Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands
Department of Neurology, Gelre Hospital Zutphen, Zutphen, The Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
Department of Pathology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
Department of Laboratory Medicine and Pediatrics, Translational Metabolic Laboratory, Radboud University Medical Centre, The Netherlands
Correspondence to: N.C. Voermans, MD, PhD, Neurologist Radboud University Medical Centre, Neurology, 935, 6500 HB Nijmegen The Netherlands. Tel.: +31 243616600; Fax: +31 243541122; E-mail: [email protected].
Note:  These authors share last authorship.
Abstract: Background: Oculopharyngeal muscular dystrophy (OPMD) has long been characterized by a combination of bilateral ptosis and dysphagia and subsequent limb girdle weakness. The role of the typical intranuclear inclusion in the pathophysiology is unresolved. Objective: The aim of this study was to describe the clinical and histopathological features of oculopharyngeal muscular dystrophy (OPMD). We examined this in a Dutch cohort including presymptomatic Ala-expanded-PABPN1 carriers and late symptomatic patients. Methods: We performed a prospective, observational study in OPMD patients and adult children of genetically confirmed OPMD patients. The study includes a structured history, a detailed neurological examination, muscle histology and biochemical analysis. Forty patients and 18 adult children participated in this study, among whom were six presymptomatic mutation carriers. One patient died during the study and had given permission to autopsy. Results: In addition to the characteristic OPMD symptoms including ptosis and dysphagia, other symptoms such as limb girdle and axial weakness, and external ophthalmoplegia were frequently observed. Intranuclear aggregates were observed in the biopsies of presymptomatic carriers. Biochemical analysis of the biopsies of the presymptomatic carriers showed no mitochondrial dysfunction. The autopsy showed that muscle weakness correlated with histopathological findings in five different muscles in an individual patient. Conclusions: The main findings of this nationwide study are the presence of intranuclear aggregates before clinical onset and the absence of mitochondrial changes in Ala-expanded-PABPN1 carriers. This indicates that the expression of Ala-expanded-PABPN1 causes the formation of nuclear aggregates before the onset of muscle weakness. Normal results of biochemical analysis in presymptomatic carriers suggest that possible mitochondrial dysfunction occurs later. Furthermore we confirmed that limb girdle weakness occurs frequently in Dutch OPMD patients. This study thus expands the OPMD research towards characterization of presymptomatic carriers.