study of resting and exercising body functioning in freeman-sheldon syndrome and related conditions

Conditions: Arthrogryposis; Craniofacial Abnormalities

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.

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.

Eligibility criteria:
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.

Keywords: exercise test bicycle ergometry test stress test