Study of Resting and Exercising Body Functioning in Freeman-Sheldon Syndrome and Related Conditions

Withdrawn

• Conditions: Craniofacial Abnormalities; Arthrogryposis
• 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

• Registration Number: NCT01306994
• Lead Sponsor: Freeman-Sheldon Research Group, Inc.

Brief 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 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.

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.

Study Timeline

• Study First Submitted: 2011-02-26
• Study First Submitted QC: 2011-02-28
• Study First Posted: 2011-03-02
• Study Start: 2014-03
• Status Verified: 2022-06
• Primary Completion: 2022-06
• Study Completion: 2022-06
• Last Update Submitted: 2022-06-01
• Last Update Posted: 2022-06-06

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Syndrome Group	Study Physical Examination	Individuals with Freeman-Sheldon, Sheldon-Hall, distal arthrogryposis type 1, or distal arthrogryposis type 3
Syndrome Group	Physiological Stress Test	Individuals with Freeman-Sheldon, Sheldon-Hall, distal arthrogryposis type 1, or distal arthrogryposis type 3
Syndrome Group	Strength, Joint ROM, Girth and Length Measurements	Individuals with Freeman-Sheldon, Sheldon-Hall, distal arthrogryposis type 1, or distal arthrogryposis type 3
Control Group	Observational Gait Analysis	Healthy individuals
Syndrome Group	Mental Health Interview	Individuals with Freeman-Sheldon, Sheldon-Hall, distal arthrogryposis type 1, or distal arthrogryposis type 3
Control Group	Study Physical Examination	Healthy individuals
Control Group	Physiological Stress Test	Healthy individuals
Syndrome Group	Functional Enquiry Form	Individuals with Freeman-Sheldon, Sheldon-Hall, distal arthrogryposis type 1, or distal arthrogryposis type 3
Control Group	Strength, Joint ROM, Girth and Length Measurements	Healthy individuals
Syndrome Group	Lactate, Glucose, and Adenosine Triphosphate Blood Levels	Individuals with Freeman-Sheldon, Sheldon-Hall, distal arthrogryposis type 1, or distal arthrogryposis type 3
Control Group	Functional Enquiry Form	Healthy individuals
Control Group	Mental Health Interview	Healthy individuals
Syndrome Group	Observational Gait Analysis	Individuals with Freeman-Sheldon, Sheldon-Hall, distal arthrogryposis type 1, or distal arthrogryposis type 3
Control Group	Lactate, Glucose, and Adenosine Triphosphate Blood Levels	Healthy individuals

Primary Outcome Measures

Name	Time	Method
Heart rate	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	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.
Oxygen Consumption	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	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.

Secondary Outcome Measures

Name	Time	Method
Non-Invasive Arterial Blood Pressure	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	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.
Spirometry (Forced Expiratory Volume/Forced Vital Capacity)	Evaluated before and after exercise, during two study visits (lasting an average of 1-3 hours)	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.
Saturation of Peripheral Oxygen	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	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.
Respiratory Rate	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	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.
Heart Rhythm	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	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.
Core Temperature	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	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.
Adenosine Triphosphate	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	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.
Muscle Rigidity	Evaluated while exercising, during second of two study visits (lasting an average of 1-3 hours)	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.
Functional and Health-Related Quality of Life	Evaluated in first of two study visits, lasting an average of 1-3 hours	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.
Lactic Acid	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	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.
Perceived Exertion	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	Increased perceived exertion, measured using the Borg scale, are used as an index of fatigue.
Glucose	Evaluated at rest and while exercising, during two study visits (lasting an average of 1-3 hours)	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.

Trial Locations

Locations (1)

Freeman-Sheldon Research Group, Inc. Headquarters; 🇺🇸 Buckhannon, West Virginia, United States