hours ] [ Designated as safety issue: Yes ]
    Electrocardiogram tracings are used as an index of cardiovascular strain.
  • Oesophageal (Core) Temperature [ Time Frame: Evaluated at rest and while exercising, during second of two study visits (lasting an average of 1-3 hours) ] [ Designated as safety issue: Yes ]
    Increased oesophageal (core) temperature is used as an index of cardiovascular strain.
  • Adenosine Triphosphate Blood Levels [ Time Frame: Evaluated at rest and while exercising, during second of two study visits (lasting an average of 1-3 hours) ] [ Designated as safety issue: No ]
    Adenosine triphosphate blood levels are used as an index of strain caused by Freeman-Sheldon syndrome and related conditions.
  • Borg Scale Ratings of Perceived Exertion [ Time Frame: Evaluated while exercising, during second of two study visits (lasting an average of 1-3 hours) ] [ Designated as safety issue: No ]
    Increased Borg scale ratings of perceived exertion are used as an index of fatigue.
  • Muscle Rigidity [ Time Frame: Evaluated while exercising, during second of two study visits (lasting an average of 1-3 hours) ] [ Designated as safety issue: Yes ]
    Increased Muscle rigidity is used as an indicator of malignant hyperthermia, when increased core temperature, heart, and respiratory rate are present.
  • Medical Outcomes Trust Short Form (36) Health Survey (SF-36) [ Time Frame: Evaluated in first of two study visits, lasting an average of 1-3 hours ] [ Designated as safety issue: No ]
    Medical Outcomes Trust Short Form (36) Health Survey (SF-36) will be used to assess physical quality of life, which correlates strongly with physical exercise capacity.
Same as current
Not Provided
Not Provided
 
Study of Resting and Exercising Body Functioning in Freeman-Sheldon Syndrome and Related Conditions
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.

This study is a research project initiated by the research student (Mikaela I. Poling) and assisted by the clinical genetics fellow (Andrés Morales) in partial fulfillment the FSRG Foundation Programme, under approval, direction, and supervision of the study PI (Rodger J. McCormick) and Sub-Investigator (Richard A. Chamberlain).

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.

Observational
Observational Model: Case Control
Time Perspective: Cross-Sectional
Not Provided
Retention:   None Retained
Description:

Blood samples will be taken but no retention is expected.

Probability Sample

Patients world-wide are welcome, so-long as they have a qualifying diagnosis. Healthy controls are welcome world-wide, as well.

  • Arthrogryposis
  • Craniofacial Abnormalities
  • Other: Lactate, Glucose, and Adenosine Triphosphate Blood Levels
    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.
    Other Names:
    • 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
  • Procedure: Physiological Stress 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).
    Other Names:
    • stress test
    • graded exercise test
    • maximal exercise test
    • VO2 max test
    • maximal oxygen uptake test
    • exercise tolerance test
    • exercise stress test
  • Other: Functional Enquiry Form
    Evaluated before clinical examination, it is a checklist of medical problems.
    Other Names:
    • FSRG Form 08
    • health history
    • review of systems
    • systems review
    • medical history
    • personal health history
  • Other: Strength, Joint ROM, Girth and Length Measurements
    Completed during the clinical examination by the researchers, it is a structured approach to evaluation of muscles, joints, arms, thighs, and legs.
    Other Names:
    • SF 527
    • Standard Form 527
    • musculoskeletal examination
    • musculoskeletal exam
    • musculoskeletal evaluation
    • musculoskeletal assessment
    • extremity examination
    • extremity evaluation
    • extremity assessment
    • extremity exam
  • Other: Study Physical Examination
    Completed during the clinical examination by the researchers, it is a structured approach to a full physical examination (minus breasts, genitalia, or rectum).
    Other Names:
    • 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
  • Other: Observational Gait Analysis
    Completed during the clinical examination by researchers, it is a structured approach to evaluation of a person's walking.
    Other Names:
    • FSRG 10
    • gait analysis
    • functional gait analysis
  • Other: Mental Health Interview
    Completed during the clinical examination by the researchers, it is a general evaluation of mental health status.
    Other Names:
    • 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
    • mental health interview
    • psychological examination
    • psychological evaluation
    • psychological assessment
    • psychological interview
    • psychological intake examination
    • psychological intake evaluation
    • psychological intake assessment
    • psychological intake interview
  • Syndrome Group
    Individuals with Freeman-Sheldon, Sheldon-Hall, distal arthrogryposis type 1, or distal arthrogryposis type 3
    Interventions:
    • 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
    Interventions:
    • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
20
Not Provided
Not Provided

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.
Both
Not Provided
Yes
Contact: Mikaela I Poling, BA 304-460-9038 poling_mi@fsrgroup.org
Contact: Andrés Morales, MD andresm452@outlook.com
United States,   Guatemala
 
NCT01306994
000079, U1111-1120-5931
No
Freeman-Sheldon Research Group, Inc.
Freeman-Sheldon Research Group, Inc.
Not Provided
Principal Investigator: Rodger J McCormick, DEd, MS Freeman-Sheldon Research Group, Inc.
Freeman-Sheldon Research Group, Inc.
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP