Angela Rosenbohm1, Susanne Hirsch1, Alexander E Volk2,3, Torsten Grehl4, Julian Grosskreutz5, Frank Hanisch6, Andreas Herrmann7, Katja Kollewe8, Wolfram Kress9, Thomas Meyer10, Susanne Petri8, Johannes Prudlo11, Carsten Wessig12, Hans-Peter Müller1, Jens Dreyhaupt13, Jochen Weishaupt1, Christian Kubisch2,3, Jan Kassubek1, Patrick Weydt1,14, Albert C Ludolph15. 1. Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany. 2. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany. 3. Institute of Human Genetics, University of Ulm, Ulm, Germany. 4. Department of Neurology, Alfried Krupp Krankenhaus Rüttenscheid, Essen, Germany. 5. Department of Neurology, University of Jena, Jena, Germany. 6. Department of Neurology, University of Halle, Halle, Germany. 7. Department of Neurology and German Center for Neurodegenerative Diseases (DZNE), Research Site Dresden, Technische Universität Dresden, Dresden, Germany. 8. Department of Neurology, Medical School Hannover, Hannover, Germany. 9. Institute of Human Genetics, University of Würzburg, Würzburg, Germany. 10. Department of Neurology, Outpatient Clinic for ALS and Other Motor Neuron Disorders, Charité-Universitätsmedizin Berlin, Berlin, Germany. 11. Department of Neurology and German Center for Neurodegenerative Diseases (DZNE), Rostock University Medical Center, Rostock, Germany. 12. Department of Neurology, Bavaria Clinic, Bad Kissingen, Germany. 13. Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany. 14. Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Bonn, Germany. 15. Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany. albert.ludolph@rku.de.
Abstract
OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is caused by an abnormal expansion of the CAG repeat in the androgen receptor gene. This study aimed to systematically phenotype a German SBMA cohort (n = 80) based on laboratory markers for neuromuscular, metabolic, and endocrine status, and thus provide a basis for the selection of biomarkers for future therapeutic trials. METHODS: We assessed a panel of 28 laboratory parameters. The clinical course and blood biomarkers were correlated with disease duration and CAG repeat length. A subset of 11 patients was evaluated with body fat MRI. RESULTS: Almost all patients reported muscle weakness (99%), followed by dysphagia (77%), tremor (76%), and gynecomastia (75%) as major complaints. Creatine kinase was the most consistently elevated (94%) serum marker, which, however, did not relate with either the disease duration or the CAG repeat length. Paresis duration and CAG repeat length correlated with dehydroepiandrosterone sulfate after correction for body mass index and age. The androgen insensitivity index was elevated in nearly half of the participants (48%). CONCLUSIONS: Metabolic alterations in glucose homeostasis (diabetes) and fat metabolism (combined hyperlipidemia), and sex hormone abnormalities (androgen insensitivity) could be observed among SBMA patients without association with the neuromuscular phenotype. Dehydroepiandrosterone sulfate was the only biomarker that correlated strongly with both weakness duration and the CAG repeat length after adjusting for age and BMI, indicating its potential as a biomarker for both disease severity and duration and, therefore, its possible use as a reliable outcome measure in future therapeutic studies.
OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is caused by an abnormal expansion of the CAG repeat in the androgen receptor gene. This study aimed to systematically phenotype a German SBMA cohort (n = 80) based on laboratory markers for neuromuscular, metabolic, and endocrine status, and thus provide a basis for the selection of biomarkers for future therapeutic trials. METHODS: We assessed a panel of 28 laboratory parameters. The clinical course and blood biomarkers were correlated with disease duration and CAG repeat length. A subset of 11 patients was evaluated with body fat MRI. RESULTS: Almost all patients reported muscle weakness (99%), followed by dysphagia (77%), tremor (76%), and gynecomastia (75%) as major complaints. Creatine kinase was the most consistently elevated (94%) serum marker, which, however, did not relate with either the disease duration or the CAG repeat length. Paresis duration and CAG repeat length correlated with dehydroepiandrosterone sulfate after correction for body mass index and age. The androgen insensitivity index was elevated in nearly half of the participants (48%). CONCLUSIONS: Metabolic alterations in glucose homeostasis (diabetes) and fat metabolism (combined hyperlipidemia), and sex hormone abnormalities (androgen insensitivity) could be observed among SBMApatients without association with the neuromuscular phenotype. Dehydroepiandrosterone sulfate was the only biomarker that correlated strongly with both weakness duration and the CAG repeat length after adjusting for age and BMI, indicating its potential as a biomarker for both disease severity and duration and, therefore, its possible use as a reliable outcome measure in future therapeutic studies.
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