Skin-impedance in Fabry Disease: A prospective, controlled, non-randomized clinical study

BMC Neurology Skin-impedance in Fabry Disease: A prospective, controlled, non-randomized clinical study Surya N Gupta 2 Markus Ries 1 4 Gary J Murray 1 Jane M Quirk 1 Roscoe O Brady 1 Jeffrey R Lidicker 0 Raphael Schiffmann 1 3 David F Moore 5 0 Temple University Center for Statistical and Information Science, Temple University School of Medicine , Philadelphia, Pennsylvania , USA 1 Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, Maryland , USA 2 Division of Pediatric Neurology, Department of Pediatrics, Penn State University College of Medicine , 500 University Drive, Hershey, Pennsylvania 17033 , USA 3 Institute of Metabolic Disease, Baylor Research Institute , 3812 Elm Street, Dallas, TX 75226 , USA 4 Shire Human Genetic Therapies , Cambridge, MA , USA 5 Section of Neurology, Department of Internal Medicine, University of Manitoba , Winnipeg, Manitoba , Canada system. Background: We previously demonstrated improved sweating after enzyme replacement therapy (ERT) in Fabry disease using the thermo-regularity sweat and quantitative sudomotor axon reflex tests. Skin-impedance, a measure skin-moisture (sweating), has been used in the clinical evaluation of burns and pressure ulcers using the portable dynamic dermal impedance monitor (DDIM) Methods: We compared skin impedance measurements in hemizygous patients with Fabry disease (22 post 3-years of bi-weekly ERT and 5 ERT naive) and 22 healthy controls. Force compensated skin-moisture values were used for statistical analysis. Outcome measures included 1) moisture reading of the 100th repetitive reading, 2) rate of change, 3) average of 60-110th reading and 4) overall average of all readings. Results: All outcome measures showed a significant difference in skin-moisture between Fabry patients and control subjects (p < 0.0001). There was no difference between Fabry patients on ERT and patients nave to ERT. Increased skin-impedance values for the four skin-impedance outcome measures were found in a small number of dermatome test-sites two days post-enzyme infusions. Conclusion: The instrument portability, ease of its use, a relatively short time required for the assessment, and the fact that DDIM system was able to detect the difference in skin-moisture renders the instrument a useful clinical tool. - Background Fabry disease is an X-linked lysosomal disorder caused by a deficiency of alpha-galactosidase A (GALA) resulting in accumulation of alpha-D-galactosyl conjugates, particularly globotriosylceramide in a variety of cell types [1,2], including dorsal root ganglia [3]. The diagnosis of Fabry disease is often made on clinical suspicion because of the presence of skin lesions (angiokeratoma) or corneal opacities that do not affect visual acuity. Other methods of diagnosis including a family pedigree ascertainment taking into account a history of renal failure or stroke of early onset, i.e. less than 50 years of age [4]. The demonstration of deficient GALA enzyme activity in white blood cells of hemizygous males or identification of a pathognomonic mutation in a heterozygous female confirms the diagnosis [5,6]. Neuropathic pain and hypohidrosis may also contribute to reduced exercise capacity and heat intolerance [7]. Extensive lipid accumulation within neurons of the autonomic nervous system may be the pathologic basis for neuropathic pain, diminished sweating, and other autonomic signs of this disorder. Enzyme replacement therapy (ERT) for Fabry disease has shown to be promising for adult hemizygous patients in the context of stabilizing renal disease and reversing less life-threatening symptoms such diarrhea [8,9]. We previously demonstrated improved sweating in adult male Fabry patients treated with ERT using thermo-regularity sweat testing (TST) and quantitative sudomotor axon reflex test (QSART) [10]. Both of these tests are difficult to implement in a routine clinical setting [11-13]. A more convenient clinical instrument allowing estimation of skin moisture uses dynamic dermal impedance (DDIM). "Impedance" is the resistance to the flow of an alternating current and is influenced by skin-moisture. The DDIM system is a portable instrument with force compensation to allow measurement of skin-moisture. DDIM has been used in the clinical setting to assess skinmoisture [14,15], but never in Fabry disease. Here, we report the ascertainment of skin moisture across surface dermatomes by DDIM in patients with Fabry disease compared to healthy control subjects [15-17]. Methods Subjects Twenty-two adult male patients with Fabry disease who were after 3 years of ERT (mean age: 40.6 8.1 years), five ERT-nave patients with Fabry disease (mean age: 33.8 8.0 years), and 22 control subjects (mean age: 36.0 14.1 years) participated in this study. All but two were non-Hispanic Caucasians. Fabry disease was confirmed by GALA enzyme assays. The clinical manifestations of patients on ERT have been described previously in detail [18]. All the patients in this study had neuropathic pain and hypohidrosis. The healthy control subjects were recruited through the National Institutes of Health Clinical Research Volunteer Program. They were interviewed and examined by the investigator and were confirmed as clinically and neurologically normal. The Institutional Review Board of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health approved this study. All patients and healthy control subjects gave their written informed consent prior to their inclusion in this study. GALA enzyme: production and treatment regimen The -galactosidase A enzyme used in this study (agalsidase alfa, Replagal) was produced in a genetically engineered continuous human cell line (Shire Human Genetic Therapies, Cambridge, MA, USA). It was administered at a dose of 0.2 mg/kg of body weight by intravenous infusion over a period of 40 minutes at a frequency of every other week [18]. Patients who were on ERT for three years were studied just before enzyme infusion (defined as pre-infusion) and two days after enzyme infusion (defined as post-infusion). Dynamic dermal impedance monitor (DDIM) (Petite) The Petite system DPM 9003 (NOVA Technology Corporation, Portsmouth, NH, USA) was used to assess the skinimpedance as a surrogate for skin moisture. [19]. Testing and data collection Fabry patients on ERT (22 patients) and ERT-nave (5 patients) were studied twice (before and two days after their ERT infusion or two days after the initial measurement for those who were not on ERT). Skin moisture of healthy controls was measured only once. All tests were performed in the same room with controlled temperature and humidity. Temperature and humidity were recorded throughout the testing. The hand-held DDIM probe connected to a personal digital assistant (PDA) was placed in a specific sequence on test-sites 1 through 26, cor (...truncated)