Thesis defense Barbara van der Sluijs (Donders series 304)

11 December 2017

Promotor: prof. dr. B. van Engelen, copromotor: dr. N. Voermans

Oculopharyngeal muscular dystrophy (OPMD) in the Netherlands. Beyond dysphagia and ptosis.

Oculopharyngeal muscular dystrophy (OPMD) is a rare muscle disorder that is autosomal dominantly inherited and caused by a mutation in the PABPN1 gene. We investigated the Dutch OPMD population in this dissertation, which contributes to the increase of the knowledge of the clinical, histopathological and genetic features of OPMD. We showed that the clinical features of OPMD are not restricted to ptosis and dysphagia. In contrast, even in the early stage of the disease weakness of the pelvic girdle and proximal leg muscles can occur. Other additional features can be pain, fatigue and cognitive impairments. Since OPMD is likely to be underdiagnosed, these findings will have a direct clinical impact on disease recognition. Based on the results of our studies we have some lifestyle advices for OPMD patients, for example: be aware of your head position during eating and drinking to reduce swallowing problems.

Furthermore, we identified a new mutation in the PABPN1 gene supporting the theory that unequal crossing-over is the molecular mechanism causing the OPMD mutation.

By inclusion of muscle biopsies of presymptomatic mutation carriers, we had the unique opportunity to study the muscle tissue before the clinical onset of the disease to shed light on the role of the typical intranuclear aggregates in the pathophysiology of OPMD. We observed that the aggregates were present in presymptomatic mutation carriers.

Finally, we showed that the hip flexors, hip adductors and hamstrings are most frequently affected and are the appropriate muscles to test clinically and radiologically to monitor the clinical course of the disease. In addition, these muscles should be taken into account in patient management as well as in the selection of outcome measures in future trials.